Digitalis Toxicity Research Articles

Comparison of non-digitalis binding properties of digoxin-specific Fabs using direct binding methods

Digibind and DigiFab are commercial formulations of polyclonal, ovine, digoxin-specific Fabs in clinical use for treatment of digoxin intoxication. Of interest for extending its use to other clinical indications, Digibind has also been reported to neutralize the effect of endogenous digoxin-like molecules, including ouabain, that are linked to clinical disorders ranging from preeclampsia to congestive heart failure. Although Digibind and DigiFab are equivalent in their digoxin-binding activity, the antigens used to produce these Fabs are different. We therefore explored, using native (3)H-digoxin and (3)H-ouabain in four different types of solution-phase binding methods, whether they might exhibit different profiles with respect to ouabain and other digoxin-like factors. Consistent with previous results, both Fab preparations bound digoxin with the same affinities and capacities. However, (3)H-ouabain was found to bind with high affinity only to Fab sub-populations present in both products. Interestingly, this sub-population was twice as large for Digibind compared to DigiFab. Competition experiments also showed differences in specificity within Fab sub-populations. Therefore, the equivalence in digoxin-binding activity of the two Fab preparations does not extend to ouabain-binding capacity and Fab specificity, with implications for clinical differentiation between the preparations in treatment of disorders related to control of non-digoxin cardenolides. The existence of a small but perhaps clinically relevant sub-population of antibodies was detected using specific radioligands. This sub-population could not have been detected nor quantified using standard cross-reactivity in an ELISA assay.

Phase I immunotherapy in women with metastatic breast cancer with activated T cells targeted with anti-CD3 x anti-Her2/neu bispecific antibody

3034 Background: Women with metastatic breast cancer (MBC) have limited treatment options. Nontoxic approaches to improve targeting and cytotoxicity directed at MBC are needed. Anti-CD3 activated T cells (ATC) can be expanded and retargeted (armed) with anti-CD3 x anti-Her2 bispecific antibody (HER2Bi). Preclinical studies showed that Her2Bi-armed ATC exhibit high levels of specific cytotoxicity, proliferate, and secrete cytokines/chemokines (Clin Canc Res 12:569, 2006). Methods: In a phase I trial using ATC armed with Her2Bi, 17 MBC (31–86 yrs) patients (pts) were treated with 8 infusions (twice/week) for 4 weeks with 5, 10, 20, and 40 billion armed ATC/dose to determine the maximum tolerated or technically feasible dose. T cells from leukopheresis were activated and expanded with anti-CD3/IL-2 for 14 days, harvested, armed with Her2Bi at 50 ng/106ATC, and cryopreserved. IL-2 (3 x 105 IU/m2/daily) and GM-CSF (250 μg/m2 twice/week) was given beginning 3 days prior to the 1st infusion and ending 1 week after the last infusion. Results: The toxicities are summarized in the Table. Restaging at 1 month revealed 1 pt who developed a PR, 9 pts with SD, 5 pts with PD. Two pts were not evaluable. Three of 5 with CA27–29 markers decreased their markers by 15–50%. In 4 patients with positive CEA markers, 2 reduced their CEA levels by >50% and 2 by >15–50%. In 5 pts with circulating Her2 receptors (Her2r), 2 decreased Her2r by >50% and 2 reduced their Her2 by >15–50%. The median follow-up was 14.9 mos for the HER2(3+) group and 15.7 mos for the HER2(0–2+) group. Median time to progression was 3 and 6 mos for the HER2(3+) and HER2 (0–2+) groups, respectively. In the HER2(3+) group, median overall survival was not been reached with median follow-up of 14.9 mos. The median survival for the HER2(0–2+) cohort is 21.3 mos. The median survival for all pts remains undefined. Conclusions: These data suggest that infusions of armed targeted T cells can be safely infused and may improve overall survival in women with MBC. Infusion Toxicities Grade I II III IV # Episodes Chills 0 4 36 0 40 Headache 0 3 14 1 17 Nausea/Vomiting 8 1 0 0 9 Fever 3 1 0 0 4 Hypotension 1 3 0 0 4 Hypertension * 0 0 0 1 1 Dyspnea 0 1 0 0 1 # Episodes/130 infusions; * hypertension associated with a subdural hematoma. 1 pt died of Digoxin toxicity Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Transtarget Transtarget Transtarget

