Anti-digoxin Fab Research Articles

Rare Poisoning With Yellow Oleander: A Case Report

All parts of the yellow oleander are toxic, but the roots and seeds are more toxic compared to other parts. Yellow oleander plants are more toxic than Nerium oleander. [1] Yellow oleander is an ornamental plant that belongs to the family Apocynaceae and is native to Mediterranean regions of Europe and Asia. It is cultivated in tropical and subtropical areas of the world. Introduction Yellow oleander, with a scientific name “Thevetia peruviana [3],” is known as the “Suicide Tree” because all parts of the tree are poisonous. The usual fatal dose of yellow oleander is 8 to 10 seeds, and the roots are around 15 to 20 grams. The most common manifestations associated with yellow oleander poisoning include bradycardia with AV block, hypertension, lethargy, dizziness, and GI distress. Convulsions, electrolyte disturbances, hypertension, and coma have been reported. Management includes gastric decontamination, specific antidotes anti-digoxin Fab and Fructose 1, 6 diphosphate administration, cardioversion, and cardiovascular supportive care. [2, 3]We came across a case of suicidal poisoning with pila kaner, anuncommon occurrence even for a major referral hospital such as ours, Rajindra Hospital Patiala (Government Medical College Patiala).

Immunosensor for Rapid and Sensitive Detection of Digoxin.

Digoxin is a cardiac glycosylated steroid-like drug with a positive inotropic effect and has been widely used in treating congestive heart failure, atrial fibrillation, atrial flutter, and other heart diseases. Digoxin is also a dangerous drug, which can cause drug poisoning at a low blood drug concentration (2.73-3.9 nmol/L, i.e., 2.14-3.05 ng/mL). Therefore, the timely detection of a patient's blood drug concentration plays a significant role in controlling blood drug concentration, reducing the occurrence of drug poisoning events, and maximizing the role of drug therapy. In this study, a DNA vector for the expression of the antidigoxin antibody Fab fragment was constructed. With the vector, Fab was expressed in E. coli and purified, and 1.2 mg of antibodies was obtained from 100 mL of culture. An immunofluorescent sensor based on the mechanism of photoinduced electron transfer was constructed by labeling additional cysteines in the heavy chain variable region and light chain variable region of the antibody Fab fragment with fluorescent dyes. The assay for digoxin with the immunosensor could be finished within 5 min with a limit of detection of 0.023 ng/mL, a detectable range of 0.023 ng/mL to 100 μg/mL, and an EC50 of 0.256 ng/mL. A new approach for the rapid detection of digoxin was developed and will contribulte to therapeutic drug monitoring.

Ten Years of Experience in Treating Patients With Digoxin Toxicity Without Using Digoxin Fab Antibody

Background: Digoxin is extensively prescribed for cardiac diseases, so its chronic or acute toxicity commonly occur. Although digoxin specific antibodies (anti-digoxin Fab) are recommended to be used in patients with cardiac symptoms of digoxin toxicity, there is ongoing controversy about the effectiveness and dose of anti-digoxin Fab. Because our department lacks access to anti-digoxin Fab and the high cost of the antidote, we evaluated 10 years of experience in treating patients with digoxin toxicity without using digoxin Fab antibodies considering outcomes. Methods: A retrospective study was performed in Khorshid Hospital, affiliated with Isfahan University of Medical Sciences, from October 2008 to September 2018. Patients with acute or chronic digoxin toxicity were included in the study. The patients’ data were gathered and analyzed according to their medical documents. Results: Out of 150 cases with digoxin toxicity, 38% (n=57) were acute and 62% (n=93) were chronic. About 64.7% (n=97) were female. The most common non-cardiac manifestations of toxicity were gastrointestinal (67.3%, n=101) and neurological symptoms (52.7%, n=79). Bradyarrhythmia (80.5%, n=33) was the most cardiac manifestation in patients with acute (15.8% n=9) and chronic (25.8%, n=24) toxicity. A total of 144 (96%) cases fully recovered with supportive care, and 6 patients (4%) died. None of the cases received anti-digoxin Fab. Conclusion: The majority of presentations with acute or chronic toxicity recovered with supportive measures without using anti-digoxin Fab.

