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International Journal of Molecular... May 2024In the area of drug research, several computational drug repurposing studies have highlighted candidate repurposed drugs, as well as clinical trial studies that have...
In the area of drug research, several computational drug repurposing studies have highlighted candidate repurposed drugs, as well as clinical trial studies that have tested/are testing drugs in different phases. To the best of our knowledge, the aggregation of the proposed lists of drugs by previous studies has not been extensively exploited towards generating a dynamic reference matrix with enhanced resolution. To fill this knowledge gap, we performed weight-modulated majority voting of the modes of action, initial indications and targeted pathways of the drugs in a well-known repository, namely the Drug Repurposing Hub. Our method, Democracy, exploits this pile of information and creates frequency tables and, finally, a disease suitability score for each drug from the selected library. As a testbed, we applied this method to a group of neurodegenerative diseases (Alzheimer's, Parkinson's, Huntington's disease and Multiple Sclerosis). A super-reference table with drug suitability scores has been created for all four neurodegenerative diseases and can be queried for any drug candidate against them. Top-scored drugs for Alzheimer's Disease include agomelatine, mirtazapine and vortioxetine; for Parkinson's Disease, they include apomorphine, pramipexole and lisuride; for Huntington's, they include chlorpromazine, fluphenazine and perphenazine; and for Multiple Sclerosis, they include zonisamide, disopyramide and priralfimide. Overall, Democracy is a methodology that focuses on leveraging the existing drug-related experimental and/or computational knowledge rather than a predictive model for drug repurposing, offering a quantified aggregation of existing drug discovery results to (1) reveal trends in selected tracks of drug discovery research with increased resolution that includes modes of action, targeted pathways and initial indications for the investigated drugs and (2) score new candidate drugs for repurposing against a selected disease.
Topics: Drug Repositioning; Humans; Drug Discovery; Neurodegenerative Diseases
PubMed: 38791356
DOI: 10.3390/ijms25105319 -
Interdisciplinary Cardiovascular and... May 2024Extended septal myectomy and alcohol septal ablation are 2 invasive treatments for hypertrophic obstructive cardiomyopathy. Our goal was to compare which of these...
OBJECTIVES
Extended septal myectomy and alcohol septal ablation are 2 invasive treatments for hypertrophic obstructive cardiomyopathy. Our goal was to compare which of these techniques achieved a higher reduction in gradients, improvement in New York Heart Association (NYHA) functional class and reduction in medical treatment.
METHODS
It is a single-centre observational and retrospective analysis. We used multivariable regression analyses to assess the association of ablation/myectomy with different outcomes. The odds ratio or coefficient along with the 95% confidence interval was estimated according to the group and adjusted for the corresponding preprocedural variables and EuroSCORE II.
RESULTS
A total of 78 patients underwent septal myectomy, and 25 patients underwent alcohol septal ablation. Basal and Valsalva gradients after myectomy were reduced to a higher degree in comparison to ablation: 21.0 mmHg [P < 0.001, 95% confidence interval -30.7; -11.3], and 34.3 mmHg (P < 0.001, -49.1; -19.5) respectively. Those patients who received a myectomy had a lower probability of having moderate mitral regurgitation (odds ratio = 0.18, P = 0.054). Patients after septal myectomy were more likely to be NYHA functional class I (80.4%), whereas patients after ablation were more likely to be NYHA functional class III (48%). Both groups continued with beta-blocker therapy, but disopyramide could be discontinued after the myectomy in more cases (20%-36% vs 59%-1.3%; P < 0.001), and there was a tendency to discontinue calcium channel blockers (48%-16% vs 15.4-3.8%; P = 0.054).
CONCLUSIONS
After adjustment using preprocedural gradients and EuroSCORE II, myectomy achieves greater reduction in left ventricular outflow tract gradients compared to septal ablation.
PubMed: 38569884
DOI: 10.1093/icvts/ivae058 -
International Journal of Molecular... Mar 2024Cisplatin (CDDP) stands out as an effective chemotherapeutic agent; however, its application is linked to the development of significant adverse effects, notably nephro-...
