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Clinical Therapeutics May 2024With the prolongation of human life expectancy and the outbreak of COVID-19, antineoplastic agents, anti-infective drugs, and cardiovascular system drugs have been...
PURPOSE
With the prolongation of human life expectancy and the outbreak of COVID-19, antineoplastic agents, anti-infective drugs, and cardiovascular system drugs have been widely applied, resulting in a growing incidence of drug-induced liver injury (DILI) year by year. This study aimed to investigate signals, clinical characteristics, and risk factors in patients with liver injury.
METHODS
A retrospective analysis was conducted on inpatients clinically diagnosed with DILI from 2019 to 2021 in one tertiary hospital in mainland China. The hepatic biochemical indices, clinical manifestations and suspected drugs of the patients were counted. We determined causality assessed by the Roussel Uclaf Causality Assessment Method in patients that the biochemistry met the diagnostic criteria recommended by the International Serious Adverse Events Consortium and compared them with contemporaneous patients diagnosed as DILI but with hepatic biochemical abnormalities only to identify the injure types and risk factors for DILI.
FINDINGS
A total of 1167 patients from 2639 initial participants with DILI were included. According to the injured target cells, it can be divided into hepatocellular injury type 351 cases (30.08%), cholestatic injury type 97 cases (8.31%), mixed injury type 27 cases (2.31%), and biochemical abnormal only type 692 cases (59.30%). It involved 1738 cases of suspected drugs, 349 drugs, and the top 3 drug categories were antineoplastic agents, anti-infectives, and traditional Chinese medicines, with Cyclophosphamide, Atorvastatin, and Liuzasulfapyridine as the top 3 in order of ranking. The main symptoms of patients were darker urine, decreased appetite, and yellow sclera. The overall prognosis of patients with DILI was favorable, with 280 recovered cases (23.99%), 691 improved cases (59.21%), 189 not improved cases (16.20%), and 7 deaths (0.60%). There were significant differences in gender, age, malignancy, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, gamma-glutamyltransferase, albumin, international normalized ratio, and prognosis among patients with different injury types (P < 0.05). Multiple logistic regression analysis showed that female (odds ratio [OR] = 1.897, P < 0.001), alcohol use (OR = 1.905, P = 0.001), malignancy (OR = 0.417, P < 0.001), and pregnancy (OR = 0.201, P = 0.011) were independent factors influencing DILI.
IMPLICATIONS
For most patients with liver injury, the manifestations are mild elevation of liver biochemistry without other symptoms (biochemical abnormal only type). The rest of the patients are predominantly of the hepatocellular injury type. Female and alcohol abuse patients are the risk factors of DILI, reminding clinicians to strengthen education on safe drug use, give individualized treatment, and regularly monitor liver function indexes in the patients.
PubMed: 38821767
DOI: 10.1016/j.clinthera.2024.04.014 -
Anticancer Research Jun 2024Pancreatic cancer is an aggressive type of cancer, with a dismally low survival rate of <5%. FDA-approved drugs like gemcitabine have shown little therapeutic success,...
Combination Treatment of Biochanin A and Atorvastatin Alters Mitochondrial Bioenergetics, Modulating Cell Metabolism and Inducing Cell Cycle Arrest in Pancreatic Cancer Cells.
BACKGROUND/AIM
Pancreatic cancer is an aggressive type of cancer, with a dismally low survival rate of <5%. FDA-approved drugs like gemcitabine have shown little therapeutic success, prolonging survival by a mere six months. Isoflavones, such as biochanin A and daidzein, are known to exhibit anti-cancer activity, whereas statins reportedly have anti-proliferative effects. This study investigated the effects of combination treatment of biochanin A and atorvastatin on pancreatic cancer cells.
MATERIALS AND METHODS
Pancreatic cancer cells AsPC-1, PANC-1, and MIA PaCa-2 were procured from ATCC. The cell viability studies were carried out using MTT & cell count assays. Flow cytometry was used to study cell apoptosis whereas cell metabolism studies were carried out using the Seahorse Mito stress test and XF-PMP assay. The effects of treatment on cell signaling pathways & cell cycle associated proteins were investigated using western blot whereas invasiveness of cancer cells was evaluated using gelatin zymography.
RESULTS
The combination treatment decreased the survival and enhanced pro-apoptotic responses compared to single treatments in the pancreatic cancer cells. In PANC-1 cells, the combination treatment decreased invasiveness, reduced expression of activated STAT3 and expression of critical mediators of cell cycle progression. Furthermore, the combination treatment induced a differential inhibition of respiratory complexes in the pancreatic cancer cells.