Cardiac Toxicity from Intentional Ingestion of Pong-Pong Seeds (Cerbera Odollam)

BackgroundA variety of plants contain cardiac glycosides. This has resulted in many of them being used to commit suicide. In southeast Asia, Cerebera odollam (pong-pong or suicide tree) is frequently used for suicidal ingestion. Seeds, or kernels, of this plant can cause hyperkalemia, heart block, and death due to the effects of its cardiac glycosides. Case ReportWe describe six cases of pong-pong seed ingestion reported to US poison centers. The most common symptoms were vomiting and bradycardia. Three patients survived and three died. All patients who died had heart block, serum digoxin levels > 1.0 ng/mL, and were treated with anti-digoxin immune FAB. Anti-digoxin immune FAB may be ineffective in a large pong-pong seed ingestion. Patients ingesting pong-pong seeds who develop a potassium level > 8.0 meq/L or have a digoxin level > 1.0 ng/mL may be at a higher risk for death. Why Should an Emergency Physician Be Aware of This?The apparent ease of acquiring C. odollam seeds on the Internet makes knowledge of it important, as it can be used as a means to commit suicide. The apparent failure of digoxin immune FAB to treat toxicity from pong-pong is important, as other lifesaving techniques, such as extracorporeal membrane oxygenation, might be needed in severely toxic patients.

Suicide tree poisoning

Poisoning accounts to 0.33-7.6% paediatric emergency admissions, which are accidental or unintentional. Yellow oleander, an ornamental plant with a scientific name “Thevetia peruviana”. All the parts of the tree are poisonous hence, known as “Suicide Tree”. Trees are easily accessible and swallowing of seeds which are the most toxic, is the preferred mode of intentional poisoning in South India. Ingestion of one seed is equivalent to 100 digoxin tablets. The phytotoxins of the plant can cause local gastric irritation and severe cardiotoxic manifested as arrhythmias, conduction defects which if left untreated is fatal. Management includes gastric decontamination, specific antidotes anti-digoxin Fab and Fructose 1,6 diphosphate administration, cardioversion and cardiovascular supportive care. Here, authors report an adolescent female presenting with sinus bradycardia following intentional consumption of the yellow oleander seeds.

Efficacy and effectiveness of anti-digoxin antibodies in chronic digoxin poisonings from the DORA study (ATOM-1)

abstractContext: We hypothesized that in chronic digoxin toxicity, anti-digoxin antibodies (Fab) would be efficacious in binding digoxin, but this may not translate into improved clinical outcomes. Objective: This study aims to investigate changes in free digoxin concentrations and clinical effects on heart rate and potassium concentrations in chronic digoxin poisoning when anti-digoxin Fab are given. Materials and methods: This is a prospective observational study. Patients were recruited if they have been treated with anti-digoxin Fab for chronic digoxin poisoning. Data was entered into a standardised prospective form, supplemented with medical records. Their serum or plasma was collected, analysed for free and bound digoxin and free anti-digoxin Fab concentrations. Results: From September 2013 to February 2015, 36 patients (median age, 78 years; 22 females) were recruited from 18 hospitals. Median heart rate (HR) was 49 beats/min. Initial median digoxin and potassium concentrations were 4.7 nmol/L (3.6 μg/L) (range: 2.3–11.2 nmol/L) and 5.3 mmol/L (range: 2.9–9.2 mmol/L) respectively. Beta-blockers (n = 18), calcium antagonists (n = 6), spironolactone and/or angiotensin blocking agents (n = 24) were also used concomitantly. Renal impairment and gastrointestinal symptoms were present in 31 (86%) and 22 (63%) patients respectively. Five patients died from conditions unrelated to digoxin toxicity. Median change in HR was 8 beats/min post-Fab with no effect on blood pressure; they were 4, 10 and 17 beats/min for the 1, 2 and ≥3 vials of anti-digoxin Fab groups respectively. Concomitant treatments with potassium lowering agents (12/36) and inotropic drugs (7/36) were used. Gastrointestinal effects resolved in all 22 patients. The median decrease for potassium was 0.3 mmol/L. Digoxin concentration reduced from 3.8 to 0 nmol/L post-Fab. There was a rebound observed in the free digoxin concentration in 25 patients but none had associated clinical deterioration. Conclusions: One to two vials of anti-digoxin Fab initially bound all free digoxin confirming Fab efficacy. However, this was associated with only a moderate improvement in HR and potassium, suggesting bradyarrhythmia and hyperkalaemia may be from other co-morbidities.

