Digoxin Concentrations Research Articles

Pharmacokinetics of the Direct Factor Xa Inhibitor Edoxaban and Digoxin Administered Alone and in Combination

The oral anticoagulant edoxaban, a factor Xa inhibitor, will likely be coadministered with digoxin in some patients with atrial fibrillation. Both drugs are substrates for P-glycoprotein. The objective of this phase 1, parallel study was to assess the effects of coadministration of both drugs on their respective pharmacokinetics (PK) and pharmacodynamics (PD). Forty-eight subjects, aged 18 to 45 years, received either edoxaban 60 mg once daily × 7 days (n = 24) or digoxin 0.25 mg twice daily × 2 days and once daily × 5 days (n = 24) and then concomitantly for 7 days. Serial blood and urine samples were collected for digoxin and edoxaban concentrations on days 7 and 14. Serial coagulation assays were measured for edoxaban on days 7 and 14. Edoxaban PK parameters demonstrated mild increases in area under the curve and peak concentrations of 9.5% and 15.6%, respectively, when coadministered with digoxin. Although digoxin PK parameters demonstrated increased area under the curve and peak concentrations of 8.3% and 28%, respectively, plasma concentrations were within the established therapeutic range. Edoxaban PD were consistent with PK. Both drugs were well tolerated alone or in combination. No clinically significant changes in PK, PD, or renal elimination were observed with concomitant administration of edoxaban and digoxin.

2012 American College of Clinical Pharmacology Annual Meeting September 23rd–25th San Diego, California

2012 American College of Clinical Pharmacology Annual Meeting September 23^rd–25^th San Diego, California

A Trap In Measuring Of Plasma Digoxin Level After Stopping Of A Treatment

Summary: In this paper, a course of the disease of a 68year-old patient treated with medigoxin for congestive heart failure is presented. After being withdrawn from his treatment at the hospital, the patient was administered spironolactone and turosemide. The plasma digoxin level at entry was 1.1 nmol/L, after five days it reached 3.2nmol/L, and after ten days was 2.3 nmol/L. The patient had a normal renal function. The interference of spironolactone and its metabolites with the thgoxin ‘radioimmunoassay was discussed as a possible explanation for this omena. Discussion: The case described here demonstrates a pr entation of a 68year-old patient with cardiac d compensation who had been treated with 0.1 mgo medigoxin daily for congestive heart failure until the admission to the hospital. On entry an e1ecu cardiogram indicated the PQinterva1 of 0.38 , suggesting the digitalis effect. During the treau the clinical picture of heart failure disappeare while plasma digoxin concentration disclosed highei and higher values, despite the withdrawal of’ medigoxin.

Intravenous application of an anticalin dramatically lowers plasma digoxin levels and reduces its toxic effects in rats

Lipocalins tailored with high affinity for prescribed ligands, so-called anticalins, constitute promising candidates as antidotes. Here, we present an animal study to investigate both pharmacokinetic and clinical effects of an anticalin specific for the digitalis compound digoxin. Intravenous digoxin (2.5–50μg/kg/min) was administered to rats until first changes in the ECG occurred (dose finding study) or a priori for 30min (kinetic study). The anticalin DigA16(H86N), dubbed DigiCal, was administered intravenously at absolute doses of 1, 5, 10 and 20mg, while the control group received isotonic saline. Hemodynamic changes, several ECG parameters and digoxin concentration in plasma were monitored at given time intervals. After DigiCal administration free digoxin concentration in plasma ultrafiltrate declined dramatically within 1min to the presumably non-toxic range. There was also a significant and DigiCal dose-dependent effect on longer survival, less ECG alterations, arrhythmia, and improved hemodynamics. Infusion of a lower digoxin dose (2.5μg/kg/min) resulted in a more sustained reduction of free digoxin in plasma after DigiCal administration compared to a higher digoxin dose (25μg/kg/min), whereas ECG and hemodynamic parameters did not markedly differ, reflecting the known relative insensitivity of rats towards digoxin toxicity. Notably, we observed a re-increase of free digoxin in plasma some time after bolus administration of DigiCal, which was presumably due to toxin redistribution from tissue in combination with the relatively fast renal clearance of the rather small protein antidote. We conclude that anticalins with appropriately engineered drug-binding activities and, possibly, prolonged plasma half-life offer prospects for next-generation antidotal therapy.

