Review of Case Reports on Adverse Events Related to Pre-workout Supplements Containing Synephrine.

The use of pre-workout supplements has become increasingly popular, including the use of supplements containing synephrine. Synephrine might stimulate weight loss and improve sports performance by its proposed adrenergic properties. However, with its increasing popularity, numerous cases of adverse events related to synephrine use have been reported. This study provides a comprehensive overview and analysis of current case reports related to the supplemental use of synephrine. The scientific literature on cases of adverse events related to synephrine intake was collected through August 2021 using Pubmed and Google Scholar and subsequently reviewed and analysed. We obtained 30 case reports describing a total of 35 patients who suffered from medical complaints following use of synephrine-containing supplements. The patients most often presented with chest pain, palpitations, syncope and dizziness. Commonly raised diagnoses were ischaemic heart disease, cardiac arrhythmias and cerebrovascular disease. Five patients were left disabled or remained on medication at last follow-up. We here show an association between the use of pre-workout supplements containing synephrine and adverse events, mainly related to the cardiovascular system. However, we cannot exclude a role of possible confounding factors such as caffeine. Thus, the use of pre-workout supplements containing synephrine may lead to serious adverse health events, and therefore, caution is needed.

PI3K/mTOR inhibitor omipalisib prolongs cardiac repolarization along with a mild proarrhythmic outcome in the AV block dog model.

Background: The phosphoinositide 3-kinase (PI3K) signaling pathway is an interesting target in cancer treatment. The awareness of the proarrhythmic risk of PI3K inhibitors was raised because PI3K is also involved in regulating signaling toward cardiac ion channels. Canine cardiomyocytes treated with PI3K inhibitors show an increased action potential duration and reduced cardiac repolarizing currents. Now, the potential proarrhythmic effect of chronic treatment of PI3K/mTOR inhibitor GSK2126458 (omipalisib) was investigated in the atrioventricular (AV) block dog model. Methods: Purpose-bred Mongrel dogs received complete AV block by ablation of the bundle of His and their hearts were paced in the right ventricular apex at VDD-mode (RVA-VDD). In this way, sinus rhythm was maintained for 15 ± 1 days and thereby bradycardia-induced cardiac remodeling was prevented. Dogs received 1 mg/kg omipalisib once (n = 3) or twice (n = 10) a day via oral administration for 7 days. Under standardized conditions (anesthesia, bradycardia at 60 beats/min, and a dofetilide challenge), potential proarrhythmic effects of omipalisib were investigated. Results: Twice daily dosing of omipalisib increased accumulative plasma levels compared to once daily dosing accompanied with adverse events. Omipalisib prolonged the QT interval at baseline and more strongly after the dofetilide challenge (490 ± 37 to 607 ± 48 ms). The arrhythmic outcome after omipalisib resulted in single ectopic beats in 30% of dogs perpetuating in multiple ectopic beats and TdP arrhythmia in 20% of dogs. Isolated ventricular cardiomyocytes from omipalisib-treated dogs showed a diminished IKs current density. Conclusion: Chronic treatment of PI3K/mTOR inhibitor omipalisib prolonged the QT interval in a preclinical model under standardized proarrhythmic conditions. Furthermore, this study showed that electrical remodeling induced by omipalisib had a mild proarrhythmic outcome.

Wrapping Up Hydrophobic Hydration: Locality Matters.

Water, being the universal solvent, acts as a competing agent in fundamental processes, such as folding, aggregation or biomolecular recognition. A molecular understanding of hydrophobic hydration is of central importance to understanding the subtle free energy differences, which dictate function. Ab initio and classical molecular dynamics simulations yield two distinct hydration water populations in the hydration shell of solvated tert-butanol noted as "HB-wrap" and "HB-hydration2bulk". The experimentally observed hydration water spectrum can be dissected into two modes, centered at 164 and 195 cm-1. By comparison to the simulations, these two bands are attributed to the "HB-wrap" and "HB-hydration2bulk" populations, respectively. We derive a quantitative correlation between the population in each of these two local water coordination motifs and the temperature dependence of the solvation entropy. The crossover from entropy to enthalpy dominated solvation at elevated temperatures, as predicted by theory and observed experimentally, can be rationalized in terms of the distinct temperature stability and thermodynamic signatures of "HB-wrap" and "HB-hydration2bulk".

