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Pharmaceutics May 2024Implementing the 3R initiative to reduce animal experiments in brain penetration prediction for CNS-targeting drugs requires more predictive in vitro and in silico...
Implementing the 3R initiative to reduce animal experiments in brain penetration prediction for CNS-targeting drugs requires more predictive in vitro and in silico models. However, animal studies are still indispensable to obtaining brain concentration and determining the prediction performance of in vitro models. To reveal species differences and provide reliable data for IVIVE, in vitro models are required. Systems overexpressing MDR1 and BCRP are widely used to predict BBB penetration, highlighting the impact of the in vitro system on predictive performance. In this study, endogenous Abcb1 knock-out MDCKII cells overexpressing MDR1 of human, mouse, rat or cynomolgus monkey origin were used. Good correlations between ERs of 83 drugs determined in each cell line suggest limited species specificities. All cell lines differentiated CNS-penetrating compounds based on ERs with high efficiency and sensitivity. The correlation between in vivo and predicted K was the highest using total ER of human MDR1 and BCRP and optimized scaling factors. MDR1 interactors were tested on all MDR1 orthologs using digoxin and quinidine as substrates. We found several examples of inhibition dependent on either substrate or transporter abundance. In summary, this assay system has the potential for early-stage brain penetration screening. IC comparison between orthologs is complex; correlation with transporter abundance data is not necessarily proportional and requires the understanding of modes of transporter inhibition.
PubMed: 38931858
DOI: 10.3390/pharmaceutics16060736 -
Biomedicines May 2024Premature ventricular complexes (PVCs) are common electrocardiographic abnormalities and may be a prognosticator in predicting mortality in patients with structurally...
BACKGROUND
Premature ventricular complexes (PVCs) are common electrocardiographic abnormalities and may be a prognosticator in predicting mortality in patients with structurally normal hearts or chronic heart diseases. Whether PVC burden was associated with mortality in patients with chronic atrial fibrillation (AF) remained unknown. We investigated the prognostic value of PVC burden in patients with persistent AF.
METHODS
A retrospective analysis of 24 h Holter recordings of 1767 patients with persistent AF was conducted. Clinical characteristics, 24 h average heart rate (HR), and PVC measures, including 24 h PVC burden and the presence of consecutive PVCs (including any PVC couplet, triplet, or non-sustained ventricular tachycardia) were examined for the prediction of all-cause and cardiovascular mortality using the Cox proportional hazards model.
RESULTS
After a median follow-up time of 30 months, 286 (16%) patients died and 1481 (84%) patients survived. Multivariate analysis revealed that age, heart failure, stroke, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, beta-blocker, digoxin, oral anticoagulant use, and estimated glomerular filtration rate were significant baseline predictors of all-cause mortality and cardiovascular mortality. Twenty-four-hour PVC burden and the presence of consecutive PVCs were significantly associated with all-cause and cardiovascular mortality after adjusting for significant clinical factors. When compared to the first quartile of PVC burden (<0.003%/day), the highest quartile (>0.3%/day) was significantly associated with an increased risk of all-cause mortality (hazard ratio, 2.46; 95% CI, 1.77-3.42) and cardiovascular mortality (hazard ratio: 2.67; 95% CI, 1.76-4.06).
CONCLUSIONS
Twenty-four-hour PVC burden is independently associated with all-cause and cardiovascular mortality in patients with persistent AF.
PubMed: 38927356
DOI: 10.3390/biomedicines12061149 -
Journal of Cardiovascular Development... Jun 2024(1) Introduction: Digitalis use in patients with severe heart failure is controversial. We assessed the effects of digitalis therapy on mortality in a large,...