The New LOCI Digoxin Assay on the Vista 1500 Analyzer Is Virtually Free From Interferences of Herbal Supplements Hawthorn and Ashwagandha (Indian Ginseng)

Herbal supplements hawthorn and ashwagandha (Indian ginseng) are indicated for cardiac illnesses and may be taken by patients receiving digoxin therapy. Because both hawthorn and ashwagandha are known to interfere with serum digoxin measurements using certain digoxin immunoassays, we investigated potential interference of these two herbal supplements with the new homogenous sequential chemiluminescent assay for digoxin based on the luminescent oxygen channeling technology (LOCI digoxin) for application on the Dimension and Vista platform. When aliquots of a drug-free serum pool were supplemented with various amounts of hawthorn (three different commercial preparations) or ashwagandha (two different commercial preparations) and apparent digoxin values were measured using LOCI digoxin assay on Dimension Vista 1500 analyzer we observed none-detected values except when aliquots were supplemented with very high amounts of the herbal extracts. When aliquots of a serum digoxin pool (prepared by pooling specimens from patients receiving digoxin) where further supplemented with various amounts of these supplements and digoxin concentrations were remeasured, statistically significant falsely higher digoxin values were observed only in specimens containing very high amounts of these supplements. Such interference may not be clinically significant. We conclude that new LOCI digoxin assay is virtually free from interferences of herbal supplements, hawthorn, and ashwagandha.

Antiarrhythmic effect of flax lignan concentrate alone and concomitantly with omega 3 fatty acid mediated through inhibition of cardiomyocyte apoptosis in digoxin induced ventricular arrhythmia and lethality in rats

The objective of the present study was to investigate antiarrhythmic effect of flax lignan concentrate (FLC) and omega 3 fatty acid (omega) in digoxin induced ventricular arrhythmia and lethality in rats. Male wistar rats (250–300g) were divided into four groups: control (received saline 1mL/kg/day p.o. for 28days); omega (received omega 1mL/kg for 28days); FLC (Animals received FLC 400mg/kg/day p.o. for 28days); FLC+omega (received concomitant treatment of FLC and omega for 28days). On last day, digoxin was infused by jugular vein until the cardiac arrest. Concomitant treatment of FLC and omega significantly increased the concentration of digoxin required to produce ectopic beats (P<0.05), ventricular fibrillation (P<0.05) and cardiac arrest (P<0.01), reduced the serum levels of CKMB (P<0.05), LDH (P<0.01) and restored the activities of endogenous antioxidant enzymes. FLC+Omega treatment showed antiapoptotic effect as evidenced by reduction in myocardial apoptosis. Transmission electron microscopy and histology of heart confirmed cardioprotective effect of concomitant treatment. The mechanism of this protective effect appears to be mediated through conservation of endogenous myocardial antioxidant enzymes and inhibition of apoptotic death of myocardial cells.

Pharmacokinetics of the Direct Factor Xa Inhibitor Edoxaban and Digoxin Administered Alone and in Combination

