Digoxin is Not Related to Mortality in Patients with Heart Failure: Results from the SELFIE-TR Registry.

AIMS: Digoxin has been used in the treatment for heart failure for centuries, but the role of this drug in the modern era is controversial. A particular concern is the recent observational findings suggesting an increase in all-cause mortality with digoxin, although such observations suffer from biased results since these studies usually do not provide adequate compensation for the severity of disease. Using a nationwide registry database, we aimed to investigate whether digoxin is associated with 1-year all-cause mortality in patients with heart failure irrespective of phenotype. METHODS: A total of 1014 out of 1054 patients in the registry, of whom 110 patients were on digoxin, were included in the study. Multivariable adjustments were done and propensity scores were calculated for various prognostic indicators, including signs and symptoms of heart failure and functional capacity. Crude mortality, mortality adjusted for covariates, mortality in the propensity score-matched cohort, and Bayesian factors (BFs) were analyzed. RESULTS: Crude 1-year mortality rate did not differ between patients on and off digoxin (17.3% vs 20.1%, log-rank p = 0.46), and digoxin was not related to mortality following multivariable adjustment (hazard ratio 0.87, 95% confidence interval 0.539-1.402, p = 0.57). Similarly, all-cause mortality was similar in 220 propensity-score adjusted patients (17.3% vs 20.0%, log-rank p = 0.55). On Bayesian analyses, there was moderate to strong evidence suggesting a lack of difference between in unmatched cohort (BF10 0.091) and weak-to-moderate evidence in the matched cohort (BF10 0.296). CONCLUSIONS: In this nationwide cohort, we did not find any evidence for an increased 1-year mortality in heart failure patients on digoxin.

Digestion of surfactants does not affect their ability to inhibit P-gp-mediated transport in vitro.

While various non-ionic surfactants at low concentrations have been shown to increase the transport of P-gp substrates in vitro, in vivo studies in rats have shown that a higher surfactant concentration is needed to increase the oral absorption of e.g. the P-gp substrates digoxin and etoposide. The aim of the present study was to investigate if intestinal digestion of surfactants could be the reason for this deviation between in vitro and in vivo data. Therefore, Kolliphor EL, Brij-L23, Labrasol and polysorbate 20 were investigated for their ability to inhibit P-gp and increase digoxin absorption in vitro. Transport studies were performed in Caco-2 cells, while P-gp inhibition and cell viability assays were performed in MDCKII-MDR1 cells. Polysorbate 20, Kolliphor EL and Brij-L23 increased absorptive transport and decreased secretory digoxin transport in Caco-2 cells, whereas only polysorbate 20 and Brij-L23 showed P-gp inhibiting properties in the MDCKII-MDR1 cells. Polysorbate 20 and Brij-L23 were chosen for in vitro digestion prior to transport- or P-gp inhibiting assays. Brij-L23 was not digestible, whereas polysorbate 20 reached a degree of digestion around 40%. Neither of the two surfactants showed any significant difference in their ability to affect absorptive or secretory transport of digoxin after pre-digestion. Furthermore, the P-gp inhibiting effects of polysorbate 20 were not decreased significantly. In conclusion, the mechanism behind the non-ionic surfactant mediated in vitro P-gp inhibition seemed independent of the intestinal digestion and the results presented here did not suggest it to be the cause of the observed discrepancy between in vitro and in vivo.

A digoxin derivative that potently reduces intraocular pressure: efficacy and mechanism of action in different animal models.