Strong correlation of total phenotypic resistance of samples from household environments and the prevalence of class 1 integrons suggests for the use of the relative prevalence of intI1 as a screening tool for multi-resistance.

One of the biggest challenges of health care systems worldwide is the increasing number of pathogenic bacteria resistant to a growing number of antibiotics. In this respect, class 1 integrons which are part of mobile genetic elements can confer several phenotypes including resistance to a broad range of antibiotic classes, heavy metals and biocides. They are linked to common resistance genes and have penetrated pathogenic and commensal bacteria likewise. Therefore its relative prevalence can be a proxy for antimicrobial resistance and anthropogenic pollution. Household environments are areas with a high influx of bacteria from humans, animals and foods, and biocides and detergents are frequently used. In this study we aimed to investigate the relative prevalence of class 1 integrons in household environments, in relation to the number of antibiotic and benzalkonium chloride resistant phenotypes of a sample point, for the validation of the relative prevalence of class 1 integrons as a screening tool for multi-resistance. Kitchen sink and bathroom sink U-bends, dishwasher, washing machines and toothbrushes of 28 households were probed. Copies /mL of class 1 integron integrase gene and 16SrDNA gene were determined by qPCR and bacteria of the respective sample were isolated on ampicillin selective agar plates, followed by the determination of the species and phenotypic resistance profiles. The relative prevalence of class 1 integrons in relation to 16SrDNA was calculated and correlated to phenotypic resistance. Our findings show a high relative prevalence of class 1 integrons in water reticulation systems of household environments and in particular shower U-bends. Furthermore, prevalence of class 1 integrons correlates strongly (rs = 0.95) with total phenotypic resistance at a sample point and suggest that a standardized assay determining the relative prevalence of class 1 integrons could be used as a useful screening tool in the assessment of multi-resistance in environmental samples.

Gold open access: the best of both worlds.

Gold open access provides free distribution of trustworthy scientific knowledge for everyone. As publication modus, it has to withstand the bad reputation of predatory journals and overcome the preconceptions of those who believe that open access is synonymous with poor quality articles and high costs. Gold open access has a bright future and will serve the scientific community, clinicians without academic affiliations and the general public.

A 2015 focus on preventing drug-induced arrhythmias.

Drug-induced Torsade de Pointes arrhythmia is a life-threatening adverse effect feared by pharmaceutical companies. For the last decade, the cardiac safety guidelines have imposed human ether-a-go-go-related gene channel blockade and prolongation of QT interval as surrogates for proarrhythmic risk propensity of a new chemical entity. Suffering from a lack of specificity, this assessment strategy led to a great amount of false positive outcomes. Therefore, this review will discuss new pharmaceutical strategies: the cardiac safety proposal that recently emerged, the Comprehensive in vitro Proarrhythmia Assay, combining in vitro assays that integrate effects on main cardiac ion channels, with computational models of human ventricular action potential as well as assays using human stem cell-derived cardiomyocytes for an improved prediction of drug's proarrhythmic liability, alternative pharmacological perspectives as well as the current treatment of drug-induced long QT syndrome.

Barium toxicity and the role of the potassium inward rectifier current.