The oral anticoagulant edoxaban, a factor Xa inhibitor, will likely be coadministered with digoxin in some patients with atrial fibrillation. Both drugs are substrates for P-glycoprotein. The objective of this phase 1, parallel study was to assess the effects of coadministration of both drugs on their respective pharmacokinetics (PK) and pharmacodynamics (PD). Forty-eight subjects, aged 18 to 45 years, received either edoxaban 60 mg once daily × 7 days (n = 24) or digoxin 0.25 mg twice daily × 2 days and once daily × 5 days (n = 24) and then concomitantly for 7 days. Serial blood and urine samples were collected for digoxin and edoxaban concentrations on days 7 and 14. Serial coagulation assays were measured for edoxaban on days 7 and 14. Edoxaban PK parameters demonstrated mild increases in area under the curve and peak concentrations of 9.5% and 15.6%, respectively, when coadministered with digoxin. Although digoxin PK parameters demonstrated increased area under the curve and peak concentrations of 8.3% and 28%, respectively, plasma concentrations were within the established therapeutic range. Edoxaban PD were consistent with PK. Both drugs were well tolerated alone or in combination. No clinically significant changes in PK, PD, or renal elimination were observed with concomitant administration of edoxaban and digoxin.

Clinically Insignificant Negative Interferences of Spironolactone, Potassium Canrenoate, and Their Common Metabolite Canrenone in New Dimension Vista LOCI Digoxin Immunoassay

Spironolactone, a potassium-sparing diuretic metabolized to canrenone is often used with digoxin to treat various conditions including congestive heart failure. Potassium canrenoate is a similar drug, which is also metabolized to canrenone. Due to reported both positive and negative interference of spironolactone, potassium canrenoate, and their common metabolite canrenone with digoxin immunoassays, we investigated potential interference of these compounds with the new homogenous sequential chemiluminescent assay for digoxin based on the luminescent oxygen channeling technology (LOCI digoxin) for application on the Dimension and Vista platform. When aliquots of a drug-free serum pool were supplemented with various amounts of spironolactone, potassium canrenoate, or canrenone and apparent digoxin values were measured using Dimension Vista LOCI digoxin assay, we observed no detected value except when aliquots were supplemented with very high amounts of potassium canrenoate or canrenone. However, we observed that apparent digoxin concentrations were very low. When aliquots of a serum digoxin pool (prepared by pooling specimens from patients receiving digoxin), were further supplemented with various amounts of spironolactone, potassium canrenoate, or canrenone and serum digoxin concentrations were remeasured using the LOCIdigoxin assay, only statistically significant falsely lower digoxin values (negative interference) were observed in specimens containing very high amounts of canrenone or potassium canrenoate. However, such small bias may not have any clinical significance. We conclude that new Dimension Vista LOCI digoxin assay is virtually free from interferences of spironolactone, potassium canrenoate, and their common metabolite canrenone.

Herb-Drug Interactions and Mechanistic and Clinical Considerations

Herbal medicines are often used in combination with conventional drugs, and this may give rise to the potential of harmful herb-drug interactions. This paper updates our knowledge on clinical herb-drug interactions with an emphasis of the mechanistic and clinical consideration. In silico, in vitro, animal and human studies are often used to predict and/or identify drug interactions with herbal remedies. To date, a number of clinically important herb-drug interactions have been reported, but many of them are from case reports and limited clinical observations. Common herbal medicines that interact with drugs include St John's wort (Hypericum perforatum), ginkgo (Ginkgo biloba), ginger (Zingiber officinale), ginseng (Panax ginseng), and garlic (Allium sativum). For example, St John's wort significantly reduced the area under the plasma concentration-time curve (AUC) and blood concentrations of cyclosporine, midazolam, tacrolimus, amitriptyline, digoxin, indinavir, warfarin, phenprocoumon and theophylline. The common drugs that interact with herbal medicines include warfarin, midazolam, digoxin, amitriptyline, indinavir, cyclosporine, tacrolimus and irinotecan. Herbal medicines may interact with drugs at the intestine, liver, kidneys, and targets of action. Importantly, many of these drugs have very narrow therapeutic indices. Most of them are substrates for cytochrome P450s (CYPs) and/or P-glycoprotein (P-gp). The underlying mechanisms for most reported herb-drug interactions are not fully understood, and pharmacokinetic and/or pharmacodynamic mechanisms are implicated in many of these interactions. In particular, enzyme induction and inhibition may play an important role in the occurrence of some herbdrug interactions. Because herb-drug interactions can significantly affect circulating levels of drug and, hence, alter the clinical outcome, the identification of herb-drug interactions has important implications.