Glaucoma is a blinding disease. Reduction of intraocular pressure (IOP) is the mainstay of treatment, but current drugs show side effects or become progressively ineffective, highlighting the need for novel compounds. We have synthesized a family of perhydro-1,4-oxazepine derivatives of digoxin, the selective inhibitor of Na,K-ATPase. The cyclobutyl derivative (DcB) displays strong selectivity for the human α2 isoform and potently reduces IOP in rabbits. These observations appeared consistent with a hypothesis that in ciliary epithelium DcB inhibits the α2 isoform of Na,K-ATPase, which is expressed strongly in nonpigmented cells, reducing aqueous humor (AH) inflow. This paper extends assessment of efficacy and mechanism of action of DcB using an ocular hypertensive nonhuman primate model (OHT-NHP) (Macaca fascicularis). In OHT-NHP, DcB potently lowers IOP, in both acute (24 h) and extended (7-10 days) settings, accompanied by increased aqueous humor flow rate (AFR). By contrast, ocular normotensive animals (ONT-NHP) are poorly responsive to DcB, if at all. The mechanism of action of DcB has been analyzed using isolated porcine ciliary epithelium and perfused enucleated eyes to study AH inflow and AH outflow facility, respectively. 1) DcB significantly stimulates AH inflow although prior addition of 8-Br-cAMP, which raises AH inflow, precludes additional effects of DcB. 2) DcB significantly increases AH outflow facility via the trabecular meshwork (TM). Taken together, the data indicate that the original hypothesis on the mechanism of action must be revised. In the OHT-NHP, and presumably other species, DcB lowers IOP by increasing AH outflow facility rather than by decreasing AH inflow.NEW & NOTEWORTHY When applied topically, a cyclobutyl derivative of digoxin (DcB) potently reduces intraocular pressure in an ocular hypertensive nonhuman primate model (Macaca fascicularis), associated with increased aqueous humor (AH) flow rate (AFR). The mechanism of action of DcB involves increased AH outflow facility as detected in enucleated perfused porcine eyes and, in parallel, increased (AH) inflow as detected in isolated porcine ciliary epithelium. DcB might have potential as a drug for the treatment of open-angle human glaucoma.

Spironolactone metabolite causes falsely increased progesterone in the Abbott Architect immunoassay.

BACKGROUND: Immunoassays are important for routine clinical testing and medical diagnosis. However, they are limited by cross-reactivity especially at low analyte concentrations. There is a critical need to investigate compounds that can interfere with immunoassays. Herein, we describe the identification of canrenone, a spironolactone metabolite that falsely increases progesterone concentrations on the Abbott Architect i2000 Immunoassay. METHODS: Serum samples and assay diluents were spiked with spironolactone or canrenone and progesterone concentrations were measured on the Architect i2000 and Immulite XPi immunoassay platforms. Blood samples from patients taking spironolactone were analyzed with liquid chromatography-tandem mass spectrometry to evaluate the intrinsic response of progesterone concentrations to the presence of canrenone. RESULTS: We measured approximately 10-fold higher progesterone concentrations on the Abbott Architect i2000 compared to reference immunoassay analyzers (Siemens Immulite XPi and Roche Cobas e601/602), suggesting an analytical error which is unique to the Architect i2000 antibody and/or assay conditions. By measuring serum progesterone after addition of spironolactone or canrenone to serum samples, we found that canrenone falsely increased progesterone on the Architect i2000 immunoassay. However, this interference was more pronounced at low serum progesterone concentrations. Moreover, a strong positive correlation was seen between canrenone and measured serum progesterone concentrations. CONCLUSIONS: Our investigations are important for individuals who require progesterone measurements using the Architect i2000 immunoassay, especially because it is unlikely for clinicians to order canrenone measurements alongside progesterone measurements for individuals taking spironolactone. Further research is needed to determine whether canrenone can influence progesterone measurements on other immunoassay systems.

Plasma exchange for the management of digoxin toxicity in an individual with an acute kidney injury: A case report.

Digoxin toxicity can be life-threatening. Digoxin-specific antibody (DSA) fragments are used in severe digoxin toxicity, binding to serum-free digoxin and enabling increased renal excretion. In severe renal impairment, clearance of these complexes is prolonged, leading to rebound toxicity. Digoxin and DSA complexes are not dialysable. We present a case of a gentleman with severe digoxin toxicity and acute kidney injury (AKI). Despite receiving DSA doses, his digoxin levels rebounded and symptoms persisted. Based on published case reports, plasma exchange (PEX) after further dosing was arranged. PEX facilitated the removal of digoxin-DSA complexes, bypassing renal excretion. During PEX, clinical signs improved and were sustained. He did not require further dialysis or PEX, renal function recovered and he was discharged. This case highlights challenges in the management of severe digoxin toxicity in patients with a concurrent AKI. The use of PEX enabled digoxin-DSA complex removal and should be considered in these circumstances.

