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JACC. Advances Oct 2023Hypertrophic cardiomyopathy-both obstructive hypertrophic cardiomyopathy (oHCM) and nonobstructive hypertrophic cardiomyopathy (nHCM) subtypes-is the most common... (Review)
Review
Hypertrophic cardiomyopathy-both obstructive hypertrophic cardiomyopathy (oHCM) and nonobstructive hypertrophic cardiomyopathy (nHCM) subtypes-is the most common monogenic cardiomyopathy. Its structural hallmarks are abnormal thickening of the myocardium and hyperdynamic contractility, while its hemodynamic consequences are left ventricular outflow tract or intracavitary obstruction (in oHCM) and diastolic dysfunction (in both oHCM and nHCM). Several medical therapies are routinely used to improve these abnormalities with the goal to decrease symptom burden in patients with HCM. Current guidelines recommend nonvasodilating beta blockers as first-line and nondihydropyridine calcium channel blockers followed by disopyramide as second- and third-line medical therapies for symptomatic oHCM and give weaker recommendations for beta blockers and calcium channel blockers in nHCM. These recommendations are based on small studies-mostly nonrandomized-and expert opinion. Our review will summarize the available data on the effectiveness of commonly prescribed medications used in oHCM and nHCM to uncover knowledge gaps, but also new data on cardiac myosin inhibitors.
PubMed: 38938334
DOI: 10.1016/j.jacadv.2023.100622 -
Molecular Pharmaceutics Jun 2024α-Acid glycoprotein (AGP) is a primary binding protein for many basic drugs in plasma. The number of drugs that bind to AGP, such as molecular target anticancer drugs,...
α-Acid glycoprotein (AGP) is a primary binding protein for many basic drugs in plasma. The number of drugs that bind to AGP, such as molecular target anticancer drugs, has been continuously increasing. Since the plasma level of AGP fluctuates under various pathological conditions such as inflammation, it is important to evaluate the contribution of AGP to drug pharmacokinetics. Here, we generated conventional AGP-knockout (AGP-KO) mice and used them to evaluate the contribution of AGP. The pharmacokinetics of drugs that bind to two AGP variants (F1*S or A variants) or albumin were evaluated. Imatinib (a F1*S-binding drug) and disopyramide (an A-binding drug) or ibuprofen (an albumin-binding drug) were administered to wild-type (WT) and AGP-KO. The plasma level of imatinib and disopyramide decreased rapidly in AGP-KO as compared to WT. In AGP-KO, AUC and were decreased, then C was increased. Compared with disopyramide, imatinib pharmacokinetics showed more marked changes in AGP-KO as compared to WT. The results seemed to be due to the difference in plasma level of each AGP variant (F1*S:A = 2-3:1). No differences were observed in ibuprofen pharmacokinetics between the WT and AGP-KO mice. In vitro experiments using plasma from WT and AGP-KO showed that unbound fractions of imatinib and disopyramide were higher in AGP-KO. These results suggest that the rapid elimination of imatinib and disopyramide in AGP-KO could be due to decreased protein binding to AGP. Taken together, the AGP-KO mouse could be a potential animal model for evaluating the contribution of AGP to the pharmacokinetics of various drugs.
PubMed: 38862418
DOI: 10.1021/acs.molpharmaceut.3c00866 -
European Journal of Preventive... Jun 2024
PubMed: 38850169
DOI: 10.1093/eurjpc/zwae198 -
Expert Opinion on Pharmacotherapy May 2024Hypertrophic cardiomyopathy (HCM) is a heterogeneous genetic heart disease with an estimated prevalence in the general population of 0.2% to 0.6%. Clinically, HCM can... (Review)
Review
INTRODUCTION
Hypertrophic cardiomyopathy (HCM) is a heterogeneous genetic heart disease with an estimated prevalence in the general population of 0.2% to 0.6%. Clinically, HCM can range from no symptoms to severe symptoms such as heart failure or sudden cardiac death. Currently, the management of HCM involves lifestyle modifications, familial screening, genetic counseling, pharmacotherapy to manage symptoms, sudden cardiac death risk assessment, septal reduction therapy, and heart transplantation for specific patients. Multicenter randomized controlled trials have only recently explored the potential of cardiac myosin inhibitors (CMIs) such as mavacamten as a directed pharmacological approach for managing HCM.