Absence of Pharmacokinetic Interaction Between Roflumilast and Digoxin in Healthy Adults

Numerous interactions are known for digoxin, which is a drug with a narrow therapeutic index and a substrate of P-glycoprotein (P-gp). This study investigated potential effects of coadministration on pharmacokinetics and safety of both drugs when a single dose of digoxin was concomitantly administered with roflumilast under steady-state conditions. Sixteen healthy male and female adults were randomly assigned in an open-label, crossover study to either of 2 treatment sequences that consisted of 2 treatment periods separated by a washout phase. Treatments were oral daily doses of roflumilast for 14 days given concomitantly on days 1 and 14 with a single oral dose of digoxin or an oral dose of digoxin once on day 1. Plasma samples for pharmacokinetic evaluations of digoxin and roflumilast concentrations with and without concomitant treatment were taken. The rate of digoxin absorption was slightly (15%) but statistically insignificantly increased, whereas the extent of absorption was not altered by concomitant medication with roflumilast. Concomitant medication with digoxin did not significantly affect steady-state pharmacokinetics of either roflumilast or its active metabolite roflumilast N-oxide. Roflumilast is not an inhibitor of P-gp. No safety or tolerability concerns were detected with coadministration of roflumilast and digoxin.

The effect of age and everyday exercise on steady-state plasma digoxin concentrations.

Age-related physiologic changes may significantly alter the disposition and pharmacologic characteristics of many drugs. The elderly are the most frequent users of digoxin because of increased prevalence of atrial fibrillation and congestive heart failure. This study was conducted to confirm the decrease in digoxin concentrations during exercise, to determine if age is a factor in this decrease, and to explore the difference between chronologic age and physiologic age. Eighteen men age 50-85 years were treated with digoxin for more than 1 month before enrolling and had serum digoxin concentrations of 0.4-2.0 micrograms/L. They were evaluated during a 3-hour period in the morning (A.M. dose withheld). Blood samples were obtained every 10 minutes during sequential 60-minute periods of rest (phase I), walking (phase II), and rest (phase III). There were no significant differences in mean concentration between phases II and I (p < 0.76), phases III and phase I (p < 0.70), or phases II and III (p < 0.37). The effect of age was positively correlated with the mean concentration of phase II but was not statistically significant (p < 0.62). Statistically significant correlations were seen only between the exercise phase and serum albumin and Mini-Mental Status Examination scores. We conclude that exercise has minimal, if any, clinically relevant effects on plasma digoxin concentrations. Increasing chronologic age has no influence on a decrease in the concentrations with exercise; a younger physiologic age may play a role.

Clinical Utility of Serum Digoxin Level in Cardiac Patients for Diagnosis of Chronic Digitalis Toxicity

Digitalis toxicity is a complication of the digitalis therapy. It could occur also due to the patient taking in a much larger dose of the drug than prescribed. The general symptoms of Digitalis toxicity are typically gastro-intestinal, neurologic and non-specific cardiac type manifestations that are strikingly similar to the clinical picture of primary Congestive Heart Failure (CHF) making a diagnosis of chronic digitalis toxicity in particular relatively difficult. Serum digoxin measurement is today becoming a crucial subject of concern because of the narrow therapeutic window of digoxin besides increasing mortality and morbidity due to its intoxication. The present work is focused on evaluating the clinical value of Serum Digoxin Concentrations (SDCs) in relation to appropriate assessment of chronic digitalis toxicity in cardiac patients. The current study was conducted in the form of a cross-sectional Electronic Medical Record (EMR) review study of patients presently on continuous prescriptions for digoxin with there being zero gaps in therapy for at least 10 days prior to SDC result entered into the Online Analytical Toxicology Request Result (OTARR). There was also a complete clinical examination report as well as a review of the results of serum potassium concentration, liver and kidney functions. Patients with digoxin toxicity (11.9%) had a significantly higher mean SDC (2.75 ± 1.2) than those with subtherapeutic (0.67 ± 0.17 ng/mL) or eutherapeutic SDC (1.19 ± 0.26 ng/mL) (p value ≤ 0.05). About 12% of the total cases showed an abnormal serum potassium concentration of electrolyte fluctuations. From this, one can conclude that a regular monitoring of serum digoxin level would be seen as mandatory for the verification of digoxin’s therapeutic effects and then the subsequent prevention and early diagnosis of chronic toxicity.