Successful management of massive digoxin overdose using DIGIFab and therapeutic plasma exchange: a case report.

BACKGROUND: Despite the efficacy and safety of DIGIFab, it is relatively expensive and has limited availability. In addition, alternative interventions, such as therapeutic plasma exchange, may need to be considered in massive digoxin overdoses. Although few case reports describe its efficacy. CASE PRESENTATION: We report a case of a 17-year-old white male patient brought by family members to our emergency department in Riyadh, Saudi Arabia. After intentionally ingesting 48 mg of digoxin tablets to commit suicide, the patient's initial digoxin serum level was 8.04 ng/mL. The patient was resuscitated in the emergency department. After admission to the intensive care unit, the patient underwent therapeutic plasma exchange, because of insufficient DIGIFab doses. Afterward, the serum digoxin levels drastically decreased, and his symptoms reverted. The patient was successfully managed and discharged 7 days after admission. CONCLUSION: Despite insufficient evidence and a limited number of case reports describing the use of extracorporeal treatment in digoxin overdose, we noted the significant impact of therapeutic plasma exchange on our patient. However, therapeutic plasma exchange's use in routine treatment requires stronger evidence to confirm its benefits.

Bronchogenic cyst: a rare cause of palpitations and atrial fibrillation.

Bronchogenic cysts are rare congenital lesions found primarily in the mediastinum. Most patients are asymptomatic and can be treated with minimally invasive resection. We present a case of a middle-aged patient who presented to a district general hospital with palpitations and shortness of breath. She underwent a computerised tomographic pulmonary angiogram that showed a likely bronchogenic cyst and was subsequently transferred to our hospital. She developed atrial fibrillation during admission requiring therapy with beta-blockers and digoxin. Cardiac MRI revealed a large cyst posterior to the left atrium, a moderate circumferential pericardial effusion and bilateral pleural effusions. There was significant left atrial compression. The patient underwent surgical removal of the cyst and was discharged. She returned to the hospital within a week with palpitations and was treated with intravenous antibiotics for sepsis. She was discharged a week later and remained clinically stable.

Serum Cystatin C as a Risk Factor for Supratherapeutic Digoxin Concentration in Elderly Patients with Heart Failure and Chronic Kidney Disease.

BACKGROUND: Digoxin is primarily metabolized by the kidney, and its toxicity is strongly associated with high concentrations, particularly in elderly patients. The purpose of this study was to evaluate the predictive performance of renal function biomarkers for supratherapeutic digoxin concentrations in elderly patients with heart failure (HF) and chronic kidney disease (CKD). METHODS: Data were retrospectively obtained from elderly patient with HF and CKD who received digoxin treatment from January 2022 and December 2022. Logistic regression was used to assess independent risk factors for supratherapeutic concentrations. The predictive performance of serum creatinine, serum cystatin C, and blood urea nitrogen on supratherapeutic concentrations was compared by receiver operating characteristic analysis. RESULTS: A total of 115 elderly patients with HF and CKD were enrolled in our study. Supratherapeutic concentrations were detected in 49 patients. Logistic regression analysis showed that estimated glomerular filtration rate calculated by serum cystatin C [eGFRCysC, odds ratio (OR): 0.962, P = 0.006], heart rate (OR: 1.024, P = 0.040), and NYHA class (OR: 3.099, P = 0.010) were independent risk factors for supratherapeutic concentration. Cutoff value for eGFRCysC between the two groups was 41 ml/min/1.73m2. Predictive performance of serum cystatin C was further improved in patients with obesity, CKD stage 4-5, and older than 75 years compared with normal weight, CKD stage 3, and aged 60-75-year-old patients. CONCLUSIONS: Serum cystatin C is a sensitive renal function biomarker to predict supratherapeutic digoxin concentration in elderly patients with HF and CKD.

Possible Digoxin-Related Toxic Effects in a Patient.