(1) Introduction: Digitalis use in patients with severe heart failure is controversial. We assessed the effects of digitalis therapy on mortality in a large, observational study in recipients of cardiac resynchronization therapy (CRT). (2) Methods: Consecutive patients receiving a CRT-defibrillator in three European tertiary referral centers were enrolled and followed-up for a mean 37 months ± 28 months. Digitalis use was assessed at the time of CRT implantation. A multivariate Cox-regression model and propensity score matching were used to determine all-cause mortality as the primary endpoint. CRT-response (defined as improvement of ≥1 NYHA class), echocardiographic improvement (defined as improvement of LVEF of ≥ 5%) and incidence of ICD shocks and rehospitalization were assessed as secondary endpoints in a subgroup of patients. (3) Results: The study comprised 552 CRT-recipients with standard indications, including 219 patients (40%) treated with digitalis. Compared to patients without digitalis, they had more often atrial fibrillation, poorer LVEF and a higher NYHA class (all ≤ 0.002). Crude analysis of all-cause mortality demonstrated a similar relative risk of death for patients with and without digitalis (HR = 1.14; 95% CI 0.88-1.5; = 0.40). After adjustment for independent predictors of mortality, digitalis therapy did not alter the risk for death (adjusted HR = 1.04; 95% CI 0.75-1.45; = 0.82). Furthermore, in comparison to 286 propensity-score-matched patients, mortality was not affected by digitalis intake (propensity-adjusted HR = 1.11; 95% CI 0.72-1.70; = 0.64). A CRT-response was predominant in digitalis non-users, concerning both improvement of HF symptoms and LVEF (NYHA < 0.01; LVEF < 0.01), while patients on digitalis had more often ventricular tachyarrhythmias requiring ICD shock ( = 0.01); although, rehospitalization for cardiac reasons was significantly lower among digitalis users compared to digitalis non-users (HR = 0.58; 95% C. I. 0.40-0.85; = 0.01). (4) Conclusions: Digitalis therapy had no effect on mortality, but was associated with a reduced response to CRT and increased susceptibility to ventricular arrhythmias requiring ICD shock treatment. Although, digitalis administration positively altered the likelihood for cardiac rehospitalization during follow-up.
PubMed: 38921673
DOI: 10.3390/jcdd11060173 -
Scientific Reports Jun 2024Alternative splicing plays a crucial role in increasing the diversity of mRNAs expressed in the genome. Serine/arginine-rich splicing factor 3 (SRSF3) is responsible for...
Alternative splicing plays a crucial role in increasing the diversity of mRNAs expressed in the genome. Serine/arginine-rich splicing factor 3 (SRSF3) is responsible for regulating the alternative splicing of its own mRNA and ensuring that its expression is balanced to maintain homeostasis. Moreover, the exon skipping of SRSF3 leads to the production of a truncated protein instead of a frameshift mutation that generates a premature termination codon (PTC). However, the precise regulatory mechanism involved in the splicing of SRSF3 remains unclear. In this study, we first established a platform for coexpressing full-length SRSF3 (SRSF3-FL) and SRSF3-PTC and further identified a specific antibody against the SRSF3-FL and truncated SRSF3 (SRSF3-TR) proteins. Next, we found that exogenously overexpressing SRSF3-FL or SRSF3-PTC failed to reverse the effects of digoxin, caffeine, or both in combination on this molecule and its targets. Endoplasmic reticulum-related pathways, transcription factors, and chemicals such as palmitic acid and phosphate were found to be involved in the regulation of SRSF3 expression. The downregulation of SRSF3-FL by palmitic acid and phosphate was mediated via different regulatory mechanisms in HeLa cells. In summary, we provide new insights into the altered expression of the SRSF3-FL and SRSF3-TR proteins for the identification of the functions of SRSF3 in cells.
Topics: Serine-Arginine Splicing Factors; Humans; HeLa Cells; Alternative Splicing; Protein Stability; Gene Expression Regulation, Neoplastic; Neoplasms; RNA, Messenger
PubMed: 38909100
DOI: 10.1038/s41598-024-64640-1 -
Annals of Indian Academy of Neurology May 2024Pharmacogenomics plays an important role in drug metabolism. A stable anticoagulation is important for primary and secondary prevention of cardioembolic stroke and...
OBJECTIVE
Pharmacogenomics plays an important role in drug metabolism. A stable anticoagulation is important for primary and secondary prevention of cardioembolic stroke and cerebral venous sinus thrombosis (CVST). We report the role of cytochrome P450 ( CYP2C9*2/*3 ) and vitamin K epoxide reductase subunit 1 ( VKORC1 ) genotypes and acquired causes in maintaining stability of anticoagulation following acenocoumarin in cardioembolic stroke and CVST.
METHODS
The study comprised 157 individuals with cardioembolic stroke and CVST who were on acenocoumarin. Their comorbidities, comedication, and dietary habits were noted. Prothrombin time and international normalized ratio (INR) were measured during follow-up, and the coagulation status was categorized as stable (>50% occasions in therapeutic range) and unstable (>50% below and above therapeutic range). Genotyping of VKORC1 , CYP2C9*2 , and CYP2C9*3 was done by polymerase chain reaction-restriction fragment length polymorphism. Bleeding and embolic complications were noted. The predictors of unstable INR were evaluated using multivariate analysis.