Abstract 17353: Effectiveness and Safety of Digoxin in Adults with Incident Systolic Heart Failure

Background: Current clinical guidelines endorse digoxin use for patients with symptomatic systolic heart failure (HF) on optimal medical therapy, but this recommendation is based on limited, older clinical trial data. We sought to evaluate the effectiveness and safety of digoxin in a contemporary cohort of patients with incident systolic heart failure and stratified by patient sex and serum digoxin concentration (SDC). Methods: We identified patients with incident systolic HF between 2006 and 2008 in the Kaiser Permanente of Northern California health system. We used multivariable extended Cox regression to examine the association between incident digoxin use and death and hospitalization for HF, controlling for patient medical history, physical exam, diagnostic tests, laboratories, and medications. Longitudinal drug use, patient characteristics and outcomes were identified based on validated algorithms using health plan automated databases. Analyses were also conducted stratifying by sex and SDC. Results: Among 2891 patients with incident systolic HF followed for a mean 2.4 years, digoxin users had higher rates of death (14.2% vs 11.3%) and HF hospitalization (28.2% vs 24.4%). In adjusted analysis, digoxin was associated with excess mortality (odds ratio (OR) 1.60, 95% confidence interval (CI) 1.18-2.17) and HF hospitalization (OR 1.40, 95% CI 1.05-1.86). Compared with non-use, new digoxin use with SDC ≥1.2 ng/mL had higher odds of HF hospitalization and borderline higher odds of death (Table); SDC ≤0.8 ng/mL had higher odds of death. Digoxin use was associated with higher adjusted rates of HF hospitalization and death in men but not in women (Table). Conclusions: Digoxin was associated with a higher risk of death and HF hospitalization, however these risks were dependent on SDC. Digoxin was linked to a higher risk of adverse events in men but not significantly so for women.

Clinical Herbal Interactions with Conventional Drugs: From Molecules to Maladies

Clinical studies and case reports have identified a number of herb-drug interactions potentiated by the concurrent use of herbal medicines with prescription drugs. The purpose of this paper is to discuss the mechanisms and clinical implications of such herb-drug interactions by reviewing published human studies. Both pharmacokinetic and pharmacodynamic components may be involved in herbdrug interactions, although metabolic induction or inhibition is a common underlying mechanism for many herb-drug interactions. Drugs that have a high potential to interact with herbal medicines usually have a narrow therapeutic index, including warfarin, digoxin, cyclosporine, tacrolimus, amitriptyline, midazolam, indinavir, and irinotecan. Many of them are substrates of cytochrome P450s (CYPs) and/or P-glycoprotein (P-gp). Herbal medicines that are reported to interact with drugs include garlic (Allium sativum), ginger (Zingiber officinale), ginkgo (Ginkgo biloba), ginseng (Panax ginseng), and St. John's wort (Hypericum perforatum). For example, garlic has been shown to increase the clotting time and international normalized ratio (INR) of warfarin, cause hypoglycaemia when taken with chlorpropamide, and reduce the area under the plasma concentration-time curve (AUC) and maximum concentration of saquinavir in humans. Similarly, case reports have demonstrated that ginkgo may potentiate bleeding when combined with warfarin or aspirin, increases blood pressure when combined with thiazide diuretics, and has even led to a coma when combined with trazodone, a serotonin antagonist and reuptake inhibitor used to treat depression. Furthermore, ginseng reduced the blood levels of warfarin and alcohol as well as induced mania if taken concomitantly with phenelzine, a non-selective and irreversible monoamine oxidase inhibitor used as an antidepressant and anxiolytic agent. Lastly, multiple herb-drug interactions have been identified with St. John's wort that involve significantly reduced AUC and blood concentrations of warfarin, digoxin, indinavir, theophylline, cyclosporine, tacrolimus, amitriptyline, midazolam, and phenprocoumon. The clinical consequence of herb-drug interactions varies, from being well-tolerated to moderate or serious adverse reactions, or possibly life-threatening events. Undoubtedly, the early and timely identification of herb-drug interactions is imperative to prevent potentially dangerous clinical outcomes. Further well-designed studies are warranted to address the mechanisms and clinical significance of important herb-drug interactions.

