US Food Research Articles

Extragenital self-collection testing for gonorrhea and chlamydia: A feasibility study for expanding STI screening in the Veterans Health Administration.

Rectal and pharyngeal infections with gonorrhea and chlamydia are of concern because they are associated with higher risk of HIV acquisition. Extragenital screening in asymptomatic persons at high risk may have the potential to reduce the incidence of these sexually transmitted infections (STIs). Several testing platforms are available for the testing of Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) using nucleic acid amplification tests (NAATs). Self-collected extragenital samples are currently not approved by the US Food and Drug Administration in any NAAT platform. This study compares the analytical performance of self-collected extragenital specimens to that of clinician-collected specimens. We performed a multicenter/multiplatform validation study as a National Veterans Health Administration Pathology and Laboratory Medicine quality improvement project, with 9 different participating sites. Self-collected specimens were obtained at the same time as clinician-collected specimens. Clinician-collected specimens were used as the gold standard to evaluate the sensitivity and specificity of self-collection. A total of 2324 individual tests were analyzed (501 rectal and 661 oropharyngeal). The sensitivity was 94.44% for CT and 100% for NG for rectal specimens, whereas it was 100% for CT and 97.22% for NG for oral specimens. Specificity for oral specimens was 99.85% for CT and 99.36% for NG, whereas for rectal specimens, it was 99% for CT and NG. Self-collected specimens for extragenital CT/NG testing are highly sensitive and specific, with negative predictive values of 100%. Self-collection has the potential to overcome a major barrier for STI screening by providing an accessible, convenient, and patient-centered alternative.

Response from the Canadian Children Inflammatory Bowel Disease Network to the US Food and Drug Administration Draft Guidance for Industry on pediatric inflammatory bowel disease: developing drugs for treatment

Response from the Canadian Children Inflammatory Bowel Disease Network to the US Food and Drug Administration Draft Guidance for Industry on pediatric inflammatory bowel disease: developing drugs for treatment

New therapy options for myelodysplastic syndrome—all for all or targeted?

SummaryThe OeGHO-Frühjahrstagung 2024 took place in Vienna. Thereby one session was dedicated specifically to the field of myelodysplastic syndrome (MDS). Just a few days before the meeting, the European Medicines Agency approved luspatercept for transfusion-dependent low-risk MDS patients in the first line. It was therefore more current than ever to discuss the future significance of this therapy for our patients in the low-risk field. In addition, there are other new substances in the pipeline; some of which already have mature phase III data (e.g., imetelstat), which have already led to the approval by the US Food and Drug Administration.

The US FDA’s New Rule for Regulating Laboratory-Developed Tests

This Viewpoint discusses potential benefits and obstacles regarding US Food and Drug Administration (FDA) oversight of laboratory-developed tests.

Real-world pharmacovigilance study of FDA adverse event reporting system events for finerenone

ABSTRACT Objective This study analyzed the signal mining of adverse events caused by finerenone based on the US Food and Drug Administration Adverse Event Reporting System (FAERS) and evaluated the drug’s safety to provide a reference for the safe administration of this medication in medical institutions. Methods FAERS data from the third quarter of 2021 to the fourth quarter of 2023 were used, and the adverse event codes of the Medical Dictionary for Regulatory Activities were compared. After the data were processed, adverse event reports that featured finerenone as the most suspected drug were extracted. Results A total of 905 reported cases of adverse events including finerenone as the first suspected drug were extracted. The ratio of male to female patients was 1.25, and most were aged 65–85 years (30.1%). The adverse events that were reported more frequently with positive signals were decreased glomerular filtration rate, hyperkalemia, increased blood creatinine, and dizziness. The adverse events that were concentrated on in investigations were metabolism and nutrition disorders and diseases of the renal and urinary system. Conclusions Our study identified significant novel adverse events (AEs) signals for finerenone that could provide support for clinical monitoring of and risk identification for finerenone.