CONCLUSION
The combination treatment of biochanin A and atorvastatin exerts enhanced anti-cancer effects, inducing apoptosis, down-regulating cell cycle associated proteins and invasiveness in pancreatic cancer cells and merits further investigation for new, improved treatments for pancreatic cancer.
Topics: Humans; Genistein; Pancreatic Neoplasms; Atorvastatin; Cell Line, Tumor; Mitochondria; Cell Cycle Checkpoints; Apoptosis; Energy Metabolism; Cell Proliferation; Cell Survival; Antineoplastic Combined Chemotherapy Protocols; Signal Transduction
PubMed: 38821627
DOI: 10.21873/anticanres.17038 -
Osteoarthritis and Cartilage May 2024Currently, no disease-modifying therapies for osteoarthritis (OA) exist, and attempts to identify novel cellular targets have been challenging. Risk factors for OA... (Review)
Review
OBJECTIVE
Currently, no disease-modifying therapies for osteoarthritis (OA) exist, and attempts to identify novel cellular targets have been challenging. Risk factors for OA include advanced age, obesity, and metabolic syndrome. This creates an attractive opportunity to repurpose existing drugs that are used to treat comorbidities commonly encountered in patients with OA, if those drugs possess OA disease modifying properties.
METHODS
This narrative review incorporates findings from knee or hand OA randomized clinical trials, post-hoc clinical trial analyses, prospective cohort studies, and observational data.
RESULTS
Drugs used for the treatment of rheumatoid arthritis (methotrexate; TNFa, IL-1, and IL-6 pathway inhibitors; hydroxychloroquine), atopic/allergic disease (anti-histamines), osteoporosis (bisphosphonates and vitamin D), type 2 diabetes (metformin and GLP-1 agonists), and cardiovascular disease (atorvastatin, fish oil, and beta blockers) were reviewed for their potential benefit in OA. This review outlines the successful attributes of repurposed drugs, the challenges in repurposing drugs, and strategies for future clinical trials to support OA drug repurposing. Potential drug candidates for OA may be identified through the use of existing datasets and via collaborations with researchers in other fields to include OA endpoints in future clinical trials.
CONCLUSION
Given the association of OA with several commonly treated comorbidities, drug repurposing is an appealing approach that could provide a favorable benefit-to-risk ratio for chronic OA treatment.
PubMed: 38821468
DOI: 10.1016/j.joca.2024.05.008 -
World Journal of Cardiology May 2024Lipid treatment practices and levels in post-acute myocardial infarction (AMI) patients, which are crucial for secondary prevention.
BACKGROUND
Lipid treatment practices and levels in post-acute myocardial infarction (AMI) patients, which are crucial for secondary prevention.
AIM
To evaluate the lipid treatment practices and lipid levels in post-myocardial infarction (MI) patients at a tertiary care hospital in Pakistan.
METHODS
In this cross-sectional study, we analyzed patients who had experienced their first AMI event in the past 3 years. We assessed fasting and non-fasting lipid profiles, reviewed statin therapy prescriptions, and examined patient compliance. The recommended dose was defined as rosuvastatin ≥ 20 mg or atorvastatin ≥ 40 mg, with target total cholesterol levels set at < 160 mg/dL and target low-density lipoprotein cholesterol (LDL-C) at < 55 mg/dL.
RESULTS
Among 195 patients, 71.3% were male, and the mean age was 57.1 ± 10.2 years. The median duration since AMI was 36 (interquartile range: 10-48) months and 60% were diagnosed with ST-segment elevation MI. Only 13.8% of patients were advised to undergo lipid profile testing after AMI, 88.7% of patients were on the recommended statin therapy, and 91.8% of patients were compliant with statin therapy. Only 11.5% had LDL-C within the target range and 71.7% had total cholesterol within the target range. Hospital admission in the past 12 months was reported by 14.4%, and the re-admission rate was significantly higher among non-compliant patients (37.5% 5.6%). Subsequent AMI event rate was also significantly higher among non-compliant patients (43.8% 11.7%).
CONCLUSION
Our study highlights that while most post-AMI patients received the recommended minimum statin therapy dose, the inadequate practice of lipid assessment may compromise therapy optimization and raise the risk of subsequent events.
PubMed: 38817645
DOI: 10.4330/wjc.v16.i5.282 -
Journal of Fluorescence May 2024Recently, dual-mode techniques have garnered considerable attention and have been shown to be effective approaches for biomedical analysis and environmental monitoring....