This case report describes a patient in their 70s with hypertension and heart failure presenting to the emergency department with chest discomfort, nausea, anorexia, and weakness.

Evaluation of therapeutic and toxic levels of serum digoxin concentration: a cross-sectional study from a tertiary hospital.

OBJECTIVE: Digoxin is a cardiac glycoside for treating heart failure and atrial fibrillation. Despite its limited therapeutic range and complex pharmacokinetic properties, this medication continues to be frequently prescribed. This study aimed to evaluate the serum digoxin concentration (SDC) at therapeutic, subtherapeutic, and toxic levels and explore the factors affecting these levels in patients receiving digoxin therapy for heart failure. PATIENTS AND METHODS: In this descriptive and cross-sectional study, the data were obtained from the electronic system of patients who presented to Afyonkarahisar Health Sciences University. For the SDC, the reference range was accepted as 0.5-0.9 ng/mL, and the upper limit was 2.0 ng/mL. The patient's demographic characteristics, comorbidities, and laboratory findings were evaluated. The Mann-Whitney U test, Chi-square test, and logistic regression analysis were used. p<0.05 was considered statistically significant. RESULTS: The data of 419 patients (mean age: 65.9±16.1 years, 68.5% women) were evaluated. The mean SDC was 1.11±1.01 ng/mL, and it was below 0.5 ng/mL in 24.3% of the patients, 0.5-0.9 ng/mL in 23.4%, 0.9-2 ng/mL in 41.3%, and over 2 ng/mL in 11.1%. Age, male gender, the presence of diabetes mellitus, and high HbA1c values were found to be associated with greater SDC levels, but this was not statistically significant. The presence of renal failure, elevated creatinine and magnesium levels, and potassium, sodium, and calcium levels outside the normal limits significantly increased the SDC. High creatinine and low/high potassium values significantly affected the detection of SDC at the toxic level. CONCLUSIONS: The measurement of SDC levels holds significance not only in the monitoring of toxicity but also in ensuring adherence to the recommended therapeutic range during therapy. It is recommended to exercise caution in terms of risk factors such as age, kidney function test results, and blood electrolyte levels.

Sensational site: the sodium pump ouabain-binding site and its ligands.

Cardiotonic steroids (CTS), used by certain insects, toads, and rats for protection from predators, became, thanks to Withering's trailblazing 1785 monograph, the mainstay of heart failure (HF) therapy. In the 1950s and 1960s, we learned that the CTS receptor was part of the sodium pump (NKA) and that the Na+/Ca2+ exchanger was critical for the acute cardiotonic effect of digoxin- and ouabain-related CTS. This "settled" view was upended by seven revolutionary observations. First, subnanomolar ouabain sometimes stimulates NKA while higher concentrations are invariably inhibitory. Second, endogenous ouabain (EO) was discovered in the human circulation. Third, in the DIG clinical trial, digoxin only marginally improved outcomes in patients with HF. Fourth, cloning of NKA in 1985 revealed multiple NKA α and ß subunit isoforms that, in the rodent, differ in their sensitivities to CTS. Fifth, the NKA is a cation pump and a hormone receptor/signal transducer. EO binding to NKA activates, in a ligand- and cell-specific manner, several protein kinase and Ca2+-dependent signaling cascades that have widespread physiological effects and can contribute to hypertension and HF pathogenesis. Sixth, all CTS are not equivalent, e.g., ouabain induces hypertension in rodents while digoxin is antihypertensinogenic ("biased signaling"). Seventh, most common rodent hypertension models require a highly ouabain-sensitive α2 NKA and the elevated blood pressure is alleviated by EO immunoneutralization. These numerous phenomena are enabled by NKA's intricate structure. We have just begun to understand the endocrine role of the endogenous ligands and the broad impact of the ouabain-binding site on physiology and pathophysiology.

Effects of Cardiac Glycoside Digoxin on Dendritic Spines and Motor Learning Performance in Mice.