Ranolazine New Potential Therapeutic Aspects

Since Ranolazine approval as an antianginal medication by the US Food and Drug Administration in 2006, it has been administered to specific patient populations with stable angina. Originally, it was thought that ranolazine's therapeutic actions were due to its inhibition of the metabolism of fatty acids. However, as research progressed, it became clear that ranolazine's primary advantageous benefits come from its influence on the heart's late sodium current. Numerous experimental and clinical studies have tested ranolazine either directly or indirectly on heart failure since late-sodium currents have been found to be involved in various heart pathologies such as ischemia, arrhythmias, systolic and diastolic dysfunctions, and all these conditions are associated with heart failure. The inhibition of the underlying mechanisms of cardiac remodeling, such as ion disruptions, oxidative stress, inflammation, apoptosis, fibrosis, metabolic dysregulation, and neurohormonal dysfunction, by ranolazine is reviewed after any kind of severe injury, along with open questions. Ranolazine additional metabolic properties contribute to its efficacy in treating conditions other than coronary artery disease. Our publication will focus on potential therapeutic applications of ranolazine, extending beyond cardiology.

Non/Low-Caloric Artificial Sweeteners and Gut Microbiome: From Perturbed Species to Mechanisms.

Non/low-caloric artificial sweeteners (NAS) are recognized as chemical additives substituting sugars to avoid caloric intake and subsequent sugar-derived diseases such as diabetes and hyperglycemia. Six NAS have been claimed safe and are authorized by the US Food and Drug Administration (FDA) for public use, with acceptable daily intake information available: aspartame, acesulfame-K, saccharin, sucralose, neotame, and advantame. However, the impacts of NAS on the gut microbiome have raised potential concerns, since sporadic research revealed NAS-induced microbial changes in the gastrointestinal tracts and alterations in the microbiome-host interactive metabolism. Given the fact that the gut microbiome influences kaleidoscopic physiological functions in host health, this review aimed to decipher the impacts of NAS on the gut microbiome by implementing a comprehensive two-stage literature analysis based on each NAS. This review documented disturbed microbiomes due to NAS exposure to a maximal resolution of species level using taxonomic clustering analysis, and recorded metabolism alterations involved in gut microbiome-host interactions. The results elucidated that specific NAS exhibited discrepant impacts on the gut microbiome, even though overlapping on the genera and species were identified. Some NAS caused glucose tolerance impairment in the host, but the key metabolites and their underlying mechanisms were different. Furthermore, this review embodied the challenges and future directions of current NAS-gut microbiome research to inspire advanced examination of the NAS exposure-gut microbiome-host metabolism axis.

Cost-effectiveness of iptacopan for paroxysmal nocturnal hemoglobinuria

AbstractIptacopan, a novel oral factor B inhibitor, recently obtained US Food and Drug Administration approval for treating paroxysmal nocturnal hemoglobinuria, a rare blood disorder characterized by persistent complement-mediated hemolytic anemia. The standard-of-care (SOC) has traditionally relied on complement C5 inhibitors eculizumab and ravulizumab, which are limited by persistent anemia from extravascular hemolysis and requirement for intravenous infusion. Recent publication of phase 3 studies in this arena reinforces iptacopan as an effective anticomplement monotherapy compared with SOC. Given ongoing price negotiations and limited literature showing its cost-ineffectiveness in the anti-C5–treated population, we conducted a comprehensive cost-effectiveness analysis of iptacopan monotherapy in anti-C5–treated patients from the societal perspective, as compared with C5 inhibition. The primary outcomes were the incremental net monetary benefit across a lifetime horizon and the cost-effective maximum monthly threshold price of iptacopan monotherapy compared with the SOC. The secondary outcome was time saved for patients and nurses with the use of oral iptacopan therapy. Iptacopan monotherapy and SOC accrued 12.6 and 10.8 quality-adjusted life-years at costs of $9.52 million and $13.5 million, respectively. Iptacopan remained cost saving across extensive sensitivity and all scenario analyses, including alternative parameterization for anemia resolution and aggregated individual-level utilities and transition probability matrix. Across all probabilistic sensitivity analyses, iptacopan therapy was favored over SOC in 100% of 10 000 Monte Carlo iterations. Cost-saving thresholds for iptacopan vs anti-C5 in are ∼1.1, 1.4, and 1.4 in Brazil, Japan, and the United States, respectively. Iptacopan monotherapy can improve quality-adjusted life expectancy for patients while saving health care costs across jurisdictions.

Novel Therapeutics and Upcoming Clinical Trials Targeting Inflammation in Cardiovascular Diseases.