AREAS COVERED
We will assess the existing medical treatments for HCM: beta-blockers, calcium channel blockers, disopyramide, and different CMIs. We will also discuss future HCM pharmacotherapy guidelines and underline this patient population's unfulfilled needs.
EXPERT OPINION
Mavacamten is the first-in-class CMI approved by the FDA to target HCM pathophysiology specifically. Mavacamten should be incorporated into the standard therapy for oHCM in case of symptom persistence despite using maximally tolerated beta blockers and/or calcium channel blockers. Potential drug-drug interactions should be assessed before initiating this drug. More studies are needed on the use of CMIs in patients with kidney and/or liver failure and pregnant/breastfeeding patients.
Topics: Adult; Humans; Benzylamines; Cardiac Myosins; Cardiomyopathy, Hypertrophic; Death, Sudden, Cardiac; Drug Interactions; Randomized Controlled Trials as Topic; Uracil
PubMed: 38813944
DOI: 10.1080/14656566.2024.2362902 -
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 -
Archives of Cardiovascular Diseases 2024The efficacy of current pharmacological therapies in hypertrophic cardiomyopathy is limited. A cardiac myosin inhibitor, mavacamten, has recently been approved as a...
Target population for a selective cardiac myosin inhibitor in hypertrophic obstructive cardiomyopathy: Real-life estimation from the French register of hypertrophic cardiomyopathy (REMY).
BACKGROUND
The efficacy of current pharmacological therapies in hypertrophic cardiomyopathy is limited. A cardiac myosin inhibitor, mavacamten, has recently been approved as a first-in-class treatment for symptomatic hypertrophic obstructive cardiomyopathy.
AIMS
To assess the profile and burden of cardiac myosin inhibitor candidates in the hypertrophic cardiomyopathy prospective Register of hypertrophic cardiomyopathy (REMY) held by the French Society of Cardiology.
METHODS
Data were collected at baseline and during follow-up from patients with hypertrophic cardiomyopathy enrolled in REMY by the three largest participating centres.
RESULTS
Among 1059 adults with hypertrophic cardiomyopathy, 461 (43.5%) had obstruction; 325 (30.7%) of these were also symptomatic, forming the "cardiac myosin inhibitor candidates" group. Baseline features of this group were: age 58±15years; male sex (n=196; 60.3%); diagnosis-to-inclusion delay 5 (1-12)years; maximum wall thickness 20±6mm; left ventricular ejection fraction 69±6%; family history of hypertrophic cardiomyopathy or sudden cardiac death (n=133; 40.9%); presence of a pathogenic sarcomere gene mutation (n=101; 31.1%); beta-blocker or verapamil treatment (n=304; 93.8%), combined with disopyramide (n=28; 8.7%); and eligibility for septal reduction therapy (n=96; 29%). At the end of a median follow-up of 66 (34-106) months, 319 (98.2%) were treated for obstruction (n=43 [13.2%] received disopyramide), 46 (14.2%) underwent septal reduction therapy and the all-cause mortality rate was 1.9/100 person-years (95% confidence interval 1.4-2.6) (46 deaths). Moreover, 41 (8.9%) patients from the initial hypertrophic obstructive cardiomyopathy group became eligible for a cardiac myosin inhibitor.
CONCLUSIONS
In this cohort of patients with hypertrophic cardiomyopathy selected from the REMY registry, one third were eligible for a cardiac myosin inhibitor.
Topics: Humans; Male; Cardiomyopathy, Hypertrophic; Female; Middle Aged; Registries; France; Treatment Outcome; Aged; Time Factors; Ventricular Function, Left; Cardiovascular Agents; Patient Selection; Prospective Studies; Cardiac Myosins; Benzylamines; Adult; Risk Factors; Ventricular Outflow Obstruction; Uracil
PubMed: 38762345
DOI: 10.1016/j.acvd.2024.04.001 -
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 -
The Medical Letter on Drugs and... Jan 2024
Topics: Humans; Atrial Fibrillation
PubMed: 38180321
DOI: 10.58347/tml.2024.1693a