Search

Potassium channels encoded by human Ether-à-go-go-Related Gene (hERG) are inhibited by diverse cardiac and non-cardiac drugs. Disopyramide is a chiral Class Ia antiarrhythmic that inhibits hERG at clinical concentrations. This study evaluated effects of disopyramide enantiomers on hERG current (IhERG) from hERG expressing HEK 293 cells at 37 °C. S(+) and R(−) disopyramide inhibited wild-type (WT) IhERG with IC50 values of 3.9 µM and 12.9 µM respectively. The attenuated-inactivation mutant N588K had little effect on the action of S(+) disopyramide but the IC50 for the R(−) enantiomer was ~ 15-fold that for S(+) disopyramide. The enhanced inactivation mutant N588E only slightly increased the potency of R(−) disopyramide. S6 mutation Y652A reduced S(+) disopyramide potency more than that of R(−) disopyramide (respective IC50 values ~ 49-fold and 11-fold their WT controls). The F656A mutation also exerted a stronger effect on S(+) than R(−) disopyramide, albeit with less IC50 elevation. A WT-Y652A tandem dimer exhibited a sensitivity to the enantiomers that was intermediate between that of WT and Y652A, suggesting Y652 groups on adjacent subunits contribute to the binding. Moving the Y (normally at site 652) one residue in the N- terminal (up) direction in N588K hERG markedly increased the blocking potency of R(−) disopyramide. Molecular dynamics simulations using a hERG pore model produced different binding modes for S(+) and R(−) disopyramide consistent with the experimental observations. In conclusion, S(+) disopyramide interacts more strongly with S6 aromatic binding residues on hERG than does R(−) disopyramide, whilst optimal binding of the latter is more reliant on intact inactivation. [ABSTRACT FROM AUTHOR]

Background: For symptomatic obstructive hypertrophic cardiomyopathy (oHCM), limited evidence exists on healthcare resource utilization (HRU) and cost for patients with symptomatic oHCM by treatment categories. We evaluated whether HRU and costs vary by initial treatment in symptomatic oHCM. Methods: This is a retrospective study of medical and pharmacy claims from 2016 to 2021 to identify (per International Classification of Disease Tenth Revision diagnosis codes) adult patients in the USA with symptomatic oHCM. Patients included in the study cohort were required to be treatment naïve (≥ 12 months' activity before first treatment) and symptomatic (fatigue, chest pain, syncope, dyspnea, heart failure, or palpitations within 3 months of index date). Patients were grouped by first index treatment [beta blocker (BB), calcium channel blockers (CCB), disopyramide, combination therapy], and HRU and costs [per person per year (PPPY), in USD] by initial treatment were reported. Results: Among 7334 patients with symptomatic oHCM, initial treatment included BB (65.8%), CCB (21.1%), disopyramide (1.2%), or BB + CCB (11.9%). Overall, 87.2% were prescribed monotherapy. Outpatient visits were the main driver of all-cause HRU (mean 11.5 PPPY), and varied by initial treatment (BB: 11.0, CCB: 10.5, disopyramide: 7.2, combination therapy: 12.1). All-cause urgent care visits were more frequent than inpatient visits (means: 5.4 and 0.83 PPPY, respectively). All-cause incurred costs were $46,628 PPPY overall and varied by treatment (BB: $47,029, CCB: $42,124, disopyramide: $27,007, combination therapy: $54,024). Conclusions: In this large, US-based cohort of patients with symptomatic oHCM, initial therapy was most commonly BB and CCB monotherapy. Costs and HRU were high for most patients, but greater for those treated initially with combination therapy. [ABSTRACT FROM AUTHOR]

Introduction: Hypertrophic cardiomyopathy (HCM) is defined by an increased left ventricular wall thickness not solely explainable by abnormal loading conditions. Estimated prevalence is 1:200–500 with roughly 60% of cases showing a familiar trait. Medical treatment and surgical interventions significantly altered prognosis in HCM. Recently, new therapies have been introduced in clinical practice and a patient-centric approach is key to HCM optimal management. This review aims to summarize the current HCM therapies focusing on the importance of personalized care and delineate therapeutic approaches under investigation. Areas covered: The review summarizes and critically evaluates the available data on currently available pharmacological and non-pharmacological therapies for HCM. The evidence in support of the use of beta-blockers, non-dihydropyridine calcium channel blockers, disopyramide, and cardiac myosin inhibitors is discussed. Furthermore, data and controversies on sudden death prevention, surgical and non-surgical septal reduction therapies are reported. Finally, future perspectives in HCM management such as new drugs and gene therapies are explored. Expert opinion: The authors stress the need for a personalized and tailored approach to managing patients with HCM, which is not only based on phenotypes and risk stratification, but also patients' preferences, needs, and beliefs. [ABSTRACT FROM AUTHOR]