Cardiovascular disease (CVD) remains a major health burden despite significant therapeutic advances accomplished over the last decades. It is widely and increasingly recognized that systemic inflammation not only represents a major cardiovascular risk and prognostic factor but also plays pivotal roles in CVD development and progression. Despite compelling preclinical evidence suggesting large potential of anti-inflammatory pharmacological interventions across numerous CVDs, clinical translation remains incomplete, mainly due to (1) yet undefined molecular signaling; (2) challenges of safety and efficacy profile of anti-inflammatory drugs; and (3) difficulties in identifying optimal patient candidates and responders to anti-inflammatory therapeutics, as well as optimal therapeutic windows. Randomized controlled trials demonstrated the safety/efficacy of canakinumab and colchicine in secondary cardiovascular prevention, providing confirmation for the involvement of a specific inflammatory pathway (NLRP3 [NACHT, LRR, and PYD domain-containing protein 3] inflammasome/IL [interleukin]-1β) in atherosclerotic CVD. Colchicine was recently approved by the US Food and Drug Administration for this indication. Diverse anti-inflammatory drugs targeting distinct inflammatory pathways are widely used for the management of other CVDs including myocarditis and pericarditis. Ongoing research efforts are directed to implementing anti-inflammatory therapeutics across a growing number of CVDs, through repurposing of available anti-inflammatory drugs and development of novel anti-inflammatory compounds, which are herein concisely discussed. This review also summarizes the main characteristics and findings of completed and upcoming randomized controlled trials directly targeting inflammation in CVDs and discusses the major challenges and future perspectives in the exciting and constantly expanding landscape of cardioimmunology.

US FDA Advisory Panel Members’ Assessment of Premarket Approval Process and Suggestions for Improvement

The manufacturing and marketing of medical devices is regulated by the US Food and Drug Administration (FDA), and the FDA premarket approval (PMA) process evaluates the safety and effectiveness of medical devices. The PMA process includes a detailed scientific, regulatory and quality system review and is critical to ensure that novel devices are safe, effective, and meet the needs of patients. To survey current voting members serving on panels of the FDA's Medical Devices Advisory Committee to better characterize panel decision-making and identify steps for improvement. This qualitative survey study included 36 questions that were mailed to FDA device panelists regarding their opinions on the influence of sources of information, pivotal trial design, quality of evidence, panel composition and internal deliberative process, time allocation, and impartiality of the FDA. The survey was mailed to the members of all 18 FDA device panels in January and February 2017. Data were collected from January to May 2017 and analyzed from 2018 to 2019. Respondents read and returned the aforementioned paper survey, while nonrespondents did not. The main outcomes included panel members' perceptions, and their implications for process improvement. χ2 or Fisher exact tests were used to test differences between subgroups. Of 64 of 92 panel members who responded (69.6%), 38 of 64 (59.4%) were male, 3 of 63 (4.8%) were Black respondents, 46 of 63 (73.0%) were White respondents, and 36 of 60 (60.0%) were in academic practice. The mean (range) panel service was 6.8 (1-22) years with 3.9 (1-19) meetings attended. Overall, respondents considered information presented by the FDA unbiased, and 28 of 61 (45.9%) believed that pivotal trials were frequently well-designed, 55 of 62 respondents (88.7%) suggested FDA consult panel members preemptively regarding trial design and 54 of 64 (84.4%) regarding the device label. Most indicated that prior FDA approval of another device serving the same medical purpose (43 of 62 [69.4%]) or approval in other countries with comparable regulatory regimes, such as Canada and Europe (39 of 62 [62.9%]), would make them more likely to recommend approval. Respondents rated written information (50 of 60 [83.3%]), live presentations (43 of 58 [74.1%]), and prior professional knowledge (41 of 60 [68.3%]) as the most important sources of information in deciding whether to recommend approval. Additionally, 52 of 58 respondents (89.7%) recommended that a panel member-only executive session would allow more clarity and honesty in deliberations, and 33 of 59 (55.9%) believed a three-fourths majority appropriate for recommending approval, which would be a deviation from the current system in which an overall vote is reported without designation of a vote threshold. In this survey study of FDA device panel members, respondents wanted improved study designs, more relevant clinical data, including from other countries, involvement of panelists in study design and device label development, and inclusion of an executive session. Demographically, panels could be made more diverse.