Synapse formation following the generation of postsynaptic dendritic spines is essential for motor learning and functional recovery after brain injury. The C-terminal fragment of agrin cleaved by neurotrypsin induces dendritic spine formation in the adult hippocampus. Since the α3 subunit of sodium-potassium ATPase (Na/K ATPase) is a neuronal receptor for agrin in the central nervous system, cardiac glycosides might facilitate dendritic spine formation and subsequent improvements in learning. This study investigated the effects of cardiac glycoside digoxin on dendritic spine turnover and learning performance in mice. Golgi-Cox staining revealed that intraperitoneal injection of digoxin less than its IC50 in the brain significantly increased the density of long spines (≥2 µm) in the cerebral cortex in wild-type mice and neurotrypsin-knockout (NT-KO) mice showing impairment of activity-dependent spine formation. Although the motor learning performance of NT-KO mice was significantly lower than control wild-type mice under the control condition, low doses of digoxin enhanced performance to a similar degree in both strains. In NT-KO mice, lower digoxin doses equivalent to clinical doses also significantly improved motor learning performance. These data suggest that lower doses of digoxin could modify dendritic spine formation or recycling and facilitate motor learning in compensation for the disruption of neurotrypsin-agrin pathway.

Navigating Heart Failure: Unveiling Sex Disparities in Guideline-Directed Medical Therapy Combinations.

Major heart failure (HF) trials remain insufficient in terms of assessing the differences in clinical characteristics, biomarkers, treatment efficacy, and safety because of the under-representation of women. The study aimed to present sex-related disparities in HF management, including differences in demographics, co-morbidities, cardiac biomarkers, prescribed medications, and treatment outcomes. The study utilized anonymized data from the Turkish Ministry of Health's National Electronic Database between January 1, 2016, and December 31, 2022. The cohort analysis included 2,501,231 adult patients with HF. Specific therapeutic combinations were analyzed using a Cox regression model to obtain relative risk reduction for all-cause death. The primary end point was all-cause mortality. In the cohort, 48.7% (n = 1,218,911) were male, whereas 51.3% (n = 1,282,320) were female. Female patients exhibited a higher median age (71 vs 68 years) and manifested higher prevalence of diabetes mellitus, anemia, atrial fibrillation, anxiety, and ischemic stroke. Male patients demonstrated higher rates of previous myocardial infarction, dyslipidemia, chronic obstructive pulmonary disease, and chronic kidney disease. Higher concentrations of natriuretic peptides were observed in female patients. Renin-angiotensin aldosterone inhibitor, ß blockers, mineralocorticoid receptor antagonists, sodium/glucose cotransporter 2 inhibitor (SGLT2i), and ivabradine were more commonly prescribed in male patients, whereas loop diuretics, digoxin, and ferric carboxymaltose were more frequent in female patients. Male patients had higher rates of cardiac resynchronization therapy and implantable cardioverter defibrillator implantation rates. All-cause mortality and hospitalization rates were higher in male patients. Compared with monotherapy, all combinations, including SGLT2i, showed a beneficial effect on all-cause mortality in both female and male patients with HF. In hospitalized patients with HF, the addition of digoxin to renin-angiotensin aldosterone inhibitor, mineralocorticoid receptor antagonists, and ß blockers was superior to monotherapy regarding all-cause mortality in female patients with HF compared with male patients with HF. In conclusion, this study highlights that sex-specific responses to HF medication combinations compared with monotherapy and differences in co-morbidities underscore the importance of tailored management strategies. Digoxin showed a contrasting effect on all-cause mortality between both sexes after hospitalization, whereas SGLT2i exhibited a consistent beneficial effect in both sexes when added to all combinations.

Drug-Drug Interactions Between Glucagon-Like Peptide 1 Receptor Agonists and Oral Medications: A Systematic Review.