BackgroundHypertrophic cardiomyopathy (HCM) is a genetic disorder for which first-line treatments for obstructive HCM (oHCM) include beta-blockers, non-dihydropyridine calcium channel blockers, and disopyramide for refractory cases. Mavacamten, a selective cardiac myosin inhibitor, is indicated for symptomatic oHCM to improve functional capacity and symptoms. Use of disopyramide and mavacamten together is not recommended due to concerns of additive negative inotropic effects. Transitioning from disopyramide to mavacamten may be preferred to avoid adverse effects and frequent administration, however, the best approach for making the transition has not been established.CasesWe present a series of seven patients with oHCM who transitioned from disopyramide to mavacamten and underwent echocardiograms mandated by a Risk Evaluation and Mitigations Strategies program. Two methods were employed. The first approach, involving washout of disopyramide before starting mavacamten, resulted in worsening of heart failure symptoms in the first two cases. The second approach, involving tapering disopyramide when starting mavacamten, was successfully implemented in the last five cases, with no adverse effects or worsening of systolic dysfunction.ConclusionOur method of tapering disopyramide when starting mavacamten using a stepwise approach is feasible and safe. Our report fulfills an unmet need by serving as a guide for other clinicians who seek to transition their patients from disopyramide to mavacamten.

Background Disopyramide is used to treat heart failure symptoms in patients with obstructive hypertrophic cardiomyopathy (HCM) with known medium‐term efficacy and safety, while long‐term outcomes are unknown. Methods and Results A total of 92 consecutive patients with symptomatic obstructive HCM with peak left ventricular outflow tract gradients of ≥30 mm Hg at rest or with provocation who were maintained on disopyramide for ≥5 years at 2 dedicated HCM centers were included: 92 patients; mean age, 62.5 years; 54% women; treated with disopyramide for median 7.2 years (left ventricular wall thickness 18±4 mm; median peak outflow gradient 95 mm Hg). At last follow‐up, 62 (67%) patients continued disopyramide, including 57 with symptom improvement ≥1 New York Heart Association class. The other 30 (33%) patients discontinued disopyramide due primarily to incomplete symptom resolution and required surgical myectomy or alcohol septal ablation (n=23) at 7.4 years from initiation. With disopyramide, resting left ventricular outflow gradients were reduced by 37% (to median 19 mm Hg), and provoked gradients decreased by 57% (to median 41 mm Hg), with no residual outflow obstruction (5 years.

Pediatric hypertrophic cardiomyopathy (HCM) has a wide range of clinical manifestations. Left ventricular outflow tract obstruction (LVOTO) at rest is present in up to one-third of children with HCM, with a further 50-60% of symptomatic children developing a gradient under exertion. Treatment options are limited, and there is a relative lack of data on the pediatric population. Disopyramide is a sodium channel blocker with negative inotropic properties. This therapy effectively reduces LVOTO in adults with HCM and delays surgical interventions, but it is not licensed for use in children. We aimed to review and analyze the influence of disopyramide over the pathophysiological, clinical, electrocardiographic, and echocardiographic characteristics of patients with HCM in infancy, childhood, adolescence, and adult age. While disopyramide remains a cornerstone in the management of pediatric HCM, the advent of mavacamten and aficamten heralds a new era of potential advancements. These emerging therapies could significantly improve the quality of life and prognosis for young patients with HCM. [ABSTRACT FROM AUTHOR]

Pediatric hypertrophic cardiomyopathy (HCM) has a wide range of clinical manifestations. Left ventricular outflow tract obstruction (LVOTO) at rest is present in up to one-third of children with HCM, with a further 50-60% of symptomatic children developing a gradient under exertion. Treatment options are limited, and there is a relative lack of data on the pediatric population. Disopyramide is a sodium channel blocker with negative inotropic properties. This therapy effectively reduces LVOTO in adults with HCM and delays surgical interventions, but it is not licensed for use in children. We aimed to review and analyze the influence of disopyramide over the pathophysiological, clinical, electrocardiographic, and echocardiographic characteristics of patients with HCM in infancy, childhood, adolescence, and adult age. While disopyramide remains a cornerstone in the management of pediatric HCM, the advent of mavacamten and aficamten heralds a new era of potential advancements. These emerging therapies could significantly improve the quality of life and prognosis for young patients with HCM.