Pharmacological treatment of cardiac glycoside poisoning.

Cardiac glycosides are an important cause of poisoning, reflecting their widespread clinical usage and presence in natural sources. Poisoning can manifest as varying degrees of toxicity. Predominant clinical features include gastrointestinal signs, bradycardia and heart block. Death occurs from ventricular fibrillation or tachycardia. A wide range of treatments have been used, the more common including activated charcoal, atropine, β-adrenoceptor agonists, temporary pacing, anti-digoxin Fab and magnesium, and more novel agents include fructose-1,6-diphosphate (clinical trial in progress) and anticalin. However, even in the case of those treatments that have been in use for decades, there is debate regarding their efficacy, the indications and dosage that optimizes outcomes. This contributes to variability in use across the world. Another factor influencing usage is access. Barriers to access include the requirement for transfer to a specialized centre (for example, to receive temporary pacing) or financial resources (for example, anti-digoxin Fab in resource poor countries). Recent data suggest that existing methods for calculating the dose of anti-digoxin Fab in digoxin poisoning overstate the dose required, and that its efficacy may be minimal in patients with chronic digoxin poisoning. Cheaper and effective medicines are required, in particular for the treatment of yellow oleander poisoning which is problematic in resource poor countries.

Digoxin antibody fragment, antigen binding (Fab), treatment of preeclampsia in women with endogenous digitalis-like factor: a secondary analysis of the DEEP Trial

Endogenous digitalis-like factors (EDLFs) are elevated in women with preeclampsia, and the use of an anti-digoxin antibody Fab (DIF) in women with preeclampsia who were remote from term reduced maternal blood pressure and preserved renal function. The objective was to determine whether DIF treatment in women with severe preeclampsia in association with positive EDLFs in maternal serum improves maternal-perinatal outcomes. This was a planned secondary analysis from a randomized, placebo-controlled, double-blind study of DIF in women with severe preeclampsia with positive EDLF status that was managed expectantly between 23 weeks 5 days and 34 weeks' gestation (19 women received placebo, and 17 women received DIF). Primary outcome variables were a change in creatinine clearance and the use of antihypertensives. Secondary outcomes were maternal and perinatal complications. Women with positive EDLFs who received DIF had an attenuated decline in creatinine clearance from baseline compared with placebo (-4.5 ± 12.9 vs -53.2 ± 12.6 mL/min; P = .005). In this same group, the use of antihypertensives (the other primary outcome) was lower but not significantly so (41% vs 63%; P = .12). However, women who were treated with DIF had a lower rate of pulmonary edema (1/17 vs 6/19 women; P = .035) and lower rates of neonatal intraventricular hemorrhage (DIF: 0/17 women vs placebo: 5/19 women; P = .015). In women with severe preeclampsia who were remote from term who were EDLF positive, the use of DIF was associated with improved maternal and neonatal outcome. These findings suggest the need for a large multicenter trial that would evaluate the benefits of DIF in the treatment of women with severe preeclampsia who are remote from term and with positive EDLF status.