BACKGROUND: Glucagon-like peptide 1 receptor agonists (GLP1RAs) are used in the treatment of diabetes and obesity. Their slowing effect of gastric emptying might change oral drug absorption, potentially affecting pharmacokinetics, particularly in the case of medications with a narrow therapeutic index. PURPOSE: The purpose of this systematic review is to summarize data on drug-drug interactions between GLP1RAs and oral drugs. DATA SOURCES: The PubMed and EMBASE databases were searched up to November, 1st 2023. STUDY SELECTION: We selected pharmacokinetic studies of any injectable GLP1RA given with an oral medication, and product prescribing sheets reporting data without access to the original study. DATA EXTRACTION: Two authors independently extracted the data. DATA SYNTHESIS: Twenty-two reports and six prescribing sheets were included. Treatment with GLP1RAs resulted in unaffected or reduced Cmax and delayed tmax of drugs with high solubility and permeability (warfarin, contraceptive pills, acetaminophen), drugs with high solubility and low permeability (angiotensin converting enzyme inhibitors), drugs with low solubility and high permeability (statins) and drugs with low solubility and permeability (digoxin). However, the use of GLP1RAs did not exert clinically significant changes in the AUC or differences in clinically relevant endpoints. LIMITATIONS: The major limitations of the studies that are included in this systematic review are the enrollment of healthy subjects and insufficient data in conditions that might affect pharmacokinetics (e.g., kidney dysfunction). CONCLUSIONS: To conclude, reduced Cmax and delayed tmax of drugs co-administered with GLP1RAs are consistent with the known delayed gastric output by the latter. Nevertheless, the overall drug exposure was not considered clinically significant. Dose adjustments are probably not required for simultaneous use of GLP1RAs with oral medications. Still, results should be carefully generalized to cases of background kidney dysfunction or when using drugs with narrow therapeutic index. The study is registered in PROSPERO: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022332339 .

MITRAL REGURGITATION IN SADDLE-BILLED STORKS (EPHIPPIORHYNCHUS SENEGALENSIS) IN HUMAN CARE: DIAGNOSIS, ECHOCARDIOGRAPHIC MEASUREMENTS, AND MANAGEMENT.

The asymptomatic and slow progressive nature of cardiopathies represents a risk to the welfare of avian species in human care. Diagnosis and treatment of cardiac disease in birds pose a challenge due to unique anatomic and physiologic characteristics. Comprehensive cardiac assessments with diagnostic tools such as echocardiography, color-Doppler, the biomarker cardiac troponin I (cTn1), and cholesterol serum concentrations have been utilized in different bird species with varying success. Saddle-billed storks (Ephippiorhynchus senegalensis) have been maintained in human care for over 80 yrs and several institutions have noted heart murmurs and cardiomegaly. Despite these findings, peer-reviewed literature describing cardiopathies is lacking for this species. This case series documents the identification of mitral valve regurgitation in saddle-billed storks in a breeding center. Transcoelomic echocardiography using a ventromedial approach with a two-chambered view and color Doppler was utilized. Echocardiographic measurements were taken and compared 1 yr later in most of the birds. There was left atrial enlargement and worsened mitral regurgitation in one geriatric patient, and no progression of the disease in two young birds. Serum samples showed that cTn1 had different concentrations depending on the severity of the disease, whereas cholesterol was within reference range for all birds. Treatment with digoxin and pimobendan was recommended in one bird, serum concentrations of digoxin were tested in a 6-mon span, results were within therapeutic range, and there were no overt adverse effects. There was a suspected genetic component in this population, as four of the five birds with confirmed mitral regurgitation were related.

A case of digoxin intoxication caused by short-term massive overdose: Case report.