BackgroundIn obstructive hypertrophic cardiomyopathy (HOCM), disopyramide is used in patients who remain symptomatic despite β-blockers or verapamil. However, effectiveness of disopyramide therapy has not been clearly established due to inconsistent definition of responders and the insufficient length of follow-ups reported in literature. To address these shortcomings, we have conducted a retrospective analysis from detailed databases with long follow-up, from two HCM Referral Centers.Methods62 symptomatic HOCM patients (43% women, age 52 ± 14 years) with left ventricular (LV) outflow tract gradient (LVOTG) ≥ 50 mmHg at rest or during provocation, were recruited from two Italian Centers. Disopyramide was added as second-line therapy in the patients in whom symptoms persisted despite classic pharmacologic treatment. Patients in NYHA class > II at baseline who reached NYHA class II or I, and patients in NYHA class II at baseline who reached NYHA class I or symptoms stabilization were defined as responders.ResultsAt follow-up, (mean 4.4 years, IQR 1.1–6.6 years), 47 patients (76%) were responders, whereas 15 (24%) were no-responders. Responders showed larger LV diastolic volume index (LVEDVi) at baseline as compared to no-responders (61 ± 14 vs. 49 ± 16 ml, respectively, p = 0.018), and, at follow-up, reached lower LVOTG than no-responders (43 ± 32 vs. 66 ± 28 mmHg, respectively, p = 0.013), with a LVOTG

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. (Level of Difficulty: Advanced.)

Aficamten is a novel cardiac myosin inhibitor that has demonstrated its ability to safely lower left ventricular outflow tract (LVOT) gradients and improve heart failure symptoms in patients with obstructive hypertrophic cardiomyopathy (HCM). Based on the REDWOOD-HCM open label extension (OLE) study, participants receiving aficamten had significantly reduced resting and Valsalva LVOT gradient within 2 weeks after initiating treatment, with ongoing improvements over 24 weeks, and recent evidence suggests effects can sustain up to 48 weeks. While beta-blockers, calcium channel blockers, and disopyramide have shown some benefits in managing HCM, they have limited direct impact on the underlying disease process in patients with obstructive HCM. Aficamten achieves its therapeutic effect by reducing hypercontractility and improving diastolic function in obstructive HCM. Mavacamten was the first cardiac myosin inhibitor approved for symptomatic obstructive HCM. However, aficamten has a shorter human half-life (t1/2) and fewer drug–drug interactions, making it a preferable treatment option. This review evaluates the long-term clinical value and safety of aficamten in patients with obstructive HCM based on available data from completed and ongoing clinical trials. Additionally, the molecular basis of sarcomere-targeted therapy in reducing LVOT gradients is explored, and its potential in managing obstructive HCM is discussed. [ABSTRACT FROM AUTHOR]

Background: Although disopyramide has been widely used to reduce left ventricular outflow obstruction (LVOTO) and to improve symptoms in patients with obstructive hypertrophic cardiomyopathy (oHCM), its use in real world as well as patient characteristics associated with a positive treatment response are still unclear. Methods: From 1980 to 2021, 1527 patients with HCM were evaluated and 372 (23%) had a LVOTO with active follow-up. The efficacy and safety of disopyramide were assessed systematically during 12 months (2-, 6-, and 12-month visits). Responders were patients with a final NYHA = I and a LVOTO < 30 mmHg; incomplete responders were those patients with NYHA > I and a LVOTO < 30 mmHg; and non-responders were symptomatic patients with no change in functional class NYHA and a LVOT gradient > 30 mmHg. Results: Two-hundred-fifty-four (66%) patients were in functional class NYHA I/II and 118 (34%) in NYHA III/IV. A total of 118/372 (32%, 55 ± 16 years) underwent disopyramide therapy. Twenty-eight (24%) patients responded to therapy, 39 (33%) were incomplete responders, and 51 (43%) did not respond. Responder were mainly patients in functional NYHA class I/II (24/28, 86%), whereas incomplete responders and non-responders were more often in functional NYHA class III/IV (50/54 (93%)). An independent predictor of response to disopyramide treatment was the presence of NYHA I/II at the initiation of therapy (HR 1.5 (95% CI 1.1–4.5), p = 0.03). No major life-threatening arrhythmic events or syncope occurred, despite 19 (16%) patients showing reduced QTc from baseline, 19 (16%) having no difference, while 80 (69%) patients had prolonged QTc interval. Thirty-one (26%) patients experienced side effects, in particular, 29 of the anticholinergic type. Conclusions: Disopyramide was underused in oHCM but effective in reducing LVOTO gradients and symptoms in slightly symptomatic patients with less severe disease phenotype with a safe pro-arrhythmic profile. [ABSTRACT FROM AUTHOR]

Cardiomyopathy is associated with structural and functional abnormalities of the ventricular myocardium and can be classified in two major groups: hypertrophic (HCM) and dilated (DCM) cardiomyopathy. Computational modeling and drug design approaches can speed up the drug discovery and significantly reduce expenses aiming to improve the treatment of cardiomyopathy. In the SILICOFCM project, a multiscale platform is developed using coupled macro- and microsimulation through finite element (FE) modeling of fluid–structure interactions (FSI) and molecular drug interactions with the cardiac cells. FSI was used for modeling the left ventricle (LV) with a nonlinear material model of the heart wall. Simulations of the drugs' influence on the electro-mechanics LV coupling were separated in two scenarios, defined by the principal action of specific drugs. We examined the effects of Disopyramide and Dygoxin which modulate Ca2+ transients (first scenario), and Mavacamten and 2-deoxy adenosine triphosphate (dATP) which affect changes of kinetic parameters (second scenario). Changes of pressures, displacements, and velocity distributions, as well as pressure–volume (P-V) loops in the LV models of HCM and DCM patients were presented. Additionally, the results obtained from the SILICOFCM Risk Stratification Tool and PAK software for high-risk HCM patients closely followed the clinical observations. This approach can give much more information on risk prediction of cardiac disease to specific patients and better insight into estimated effects of drug therapy, leading to improved patient monitoring and treatment. [ABSTRACT FROM AUTHOR]