Unbiased high-throughput screening of drug-repurposing libraries identifies small-molecule inhibitors of clot retraction

AbstractPlatelet clot retraction, the ultimate phase of platelet thrombus formation, is critical for clot stabilization. It requires functional αIIbβ3 receptors, fibrin, and the integrated actions of the actin-myosin contractile and cytoskeletal systems. Disturbances in clot retraction have been associated with both bleeding and thrombosis. We recently demonstrated that platelets treated with the αIIbβ3 antagonist peptide RGDW, which eliminates fibrinogen-mediated platelet aggregation, are still able to retract clots. We have exploited this observation to develop an unbiased, functional high-throughput assay to identify small-molecule inhibitors of fibrin-mediated clot retraction adapted for a 384-well plate format. We tested 9710 compounds from drug-repurposing libraries (DRLs). These libraries contain compounds that are either US Food and Drug Administration approved or have undergone preclinical/clinical development. We identified 27 compounds from the Library of Pharmacologically Active Compounds library as inhibitors of clot retraction, of which 14 are known inhibitors of platelet function. From the DRLs, we identified 135 compounds (1.6% hit rate). After extensive curation, these compounds were categorized based on the activity of their reported target. Multiple kinase and phosphodiesterase inhibitors with known antiplatelet effects were identified, along with multiple deubiquitination and receptor inhibitors, as well as compounds that have not previously been reported to have antiplatelet activity. Studies of 1 of the deubiquitination inhibitors (degrasyn) suggest that its effects are downstream of thrombin-induced platelet-fibrinogen interactions and thus may permit the separation of platelet thrombin-induced aggregation-mediated events from clot retraction. Additional studies of the identified compounds may lead to novel mechanisms of inhibiting thrombosis.

Accelerated approvals: Early-phase success or premature authorization?

We compare the clinical trial success rates of products receiving US Food and Drug Administration (FDA) accelerated approval (AA) to those approved without using this pathway. Our findings raise important questions about how the AA pathway can best optimize early access to therapeutics that are ultimately proven safe and effective.

Drug Development Considerations for Additives to Organ Preservation Solutions.

The addition of a novel therapeutic agent to an organ preservation solution has the potential to address unmet needs in organ transplantation and enhance outcomes for transplant recipients. However, the development expectations for novel therapeutic agents in this context are unclear because of limited precedence and published regulatory guidance documents. To address these gaps, we have articulated a drug development strategy that leverages expectations for parenteral drug products administered via more conventional routes (eg, intravenous) and provided considerations for when deviations may be justified. We have supplemented this strategy with a comparison to available regulatory guidance from the US Food and Drug Administration to highlight potential areas for further clarification. The strategy articulated here is based on Genentech's internal experience for a program intended for use in kidney transplantation.

A maturity assessment methodology for ISO 13485 implementation in the medical devices industry

PurposeThis study aims to develop a novel diagnostic methodology for implementing ISO13485:2016 and test its applicability to improve quality management systems (QMS) in the medical devices industry context.Design/methodology/approachFirst, a literature review on the topic was conducted. Second, insights gained from the literature and expert interviews were employed to develop the new maturity assessment methodology. Subsequently, the methodology was tested on a medical device manufacturer. Next, based on the evaluation of the intervention, actions were recommended to improve the QMS.FindingsResearch findings have developed a maturity assessment methodology comprising 52 certifiable requirements structured into four macro-requirements derived from ISO 13485:2016. Findings show that the methodology is valuable for aiding QMS implementation, and the diagnosed maturity levels corresponded with the company’s empirical perceptions of the requirement’s maturity.Practical implicationsEmpirical evidence validates the significance and practical utility of the proposed methodology, as evidenced by the company’s attainment of FDA (US Food and Drug Administration) approval after the intervention. Findings suggest that the methodology could be replicated within the medical products industry or adapted to assess other QMS, leveraging the organizational alignment with the international regulations of the sector and the ISO 9000 requirements.Originality/valueThe developed methodology fills existing gaps in both literature and practice within the medical devices industry, providing a valuable contribution by addressing the limited research on diagnostic methodologies designed for ISO 13485:2016 implementation. The article assists medical device enterprises in addressing QMS maturity levels as a metric for evaluating QMS requirements, which is an underexplored avenue in existing QMS evaluation approaches.

IMPACT OF REAL-LIFE ENVIRONMENTAL EXPOSURES ON REPRODUCTION: A contemporary review of machine learning to predict adverse pregnancy outcomes from pharmaceuticals, including DDIs.