Applied clinical pharmacology and public health in rural Asia – preventing deaths from organophosphorus pesticide and yellow oleander poisoning

Self-poisoning with pesticides or plants is a major clinical problem in rural Asia, killing several hundred thousand people every year. Over the last 17 years, our clinical toxicology and pharmacology group has carried out clinical studies in the North Central Province of Sri Lanka to improve treatment and reduce deaths. Studies have looked at the effectiveness of anti-digoxin Fab in cardiac glycoside plant poisoning, multiple dose activated charcoal in all poisoning, and pralidoxime in moderate toxicity organophosphorus insecticide poisoning. More recently, using a Haddon matrix as a guide, we have started conducting public health and animal studies to find strategies that may work outside of the hospital. Based on the 2009 GSK Research in Clinical Pharmacology prize lecture, this review shows the evolution of the group's research from a clinical pharmacology approach to one that studies possible interventions at multiple levels, including the patient, the community and government legislation.

Anti-Digoxin Fab Variants Generated by Phage Display

Digoxin is a pharmaceutical used in the control of cardiac dysfunction. Its therapeutic window is narrow, with effect dosage very close to the toxic dosage. To counteract the toxic effect, polyclonal Fab fragments are commercially available. Our study is based on a monoclonal anti-digoxin antibody, which would provide a product with a specific potency and more precise dosage for the detoxification of patients under digoxin treatment. Phage display technology was used to select variants with high affinity. From an anti-digoxin hybridoma, RNA was extracted for subsequent cDNA synthesis. Specific primers were used for the LC and Fd amplifications, then cloned sequentially in a phagemid vector (pComb3X) for the combinatorial Fab library construction. Clones were selected for their ability to bind to digoxin-BSA. The presence of light and heavy chains was checked, randomly selected clones then sequenced and induced to produce soluble Fabs, and subsequently analyzed for anti-digoxin expression. Out of ten clones randomly chosen, six resulted positive expression of the product. The sequencing of these revealed two identical clones and one presenting a pseudogene in the LC. Four clones presenting variations in the framework1 showed binding to digoxin-BSA by ELISA and western blotting. The specific binding was further confirmed by Biacore(®), which allowed ranking of the clones. The development of these clones allowed the selection of variants with higher affinity than the original version.

Increasing Evidence for and Regulation of a Human Placental Endogenous Digitalis-Like Factor

Endogenous digitalis-like factors (EDLFs) appear to be hypertensiogenic and increased in the serum and placenta of women with preeclampsia (PE), a complication of pregnancy. Digibind, an anti-digoxin antibody Fab fragment, reverses in vitro effects of EDLF and in vivo features of PE. We used Digibind in a radioimmunoassay to measure EDLF and compared this to a bio-functional assay of EDLF with good agreement. These methods confirmed that human placenta was a source of EDLF, synthesizing and releasing EDLF into the media of cultured human placental tissue. Ketoconazole, a steroid synthesis inhibitor, and 17-OH progesterone, a possible substrate of steroid synthesis, were shown to inhibit or increase EDLF release respectively, suggesting overlap of synthetic pathways. Abnormalities of PE such as placental hypoxia, increased reactive oxygen species and increased pro-inflammatory cytokines were demonstrated to increase placental EDLF release. These findings strongly support placental production of EDLF with increased release due to features of PE.