RESULTS
INR was stable in 47.8% and unstable in 52.2% of patients. Patients with mutant genotypes required low dose of acenocoumarin. The predictors of unstable INR were metallic valve (odds ratio [OR] 4.07, 95% confidence interval [CI] 1.23-13.49, P = 0.02), use of digoxin (OR 0.031, 95% CI 0.13-0.74, P = 0.09), proton pump inhibitor (OR 0.23, 95% CI 0.06-0.91, P = 0.037), sodium valproate (OR 0.22, 95% CI 0.05-0.85, P = 0.029), and CYP2C9*2 genotype (OR 5.57, 95% CI 1.19-26.06, P = 0.02).
CONCLUSIONS
Variant genotypes of VKORC1 , CYP2C9*2 , and CYP2C9*3 required lower dose of acenocoumarin, and CYP2C9*2 was associated with unstable INR. Comedication is a modifiable risk factor that needs attention.
PubMed: 38907686
DOI: 10.4103/aian.aian_886_23 -
Archives of Dermatological Research Jun 2024There are many therapeutic modalities for plantar warts, however treating it remains challenging. Intralesional injection of 5-fluorouarcil and combined digoxin and... (Randomized Controlled Trial)
Randomized Controlled Trial Comparative Study
There are many therapeutic modalities for plantar warts, however treating it remains challenging. Intralesional injection of 5-fluorouarcil and combined digoxin and furosemide were observed to be effective and safe, however no comparison study between them was done. Our study was conducted to evaluate the efficacy of both therapies in the treatment of plantar warts. 90 adult patients with multiple recalcitrant plantar warts were included in our study. They were randomly allocated to one of three groups; combined digoxin and furosemide, 5-fluorouarcil, or normal saline group. Fortnightly injections were done into all studied warts till complete clearance or up to 5 sessions. Warts were evaluated clinically and dermoscopically. Clinical response was reported in 24 patients (80%) of the combined digoxin and furosemide group with 40% complete response and in 24 patients (80%) of the 5-fluorouarcil group with 33.3% complete response. No statistically significant difference was observed between the two groups concerning efficacy and safety. Intralesional injection of 5-fluorouarcil and combined digoxin and furosemide are nearly equivalent in efficacy and safety for plantar wart treatment. Dermoscopy helps to take the truthful judgment about complete clearance of warts.
Topics: Humans; Furosemide; Male; Female; Adult; Warts; Digoxin; Injections, Intralesional; Treatment Outcome; Prospective Studies; Young Adult; Middle Aged; Drug Therapy, Combination; Adolescent; Dermoscopy; Flucytosine
PubMed: 38878078
DOI: 10.1007/s00403-024-03014-z -
Journal of Medical Case Reports Jun 2024Bradycardia, renal failure, atrioventricular (AV) node blocking, shock, and hyperkalemia syndrome is a potentially life-threatening clinical condition characterized by...
BACKGROUND
Bradycardia, renal failure, atrioventricular (AV) node blocking, shock, and hyperkalemia syndrome is a potentially life-threatening clinical condition characterized by bradycardia, renal failure, atrioventricular (AV) node blocking, shock, and hyperkalemia. It constitutes a vicious circle in which the accumulation of pharmacologically active compounds and hyperkalemia lead to hemodynamic instability and heart failure.
CASE PRESENTATION
A 66-year-old Caucasian female patient was admitted to the emergency department presenting with fatigue and bradycardia. Upon examination, the patient was found to be anuric and hypotensive. Laboratory investigations revealed metabolic acidosis and hyperkalemia. Clinical evaluation suggested signs of digoxin toxicity, with serum digoxin concentrations persistently elevated over several days. Despite the implementation of antikalemic measures, the patient's condition remained refractory, necessitating renal dialysis and administration of digoxin immune fab.
CONCLUSION
Bradycardia, renal failure, atrioventricular (AV) node blocking, shock, and hyperkalemia syndrome is a life-threatening condition that requires prompt management. It is important to also consider potential coexisting clinical manifestations indicative of intoxication from other pharmacological agents. Specifically, symptoms associated with the accumulation of drugs eliminated via the kidneys, such as digoxin. These manifestations may warrant targeted therapeutic measures.