Background: Disopyramide is a class Ia antiarrhythmic drug that has been used for the second-line treatment of symptomatic hypertrophic obstructive cardiomyopathy (HOCM). The aim of the study was to assess the impact of short-acting disopyramide in patients with hypertrophic obstructive cardiomyopathy (HOCM) using two-dimensional speckle-tracking echocardiography. Methods: This prospective study included patients with HOCM on chronic treatment with short-acting disopyramide. Two sequential comprehensive echocardiographic examinations were performed: after temporary disopyramide suspension and 2.5 h after disopyramide intake. Results: 19 patients were included in the study. The effect of disopyramide on the left ventricle was not uniform. After the intake of disopyramide, the mean global strain peak was −17 ± 2% before disopyramide intake and −14 ± 2% after (p < 0.0001). There was a significant reduction in strain in the basal septal (p = 0.015), basal inferior (p = 0.019), basal posterior (p = 0.05), apical anterior (p = 0.0001), and apical lateral segments (p = 0.021). In all other segments, there was no significant change. Disopyramide also caused a significant accentuation of the base-apex strain gradients (p = 0.036). No change was noted in circumferential and left atrial strain. While the left ventricular ejection fraction and outflow gradients did not change, the significant reduction in global and segmental longitudinal strain demonstrated the acute negative inotropic effect of disopyramide on the myocardium in patients with HOCM. Conclusion: A strain analysis may be a useful tool to assess the negative inotropic effect of cardiovascular medication on the left ventricle in patients with HOCM. [ABSTRACT FROM AUTHOR]

Hypertrophic cardiomyopathy (HCM), the most common inherited heart disease, is still orphan of a specific drug treatment. The erroneous consideration of HCM as a rare disease has hampered the design and conduct of large, randomized trials in the last 50 years, and most of the indications in the current guidelines are derived from small non-randomized studies, case series, or simply from the consensus of experts. Guideline-directed therapy of HCM includes non-selective drugs such as disopyramide, non-dihydropyridine calcium channel blockers, or β-adrenergic receptor blockers, mainly used in patients with symptomatic obstruction of the outflow tract. Following promising preclinical studies, several drugs acting on potential HCM-specific targets were tested in patients. Despite the huge efforts, none of these studies was able to change clinical practice for HCM patients, because tested drugs were proven to be scarcely effective or hardly tolerated in patients. However, novel compounds have been developed in recent years specifically for HCM, addressing myocardial hypercontractility and altered energetics in a direct manner, through allosteric inhibition of myosin. In this paper, we will critically review the use of different classes of drugs in HCM patients, starting from "old" established agents up to novel selective drugs that have been recently trialed in patients. [ABSTRACT FROM AUTHOR]

The plasma protein α 1 -acid glycoprotein (AGP) primarily affects the pharmacokinetics of basic drugs. There are two AGP variants in humans, A and F1*S, exhibiting distinct drug-binding selectivity. Elucidation of the drug-binding selectivity of human AGP variants is essential for drug development and personalized drug therapy. Herein, we aimed to establish the contribution of amino acids 112 and 114 of human AGP to drug-binding selectively. Both amino acids are located in the drug-binding region and differ between the variants. Phe112/Ser114 of the A variant and its equivalent residues in the F1*S variant (Leu112/Phe114) were swapped with each other. Binding experiments were then conducted using the antiarrhythmic drug disopyramide, which selectively binds to the A variant. A significant decrease in the bound fraction was observed in each singly mutated A protein (Phe112Leu or Ser114Phe). Moreover, the bound fraction of the double A mutant (Phe112Leu/Ser114Phe) was decreased to that of wild-type F1*S. Intriguingly, the double F1*S mutant (Leu112Phe/Phe114Ser), in which residues were swapped with those of the A variant, showed only partial restoration in binding. The triple F1*S mutant (Leu112Phe/Phe114Ser/Asp115Tyr), where position 115 is thought to contribute to the difference in pocket size between variants, showed a further recovery in binding to 70% of that of wild-type A. These results were supported by thermodynamic analysis and acridine orange binding, which selectively binds the A variant. Together, these data indicate that, in addition to direct interaction with Phe112 and Ser114, the binding pocket size contributed by Tyr115 is important for the drug-binding selectivity of the A variant.