A Dual-Mode Spectrophotometric and Fluorescent Probe Based on Lignin-Derived Carbon Dots for the Detection of Atorvastatin Calcium in a Bulk Powder and a Commercial Product.
Recently, dual-mode techniques have garnered considerable attention and have been shown to be effective approaches for biomedical analysis and environmental monitoring. A novel and simple dual-mode spectrophotometric and fluorometric probe based on lignin-derived carbon dots (LCDs) was developed to detect atorvastatin calcium (ATS) in a bulk powder and its commercial product. The synthesized LCDs exhibit exceptional fluorescence characteristics and are highly soluble in water while maintaining reasonable stability. The average particle size of the LCDs was 3.42 ± 1.03 nm. The characterization of the produced LCDs indicated a structure resembling graphene oxide with the presence of several functional groups. The developed LCDs show a good fluorescence quantum yield of 32.2%. The fluorescence of the LCDs is quenched by ATS at an emission wavelength of 315 nm after excitation at 275 nm through dynamic and static quenching mechanisms. The optimal reaction conditions for the dual-mode reaction were a pH of 9 and 0.05 mL of the LCDs, which were measured after 3 min at 30 °C by spectrophotometry, followed by 7 min at 20 °C by fluorometric methods. According to the spectrophotometric results, the response of ATS was linear in the range of 4.0-100.0 µg/mL, while according to the fluorometric results, the dynamic range was 3.0-50.0 µg/mL. The limits of detection (LODs) and the limits of quantification (LOQs) were 0.97 µg/mL and 2.95 µg/mL for the fluorometric method, respectively. The nanoprobe effectively analyzed ATS in medication samples and yielded good results.
PubMed: 38814526
DOI: 10.1007/s10895-024-03745-2 -
Drug Development Research Jun 2024It has been reported that lipophilic statins such as atorvastatin can more readily penetrate into β-cells and reach the mitochondria, resulting in mitochondrial...
Hesperidin, vanillic acid, and sinapic acid attenuate atorvastatin-induced mitochondrial dysfunction via inhibition of mitochondrial swelling and maintenance of mitochondrial function in pancreas isolated mitochondria.
It has been reported that lipophilic statins such as atorvastatin can more readily penetrate into β-cells and reach the mitochondria, resulting in mitochondrial dysfunction, oxidative stress, decrease in insulin release. Many studies have shown that natural products can protect mitochondrial dysfunction induced by drug in different tissue. We aimed to explore mitochondrial protection potency of hesperidin, vanillic acid, and sinapic acid as natural compounds against mitochondrial dysfunction induced by atorvastatin in pancreas isolated mitochondria. Mitochondria were isolated form rat pancreas and directly treated with toxic concentration of atorvastatin (500 µM) in presence of various concentrations hesperidin, vanillic acid, and sinapic acid (1, 10, and 100 µM) separately. Mitochondrial toxicity parameters such as the reactive oxygen species (ROS) formation, succinate dehydrogenases (SDH) activity, mitochondrial swelling, depletion of glutathione (GSH), mitochondrial membrane potential (MMP) collapse, and malondialdehyde (MDA) production were measured. Our findings demonstrated that atorvastatin directly induced mitochondrial toxicity at concentration of 500 μM and higher in pancreatic mitochondria. Except MDA, atorvastatin caused significantly reduction in SDH activity, mitochondrial swelling, ROS formation, depletion of GSH, and collapse of MMP. While, our data showed that all three protective compounds at low concentrations ameliorated atorvastatin-induced mitochondrial dysfunction with the increase of SDH activity, improvement of mitochondrial swelling, MMP collapse and mitochondrial GSH, and reduction of ROS formation. We can conclude that hesperidin, vanillic acid, and sinapic acid can directly reverse the toxic of atorvastatin in rat pancreas isolated mitochondria, which may be beneficial for protection against diabetogenic-induced mitochondrial dysfunction in pancreatic β-cells.
Topics: Animals; Atorvastatin; Mitochondria; Pancreas; Coumaric Acids; Rats; Reactive Oxygen Species; Male; Mitochondrial Swelling; Membrane Potential, Mitochondrial; Vanillic Acid; Hesperidin; Glutathione; Rats, Wistar; Succinate Dehydrogenase; Malondialdehyde
PubMed: 38812443
DOI: 10.1002/ddr.22199 -
The Laryngoscope May 2024Recent insights suggest that lipids and statin medication play a role in the development of sensorineural hearing loss (SNHL), yet the exact role remains controversial....