Availability of antidotes for the treatment of acute poisoning in Queensland public hospitals

To determine the sufficiency of stock levels of 13 antidotes in Queensland hospitals. A self-report survey was sent to 128 Queensland hospitals with acute care facilities. The stock level of the following antidotes was determined: acetylcysteine, anti-digoxin Fab antibodies (digibind), atropine, calcium gluconate, cyanokit, desferrioxamine, flumazenil, glucagon, intravenous ethanol, methylene blue, naloxone, pralidoxime and pyridoxine. Other factors sampled were bed capacity, rural, remote and metropolitan areas classification, use of formal stock reviews by pharmacists or nurses, existence of formal borrowing agreements with other facilities for non-stocked antidotes, distance to the nearest referral hospital and time taken to transfer antidotes from another hospital. Pharmacists or nurses responsible for maintaining antidote stocks in Queensland hospitals. Proportions of hospitals with sufficient antidote stock to treat a 70-kg adult for four or more hours using previously published guidelines. Survey response rate was 73.4%. No hospital had sufficient stock of all 13 antidotes. The proportion of hospitals with sufficient stocks varied from 0% (pyridoxine) to 68.1% (acetylcysteine). Larger hospitals had a higher frequency of sufficient antidote stocks. Only 16% of hospitals claimed to be able to acquire an antidote from another facility within 30 min. Most Queensland hospitals stocked some important antidotes, but few had sufficient stock to treat a 70-kg patient or acquire an antidote within the recommended time frame of 30 min. Specific antidote stocking guidelines might be required for Queensland hospitals. A formalised program for stock rotation with rural facilities should be explored.

Vergiftungen mit Pflanzen

Ingestions of plants rarely lead to life-threatening intoxications. Highly toxic plants, which can cause death, are monkshood (Aconitum sp.), yew (Taxus sp.) and autumn crocus (Colchicum autumnale). Lethal ingestions of monkshood and yew are usually suicides, intoxications with autumn crocus are mostly accidental ingestions of the leaves mistaken for wild garlic (Allium ursinum). Severe intoxications can occur with plants of the nightshade family like deadly nightshade (Atropa belladonna), angel's trumpet (Datura suaveolens) or jimsonweed (Datura stramonium). These plants are ingested for their psychoactive effects. Ingestion of plant material by children most often only causes minor symptoms or no symptoms at all, as children usually do not eat great quantities of the plants. They are especially attracted by the colorful berries. There are plants with mostly cardiovascular effects like monkshood, yew and Digitalis sp. Some of the most dangerous plants belong to this group. Plants of the nightshade family cause an anticholinergic syndrome. With golden chain (Laburnum anagyroides), castor bean (Ricinus communis) and raw beans (Phaseolus vulgaris) we see severe gastrointestinal effects. Autumn crocus contains a cell toxin, colchicine, which leads to multiorgan failure. Different plants are irritative or even caustic to the skin. Treatment is usually symptomatic. Activated charcoal is administered within one hour after ingestion (1 g/kg). Endoscopic removal of plant material can be considered with ingestions of great quantities of highly toxic plants. Administration of repeated doses of charcoal (1-2 g/h every 2-4 hours) may be effective in case of oleander poisoning. There exist only two antidotes: Anti-digoxin Fab fragments can be used with cardenolide glycoside-containing plants (Digitalis sp., Oleander). Physostigmine is the antidote for severe anticholinergic symptoms of the CNS. Antibodies against colchicine, having been developed in France, are not available at the moment.

Fatal injury in Eastern Sri Lanka, with special reference to cardenolide self-poisoning with Cerbera manghas fruits

Objective. Self-poisoning with plant seeds or fruits is a common method of self-harm in South Asia. While most deaths follow ingestion of Thevetia peruviana (yellow oleander) seeds, other plants are locally common. During review of fatal injuries seen in a teaching hospital in eastern Sri Lanka, we noted cases of fatal self-poisoning with Cerbera manghas (sea mango, pink eyed cerbera, odollam tree) fruits. Methods. We reviewed the post-mortem records of the Batticaloa Teaching Hospital and extracted data on all cases of fatal injury. Results. During 2001 and 2002, 315 post mortems for injury were performed in Batticaloa Teaching Hospital. Intentional self-harm was responsible for 48.6% of cases. While T. peruviana was responsible for 33 deaths, C. manghas self-poisoning caused seven deaths. C. manghas cases had typical features of cardenolide poisoning with cardiac dysrhythmias and hyperkalemia. In the absence of pacing facilities and anti-digoxin Fab, management involved administration of atropine and of insulin and dextrose to lower serum potassium concentrations. Conclusions. C. manghas self-poisoning has only previously been reported from Kerala and Tamil Nadu in south India. While uncommon in other parts of Sri Lanka, it has become a common method of self-harm in one east coast district, accounting for 20% of fatal self-harm with plants in one hospital. Management was inadequate with the available resources, emphasising the need for an affordable antitoxin for plant cardenolide poisoning.