Clinical drug trials often do not include pregnant people due to health risks; therefore, many medications have an unknown effect on the developing fetus. Machine learning QSAR models have been used successfully to predict the fetal risk of pharmaceutical use during pregnancy. Those undergoing pregnancy are often excluded from clinical drug trials due to the risk that participation would pose to their health and the health of the developing fetus. However, they often require pharmaceuticals to manage health conditions that, if left untreated, could harm themselves or the fetus. This can mean that such individuals take one or more pharmaceuticals during pregnancy, many of which have unknown reproductive effects. Machine learning models have been used to successfully predict a number of reproductive toxicological outcomes for pharmaceuticals, including transplacental transfer, US Food and Drug Administration safety rating, and drug interactions. Models use quantitative chemical and structural features of active compounds as inputs to make predictions concerning the outcome of interest using computational algorithms. Models are validated and evaluated rigorously with metrics such as accuracy, area under the receiver operator curve, sensitivity, and precision. Results from these models can be a potential source of valuable information for pregnant people and their medical providers when making decisions regarding therapeutic drug use. This review summarizes current machine learning applications to make predictions about the risk and toxicity of medication use during pregnancy. Our review of the recent literature revealed that machine learning quantitative structure-activity relationship models can be used successfully to predict the transplacental transfer and the US Food and Drug Administration pregnancy safety category of pharmaceuticals; such models have also been employed to predict drug interactions, though not specifically during pregnancy. This latter topic is a potential area for future research. In this review, no single algorithm or descriptor-calculation software emerged as the most widely used, and their performances depend on a variety of factors, including the outcome of interest and combination of such algorithms and software.

Innovations through crop switching happen on the diverse margins of US agriculture

Crop switching, in which farmers grow a crop that is novel to a given field, can help agricultural systems adapt to changing environmental, cultural, and market forces. Yet while regional crop production trends receive significant attention, relatively little is known about the local-scale crop switching that underlies these macrotrends. We characterized local crop-switching patterns across the United States using the US Department of Agriculture (USDA) Cropland Data Layer, an annual time series of high resolution (30 m pixel size) remote-sensed cropland data from 2008 to 2022. We found that at multiple spatial scales, crop switching was most common in sparsely cultivated landscapes and in landscapes with high crop diversity, whereas it was low in homogeneous, highly agricultural areas such as the Midwestern corn belt, suggesting a number of potential social and economic mechanisms influencing farmers' crop choices. Crop-switching rates were high overall, occurring on more than 6% of all US cropland in the average year. Applying a framework that classified crop switches based on their temporal novelty (crop introduction versus discontinuation), spatial novelty (locally divergent versus convergent switching), and categorical novelty (transformative versus incremental switching), we found distinct spatial patterns for these three novelty dimensions, indicating a dynamic and multifaceted set of cropping changes across US farms. Collectively, these results suggest that innovation through crop switching is playing out very differently in various parts of the country, with potentially significant implications for the resilience of agricultural systems to changes in climate and other systemic trends.

Changes in Internet Search Behavior After a Direct-to-Consumer Advertising Campaign for Faricimab-svoa.

Purpose: To analyze changes in Google search volume after US Food and Drug Administration (FDA) approval and initiation of a direct-to-consumer marketing campaign for faricimab-svoa. Methods: Google Trends data between December 26, 2021, and June 17, 2023, were downloaded and searched for terms prominently featured in the marketing campaign, including "wet AMD", "diabetic macular edema", "Vabysmo", and "faricimab-svoa". Data were standardized to the week and the term with the highest search volume, resulting in weekly relative search volumes for each term. The mean relative search volume and percentage change in relative search volume were calculated for the time periods of interest. Results: The direct-to-consumer campaign was associated with an increase in relative search volume in the first month for the terms "Vabysmo" (2.5% to 18.0%) and "wet AMD" (3.0% to 77.3%) and was sustained in the second month (P < .01). No significant changes in relative search volume were seen for the terms "diabetic macular edema" or "faricimab-svoa". After FDA approval, "Vabysmo" had the only significant increase in relative search volume (0.3% to 2.8%; P = .02). Conclusions: A direct-to-consumer advertising campaign for faricimab-svoa was associated with a surge in Google search volume of 620% and 2475% for "Vabysmo" and "wet AMD," respectively (P < .01), without a corresponding increase for "diabetic macular edema". Although FDA approval was associated with an increase in search volume for "Vabysmo" (P = .02), the marketing campaign was more influential at driving internet search behavior.