INTRODUCTION: Barium is a stable divalent earth metal and highly toxic upon acute and chronic exposure. Barium is present in many products and involved in a number of industrial processes. Barium targets the potassium inward rectifier channels (IRCs) of the KCNJx gene family. Extracellular barium enters and strongly binds the potassium selectivity filter region resulting in blockade of the potassium conducting pore. IRCs are involved in numerous physiological processes of the human body and the most barium sensitive IRCs are highly expressed in all muscle types. OBJECTIVE: Our purpose was correlate to the clinical outcome of acute barium poisoning in man to current knowledge on IRC function. METHODOLOGY: The primary literature search was performed using Medline, Scopus and Google Scholar using search terms "barium AND poisoning"; "barium AND intoxication"; "barium AND case report" and retrieved publications from 1945 through 2012. Additional case reports were retrieved based on the reference lists of the primary hits. Duplicate publications, or publications presenting identical cases were omitted. A total of 39 case reports on acute barium poisoning containing 226 human subjects were identified for review. RESULTS: BaCO3 was the most frequent source and food the most frequent mode of poisoning. Patients suffered from gastrointestinal (vomiting, diarrhea), cardiovascular (arrhythmias, hypertension), neuromuscular (abnormal reflexes, paralysis), respiratory (respiratory arrest/failure) and metabolic (hypokalemia) symptoms. Severe hypokalemia (< 2.5 mM) was observed from barium serum concentrations greater than or equal to 0.0025 mM. Review of the ECG outcomes demonstrated ventricular extrasystoles, ST changes and profound U-waves to be associated strongly with poisoning. Most common treatment modalities were gastric lavage, oral sulfates, potassium i.v. and cardiorespiratory support. 27 patients (12%) died from barium poisoning. CONCLUSIONS: Barium is a potent, non-specific inhibitor of the potassium IRC current and affects all types of muscle at micromolar concentrations. Gastrointestinal symptoms frequently occur early in the course of barium poisoning. Hypokalemia resulting from an intracellular shift of potassium and the direct effect of barium at the potassium channels explain the cardiac arrhythmias and muscle weakness which commonly occur in barium poisoning. Treatment of barium poisoning is mainly supportive. Orally administered sulfate salts to form insoluble barium sulfate in the intestinal tract and potassium supplementation have potential but unproven benefit.

Structure-activity relationships of pentamidine-affected ion channel trafficking and dofetilide mediated rescue.

BACKGROUND AND PURPOSE: Drug interference with normal hERG protein trafficking substantially reduces the channel density in the plasma membrane and thereby poses an arrhythmic threat. The chemical substructures important for hERG trafficking inhibition were investigated using pentamidine as a model drug. Furthermore, the relationship between acute ion channel block and correction of trafficking by dofetilide was studied. EXPERIMENTAL APPROACH: hERG and K(IR)2.1 trafficking in HEK293 cells was evaluated by Western blot and immunofluorescence microscopy after treatment with pentamidine and six pentamidine analogues, and correction with dofetilide and four dofetilide analogues that displayed different abilities to inhibit IKr . Molecular dynamics simulations were used to address mode, number and type of interactions between hERG and dofetilide analogues. KEY RESULTS: Structural modifications of pentamidine differentially affected plasma membrane levels of hERG and K(IR)2.1. Modification of the phenyl ring or substituents directly attached to it had the largest effect, affirming the importance of these chemical residues in ion channel binding. PA-4 had the mildest effects on both ion channels. Dofetilide corrected pentamidine-induced hERG, but not K(IR)2.1 trafficking defects. Dofetilide analogues that displayed high channel affinity, mediated by pi-pi stacks and hydrophobic interactions, also restored hERG protein levels, whereas analogues with low affinity were ineffective. CONCLUSIONS AND IMPLICATIONS: Drug-induced trafficking defects can be minimized if certain chemical features are avoided or 'synthesized out'; this could influence the design and development of future drugs. Further analysis of such features in hERG trafficking correctors may facilitate the design of a non-blocking corrector for trafficking defective hERG proteins in both congenital and acquired LQTS.

Inhibition of cardiac inward rectifier currents by cationic amphiphilic drugs.

Cardiac inward rectifier channels belong to three different classes of the KIR channel protein family. The KIR2.x proteins generate the classical inward rectifier current, IK1, while KIR3 and KIR6 members are responsible for the acetylcholine responsive and ATP sensitive inward rectifier currents IKAch and IKATP, respectively. Aberrant function of these channels has been correlated with severe cardiac arrhythmias, indicating their significant contribution to normal cardiac electrophysiology. A common feature of inward rectifier channels is their dependence on the lipid phosphatidyl-4,5-bisphospate (PIP2) interaction for functional activity. Cationic amphiphilic drugs (CADs) are one of the largest classes of pharmaceutical compounds. Several widely used CADs have been associated with inward rectifier current disturbances, and recent evidence points to interference of the channel-PIP2 interaction as the underlying mechanism of action. Here, we will review how six of these well known drugs, used for treatment in various different conditions, interfere in cardiac inward rectifier functioning. In contrast, KIR channel inhibition by the anionic anesthetic thiopental is achieved by a different mechanism of channel-PIP2 interference. We will discuss the latest basic science insights of functional inward rectifier current characteristics, recently derived KIR channel structures and specific PIP2-receptor interactions at the molecular level and provide insight in how these drugs interfere in the structure-function relationships.