BACKGROUND
Recent insights suggest that lipids and statin medication play a role in the development of sensorineural hearing loss (SNHL), yet the exact role remains controversial. This research applied Mendelian randomization (MR) to assess whether lipids and statin medication are associated with an increased risk of SNHL.
METHODS
A two-sample MR was used in this study. Genetic instruments were constructed from variants associated with risk factors. Data for lipids and statin medication were obtained from the IEU OpenGWAS project, and for SNHL from the Finngen research project, which comprises 32,487 individuals with SNHL and 331,736 control individuals.
RESULTS
Genetically predicted higher levels of triglycerides were associated with an increased risk of SNHL. The use of genetically predicted atorvastatin was associated with a lower risk of SNHL. Rosuvastatin has demonstrated potential in treating SNHL, yet further investigations are warranted to elucidate its relationship with SNHL. Insufficient evidence was available to suggest that the genetically predicted level of high-density lipoprotein cholesterol or low-density lipoprotein cholesterol or the use of simvastatin were associated with SNHL.
CONCLUSIONS
The study provides genetic evidence suggesting that increased levels of triglycerides in the blood could be a risk factor for SNHL and that the use of certain statin medications, including atorvastatin and rosuvastatin, could reduce the risk of SNHL. These results align with findings from previous observational studies that have linked hyperlipidemia with the risk of SNHL.
LEVEL OF EVIDENCE
According to the Oxford Centre for Evidence-Based Medicine 2011 levels of Evidence, the study has a third level of Evidence Laryngoscope, 2024.
PubMed: 38807496
DOI: 10.1002/lary.31500 -
Drug Development Research Jun 2024The World Health Organization (WHO) has published a list of priority pathogens that urgently require research to develop new antibiotics. The main aim of the current...
The World Health Organization (WHO) has published a list of priority pathogens that urgently require research to develop new antibiotics. The main aim of the current study is to identify potential marketed drugs that can be repurposed against bacterial infections. A pharmacovigilance-based drug repurposing approach was used to identify potential drugs. OpenVigil 2.1 tool was used to query the FDA Adverse Event Reporting System database. The reporting odds ratio (ROR) < 1, ROR95CI upper bound <1, and no. of cases ≥30 were used for filtering and sorting of drugs. Sunburst plot was used to represent drugs in a hierarchical order using the Anatomical Therapeutic Chemical classification. Molecular docking and dynamics were performed using the Maestro and Desmond modules of Schrodinger 2023 software respectively. A total of 40 drugs with different classes were identified based on the pharmacovigilance approach which has antibacterial potential. The molecular docking results have shown energetically favored binding conformation of lisinopril against 3-deoxy-manno-octulosonate cytidylyltransferase, UDP-2,3-diacylglucosamine hydrolase, and penicillin-binding protein 3 (PBP3) of Pseudomonas aeruginosa; olmesartan, atorvastatin against lipoteichoic acids flippase LtaA and rosiglitazone and varenicline against d-alanine ligase of Staphylococcus aureus; valsartan against peptidoglycan deacetylase (SpPgdA) and atorvastatin against CDP-activated ribitol for teichoic acid precursors of Streptococcus pneumoniae. Further, molecular dynamic results have shown the stability of identified drugs in the active site of bacterial targets except lisinopril with PBP3. Lisinopril, olmesartan, atorvastatin, rosiglitazone, varenicline, and valsartan have been identified as potential drugs for repurposing against bacterial infection.
Topics: Data Mining; Drug Repositioning; Humans; Molecular Docking Simulation; Pharmacovigilance; Anti-Bacterial Agents; Bacterial Infections; Adverse Drug Reaction Reporting Systems
PubMed: 38807372
DOI: 10.1002/ddr.22211 -
JAMA Neurology May 2024Comparisons are limited for immediate-intensive and delayed-intensive statin for secondary stroke prevention and neuroprotection in patients with acute mild ischemic...
IMPORTANCE
Comparisons are limited for immediate-intensive and delayed-intensive statin for secondary stroke prevention and neuroprotection in patients with acute mild ischemic stroke or transient ischemic attack (TIA) from atherosclerosis.
OBJECTIVE
To estimate whether immediate-intensive statin therapy is safe and can lower the risk of recurrent stroke compared with delayed-intensive statin in patients with acute mild ischemic stroke or high-risk TIA from atherosclerosis.
DESIGN, SETTING, AND PARTICIPANTS
The Intensive Statin and Antiplatelet Therapy for High-Risk Intracranial or Extracranial Atherosclerosis (INSPIRES) trial, a double-blind, placebo-controlled, 2 × 2 factorial, randomized clinical trial enrolled patients from September 2018 to October 2022. The trial was conducted at 222 hospitals in China. Patients aged 35 to 80 years with mild ischemic stroke or high-risk TIA of presumed atherosclerosis within 72 hours of symptom onset were assessed.