Radioligand therapy in sympathetic-adrenal-medullary axis tumors: state of art and perspectives.

The approval in 2017 by the European Medicines Agency (EMA) and in 2018 by the US Food and Drug Administration (FDA) of radioligand therapy (RLT) led to its wide application in therapeutic management of neuroendocrine neoplasms (NENs). However, the indications are currently limited to certain specific histotypes belonging to the broader NEN's family, mainly advanced well-differentiated gastro-entero-pancreatic NENs. As a consequence, several other tumors of the NEN spectrum that can potentially benefit, due to their biological characteristics, from RLT are still ineligible and can be considered "RLT-orphans". Among those, the subgroup of NENs originating from the sympathetic-adrenal-medullary (SAM) axis can be listed. This paper discusses the state of art and perspectives of the theragnostic applications in pheochromocytomas and paragangliomas, considering both the traditional theragnostic model - with radiolabelled metaiodobenzylguanidine (MIBG) - and the innovative one with radiolabeled somatostatin analogs (SSAs), that will hopefully become available for these patients in the near future.

Bioactives from marine resources as natural health products: A review.

The oceans are a rich source of a myriad of structurally different and unique natural products that are mainly found in invertebrates with potential applications in different disciplines. Microbial infection and cancer are the leading causes of death worldwide. Discovery of new sources of therapy for microbial infections is an urgent requirement due to the emergence of pathogenic microorganisms that are resistant to existing therapies. Marine bioactives have demonstrated to be promising sources for the discovery and development of novel antimicrobial and anticancer compounds. Several marine compounds are confirmed to have antibacterial effects and most marine-based antifungal compounds are cytotoxic. Numerous antitumor marine natural products, derived mainly from sponges or molluscs, and also bryozoans and cyanobacteria, exhibit potent antimitotic activity. In addition, marine biodiversity offers some possible leads or new drugs to treat human immunodeficiency virus (HIV). A majority of marine derived drugs are currently in clinical trials or under preclinical evaluation. Furthermore, marine-based drugs, approved by the US Food and Drug Administration (FDA) are available in the market. This review summarizes the sources, mechanisms of action and potential utilization of marine natural products such as peptides, alkaloids, polyketides, polyphenols, terpenoids and sterols as antifungal, antibacterial, antiviral, and anticancer compounds. Significance Statement Utilization of marine bioactives as natural health products leads to crucial advancement in providing dietary supplements, nutraceuticals, functional foods and pharmaceuticals. Their myriad of application promotes health and plays a role in disease risk reduction. Therapeutic potential of potent compounds from marine organisms and use of their bioactives have promising medicinal value for preventing ailments and advancing pharmaceutical and nutraceutical industries. Their utilization benefits human health globally and contributes to the conservation of marine ecosystem in a transformative / sustainable approach.

Inhibitors of Intracellular RyR2 Calcium Release Channels as Therapeutic Agents in Arrhythmogenic Heart Diseases.

Ryanodine receptor type 2 (RyR2) is the principal intracellular calcium release channel in the cardiac sarcoplasmic reticulum (SR). Pathological RyR2 hyperactivity generates arrhythmia risk in genetic and structural heart diseases. RYR2 gain-of-function mutations cause catecholaminergic polymorphic ventricular tachycardia. In structural heart diseases (i.e., heart failure), posttranslation modifications render RyR2 channels leaky, resulting in pathologic calcium release during diastole, contributing to arrhythmogenesis and contractile dysfunction. Hence, RyR2 represents a therapeutic target in arrhythmogenic heart diseases. We provide an overview of the structure and function of RyR2, and then review US Food and Drug Administration-approved and investigational RyR2 inhibitors. A therapeutic classification of RyR2 inhibitors is proposed based on their mechanism of action. Class I RyR2 inhibitors (e.g., flecainide) do not change SR calcium content and are primarily antiarrhythmic. Class II RyR2 inhibitors (e.g., dantrolene) increase SR calcium content, making them less effective as antiarrhythmics but preferable in conditions with reduced SR calcium content such as heart failure.