Assessment of the appropriateness of serum digoxin concentration measurement in a medical group setting.

Recent quality initiatives require that the routine annual therapeutic drug-monitoring (TDM) parameters for the high-risk medication digoxin include a measure of renal function and a serum potassium level but not a serum digoxin concentration (SDC) measurement. Several studies have shown that the majority of the SDCs obtained in hospital settings provide little clinically actionable information. To evaluate the appropriateness and utility of SDCs ordered in a medical group practice setting by categorizing the reason the SDC was ordered and identifying action taken in response to the result. The descriptive study was conducted as a retrospective, electronic medical record (EMR) review of 90 primary care patients with continuous prescriptions for digoxin current on their medication profile with no gaps in therapy for at least 2 years prior to an SDC result entered into the EMR between January 1, 2009, and September 30, 2009. The reason the SDC was ordered was abstracted independently by 2 reviewers, who then assigned it to 1 of 8 predefined indication categories based on previously published criteria and practice guidelines. A third reviewer resolved inter-reviewer discrepancy (n = 1). A total of 90 patients with at least 1 SDC met inclusion criteria. Routine monitoring was the most frequent SDC order indication category with 35 patients (38.9%), 17 (48.6%) of whom did not have the recommended monitoring measures of potassium or renal function drawn concurrently. Patients were included in other categories as follows: confirmation of signs/symptoms of toxicity 30 (33.3%); assessment of factors altering pharmacokinetics 5 (5.6%); assessment of dosage change 5 (5.6%); assessment of drug interaction 3 (3.3%); assessment of clinical response 3 (3.3%); assessment of adherence 1 (1.1%); and other 2 (2.2%). Across all categories, a total of 19 (21.1%) of SDC results were outside the therapeutic range of 0.5 nanograms (ng) per mL and 2.0 ng per mL, 18 of which were below 0.5 ng per mL, with none of the subtherapeutic levels leading to a change in digoxin therapy. Only 1 patient (1.1%) had therapy changed in response to an elevated abnormal SDC result of 2.1 ng per mL and was in the routine monitoring category. The majority of SDC results obtained in our medical group setting did not lead to clinical action, such as dose adjustment or drug discontinuation. SDCs were commonly measured as part of routine monitoring, which is considered an inappropriate indication, and often without being accompanied by better markers for digoxin toxicity such as serum potassium levels and measures of renal function as recommended by drug-monitoring quality initiatives. Provider education is needed regarding the most indicative digoxin TDM parameters to obtain in order to satisfy quality initiatives.

Fitting the Elementary Rate Constants of the P-gp Transporter Network in the hMDR1-MDCK Confluent Cell Monolayer Using a Particle Swarm Algorithm