Geographical distribution of plakophilin-2 mutation prevalence in patients with arrhythmogenic cardiomyopathy.

Arrhythmogenic cardiomyopathy (AC) is characterised by myocardial fibrofatty tissue infiltration and presents with palpitations, ventricular arrhythmias, syncope and sudden cardiac death. AC is associated with mutations in genes encoding the desmosomal proteins plakophilin-2 (PKP2), desmoplakin (DSP), desmoglein-2 (DSG2), desmocollin-2 (DSC2) and junctional plakoglobin (JUP). In the present study we compared 28 studies (2004-2011) on the prevalence of mutations in desmosomal protein encoding genes in relation to geographic distribution of the study population. In most populations, mutations in PKP2 showed the highest prevalence. Mutation prevalence in DSP, DSG2 and DSC2 varied among the different geographic regions. Mutations in JUP were rarely found, except in Denmark and the Greece/Cyprus region.

Comparison of the IKr blockers moxifloxacin, dofetilide and E-4031 in five screening models of pro-arrhythmia reveals lack of specificity of isolated cardiomyocytes.

BACKGROUND AND PURPOSE: Drug development requires the testing of new chemical entities for adverse effects. For cardiac safety screening, improved assays are urgently needed. Isolated adult cardiomyocytes (CM) and human embryonic stem cell-derived cardiomyocytes (hESC-CM) could be used to identify pro-arrhythmic compounds. In the present study, five assays were employed to investigate their sensitivity and specificity for evaluating the pro-arrhythmic properties of I(Kr) blockers, using moxifloxacin (safe compound) and dofetilide or E-4031 (unsafe compounds). EXPERIMENTAL APPROACH: Assays included the anaesthetized remodelled chronic complete AV block (CAVB) dog, the anaesthetized methoxamine-sensitized unremodelled rabbit, multi-cellular hESC-CM clusters, isolated CM obtained from CAVB dogs and isolated CM obtained from the normal rabbit. Arrhythmic outcome was defined as Torsade de Pointes (TdP) in the animal models and early afterdepolarizations (EADs) in the cell models. KEY RESULTS: At clinically relevant concentrations (5-12 µM), moxifloxacin was free of pro-arrhythmic properties in all assays with the exception of the isolated CM, in which 10 µM induced EADs in 35% of the CAVB CM and in 23% of the rabbit CM. At supra-therapeutic concentrations (≥100 µM), moxifloxacin was pro-arrhythmic in the isolated rabbit CM (33%), in the hESC-CM clusters (18%), and in the methoxamine rabbit (17%). Dofetilide and E-4031 induced EADs or TdP in all assays (50-83%), and the induction correlated with a significant increase in beat-to-beat variability of repolarization. CONCLUSION AND IMPLICATIONS: Isolated cardiomyocytes lack specificity to discriminate between TdP liability of the I(Kr) blocking drugs moxifloxacin and dofetilide or E4031.

Robust anti-arrhythmic efficacy of verapamil and flunarizine against dofetilide-induced TdP arrhythmias is based upon a shared and a different mode of action.

BACKGROUND AND PURPOSE: The high predisposition to Torsade de Pointes (TdP) in dogs with chronic AV-block (CAVB) is well documented. The anti-arrhythmic efficacy and mode of action of Ca(2+) channel antagonists, flunarizine and verapamil against TdP were investigated. EXPERIMENTAL APPROACH: Mongrel dogs with CAVB were selected based on the inducibility of TdP with dofetilide. The effects of flunarizine and verapamil were assessed after TdP and in different experiments to prevent dofetilide-induced TdP. Electrocardiogram and ventricular monophasic action potentials were recorded. Electrophysiological parameters and short-term variability of repolarization (STV) were determined. In vitro, flunarizine and verapamil were added to determine their effect on (i) dofetilide-induced early after depolarizations (EADs) in canine ventricular myocytes (VM); (ii) diastolic Ca(2+) sparks in RyR2(R4496+/+) mouse myocytes; and (iii) peak and late I(Na) in SCN5A-HEK 293 cells. KEY RESULTS: Dofetilide increased STV prior to TdP and in VM prior to EADs. Both flunarizine and verapamil completely suppressed TdP and reversed STV to baseline values. Complete prevention of TdP was achieved with both drugs, accompanied by the prevention of an increase in STV. Suppression of EADs was confirmed after flunarizine. Only flunarizine blocked late I(Na). Ca(2+) sparks were reduced with verapamil. CONCLUSIONS AND IMPLICATIONS: Robust anti-arrhythmic efficacy was seen with both Ca(2+) channel antagonists. Their divergent electrophysiological actions may be related to different additional effects of the two drugs.