Left ventricular outflow tract obstruction (LVOTO) is present in 1/3 of children with Hypertrophic Cardiomyopathy (HCM). Disopyramide improves symptoms associated with LVOTO and delays surgical intervention in adults, but it is not licensed in children. To describe a single-centre thirty-year experience of using disopyramide to treat LVOTO-related symptoms in a paediatric HCM cohort. Clinical data were collected for all patients meeting diagnostic criteria for HCM (<18 years) at the time of initiation, 6 months after, and last follow-up or end of disopyramide treatment. It included demographics, clinical history, 12‑lead electrocardiography, and echocardiography. Comparisons between baseline and 6 month follow up, and end of follow up respectively were performed. Fifty-one patients with HCM were started on disopyramide at a mean age 10.2±5.3 years. At 6 months, of those previously symptomatic, 33(86.8%) reported an improvement of symptoms and 12(31.6%) were asymptomatic. PR interval, corrected QT interval and maximal LVOT gradient had not significantly changed, but fewer participants were noted to have systolic anterior motion of the mitral valve 31 (72.1%) vs. 26 (57.80%). Patients were followed up for a median of 1.9 years (IQR 0.83–4.5). Nine patients (17.6%) reported side effects, and eleven patients (33.3%) with initial improvement in symptoms reported a return or worsening of symptoms requiring a change in medication (n = 4, 12.1%) or left ventricular septal myomectomy (n = 7, 21.2%) during follow up. Disopyramide is a safe and effective treatment for LVOTO-related symptoms in childhood obstructive HCM. Any delay in the need for invasive intervention, particularly during childhood, is of clear clinical benefit. • Disopyramide is safe and effective in symptomatic children with obstructive HCM. • Early symptomatic improvement was reported in >80%. • Longer-term tachyphylaxis was seen in 1/3, requiring additional treatment. [ABSTRACT FROM AUTHOR]

Objective To synthesize the natural cyclopeptide auyuittuqamide A by Fmoc-based solid phase linear synthesis and liquid phase cyclization. Methods Using 2-chlorotriphenylmethyl chloride (CTC) resin as the solid support, 1,3-diisopropylcarbodiimide (DIC) and 1-hydroxybenzotriazole (HOBt) as the condensing agents, 9-fluorenylmethoxycarbonyl (Fmoc) to protect amino acids were assembled in sequence, and then the linear peptide bearing the protected groups was obtained in presence of trifluoroethanol (TFE) cutting reagent. The protected linear peptide was cyclized with the aid of benzotriazole hexafluorophosphate (PyBOP) and 1-hydroxybenzotriazole (HOBt) in dichloromethane (DCM) solution, followed by trifluoroacetic acid (TFA) deprotection to obtain the cyclic peptide, auyuittuqamide A that was purified by preparative HPLC and characterized by HR-MS and 500MHz ¹H-NMR. Results The purity of auyuittuqamide A was more than 95% and the total yield was 5.48%. Conclusion This method has simple synthesis steps and high yield. It is the first to establish a fully synthesis method for the natural cyclic peptide auyuittuqamide A, which lays the foundation for further research of auyuittuqamide A. [ABSTRACT FROM AUTHOR]

Background: Anticholinergic burden potentially increases the risk of fracture. Although there are various anticholinergic burden scales, little is known about the inter-scale compatibility regarding the relationship of anticholinergic burden with fracture risk. We performed meta-analysis to examine the association of fracture risk with anticholinergic burden measured using various scales. Methods: Primary literature was retrieved from PubMed (1966 to March, 2021), the Cochrane Library (1974 to March, 2021), Scopus (1970 to March, 2021), and Ichushi-web (1983 to March, 2021). Cohort and case-control studies that evaluated the association between any fracture and anticholinergic drugs were included. Additionally, we included studies in which patients were administered anticholinergic drugs included on the anticholinergic risk scale (ARS), anticholinergic cognitive burden (ACB), anticholinergic drug scale, or drug burden index-anticholinergic component. Random effects models were used to calculate pooled relative risk (RR) and 95% confidence interval (CI) due to heterogeneity among the studies. Publication bias was examined by funnel plots and the Begg's test. Results: A total of 49 datasets from 10 studies were included in the meta-analysis. Six of the 10 studies included only patients aged over 65 years, who accounted for 93% of the total study population (453,186/487,247). Meta-analysis indicated a positive relationship between use of anticholinergic drugs and fracture risk, regardless of the anticholinergic burden scale used. However, the relationship between anticholinergic burden and fracture risk varied depending on the scale used. Fracture risk increased linearly with increasing anticholinergic burden measured using ARS. ARS 1 point was associated with 28% increase in fracture risk, ARS 1–2 point(s) with 39%, ARS 2 points with 54%, ARS 3 points with 66%, and ARS ≥ 4 points with 77%. On the other hand, ACB 1 point and ACB 2 points were associated with similar fracture risk (pooled RR [95% CI]: overall; 1.28 [1.18–1.39], 1 point; 1.12 [1.06–1.18], 2 points; 1.15 [1.08–1.23]). Conclusions: This result suggests that the relationship between anticholinergic drug burden and fracture risk may differ depending on the anticholinergic burden scale used. [ABSTRACT FROM AUTHOR]