INTERVENTIONS
Patients were randomly assigned to receive immediate-intensive atorvastatin (80 mg daily on days 1-21; 40 mg daily on days 22-90) or 3-day delayed treatment (placebo for days 1-3, followed by placebo and atorvastatin, 40 mg daily on days 4-21, and then atorvastatin, 40 mg daily on days 22-90).
MAIN OUTCOMES AND MEASURES
The primary efficacy outcome was new stroke within 90 days, and a secondary efficacy outcome was poor functional outcome. Moderate to severe bleeding was the primary safety outcome.
RESULTS
A total of 11 431 patients were assessed for eligibility, and 6100 patients (median [IQR] age, 65 [57-71] years; 3915 men [64.2%]) were enrolled, with 3050 assigned to each treatment group. Within 90 days, new stroke occurred in 245 patients (8.1%) in the immediate-intensive statin group and 256 patients (8.4%) in the delayed group (hazard ratio, 0.95; 95% CI, 0.80-1.13). Poor functional outcome occurred in 299 patients (9.8%) and 348 patients (11.4%) in the immediate-intensive and delayed-intensive statin groups, respectively (odds ratio, 0.83; 95% CI, 0.71-0.98). Moderate to severe bleeding occurred in 23 of 3050 patients (0.8%) and 17 of 3050 patients (0.6%), in the immediate-intensive and delayed-intensive statin groups, respectively.
CONCLUSIONS AND RELEVANCE
Immediate-intensive statin initiated within 72 hours did not reduce the risk of stroke within 90 days and may be associated with improved functional outcomes without significant difference in moderate to severe bleeding, compared with 3-day delayed-intensive statin in Chinese patients with acute mild ischemic stroke or TIA from atherosclerosis.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03635749.
PubMed: 38805216
DOI: 10.1001/jamaneurol.2024.1433 -
Circulation Jun 2024Ascending aorta dilation and aortic valve degeneration are common complications in patients with bicuspid aortic valve. Several retrospective studies have suggested the... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Ascending aorta dilation and aortic valve degeneration are common complications in patients with bicuspid aortic valve. Several retrospective studies have suggested the benefit of statins in reducing these complications. This study aimed to determine whether atorvastatin treatment is effective in reducing the growth of aortic diameters in bicuspid aortic valve and if it slows the progression of valve calcification.
METHODS
In a randomized clinical trial, 220 patients with bicuspid aortic valve (43 women; 46±13 years of age) were included and treated with either 20 mg of atorvastatin per day or placebo for 3 years. Inclusion criteria were ≥18 years of age, nonsevere valvular dysfunction, nonsevere valve calcification, and ascending aorta diameter ≤50 mm. Computed tomography and echocardiography studies were performed at baseline and after 3 years of treatment.
RESULTS
During follow-up, 28 patients (12.7%) discontinued medical treatment (15 on atorvastatin and 13 taking placebo). Thus, 192 patients completed the 36 months of treatment. Low-density lipoprotein cholesterol levels decreased significantly in the atorvastatin group (median [interquartile range], -30 mg/dL [-51.65 to -1.75 mg/dL] versus 6 mg/dL [-4, 22.5 mg/dL]; <0.001). The maximum ascending aorta diameter increased with no differences between groups: 0.65 mm (95% CI, 0.45-0.85) in the atorvastatin group and 0.74 mm (95% CI, 0.45-1.04) in the placebo group (=0.613). Similarly, no significant differences were found for the progression of the aortic valve calcium score (=0.167) or valvular dysfunction.
CONCLUSIONS
Among patients with bicuspid aortic valve without severe valvular dysfunction, atorvastatin treatment was not effective in reducing the progression of ascending aorta dilation and aortic valve calcification during 3 years of treatment despite a significant reduction in low-density lipoprotein cholesterol levels.
REGISTRATION
URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2015-001808-57. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02679261.
Topics: Humans; Atorvastatin; Female; Male; Middle Aged; Aortic Valve; Disease Progression; Calcinosis; Bicuspid Aortic Valve Disease; Heart Valve Diseases; Adult; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Dilatation, Pathologic; Follow-Up Studies; Double-Blind Method; Treatment Outcome; Aorta; Aortic Valve Disease; Aortic Valve Stenosis
PubMed: 38804148
DOI: 10.1161/CIRCULATIONAHA.123.067537