Declining Public Health Burden of Digoxin Toxicity From 1991 to 2004

We hypothesized that digoxin toxicity has declined in recent years, and that the decline is accompanied by reductions in overall utilization and dose. To analyze trends in digoxin toxicity and utilization from 1991 to 2004, we used surveys from the National Center for Health Statistics and Medicaid data in the United States and The Health Improvement Network (THIN) database in the United Kingdom. There was a significant decline in digoxin toxicity hospitalizations in the United States and a decline in ambulatory digoxin toxicity in the United Kingdom. The study demonstrated a reduction in the use of digoxin in the United States, but found no change in digoxin use in the United Kingdom. Finally, the number of prescriptions written for at least 250 microg decreased in the United States and the United Kingdom. The public health burden of digoxin toxicity declined dramatically from 1991 to 2004 in the United Kingdom and the United States.

Identification of severe potential drug-drug interactions using an Italian general-practitioner database

To analyze prescriptions in a general-practitioner database over 1 year to determine the frequency, the characteristics, and the monitoring of the severe potential drug-drug interactions (DDIs). We retrospectively analyzed the clinical records from 16 general practitioners in the Veneto region, an area in northern Italy. The study covered the period from January 1 to December 31, 2004. We selected all severe and well-documented interactions according to the book Drug Interaction Facts by David S. Tatro (Facts and Comparisons, St. Louis, MO, 2006). We grouped severe potential DDIs according to their specific potential risk, and for the most frequently interacting drug pairs, we investigated whether some specific tests had been prescribed by physicians for safety monitoring. During the study period, 16,037 patients (55% female) with at least one drug prescription were recorded, and a total of 185,704 prescriptions relating to 1,020 different drugs were analyzed. Ramipril was the most frequently prescribed drug followed by acetylsalicylic acid and atorvastatin. The final number of different types of severe potential DDIs was 119, which occurred 1,037 times in 758 patients (4.7% of the total number of patients). More than 80% of drugs involved in severe potential DDIs were cardiovascular drugs. Digoxin was the most frequently involved drug. Electrolyte disturbances, increase in serum digoxin levels, risk of hemorrhage, severe myopathy or rhabdomyolysis, and cardiac arrhythmias were the most commonly implicated potential risks. When considering patients using digoxin with loop or thiazide diuretics for more than 5 months, 72% had at least one test to monitor potential digoxin toxicity, whereas 28% had no tests. Sixty-four percent of patients using digoxin with amiodarone, verapamil, or propafenone had an ECG and/or digoxin monitoring, and 36% of them did not have any tests. The present study revealed that, in a group of Italian general practitioners, the risks of severe potential drug interactions are relatively low and the drugs concerned are few. Analyses of specific tests showed that physicians are generally aware of the potential risks caused by digoxin drug associations. However not all patients were closely monitored and this should be improved.

Pharmaceutical Support at Cardiovascular and Cardiovascular Surgery Ward

Pharmacological support for the appropriate use of drugs is important. To promote such support, it is necessary to be involved in drug therapy from viewpoints different from those of physicians and nurses, using tools unique to pharmacists, pharmacologically discuss individual cases, and investigate the validity of prescriptions by accumulating data. In Chapter 1, digoxin is necessary to monitor therapy very closely. In addition, patients with an impaired renal dysfunction have a predisposition for developing digitalis toxicity. In clinical cases, digoxin and verapamil are often co-administered for heart rate control, and we have observed the serum trough level of beta-methyldigoxin to be elevated due to drug-interaction. We build upon our previous findings and generated a simple index for the adequate administration dosage of beta-methyldigoxin based on variable degrees of renal function and the serum trough level of beta-methyldigoxin. In Chapter 2, to investigate risk factors of postoperative infection following cardiac surgery, we conducted a retrospective analysis of two surgical procedures, off-pump coronary artery bypass grafting (OPCAB) and surgery for valvular heart disease (valve operation). After discussing the analysis results with the respective physicians, the dosing guidelines for cefazolin (CEZ) were changed. We also analyzed the rate of CEZ replacement with other antibiotics after surgery finding that it decreased in both groups for OPCAB and valve operations. From these results, we conclude that, if CEZ is also administered intra-operatively when surgery is prolonged, its administration for two days following surgery is adequate for prophylaxis against postoperative infection.