Mavacamten (Camzyos) is a cardiac myosin inhibitor indicated for the treatment of symptomatic obstructive hypertrophic cardiomyopathy. This article discusses its efficacy, adverse effects and place in therapy. [ABSTRACT FROM AUTHOR]

α 1 -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 t 1/2 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.L tot 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.

Short QT syndrome (SQTS) is associated with tachyarrhythmias and sudden cardiac death. So far, only quinidine has been demonstrated to be effective in patients with SQTS type 1(SQTS1). The aim of this study was to investigate the mechanisms of disopyramide underlying its antiarrhythmic effects in SQTS1 with the N588K mutation in HERG channel. Human-induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) from a patient with SQTS1 and a healthy donor, patch clamp, and calcium imaging measurements were employed to assess the drug effects. Disopyramide prolonged the action potential duration (APD) in hiPSC-CMs from a SQTS1-patient (SQTS1-hiPSC-CMs). In spontaneously beating SQTS1-hiPSC-CMs challenged by carbachol plus epinephrine, disopyramide reduced the arrhythmic events. Disopyramide enhanced the inward L-type calcium channel current (ICa-L), the late sodium channel current (late INa) and the Na/Ca exchanger current (INCX), but it reduced the outward small-conductance calcium-activated potassium channel current (ISK), leading to APD-prolongation. Disopyramide displayed no effects on the rapidly and slowly activating delayed rectifier and ATP-sensitive potassium channel currents. In hiPSC-CMs from the healthy donor, disopyramide reduced peak INa, ICa-L, IKr, and ISK but enhanced late INa and INCX. The results demonstrated that disopyramide may be effective for preventing tachyarrhythmias in SQTS1-patients carrying the N588K mutation in HERG channel by APD-prolongation via enhancing ICa-L, late INa, INCX, and reducing ISK.

Short QT syndrome (SQTS) is associated with tachyarrhythmias and sudden cardiac death. So far, only quinidine has been demonstrated to be effective in patients with SQTS type 1(SQTS1). The aim of this study was to investigate the mechanisms of disopyramide underlying its antiarrhythmic effects in SQTS1 with the N588K mutation in HERG channel. Human-induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) from a patient with SQTS1 and a healthy donor, patch clamp, and calcium imaging measurements were employed to assess the drug effects. Disopyramide prolonged the action potential duration (APD) in hiPSC-CMs from a SQTS1-patient (SQTS1-hiPSC-CMs). In spontaneously beating SQTS1-hiPSC-CMs challenged by carbachol plus epinephrine, disopyramide reduced the arrhythmic events. Disopyramide enhanced the inward L-type calcium channel current (ICa-L), the late sodium channel current (late INa) and the Na/Ca exchanger current (INCX), but it reduced the outward small-conductance calcium-activated potassium channel current (ISK), leading to APD-prolongation. Disopyramide displayed no effects on the rapidly and slowly activating delayed rectifier and ATP-sensitive potassium channel currents. In hiPSC-CMs from the healthy donor, disopyramide reduced peak INa, ICa-L, IKr, and ISK but enhanced late INa and INCX. The results demonstrated that disopyramide may be effective for preventing tachyarrhythmias in SQTS1-patients carrying the N588K mutation in HERG channel by APD-prolongation via enhancing ICa-L, late INa, INCX, and reducing ISK. [ABSTRACT FROM AUTHOR]

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 lck 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 50 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 lck tyrosine kinase. Interestingly, only the inhibition of p56 lck 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.