RATIONALE: Digoxin is a frequently prescribed medication for the management of both acute and chronic cardiac insufficiency. The overdose ingestion of digoxin can result in a range of arrhythmias, with severe cases potentially leading to malignant arrhythmias and fatal outcomes. To date, there is a lack of documented cases related to acute digoxin intoxication resulting from the administration of massive digoxin overdose in the short term. PATIENT CONCERNS: A 37-year-old female patient was admitted to the emergency department following a suicide attempt involving the administration of 330 tablets of digoxin (each tablet containing 0.25 mg). The patient exhibited symptoms of confusion, nausea, and vomiting for around 30 minutes. The patient had a history of depression. DIAGNOSES: The patient was diagnosed with digoxin intoxication. INTERVENTIONS: The patient underwent many medical interventions including stomach lavage, administration of laxatives, correction of cardiac arrhythmias, provision of myocardial nutrition, diuresis, correction of acid-base balance, and management of electrolyte disturbances, among others. OUTCOMES: Following a treatment of 9 days, the patient exhibited no signs of discomfort, maintained consciousness, and the serum concentration of digoxin was indeterminable. Upon reevaluation of the electrocardiogram, it was determined that no arrhythmia was present. Consequently, the patient was authorized to be discharged from the hospital. CONCLUSIONS: There is currently no documented evidence of cases involving a significant overdose of digoxin resulting in intoxication. The patient had a comprehensive treatment regimen consisting of stomach lavage, administration of a laxative, correction of cardiac arrhythmias, provision of myocardial nutrition, fluid replacement, diuresis, and supportive therapy, resulting in successful outcomes. LESSONS: There have been no known cases of intoxication resulting from a significant overdose of digoxin, specifically with the consumption of 330 tablets (0.25 mg/tablet). However, in the event of ingesting excessive amounts of digoxin, it is imperative to promptly administer stomach lavage, administration of a laxative, and arrhythmia correction. The administration of temporary pacemaker therapy is recommended for patients presenting with high atrioventricular block, whereas hemoperfusion is advised for patients with renal insufficiency as a means to eliminate digoxin from the body.

Determining the Risk of Elevated Digoxin Concentrations Following Loading Dose in Patients With Acute and Chronic Kidney Disease.

BACKGROUND: The optimal loading dose of digoxin in patients with reduced kidney function is unknown. Tertiary references recommend reduced loading doses; however, these recommendations are based on immunoassays that are falsely elevated by the presence of digoxin-like immunoreactive substances, a problem that is minimized in modern assays. OBJECTIVE: To determine whether chronic kidney disease (CKD) or acute kidney injury (AKI) is associated with supratherapeutic digoxin concentrations after a digoxin loading dose. METHODS: A retrospective analysis on patients who received an intravenous loading dose of digoxin with a digoxin concentration collected 6 to 24 hours after the end of the dose. Patients were stratified into 3 groups: AKI, CKD, and non-AKI/CKD (NKI) based on glomerular filtration rate and serum creatinine. The primary outcome was frequency of supratherapeutic digoxin concentrations (>2 ng/mL) and secondary outcomes included frequency of adverse events. RESULTS: A total of 146 digoxin concentrations were included (AKI = 59, CKD = 16, NKI = 71). Frequencies of supratherapeutic concentrations were similar between groups (AKI: 10.2%, CKD: 18.8%, NKI: 11.3%; P = 0.61). Pre-planned logistic regression demonstrated no significant relationship between kidney function group and the development of a supratherapeutic concentration (AKI: odds ratio [OR]: 1.3, 95% confidence interval [CI]: 0.4-4.5; CKD: OR 4.3, 95% CI: 0.7-23). CONCLUSION AND RELEVANCE: This is the first study in routine clinical practice evaluating the relationship between kidney function and digoxin peak concentrations that differentiates AKI from CKD. We did not find a relationship between kidney function and peak concentrations; however, the group with CKD was underpowered.

Fecal Deployment: An Alternative Way of Defensive Host Plant Cardenolide Use by Lilioceris merdigera Larvae.

The brilliant red Lilioceris merdigera (Coleoptera, Chrysomelidae) can spend its entire life cycle on the cardenolide-containing plant Convallaria majalis (lily of the valley) and forms stable populations on this host. Yet, in contrast to many other insects on cardenolide-containing plants L. merdigera does not sequester these plant toxins in the body but rather both adult beetles and larvae eliminate ingested cardenolides with the feces. Tracer feeding experiments showed that this holds true for radioactively labeled ouabain and digoxin, a highly polar and a rather apolar cardenolide. Both compounds or their derivatives are incorporated in the fecal shields of the larvae. The apolar digoxin, but not the polar ouabain, showed a deterrent effect on the generalist predatory ant Myrmica rubra, which occurs in the habitat of L. merdigera. The deterrent effect was detected for digoxin both in choice and feeding time assays. In a predator choice assay, a fecal shield derived from a diet of cardenolide-containing C. majalis offered L. merdigera larvae better protection from M. rubra than one derived from non-cardenolide Allium schoenoprasum (chives) or no fecal shield at all. Thus, we here present data suggesting a new way how insects may gain protection by feeding on cardenolide-containing plants.