Cisplatin (CDDP) stands out as an effective chemotherapeutic agent; however, its application is linked to the development of significant adverse effects, notably nephro- and ototoxicity. The human organic cation transporter 2 (hOCT2), found in abundance in the basolateral membrane domain of renal proximal tubules and the Corti organ, plays a crucial role in the initiation of nephro- and ototoxicity associated with CDDP by facilitating its uptake in kidney and ear cells. Given its limited presence in cancer cells, hOCT2 emerges as a potential druggable target for mitigating unwanted toxicities associated with CDDP. Potential strategies for mitigating CDDP toxicities include competing with the uptake of CDDP by hOCT2 or inhibiting hOCT2 activity through rapid regulation mediated by specific signaling pathways. This study investigated the interaction between the already approved cationic drugs disopyramide, imipramine, and orphenadrine with hOCT2 that is stably expressed in human embryonic kidney cells. Regarding disopyramide, its influence on CDDP cellular transport by hOCT2 was further characterized through inductively coupled plasma isotope dilution mass spectrometry. Additionally, its potential protective effects against cellular toxicity induced by CDDP were assessed using a cytotoxicity test. Given that hOCT2 is typically expressed in the basolateral membrane of polarized cells, with specific regulatory mechanisms, this work studied the regulation of hOCT2 that is stably expressed in Madin-Darby Canine Kidney (MDCK) cells. These cells were cultured in a matrix to induce the formation of cysts, exposing hOCT2 in the basolateral plasma membrane domain, which was freely accessible to experimental solutions. The study specifically tested the regulation of ASP uptake by hOCT2 in MDCK cysts through the inhibition of casein kinase II (CKII), calmodulin, or p56 tyrosine kinase. Furthermore, the impact of this manipulation on the cellular toxicity induced by CDDP was examined using a cytotoxicity test. All three drugs-disopyramide, imipramine, and orphenadrine-demonstrated inhibition of ASP uptake, with IC values in the micromolar (µM) range. Notably, disopyramide produced a significant reduction in the CDDP cellular toxicity and platinum cellular accumulation when co-incubated with CDDP. The activity of hOCT2 in MDCK cysts experienced a significant down-regulation under inhibition of CKII, calmodulin, or p56 tyrosine kinase. Interestingly, only the inhibition of p56 tyrosine kinase demonstrated the capability to protect the cells against CDDP toxicity. In conclusion, certain interventions targeting hOCT2 have demonstrated the ability to reduce CDDP cytotoxicity, at least in vitro. Further investigations in in vivo systems are warranted to ascertain their potential applicability as co-treatments for mitigating undesired toxicities associated with CDDP in patients.
Topics: Humans; Animals; Dogs; Organic Cation Transporter 2; Organic Cation Transport Proteins; Cisplatin; Disopyramide; Calmodulin; Imipramine; Orphenadrine; Ototoxicity; Madin Darby Canine Kidney Cells; Protein-Tyrosine Kinases; Cysts
PubMed: 38474165
DOI: 10.3390/ijms25052922 -
JACC. Case Reports Dec 2023An adult with unrepaired tetralogy of Fallot presented with frequent tet spells. Her course was complicated by severe cyanotic spells and tachycardia-bradycardia...
An adult with unrepaired tetralogy of Fallot presented with frequent tet spells. Her course was complicated by severe cyanotic spells and tachycardia-bradycardia syndrome that limited beta blocker use to stabilize her spells. She markedly improved after disopyramide initiation and underwent successful tetralogy of Fallot repair with excellent functional outcome.
PubMed: 38204534
DOI: 10.1016/j.jaccas.2023.102093 -
European Heart Journal. Case Reports Oct 2023Left ventricular outflow tract obstruction (LVOTO) sometimes presents with aortic stenosis (AS). Echocardiography is used to assess the diagnosis and severity of LVOTO...
Usefulness of catheter pressure measurement using the Navvus RXi system to determine left ventricular outflow tract obstruction and aortic stenosis severity: a case report.
BACKGROUND
Left ventricular outflow tract obstruction (LVOTO) sometimes presents with aortic stenosis (AS). Echocardiography is used to assess the diagnosis and severity of LVOTO or AS. However, LVOTO is one of the conditions that makes AS assessment difficult, and catheter pressure measurement is frequently useful in such cases.
CASE SUMMARY
An 84-year-old female patient presented with New York Heart Association functional Class III dyspnoea. Transthoracic echocardiography revealed LVOTO caused by upper septal hypertrophy, mitral valve systolic anterior motion with moderate mitral regurgitation, and a highly calcified aortic valve, which suggested the possibility of severe AS. The continuous Doppler echocardiography revealed a late-systolic peaking dagger-shaped profile with a peak jet velocity of 5.6 m/s. Cardiac catheterization was performed to determine the contribution of AS or LVOTO to her symptoms. Catheter pressures were measured at the ascending aorta (using a coronary catheter) and the LV (using the Navvus RXi system). The initial mean pressure gradient between the apex of the LV, just below the aortic valve and aorta, was measured at 65 and 25 mmHg, respectively. The mean pressure gradient between the apex and the aorta decreased from 65 to 40 mmHg after a 50 mg disopyramide administration. Oral medication therapy effectively stabilized her symptom after catheterization.
DISCUSSION
To the best of our knowledge, this is the first reported case of assessing the severity of LVOTO and AS using the Navvus RXi system. Catheter pressure measurement using the Navvus RXi system is a useful method of determining the severity of LVOTO and AS.