Significant left-ventricular outflow tract obstruction (LVOTO) in hypertrophic cardiomyopathy (HCM) may result in symptoms and is associated with adverse outcomes. Although disopyramide can reduce resting gradients, nearly 30% of HCM patients do not respond. We sought to study the clinical and echocardiographic variables associated with disopyramide-induced LVOT-gradient reduction. Forty-one disopyramide-treated HCM patients (average daily-dose 305 mg) were subdivided into two groups: (1) nineteen responders, with a reduction of LVOT-gradients of at least 30% from baseline, and (2) twenty-two non-responders, in whom LVOT-gradients did not change or increased following treatment. All patients had a thorough clinical and echocardiographic assessment pre- and post-treatment initiation. Patients who responded to disopyramide had better pretreatment left ventricular (LV) systolic function (LV ejection fraction of 67.9 ± 5.6% vs. 59.7 ± 5.8%, p = 0.0001), better LV global longitudinal strain (−17.9 ± 2.3% vs. −16.1 ± 2.5%, p = 0.048), less mitral regurgitation, smaller LV size (indexed LV end-systolic volume of 16.2 ± 5.1 ml/m2 vs. 23.2 ± 6.8 ml/m2, p = 0.001), and lower LV maximal wall thickness (17.2±3 mm vs.19.2 ± 3.4 mm, p = 0.046). Baseline left atrial (LA) volumes were significantly lower in the responders, with higher indices of LA ejection fraction (62 ± 11.2% vs. 50.5 ± 12.2%, p = 0.005), systolic LA strain (34 ± 12.4% vs. 25.8 ± 10.6%, p = 0.04), and LA strain-rate (1.34 ± 0.49%/sec vs. 0.99 ± 0.24%/sec, p = 0.012). In multivariable analysis, the presence of reduced LV systolic function and systolic LA strain-rate remained independently associated with poor response to disopyramide. Obstructive HCM patients with more severe disease at baseline tend to respond less to disopyramide treatment. In those patients, early referral for alcohol septal ablation or myectomy surgery should be considered. • Response to disopyramide is associated with better left ventricular function. • Response to disopyramide correlates with smaller and better functioning left atrium. • Response to disopyramide was not associated with degree of obstruction. • Response to disopyramide was not associated with severity of symptoms. • These markers can aid in decision making regarding disopyramide therapy. [ABSTRACT FROM AUTHOR]

Disopyramide (DPA) is as a class IA antiarrhythmic drug and its crystallization from cyclohexane at ambient condition yields lower melting form crystals which belong to the monoclinic centrosymmetric space group P21/n, having two molecules in an asymmetric unit. Crystal structure analysis of pure DPA revealed closely associated DPA molecules aggregates via amide–amide dimer synthon through the N–H∙∙∙O hydrogen bond whereas the second amide hydrogen N–H engaged in an intramolecular N–H∙∙∙N hydrogen bond with N-nitrogen of 2-pyridine moieties. Crystallization of DPA and phthalic acid (PA) in 1: 1 stoichiometric molar ratio from acetone at ambient condition yielded block shape crystals of 1:1 DPA_PA salt. Its X-ray single crystal structure revealed the formation of salt by transfer of acidic proton from one of the carboxylic acidic groups of PA to the tertiary amino group of chain moiety (N3-nitrogen atom) of DPA molecules. DPA_PA salt crystals belong to the monoclinic centrosymmetric space group P21/n, comprising one protonated DPA and one PA¯ anion (hydrogen phthalate counterion) in an asymmetric unit and linked by N–H∙∙∙O and C–H∙∙∙O hydrogen bonds. Pure DPA and DPA_PA salt were further characterized by differential calorimetric analysis, thermal gravimetric analysis, powder x-ray diffraction and infrared spectroscopy.

1:1 salt of Disopyramide (DPA) with Terephthalic acid (TA) was obtained by the slow solvent evaporation and the slurry crystallization methods. X-ray single crystal diffraction of DPA:TA confirmed the formation of salt by the transfer of an acidic proton from one of the carboxylic acidic groups of TA to the tertiary amino group of the chain moiety (N3-nitrogen atom) of the DPA molecules. DPA:TA salt crystals crystalize in the triclinic system with space group P-1. The asymmetric unit, comprising one protonated DPA and one TA anion, are linked by a strong charge assisted N+–H∙∙∙O¯ hydrogen bond and a C–H∙∙∙O¯ hydrogen bond. Moreover, structural characterization of DPA:TA salt was carried out using Fourier transform infrared spectroscopy, differential scanning calorimeter, thermogravimetric analysis, and powder X-ray diffraction techniques

Abstract Disopyramide as an antiarrhythmic agent has been used for treating ventricular tachycardia and metabolized into its major metabolite, mono-isopropyl-disopyramide, by CYP3A4. We developed a novel, selective, highly sensitive, accurate, rapid method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the simultaneous determination of disopyramide and mono-isopropyl-disopyramide in rat plasma. This study is the first report for the assay validation using LC-MS/MS in biological fluids after simple protein-precipitation method. The most sensitive signals by multiple reaction monitoring (MRM) showed at m/z 340.2 → 239.2 and 298.2 → 239.2 with same fragment ion for disopyramide and mono-isopropyl-disopyramide, respectively. The lower limit of quantification (LLOQ) was determined at 2 ng/mL for both analytes and the linear concentration ranges were found to be 2–2000 ng/mL for disopyramide and 2–1000 ng/mL for mono-isopropyl-disopyramide. Finally, this assay was successfully applied to pharmacokinetic analysis of disopyramide and mono-isopropyl-disopyramide after oral and intravenous administration of disopyramide. [ABSTRACT FROM AUTHOR]