Regulatory roles of the ubiquitin-proteasome system in cardiomyocyte apoptosis.

Cardiovascular disease is the leading cause of death in the western world. The major contributor of all cardiovascular deaths is myocardial infarction, which often progresses into end-stage heart failure. The loss of cardiomyocytes is a key problem in the development of cardiovascular disease. Two main processes mediate cardiomyocyte loss: necrosis and apoptosis. In contrast to necrosis, apoptosis is a well regulated process essential in normal development and tissue homeostasis. Tight regulation of this process is crucial, especially in post mitotic cells lacking regenerative capacity, like cardiomyocytes. The ubiquitin-proteasome system, accounting for 80 to 90% of intracellular protein degradation, appears to be involved in the regulation of apoptosis. In this process, regulation is performed through the degradation of pro- and anti-apoptotic proteins involved in cell cycle control and specific apoptotic pathways. On the one hand, disturbances in this normally well regulated process are associated with a number of cardiovascular diseases. On the other hand, proteasomal dysfunction may result from ischemia, hypertrophy and heart failure, and a number of cardiomyopathies. This paper reviews the current knowledge on the role of the ubiquitin-proteasome system-mediated regulation of cardiomyocyte apoptosis in cardiovascular disease. Finally, within the ubiquitin-proteasome system new molecular targets for treatment of cardiovascular disease are suggested.

The mammalian K(IR)2.x inward rectifier ion channel family: expression pattern and pathophysiology.

Inward rectifier currents based on K(IR)2.x subunits are regarded as essential components for establishing a stable and negative resting membrane potential in many excitable cell types. Pharmacological inhibition, null mutation in mice and dominant positive and negative mutations in patients reveal some of the important functions of these channels in their native tissues. Here we review the complex mammalian expression pattern of K(IR)2.x subunits and relate these to the outcomes of functional inhibition of the resultant channels. Correlations between expression and function in muscle and bone tissue are observed, while we recognize a discrepancy between neuronal expression and function.

The anti-protozoal drug pentamidine blocks KIR2.x-mediated inward rectifier current by entering the cytoplasmic pore region of the channel.

BACKGROUND AND PURPOSE: Pentamidine is a drug used in treatment of protozoal infections. Pentamidine treatment may cause sudden cardiac death by provoking cardiac arrhythmias associated with QTc prolongation and U-wave alterations. This proarrhythmic effect was linked to inhibition of hERG trafficking, but not to acute block of ion channels contributing to the action potential. Because the U-wave has been linked to the cardiac inward rectifier current (I(K1)), we examined the action and mechanism of pentamidine-mediated I(K1) block. EXPERIMENTAL APPROACH: Patch clamp measurements of I(K1) were made on cultured adult canine ventricular cardiomyocytes, K(IR)2.1-HEK293 cells and K(IR)2.x inside-out patches. Pentamidine binding to cytoplasmic amino acid residues of K(IR)2.1 channels was studied by molecular modelling. KEY RESULTS: Pentamidine application (24 h) decreased I(K1) in cultured canine cardiomyocytes and K(IR)2.1-HEK293 cells under whole cell clamp conditions. Pentamidine inhibited I(K1) in K(IR)2.1-HEK293 cells 10 min after application. When applied to the cytoplasmic side under inside-out patch clamp conditions, pentamidine block of I(K1) was acute (IC(50)= 0.17 microM). Molecular modelling predicted pentamidine-channel interactions in the cytoplasmic pore region of K(IR)2.1 at amino acids E224, D259 and E299. Mutation of these conserved residues to alanine reduced pentamidine block of I(K1). Block was independent of the presence of spermine. K(IR)2.2, and K(IR)2.3 based I(K1) was also sensitive to pentamidine blockade. CONCLUSIONS AND IMPLICATIONS: Pentamidine inhibits cardiac I(K1) by interacting with three negatively charged amino acids in the cytoplasmic pore region. Our findings may provide new insights for development of specific I(K1) blocking compounds.