Antidote property of polyclonal antibody against Digoxin toxicity

Antidote property of polyclonal antibody against Digoxin toxicity

Development of rapid one-step assay for detecting digoxin toxicity

Development of rapid one-step assay for detecting digoxin toxicity

Decision-Support Software for the Industrial-Scale Chromatographic Purification of Antibodies

The high therapeutic and financial value offered by polyclonal antibodies and their fragments has prompted extensive commercialization for the treatment of a wide range of acute clinical indications. Large-scale manufacture typically includes antibody-specific chromatography steps that employ custom-made affinity matrices to separate product-specific IgG from the remainder of the contaminating antibody repertoire. The high cost of such matrices necessitates efficient process design in order to maximize their economic potential. Techniques that identify the most suitable operating conditions for achieving desired levels of manufacturing performance are therefore of significant utility. This paper describes the development of a computer model that incorporates the effects of capacity changes over consecutive chromatographic operational cycles in order to identify combinations of protein load and loading flowrate that satisfy preset constraints of product yield and throughput. The method is illustrated by application to the manufacture of DigiFab, an FDA-approved polyclonal antibody fragment purified from ovine serum, which is used to treat digoxin toxicity (Protherics U.K. Limited). The model was populated with data obtained from scale-down experimental studies of the commercial-scale affinity purification step, which correlated measured changes in matrix capacity with the total protein load and number of resin re-uses. To enable a tradeoff between yield and throughput, output values were integrated together into a single metric by multi-attribute decision-making techniques to identify the most suitable flowrate and feed concentration required for achieving target levels of DigiFab yield and throughput. Results indicated that reducing the flowrate by 70% (from the current level) and using a protein load at the midpoint of the range currently employed at production scale (approximately 200-500 g/L) would provide the most satisfactory tradeoff between yield and throughput.

Digoxin toxicity caused by a decline in renal function

AbstractIn this Drug Points article the author describes a case of digoxin toxicity in an older patient caused by reduced digoxin clearance due to age‐related decline in renal function Copyright © 2007 Wiley Interface Ltd

A misread abbreviation that led to a digoxin overdose

AbstractIn this Drug Points article the author describes how misinterpretation of an abbreviation on a drug endorsement led to a digoxin overdose and comments on the issues it raises. Copyright © 2007 Wiley Interface Ltd

Communicating information about drug interactions

Drug interactions are bread and butter to journals of clinical pharmacology, and their ramifications are varied. In this issue, for example, we publish evidence that clarithromycin increases plasma glibenclamide concentrations, probably by inhibition of P glycoprotein [1]; this presumably explains previous reports of hypoglycaemia in patients taking this combination. In another report, a suspected interaction of fluvoxamine and tizanidine, via inhibition of CYP1A2, caused fatigue, loss of energy, drowsiness, and dizziness; when milnacipran was used instead of fluvoxamine, piloerection occurred and was attributed to α1-adrenoceptor stimulation by endogenous noradrenaline, after re-uptake inhibition by milnacipran [2]. Elsewhere, we learn that artemisinin can induce its own metabolism [3], in what might be regarded as a narcissistic drug interaction; the semiphysiological model that was used to analyse this phenomenon was also of interest.