The unbound fraction of a drug in plasma can profoundly influence both its pharmacokinetics and pharmacodynamics. For most drugs, the unbound fraction is relatively constant across the clinically relevant range of concentrations in a given individual. Nonlinear plasma protein binding involving saturation of binding sites results in increasing unbound fraction as the concentration of the drug increases, a phenomenon that is consistent with the law of mass action and is well recognized. Not widely appreciated is that some drugs undergo atypical concentration-dependent binding to plasma proteins, whereby the unbound fraction decreases with increasing concentration. In this article we review the drugs for which atypical nonlinear plasma protein binding has been reported. For each drug, the evidence for the phenomenon is presented and the proposed mechanism discussed. Also reviewed are the potential implications of atypical nonlinearity in plasma protein binding. Highlighted is the importance of understanding the relationship between unbound fraction and plasma drug concentration during the preclinical and early clinical stages of drug development, and during the routine clinical use of a drug especially if therapeutic drug monitoring is used to assist in optimization of the dosing regimen. The lesson is that the unexpected concentration-dependent behavior that has been observed for a number of drugs should be expected to occur for some other drugs. [ABSTRACT FROM AUTHOR]

Background and Purpose: In 30-40% of hypertrophic cardiomyopathy (HCM) patients, symptomatic left ventricular (LV) outflow gradients develop only during exercise due to catecholamine-induced LV hypercontractility (inducible obstruction). Negative inotropic pharmacological options are limited to β-blockers or disopyramide, with low efficacy and tolerability. We assessed the potential of late sodium current (INaL )-inhibitors to treat inducible obstruction in HCM.Experimental Approach: The electrophysiological and mechanical responses to β-adrenoceptor stimulation were studied in human myocardium from HCM and control patients. Effects of INaL -inhibitors (ranolazine and GS-967) in HCM samples were investigated under conditions simulating rest and exercise.Key Results: In cardiomyocytes and trabeculae from 18 surgical septal samples of patients with obstruction, the selective INaL -inhibitor GS-967 (0.5 μM) hastened twitch kinetics, decreased diastolic [Ca2+ ] and shortened action potentials, matching the effects of ranolazine (10μM). Mechanical responses to isoprenaline (inotropic and lusitropic) were comparable in HCM and control myocardium. However, isoprenaline prolonged action potentials in HCM myocardium, while it shortened them in controls. Unlike disopyramide, neither GS-967 nor ranolazine reduced force at rest. However, in the presence of isoprenaline, they reduced Ca2+ -transient amplitude and twitch tension, while the acceleration of relaxation was maintained. INaL -inhibitors were more effective than disopyramide in reducing contractility during exercise. Finally, INaL -inhibitors abolished arrhythmias induced by isoprenaline.Conclusions and Implications: Ranolazine and GS-967 reduced septal myocardium tension during simulated exercise in vitro and therefore have the potential to ameliorate symptoms caused by inducible obstruction in HCM patients, with some advantages over disopyramide and β-blockers. [ABSTRACT FROM AUTHOR]

A novel method to access 1,1-diarylalkanes from readily available, nonactivated alkyl bromides and aryl bromides via visible-light-driven nickel and iridium dual catalysis, wherein diisopropylamine (iPr2NH) is used as the terminal stoichiometric reductant, is reported. Both primary and secondary alkyl bromides can be successfully transformed into the migratory benzylic arylation products with good selectivity. Additionally, this method showcases tolerance toward a wide array of functional groups and the presence of bases. [ABSTRACT FROM AUTHOR]

BackgroundDisopyramide is effective in ameliorating symptoms in patients with hypertrophic cardiomyopathy; however, its potential for proarrhythmic effect has raised concerns about its use in the ambulatory setting. The risk of initiating disopyramide in this manner has never been evaluated. Methods and ResultsAll charts of patients seen in the outpatient hypertrophic cardiomyopathy clinic between 2010 and 2014 were screened for initiation of disopyramide and data were extracted. Disopyramide in our clinic is usually initiated at a dose of 300 mg daily and titrated during follow‐up. A total of 2015 patients were seen in the clinic, including 168 who were started on disopyramide. There were no cardiac events within 3 months of disopyramide initiation. During long‐term follow‐up (255 patient‐years; mean, 447 days; interquartile range, 201–779), only 2 patients developed cardiac events (syncope of unknown cause in both). Thirty‐eight patients (23%) developed side effects of disopyramide and 18 (11%) stopped the drug because of these side effects. Of the patients continuing disopyramide long term, 63% remained free of septal reduction interventions at end of follow‐up. Disopyramide at a dose of 300 mg prolonged the mean QTc interval by 19±23 ms; however, increasing the dose to 600 mg had no further significant effect. ConclusionsInitiation of disopyramide in the outpatient setting is safe and the risk of subsequent sudden cardiac death is low. Because of its QT‐prolonging effect, precautions may be necessary in patients at higher risk of torsades de pointes.