P-glycoprotein, a human multidrug resistance transporter, has been extensively studied due to its importance to human health and disease. In order to understand transport kinetics via P-gp, confluent cell monolayers overexpressing P-gp are widely used. The purpose of this study is to obtain the mass action elementary rate constants for P-gp's transport and to functionally characterize members of P-gp's network, i.e., other transporters that transport P-gp substrates in hMDR1-MDCKII confluent cell monolayers and are essential to the net substrate flux. Transport of a range of concentrations of amprenavir, loperamide, quinidine and digoxin across the confluent monolayer of cells was measured in both directions, apical to basolateral and basolateral to apical. We developed a global optimization algorithm using the Particle Swarm method that can simultaneously fit all datasets to yield accurate and exhaustive fits of these elementary rate constants. The statistical sensitivity of the fitted values was determined by using 24 identical replicate fits, yielding simple averages and standard deviations for all of the kinetic parameters, including the efflux active P-gp surface density. Digoxin required additional basolateral and apical transporters, while loperamide required just a basolateral tranporter. The data were better fit by assuming bidirectional transporters, rather than active importers, suggesting that they are not MRP or active OATP transporters. The P-gp efflux rate constants for quinidine and digoxin were about 3-fold smaller than reported ATP hydrolysis rate constants from P-gp proteoliposomes. This suggests a roughly 3∶1 stoichiometry between ATP hydrolysis and P-gp transport for these two drugs. The fitted values of the elementary rate constants for these P-gp substrates support the hypotheses that the selective pressures on P-gp are to maintain a broad substrate range and to keep xenobiotics out of the cytosol, but not out of the apical membrane.

Effect of Chinese Medicines Chan Su, Asian Ginseng, Siberian Ginseng, and American Ginseng on a New Digoxin Immunoassay Based on Luminescent Oxygen Channeling Technology

Chan Su, Asian ginseng, Siberian ginseng, and American ginseng are known to interfere with various digoxin immunoassays. Recently, a homogeneous sequential chemiluminescent assay for digoxin based on the luminescent oxygen channeling technology (LOCI digoxin) for application on the Dimension and Vista platform has been introduced into the market. The effects of interference by Chan Su and various ginsengs on this new immunoassay have not yet been reported. Aliquots of a drug-free serum pool were supplemented with Chan Su, Asian ginseng, Siberian ginseng, and American ginseng representing the expected in vivo concentrations after normal usage and cases of overdose. Serum digoxin concentrations were measured using the LOCI digoxin assay on the Vista 1500 analyzer. We also prepared 3 digoxin pools from patients receiving digoxin. Two digoxin pools were supplemented with these traditional medicines to investigate their effect on serum digoxin measurements. Mice were fed Chan Su extract to determine the potential of in vivo derived interfering factors. The possibility of eliminating interference of Chan Su on serum digoxin measurement was also investigated, by measuring free digoxin concentration after supplementing aliquots of the third digoxin pool with various amounts of Chan Su extract. A clinically significant interference by Chan Su with serum digoxin measurement was observed using the LOCI digoxin assay. The various ginsengs demonstrated negligible effects. In addition, apparent digoxin concentrations were observed in sera of mice after feeding them with Chan Su; the half-life of digoxin-like immunoreactive components was approximately 1 hour. Moreover, serum digoxin concentrations were significantly elevated in the presence of Chan Su, whereas the various ginsengs exhibited no effect. Monitoring free digoxin can only partly eliminate the interference of Chan Su in serum digoxin measurement. Chan Su interferes with serum digoxin measurement using the LOCI Digoxin, whereas the ginsengs demonstrated no measurable interference at clinically relevant concentrations.

Determination of Digoxin Clearance in Japanese Elderly Patients for Optimization of Drug Therapy