Leaky ryanodine receptors cause delayed afterdepolarizations and ventricular arrhythmias

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disease characterized by the absence of structural heart disease, syncope, and sudden cardiac death.1 Typically, acceleration of the heart rate during physical exercise or emotional distress provokes an increasing number of ventricular premature complexes followed by runs of bidirectional or polymorphic ventricular tachycardia (VT). During clinical testing, about 30–50% of the patients will reproducibly develop VT following exercise testing or catecholamine injection.1,2 The ECG morphology of ventricular tachyarrhythmias observed in patients with CPVT resembles that of VTs commonly described in digitalis toxicity (which is associated with cellular calcium overload), and in metabolic disturbances as seen in severe HF (which is associated with high adrenergic tone).3 In conditions of cytoplasmic Ca2+ overload or enhanced β-adrenergic signalling, cardiac myocytes exhibit greater ectopic activity. It has therefore been suggested that arrhythmias in CPVT are mediated by triggered activity and delayed afterdepolarizations (DADs), which are defined as oscillations in the membrane potential of the cardiac myocyte after repolarization of an action potential has been completed.1 The most common, autosomal-dominant form of CPVT is caused by genetic mutations in the gene encoding the cardiac ryanodine receptor ( RyR2 ), the principal intracellular Ca2+ release channel involved in excitation-contraction coupling.4 Although experimental studies have provided evidence that mutant RyR2 channels can give rise to DADs in isolated cardiomyocytes,5 the study by Paavola et al .6 demonstrates DADs in monophasic action potential (MAP) recordings for the first time in CPVT patients with RyR2 mutations. In contrast to conventional electrode catheter recordings, MAP recordings provide precise information not only about the local activation time, but also about the entire repolarization time course. Electrophysiological data for the occurrence of DADs in patients with CPVT have been scarce in the literature, with … *Corresponding author. Tel: +1 713 798 4261; fax: +1 713 798 3475. E-mail address : wehrens{at}bcm.edu

Digoxin Toxicity

Digoxin Toxicity

Digoxin toxicity in renal failure: role of the electrocardiogram

Digoxin toxicity in renal failure: role of the electrocardiogram

Omeprazole-associated Digoxin Toxicity

Omeprazole is a commonly prescribed inhibitor of the gastric proton pump and has numerous indications in the treatment of gastrointestinal diseases. It is primarily metabolized through the CYP2C19 enzyme, a member of the P450 mixed-function oxidase group, although a minor pathway of metabolism is through CYP3A4, another P450 enzyme. Digoxin is primarily metabolized outside the P450 system, but a minor pathway of metabolism is by CYP3A4. To our knowledge, this is the first known case of digoxin toxicity associated with omeprazole. The possible pathways for such an interaction are reviewed, including increased stomach absorption, p-glycoprotein activity and interactions in the P450 system.

Plasma Digoxin Concentration Fluctuations Associated with Timing of Plasma Sampling and Amiodarone Administration

A 31-year-old man with dilated cardiomyopathy was hospitalized for new-onset atrial fibrillation. Oral amiodarone 600 mg/day was started to control his arrhythmia, and the patient continued to receive digoxin 0.125 mg/day, which was prescribed 4 days earlier at a heart failure clinic. The patient's digoxin plasma concentration peaked early on hospital day 3 at 2.93 ng/ml; digoxin was withheld. Over the next 3 days, the patient's digoxin plasma concentrations rose and fell daily. These fluctuations correlated with the timing of blood sampling in relation to oral amiodarone administration. The patient's renal function remained stable, and he developed no signs or symptoms of digoxin toxicity. To our knowledge, no case reports have associated significant fluctuations of digoxin plasma concentrations that correspond to the timing of oral amiodarone administration. Tissue-to-plasma redistribution appears to be a possible mechanism for this interaction, with the most significant effect occurring 8-10 hours after amiodarone administration. Clinicians should be aware that digoxin plasma concentrations may not correlate with digoxin tissue concentrations in this setting. When a loading dose of oral amiodarone is required in a patient receiving digoxin, the digoxin dosage should first be reduced, and digoxin therapy should be adjusted based on signs and symptoms of digoxin toxicity.