Detection and quantification of affinity ligand leaching and specific antibody fragment concentration within chromatographic fractions using surface plasmon resonance

Rapid analyses of chromatographic steps within a biopharmaceutical manufacturing process are often desirable to evaluate column performance, provide mass balance data and to permit accurate calculations of yields and recoveries. Using SPR (surface plasmon resonance) biosensor (Biacore) technology, we have developed a sandwich immunoassay to quantify polyclonal anti-digoxin Fab fragments used for the production of the FDA (Food and Drug Administration)-approved biotherapeutic DigiFab. The results show that specific Fab may be quantified in all affinity process streams and accurate yield and mass balance data calculated. Control experiments using sheep Fab and Fc indicate that the assay is specific to DigiFab. The quantification of potential leached ligand within chromatographic fractions may also be technically challenging, particularly when low-molecular-mass ligands are covalently coupled with an affinity absorbent. Typical methods to assess ligand leakage such as DDMA (digoxin-dicarboxymethoxylamine; digoxin analogue) often involve the use of labelled ligands and relatively complex and labour-intensive analytical techniques. Using the same analytical methodologies, an assay to detect leached or eluted ligand off the column was developed. The results indicate minimal levels of leached ligand in all chromatographic fractions, with total levels of leached DDMA calculated to be 1.52 microg. This is less than 0.01% of the total amount of DDMA coupled with the laboratory-scale affinity column. The SPR methods described in the present study may be applicable for the rapid in-process analysis of specific polyclonal Fab fragments (within a polyclonal mixture) and to rapidly assess leakage of small molecule ligands covalently attached to chromatographic supports.

Antidotes for acute cardenolide (cardiac glycoside) poisoning

Cardenolides are naturally occurring plant toxins which act primarily on the heart. While poisoning with the digitalis cardenolides (digoxin and digitoxin) are reported worldwide, cardiotoxicity from other cardenolides such as the yellow oleander are also a major problem, with tens of thousands of cases of poisoning each year in South Asia. Because cardenolides from these plants are structurally similar, acute poisonings are managed using similar treatments. The benefit of these treatments is of interest, particularly in the context of cost since most poisonings occur in developing countries where resources are very limited. To determine the efficacy of antidotes for the treatment of acute cardenolide poisoning, in particular atropine, isoprenaline (isoproterenol), multiple-dose activated charcoal (MDAC), fructose-1,6-diphosphate, sodium bicarbonate, magnesium, phenytoin and anti-digoxin Fab antitoxin. We searched MEDLINE, EMBASE, the Controlled Trials Register of the Cochrane Collaboration, Current Awareness in Clinical Toxicology, Info Trac, www.google.com.au, and Science Citation Index of studies identified by the previous searches. We manually searched the bibliographies of identified articles and personally contacted experts in the field. Randomised controlled trials where antidotes were administered to patients with acute symptomatic cardenolide poisoning were identified. We independently extracted data on study design, including the method of randomisation, participant characteristics, type of intervention and outcomes from each study. We independently assessed methodological quality of the included studies. A pooled analysis was not appropriate. Two randomised controlled trials were identified, both were conducted in patients with yellow oleander poisoning. One trial investigated the effect of MDAC on mortality, the relative risk (RR) was 0.31 (95% confidence interval (CI) 0.12 to 0.83) indicating a beneficial effect. The second study found a beneficial effect of anti-digoxin Fab antitoxin on the presence of cardiac dysrhythmias at two hours post-administration; the RR was 0.60 (95% CI 0.44 to 0.81). Other benefits were also noted in both studies and serious adverse effects were minimal. Studies assessing the effect of antidotes on other cardenolides were not identified. One ongoing study investigating the activated charcoal for acute yellow oleander self-poisoning was also identified. There is some evidence to suggest that MDAC and anti-digoxin Fab antitoxin may be effective treatments for yellow oleander poisoning. However, the efficacy and indications of these interventions for the treatment of acute digitalis poisoning is uncertain due to the lack of good quality controlled clinical trials. Given pharmacokinetic differences between individual cardenolides, the effect of antidotes administered to patients with yellow oleander poisoning cannot be readily translated to those of other cardenolides. Unfortunately cost limits the use of antidotes such as anti-digoxin Fab antitoxin in developing countries where cardenolide poisonings are frequent. More research is required using relatively cheap antidotes which may also be effective.