PubMed: 37811156
DOI: 10.1093/ehjcr/ytad471 -
Annals of Medicine and Surgery (2012) Oct 2023Aluminum phosphide (ALP) is a commonly used suicidal agent in an agrarian country like Nepal. The unmasking of the Brugada pattern in the electrocardiogram (ECG)...
INTRODUCTION AND IMPORTANCE
Aluminum phosphide (ALP) is a commonly used suicidal agent in an agrarian country like Nepal. The unmasking of the Brugada pattern in the electrocardiogram (ECG) associated with ALP poisoning is a rare phenomenon, and studies pertaining to it are scarce in the medical literature.
CASE PRESENTATION
An 18-year-old female presented to the emergency department with multiple episodes of vomiting, headache, blurring of vision, and abdominal pain after 4 h of consumption of ALP with suicidal intent. A 12-lead ECG revealed a coved ST-segment elevation and T-wave inversion in leads V1-V3 with right bundle branch block suggestive of a type 1 Brugada pattern. Her past medical and family history was not significant. The patient made an uneventful recovery with the required supportive treatments.
CLINICAL DISCUSSION
Cardiac arrhythmias are the major cause of death in ALP poisoning. Unmasking of the Brugada ECG pattern is a rare but potentially fatal complication implicated in various pharmacological toxicities, including tricyclic antidepressants, cocaine, procainamide, disopyramide, flecainide, and rarely with ALP.
CONCLUSIONS
ALP poisoning can unmask the Brugada ECG pattern, which can lead to ventricular fibrillation and/or sudden cardiac death.
PubMed: 37811028
DOI: 10.1097/MS9.0000000000001129 -
Cardiology Research Aug 2023Hypertrophic cardiomyopathy is one of the most common genetic inherited diseases of myocardium, which is caused by mutation in genes encoding proteins for the cardiac... (Review)
Review
Hypertrophic cardiomyopathy is one of the most common genetic inherited diseases of myocardium, which is caused by mutation in genes encoding proteins for the cardiac sarcomere. It is the most frequent cause of sudden death in young people and trained athletes. All diagnostic methods, including heart catheterization, transthoracic and transesophageal echocardiography, magnetic resonance imaging, genetic counseling and tissue biopsy are required for risk and therapy stratification and should be individualized depending on phenotype and genotype. Current therapy has not been tested adequately. Beta-blockers and verapamil can cause hypotension which can make hypertrophic cardiomyopathy worse. Disopyramide has been inadequately studied, and mavacamten was only studied in small trials. More definitive trials are currently ongoing. Novel invasive and noninvasive diagnostics, medical therapies, interventional and surgical approaches tend to influence the natural history of the disease, favoring a better future for this patient population.
PubMed: 37559708
DOI: 10.14740/cr1514 -
Journal of Cardiac Failure Nov 2023
Topics: Humans; Disopyramide; Sequoia; Heart Failure; Anti-Arrhythmia Agents; Cardiomyopathy, Hypertrophic
PubMed: 37473912
DOI: 10.1016/j.cardfail.2023.07.003 -
Journal of Pharmacological and... 2023Pharmacological blockade of the I channel (hERG) by diverse drugs in clinical use is associated with the Long QT Syndrome that can lead to life threatening arrhythmia....
Pharmacological blockade of the I channel (hERG) by diverse drugs in clinical use is associated with the Long QT Syndrome that can lead to life threatening arrhythmia. Various computational tools including machine learning models (MLM) for the prediction of hERG inhibition have been developed to facilitate the throughput screening of drugs in development and optimise thus the prediction of hERG liabilities. The use of MLM relies on large libraries of training compounds for the quantitative structure-activity relationship (QSAR) modelling of hERG inhibition. The focus on inhibition omits potential effects of hERG channel agonist molecules and their associated QT shortening risk. It is instructive, therefore, to consider how known hERG agonists are handled by MLM. Here, two highly developed online computational tools for the prediction of hERG liability, Pred-hERG and HergSPred were probed for their ability to detect hERG activator drug molecules as hERG interactors. In total, 73 hERG blockers were tested with both computational tools giving overall good predictions for hERG blockers with reported ICs below Pred-hERG and HergSPred cut-off threshold for hERG inhibition. However, for compounds with reported ICs above this threshold such as disopyramide or sotalol discrepancies were observed. HergSPred identified all 20 hERG agonists selected as interacting with the hERG channel. Further studies are warranted to improve online MLM prediction of hERG related cardiotoxicity, by explicitly taking into account channel agonism as well as inhibition.
Topics: Humans; Potassium Channel Blockers; Ether-A-Go-Go Potassium Channels; Arrhythmias, Cardiac; Machine Learning; Internet
PubMed: 37468081
DOI: 10.1016/j.vascn.2023.107293