Optimal use of digoxin in the elderly population requires information about the drug's pharmacokinetics and the influence of various factors on the drug's disposition. However, because of sampling restrictions, it is often difficult to perform traditional pharmacokinetic studies in elderly patients. This study was conducted to determine the apparent total clearance of digoxin from serum after oral administration (CL/F) and to establish the role of patient characteristics in estimating doses of digoxin for elderly patients (age ≥65 years), using routine therapeutic drug monitoring data. Analyses of the pharmacokinetics of digoxin were conducted using the nonlinear mixed-effects modelling (NONMEM®) software, a computer program designed to analyse pharmacokinetics in study populations by allowing pooling of data. Steady-state data (140 observations) obtained by routine therapeutic drug monitoring following repeated oral administration of digoxin in 94 hospitalized elderly patients (age ≥65 years) were analysed to establish the role of patient characteristics in estimating doses of digoxin for elderly patients. Estimates generated by NONMEM® indicated that digoxin CL/F was influenced by the demographic variables of total bodyweight (TBW), serum creatinine (SCr), age (AGE), presence of congestive heart failure (CHF), concomitant administration of the calcium channel antagonists (calcium channel blockers [CCBs]: verapamil, diltiazem or nifedipine), sex (SEX) and elderly clearance factor (trough serum concentration of digoxin; [C(trough)] θ). The full version of the final NONMEM® model was where CCB is 1 for concomitant administration of a CCB and is 0 otherwise; CHF is 1 for patients with CHF and is 0 otherwise; SEX is 0 for male and is 1 for female; and the elderly clearance factor C(trough)-0.180 is 1 for digoxin C(trough) <1.7 ng/mL. We developed a new model for elderly patient dosing of digoxin with good predictive performance. Clinical application of the findings of the present study to patient care may permit selection of an appropriate initial digoxin maintenance dose, thus enabling the clinician to achieve a desired therapeutic effect. However, the digoxin dosage regimen should be based on an appraisal of the individual patient's clinical need for the drug.

Digoxin intoxication–induced encephalopathy in a patient with chronic kidney disease

Digoxin is a drug with a narrow therapeutic range. We present an 88-year-old woman with chronic kidney failure who was suspected of having digoxin intoxication when she developed nausea, vomiting, loss of appetite, lethargy, and unconsciousness after taking digoxin 0.25 mg daily for 1 week. A blood test revealed a high digoxin concentration of 5.42 ng/mL. The patient experienced bradycardia, hypotension, acute renal failure, and hyperkalemia. Electroencephalography revealed global brain dysfunction. She was given a temporary pacemaker and several rounds of dialysis. The digoxin concentration in the patient’s blood was monitored every 2 days, and she gradually regained consciousness as the level of digoxin decreased to the normal range within 2 weeks. Patients with chronic renal failure should be monitored and tested before the administration of digoxin to titrate the dose. The drug plasma concentration should be carefully monitored for 5–7 days after drug administration. Patients’ renal function, associated electrolyte concentrations, and drug levels should be tested regularly to ensure drug safety.

Transplacental digoxin therapy for fetal tachyarrhythmia with multiple evaluation systems

Background. Sustained fetal tachyarrhythmia may result in congestive heart failure, hydrops fetalis, and fetal/neonatal death, which requires timely and appropriate therapy.Aim. To determine the value of transplacental digoxin therapy for fetal tachyarrhythmia with multiple evaluations.Methods. Four cases of fetal tachyarrhythmia were diagnosed with fetal echocardiography and treated with transplacental digoxin therapy with an initial dosage of 0.25 mg qd. Fetal echocardiography and measurement of maternal serum digoxin concentrations were performed every 5–7 days. Echocardiographic information was further used for the calculation of three evaluation systems including, Tei index, cardiovascular profile score (CVPS), and umbilical artery resistance index (UARI). The dosage of digoxin was adjusted according to the serum concentration, as well as results from three evaluation systems.Results. During the course of digoxin treatment, our patients show an increase of CVPS and decrease of Tei index and UARI, suggesting the recovery of heart function. Sinus rhythm was restored in 3–10 days in three cases and 42 days in one case. At the time of delivery, the placental transportation efficiency (neonate/mother ratio of serum digoxin concentration) was 76.45–84.31%. Following delivery, the general conditions of neonates were favorable. During the 4- to 14-month follow-up, reoccurrence of arrhythmia, neurological deficit, and retarded growth and development were not observed.Conclusions. Transplacental digoxin therapy with combined evaluation of Tei index, CVPS, and UARI systems is useful for treating fetal atrial flutter (AF) and supraventricular tachycardia (SVT).