Mechanisms, Manifestations, and Management of Digoxin Toxicity in the Modern Era

Because of the common use of digoxin and because of its narrow therapeutic index, digoxin toxicity has been prevalent historically and, therefore, most clinicians are well aware of the classical dose/concentration-related signs and symptoms of toxicity. Yet, in the modern era the incidence of digoxin toxicity has been declining for a variety of reasons, including a new (lower) therapeutic range, the development of more effective drug therapies for heart failure, and more accurate dosing methods. In addition, digoxin toxicity, once commonly fatal, can now be quickly and effectively treated by the emergency administration of antidigoxin Fab fragments. Indeed, it may be possible to expand the use of Fab fragments to select patients with non-life-threatening digoxin toxicity, in order to save costs and improve patient comfort. Most cases of digoxin toxicity are caused by inappropriately high dosages, which are usually prescribed in the setting of renal dysfunction, while other cases can be attributed to system errors such as multiple prescriptions, poor patient counseling, or errors in transcribing. With modern computerized prescribing systems, such as direct physician order entry and prompts that alert the clinician to the potential for error, it is possible to decrease the incidence of digoxin toxicity even further. A realistic goal is to nearly eradicate once commonplace digoxin toxicity or at least make its occurrence a rare event.

Characterization of the neutralizing activity of digoxin-specific Fab toward ouabain-like steroids.

Digoxin-specific Fab (Digibind) is a mixture of antidigoxin Fab fragments prepared from sheep sera and is used as a treatment for digoxin poisoning. Digoxin-specific Fab has been shown to neutralize an endogenous Na+/K+ ATPase inhibitor (endogenous digoxin-like Na+/K+ ATPase regulatory factor; EDLF) in rats and humans and to lower blood pressure. Although the exact structure of EDLF is unknown, compounds identical to or structurally related to ouabain, bufalin, and marinobufagenin have been detected in mammalian plasma. In this study, some structural characteristics of EDLF were inferred from the ability of digoxin-specific Fab to neutralize the Na+/K+ ATPase inhibitory activity of several known cardenolides and bufodienolides. Additional structural information was obtained from [3H]ouabain binding and enzyme-linked immunosorbent assay experiments. Digoxin-specific Fab had the ability to interact to some extent with all of the cardenolides and bufodienolides tested. However, digoxin-specific Fab was more than 20-fold more potent in neutralizing ouabain and bufalin than marinobufagenin. The antihypertensive effect of digoxin-specific Fab seen in preeclampsia and animal models of hypertension may therefore be due to a molecule identical to or structurally similar to ouabain or bufalin.