Fraud and misconduct in science: the stem cell seduction: Implications for the peer-review process.

Scientific misconduct and fraud occur in science. The (anonymous) peer review process serves as goalkeeper of scientific quality rather than scientific integrity. In this brief paper we describe some limitations of the peer-review process. We describe the catastrophic facts of the 'Woo-Suk Hwang fraud case' and raise some ethical concerns about the issue. Finally, we pay attention to plagiarism, autoplagiarism and double publications. (Neth Heart J 2009;17:25-9.).

Characterization of interfacial water in MOF-5 (Zn4(O)(BDC)3)--a combined spectroscopic and theoretical study.

In this article we report the detection and characterization of adsorbed interfacial water within the cages of the metal-organic framework MOF-5 (Zn(4)O(BDC)(3)) by terahertz time-domain spectroscopy (THz TDS) in the frequency range from 5 to 46 cm(-1). The experimental spectra suggest a coupling of the intermolecular motions of the water molecules adsorbed to the collective vibrations of the network at 4 wt% hydration. This finding is supported by the results of MD simulations. When increasing the water content to 8 wt% we observed a non reversible decomposition of MOF-5.

Long-range influence of carbohydrates on the solvation dynamics of water--answers from terahertz absorption measurements and molecular modeling simulations.

We present new terahertz (THz) spectroscopic measurements of solvated sugars and compare the effect of two disaccharides (trehalose and lactose) and one monosaccharide (glucose) with respect to the solute-induced changes in the sub-picosecond network dynamics of the hydration water. We found that the solute affects the fast collective network motions of the solvent, even beyond the first solvation layer. For all three carbohydrates, we find an increase of 2-4% in the THz absorption coefficient of the hydration water in comparison to bulk water. Concentration-dependent changes in the THz absorption between 2.1 and 2.8 THz of the solute-water mixture were measured with a precision better than 1% and were used to deduce a dynamical hydration shell, which extends from the surface up to 5.7 +/- 0.4 and 6.5 +/- 0.9 A for the disaccharides lactose and trehalose, respectively, and 3.7 +/- 0.9 A for the glucose. This exceeds the values for the static hydration shell as determined, for example, by scattering, where the long-range structure was found to be not significantly affected by the solute beyond the first hydration shell. When comparing all three carbohydrates, we found that the solute-induced change in the THz absorption depends on the product of molar concentration of the solute and the number of hydrogen bonds between the carbohydrate and water molecules. We can conclude that the long-range influence on the sub-picosecond collective water network motions of the hydration water is directly correlated with the average number of hydrogen bonds between the molecule and adjacent water molecules for carbohydrates. This implies that monosaccharides have a smaller influence on the surrounding water molecules than disaccharides. This could explain the bioprotection mechanism of sugar-water mixtures, which has been found to be more effective for disaccharides than for monosaccharides.

Adrenergic regulation of conduction velocity in cultures of immature cardiomyocytes.

During cardiac maturation, increased exposure of the heart to circulating catecholamines correlates with increased conduction velocity and growth of the heart. We used an in vitro approach to study the underlying mechanisms of adrenergic stimulation induced changes in conduction velocity. By combining functional measurements and molecular techniques, we were able to demonstrate that the increased conduction velocity after beta-adrenergic stimulation is probably not caused by changes in intercellular coupling. Instead, RT-PCR experiments and action potential measurements have shown an increased excitability that may well explain the observed increase in conduction velocity. Apart from being relevant to cardiac maturation, our findings are relevant in the context of stem cells and cardiac repair. Preconditioning of stem cell derived cardiomyocytes may help to enhance electrical maturation of de novo generated cardiomyocytes and consequently reduce their proarrhythmogenic potential. (Neth Heart J 2008;16:106-9.).