Understanding the mechanisms and manifestations of digoxin toxicity helps in its management and treatment

Understanding the mechanisms and manifestations of digoxin toxicity helps in its management and treatment

Age- and Gender-Specific Incidence of Hospitalisation for Digoxin Intoxication

The safety of digoxin (digitalis) therapy has greatly improved over the past three decades, but recent incidence rates for digoxin intoxication-related hospitalisation are not available. Recent literature suggests that women are at higher risk of digoxin toxicity. To provide age- and gender-specific incidence rates for digoxin intoxication-related hospitalisation and mortality during digoxin intoxication-related hospitalisation in The Netherlands in the period 2001-4. We conducted a nationwide population-based cohort-study of all hospital admissions in the years 2001-4 using a national computerised hospital admission registry. All patients with acute admissions were included in the study (n = 2 987 580). From these admissions, we selected all hospitalisations that had digoxin intoxication coded as either a primary or secondary diagnosis. We obtained data on digoxin prescriptions from the Foundation for Pharmaceutical Statistics (Stichting Farmaceutische Kengetallen) pharmacy database, which extrapolates drug figures for The Netherlands from prescriptions dispensed by 90% of all community pharmacies. We computed age- and gender-specific incidence rates of digoxin intoxication. Digoxin intoxication was identified in 0.04% (n = 1286) of acute admissions. The incidence rate for digoxin intoxication-related admission was 48.5 ( 95% CI 45.9, 51.2) per 100 000 prescriptions, which corresponds to 1.94 admissions for intoxication per 1000 treatment-years. Women had a 1.4-fold higher risk of intoxication than men (95% CI 1.3, 1.6). The age- and gender-adjusted relative risk of mortality in patients with digoxin intoxication compared with those admitted for other reasons was 0.7 (95% CI 0.5, 0.8). This study shows that digoxin intoxication in patients receiving current therapy is presently infrequent and that women are at higher risk of digoxin intoxication than men.

Age- and Gender-Specific Incidence of Hospitalisation for Digoxin Intoxication

Background: The safety of digoxin (digitalis) therapy has greatly improved over the past three decades, but recent incidence rates for digoxin intoxication-related hospitalisation are not available. Recent literature suggests that women are at higher risk of digoxin toxicity. Objective: To provide age- and gender-specific incidence rates for digoxin intoxication-related hospitalisation and mortality during digoxin intoxication-related hospitalisation in The Netherlands in the period 2001-4. Study design and methods: We conducted a nationwide population-based cohort-study of all hospital admissions in the years 2001-4 using a national computerised hospital admission registry. All patients with acute admissions were included in the study (n = 2 987 580). From these admissions, we selected all hospitalisations that had digoxin intoxication coded as either a primary or secondary diagnosis. We obtained data on digoxin prescriptions from the Foundation for Pharmaceutical Statistics (Stichting Farmaceutische Kengetallen) pharmacy database, which extrapolates drug figures for The Netherlands from prescriptions dispensed by 90% of all community pharmacies. We computed age- and gender-specific incidence rates of digoxin intoxication. Results: Digoxin intoxication was identified in 0.04% (n = 1286) of acute admissions. The incidence rate for digoxin intoxication-related admission was 48.5 ( 95% CI 45.9, 51.2) per 100 000 prescriptions, which corresponds to 1.94 admissions for intoxication per 1000 treatment-years. Women had a 1.4-fold higher risk of intoxication than men (95% CI 1.3, 1.6). The age- and gender-adjusted relative risk of mortality in patients with digoxin intoxication compared with those admitted for other reasons was 0.7 (95% CI 0.5, 0.8). Conclusion: This study shows that digoxin intoxication in patients receiving current therapy is presently infrequent and that women are at higher risk of digoxin intoxication than men.

Digitalis Toxicity and Fab Fragment

This article presents a brief overview of digitalis toxicity, class of medication that is notoriously know for its toxicity, but which still has significant use in clinical practice. We hereby briefly outline on the use of digoxin specific Fab fragment in the treatment of digitalis toxicity