Fab Antibody Fragments

This review provides current information on the use of antigen-binding fragments (Fab) from cleaved antibodies to treat poisoning with digoxin and other potent, low formula mass poisons, such as colchicine and tricyclic antidepressants. Anti-digoxin Fab fragments have been used successfully for many years in the management of severe poisoning with digoxin, digitoxin, and a range of other structurally related compounds, including cardiotoxins from Nerium and Thevetia sp. (oleander) and Bufo sp. (toads). However, their main use remains treating digoxin poisoning. Equimolar doses of anti-digoxin Fab fragments completely bind digoxin in vivo. The approximate dose of Fab fragments (mg) is 80 times the digoxin body burden (mg). If neither the dose ingested nor the plasma digoxin/digitoxin concentration is known, in an adult 380 mg of anti-digoxin Fab fragments should be given. The dose for elderly patients or those with renal impairment should be similar to that for those with normal renal function. Fab fragments have a plasma half-life of 12-20 hours, but this can be prolonged in patients with renal impairment. Analysis of serum ultrafiltrate using an immunoassay shown not to have matrix bias remains the most accurate approach to measuring free digoxin in the presence of anti-digoxin Fab fragments. The antibody fragments are given intravenously over 15-30 minutes after dilution to at least 250 mL with plasma protein solution, 0.9% (w/v) sodium chloride, or deionised water, except in infants where the volume infused can be reduced. Factors limiting the efficacy of Fab fragments are the dose, the duration of the infusion and any delay in administration. Guidelines for Fab fragment administration in children include (i) dilution to a final Fab concentration of 10 g/L in either 5% (w/v) dextrose or 0.9% (w/v) sodium chloride; (ii) infusion through a 0.22 microm filter; (iii) administration of the total dose over a minimum of 30 minutes; and (iv) avoiding coadministration of other drugs and/or electrolyte solutions. Fab fragments are generally well tolerated. Adverse effects attributable to Fab treatment include hypokalaemia and exacerbation of congestive cardiac failure; renal function could be impaired in some patients. Fab fragment preparations for treating acute colchicine and tricyclic antidepressant poisoning have been developed, but are not available commercially. Colchicine poisoning is rare in Western countries, and pharmacological management together with supportive care is usually effective even in severe tricyclic antidepressant overdosage. Attempts have been made to produce anti-paraquat antibodies capable of enhancing paraquat elimination from the lung, but thus far all such attempts have proved unsuccessful.

Multiple-dose activated charcoal for treatment of yellow oleander poisoning: a single-blind, randomised, placebo-controlled trial

Deliberate self-poisoning with yellow oleander seeds is common in Sri Lanka and is associated with severe cardiac toxicity and a mortality rate of about 10%. Specialised treatment with antidigoxin Fab fragments and temporary cardiac pacing is expensive and not widely available. Multiple-dose activated charcoal binds cardiac glycosides in the gut lumen and promotes their elimination. We aimed to assess the efficacy of multiple-dose activated charcoal in the treatment of patients with yellow-oleander poisoning. On admission, participants received one dose of activated charcoal and were then randomly assigned either 50 g of activated charcoal every 6 h for 3 days or sterile water as placebo. A standard treatment protocol was used in all patients. We monitored cardiac rhythm and did 12-lead electocardiographs as needed. Death was the primary endpoint, and secondary endpoints were life-threatening cardiac arrhythmias, dose of atropine used, need for cardiac pacing, admission to intensive care, and number of days in hospital. Analysis was by intention to treat. 201 patients received multiple-dose activated charcoal and 200 placebo. There were fewer deaths in the treatment group (five [2.5%] vs 16 [8%]; percentage difference 5.5%; 95% CI 0.6-10.3; p=0.025), and we noted difference in favour of the treatment group for all secondary endpoints, apart from number of days in hospital. The drug was safe and well tolerated. Multiple-dose activated charcoal is effective in reducing deaths and life-threatening cardiac arrhythmias after yellow oleander poisoning and should be considered in all patients. Use of activated charcoal could reduce the cost of treatment.