Topics: Humans; Female; Aged; Digoxin; Hyperkalemia; Bradycardia; Renal Dialysis; Renal Insufficiency; Anti-Arrhythmia Agents; Syndrome; Acidosis; Shock; Atrioventricular Block; Immunoglobulin Fab Fragments
PubMed: 38851740
DOI: 10.1186/s13256-024-04600-5 -
BioRxiv : the Preprint Server For... May 2024Thrombosis is a major cause of myocardial infarction and ischemic stroke. The sodium/potassium ATPase (NKA), comprising α and β subunits, is crucial in maintaining...
BACKGROUND
Thrombosis is a major cause of myocardial infarction and ischemic stroke. The sodium/potassium ATPase (NKA), comprising α and β subunits, is crucial in maintaining intracellular sodium and potassium gradients. However, the role of NKA in platelet function and thrombosis remains unclear.
METHODS
We utilized wild-type (WT, α) and NKA α1 heterozygous (α) mice, aged 8 to 16 weeks, of both sexes. An intravital microscopy-based, FeCl-induced carotid artery injury thrombosis model was employed for in vivo thrombosis assessment. Platelet transfusion assays were used to evaluate platelet NKA α1 function on thrombosis. Human platelets isolated from healthy donors and heart failure patients treated with/without digoxin were used for platelet function and signaling assay. Complementary molecular approaches were used for mechanistic studies.
RESULTS
NKA α1 haplodeficiency significantly reduced its expression on platelets without affecting sodium homeostasis. It significantly inhibited 7.5% FeCl-induced thrombosis in male but not female mice without disturbing hemostasis. Transfusion of α, but not α, platelets to thrombocytopenic WT mice substantially prolonged thrombosis. Treating WT mice with low-dose ouabain or marinobufagenin, both binding NKA α1 and inhibiting its ion-transporting function, markedly inhibited thrombosis in vivo. NKA α1 formed complexes with leucine-glycine-leucine (LGL)-containing platelet receptors, including P2Y12, PAR4, and thromboxane A2 receptor. This binding was significantly attenuated by LGL>SFT mutation or LGL peptide. Haplodeficiency of NKA α1 in mice or ouabain treatment of human platelets notably inhibited ADP-induced platelet aggregation. While not affecting 10% FeCl-induced thrombosis, NKA α1 haplodeficiency significantly prolonged thrombosis time in mice treated with an ineffective dose of clopidogrel.
CONCLUSION
NKA α1 plays an essential role in enhancing platelet activation through binding to LGL-containing platelet GPCRs. NKA α1 haplodeficiency or inhibition with low-dose ouabain and marinobufagenin significantly inhibited thrombosis and sensitized clopidogrel's anti-thrombotic effect. Targeting NKA α1 emerges as a promising antiplatelet and antithrombotic therapeutic strategy.
PubMed: 38798556
DOI: 10.1101/2024.05.13.593923 -
Scientific Reports May 2024Therapeutic drug monitoring (TDM) is a crucial clinical practice that improves pharmacological effectiveness and prevent severe drug-related adverse events. Timely...
Therapeutic drug monitoring (TDM) is a crucial clinical practice that improves pharmacological effectiveness and prevent severe drug-related adverse events. Timely reporting and intervention of critical values during TDM are essential for patient safety. In this study, we retrospectively analyzed the laboratory data to provide an overview of the incidence, distribution pattern and biochemical correlates of critical values during TDM. A total of 19,110 samples were tested for nine drug concentrations between January 1, 2019, and December 31, 2020. Of these, 241 critical values were identified in 165 patients. The most common critical values were vancomycin trough (63.4%), followed by tacrolimus trough (16.9%) and digoxin (15.2%). The primary sources of drug critical values were the department of general intensive care unit (ICU), cardiology, and surgery ICU. At baseline or the time of critical value, significant differences were found between the vancomycin, digoxin, and tacrolimus groups in terms of blood urea nitrogen (BUN), creatinine, N-terminal Pro-B-Type Natriuretic Peptide (NT-proBNP), and lymphocyte percentage, P < 0.05. Therefore, it is important to prioritize and closely monitor drug concentrations to reduce laboratory critical values during TDM.
Topics: Humans; Drug Monitoring; Retrospective Studies; Male; Female; Tacrolimus; Vancomycin; Middle Aged; Aged; Digoxin; Intensive Care Units; Adult; Creatinine; Blood Urea Nitrogen; Natriuretic Peptide, Brain
PubMed: 38769456
DOI: 10.1038/s41598-024-62402-7