Hawthorne root (Crataegus mexicana) toxicity.

Here we present the case of a patient who purchased a Hawthorne root (Crataegus mexicana) product, Raiz de Tejocote, for weight loss purposes. She presented with diffuse myalgias, dizziness and a heart rate of 52 beats per minute. At triage and at initial evaluation, the patient denied taking any medications, but on iterative questioning concerning over-the-counter, over-the-internet and herbal medications, she reported taking Hawthorne root tablets in the three days prior to the emergency department (ED) visit for the purpose of weight loss. The product was purchashed through the internet. Her plasma digoxin concentration was 0.4 ng/ml the patient's constellation of symptoms, as well as the detectable plasma digoxin concentration, were consistent with hawthorne root toxicity. Hawthorne root has intrinsic cardiac glycoside activity. In addition, Hawthorne root may cause a range of toxicity. Mild symptoms can include flu-like syndrome with significant myalgias. However, in the more severe exposures the cardiac glycoside effects can result in bradycardia and hemodynamic instability. Symptoms resolved with ED observation. The heart rate normalized. This case reinforces the importance of asking a patient about all medications, including over-the-counter, over-the-internet and herbal medications.

Pharmacological Treatments in Heart Failure With Mildly Reduced and Preserved Ejection Fraction: Systematic Review and Network Meta-Analysis.

BACKGROUND: Medical treatment for heart failure with preserved ejection (HFpEF) and heart failure with mildly reduced ejection fraction (HFmrEF) has weaker evidence compared with reduced ejection fraction, despite recent trials with an angiotensin receptor neprilysin inhibitor (ARNI) and sodium glucose co-transporter 2 inhibitors (SGLT2is). OBJECTIVES: The authors aimed to estimate the aggregate therapeutic benefit of drugs for HFmrEF and HFpEF. METHODS: The authors performed a systematic review of MEDLINE, CENTRAL, and Web of Science for randomized trials including patients with heart failure (HF) and left ventricular ejection fraction (LVEF) >40%, treated with angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (analyzed together as renin-angiotensin system inhibitors [RASi]), beta-blockers (BBs), mineralocorticoid receptor antagonists (MRAs), digoxin, ARNI, and SGLT2i. An additive component network meta-analysis was performed. The primary outcome was a composite of cardiovascular (CV) death and first hospitalization for heart failure (HHF); secondary outcomes were CV death, total HHF, and all-cause mortality. RESULTS: The authors identified 13 studies with a total of 29,875 patients and a mean LVEF of 56.3% ± 8.7%. ARNI, MRA, and SGLT2i separately, but not RASi, BB, or digoxin, reduced the primary composite outcome compared with placebo. The combination of ARNI, BB, MRA, and SGLT2i was the most effective (HR: 0.47 [95% CI: 0.31-0.70]); this was largely explained by the triple combination of ARNI, MRA, and SGLT2i (HR: 0.56 [95% CI 0.43-0.71]). Results were similar for CV death (HR: 0.63 [95% CI 0.43-0.91] for ARNI, MRA, and SGLT2i) or total HHF (HR: 0.49 [95% CI 0.33-0.71] for ARNI, MRA, and SGLT2i) alone. In a subgroup analysis, only SGLT2i had a consistent benefit among all LVEF subgroups, whereas the triple combination had the greatest benefit in HFmrEF, robust benefit in patients with LVEF 50% to 59%, and a statistically marginal benefit in patients with LVEF ≥60%. CONCLUSIONS: In patients with HF and LVEF>40%, the quadruple combination of ARNI, BB, MRA, and SGLT2i provides the largest reduction in the risk of CV death and HHF; driven by the robust effect of the triple combination of ARNI, MRA, and SGLT2i. The benefit was more pronounced in HFmrEF patients.