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PubMed1984

Lowering of blood pressure in chronic aortic coarctate hypertensive rats with anti-digoxin antiserum.

A marked lowering of arterial blood pressure was observed in chronic aortic coarctate (CAC) hypertensive rats after intravenous administration of anti-digoxin antiserum. The hypotensive effect lasted for about 30 min after dosing. In contrast to the pronounced changes observed following treatment with anti-digoxin antiserum in CAC rats, only a transient pressor effect was observed in both water- and saline-drinking CAC rats following injection of normal goat serum. In addition, a transient depressor effect was observed in normotensive rats after injection of anti-digoxin antiserum. The results of this study provide additional evidence indicating that an endogenous digoxin-like substance may play an important role in the maintenance of chronic low-renin hypertension induced by aortic coarctation.

Animals↗
PubMed1984

Phenotypic and genotypic characterization of monoclonal anti-digoxin antibodies.

Eleven hybridoma cell lines secreting monoclonal anti-digoxin antibody have been produced. They are primarily gamma heavy chain and kappa light chain molecules. Affinity constants for digoxin range from 2 X 10(6) to 3.5 X 10(8) liters/mole. Fine specificity analysis using a series of digoxin congeners demonstrates that an unsaturated lactone ring attached to the aglycone at the C-17 position is necessary for hapten recognition. The impact of other changes in digoxin's structure on antibody binding were also studied. DNA hybridization analysis demonstrates that there are at least three different variable region gene arrangements used to produce the heavy chains of the different hybridoma antibodies. Correlations between antigen binding characteristics and antibody V-gene arrangements are demonstrable.

Animals↗
PubMed1988

Study of digoxin as inhibitor of the in vivo effects of acetyl glyceryl ether phosphorylcholine (AGEPC) in mice.

Acetyl glyceryl ether phosphorylcholine (AGEPC) and the cardiac glycoside digoxin were administered intravenously through the tail vein into ether-anesthetized SWR mice (two months old). The administered doses were 0.18 nmol AGEPC/g b.w. (a lethal one) and 75 or 125 ng digoxin/b.w. Digoxin ameliorates the effects of the lethal dose of AGEPC showing maximum activity when given 5 or 10 min after AGEPC administration to female and male animals respectively. Digoxin shows also a protective action towards the effects of AGEPC and maximum activity appears when it is given 10 min before AGEPC administration. In agreement with the picture of increased survival in digoxin pretreated animals, are our findings on life prolongation of mice which finally die from AGEPC, the amelioration of the expected fall in blood platelet counts after AGEPC administration as well as the improved performance of the animals in a series of physical tests.

Animals↗
PubMed1989

Endogenous digoxin-like factor raises blood pressure and protects against digitalis toxicity.

Digoxin-like immunoreactive factor (DLIF) is an endogenous natriuretic material which causes diuresis and natriuresis after salt or fluid loading and which may play a pathogenetic role in various hypertensive states. In order to study the cardiovascular effects of DLIF, we administered partially purified material (500 ng/kg) iv to normal rats. DLIF administration caused a significant rise in blood pressure, induced a brisk diuresis, and slowed the heart rate. In addition, DLIF protected against digitalis toxicity. While iv digoxin, 1 mg/kg, uniformly produced lethal arrhythmias, administration of DLIF 15 min prior to digoxin infusion consistently protected against arrhythmias. These findings support the theory that DLIF may play a role in hypertension. In addition, DLIF may compete with digoxin for cardiac receptors.

Animals↗
PubMed1991

Digoxin-like immunoreactivity: is it still worth measuring?

On the assumption that digoxin-like immunoreactivity may represent digitalis-like sodium pump inhibitors in the mammalian body, many investigators have used radioimmunoassay for digoxin to monitor such factors during the past decade. The presence of digoxin-like immunoreactivity has been confirmed by numerous studies using biochemical, immunological or morphological methods. Very recently, ouabain or a very similar substance, which did not cross-react with antidigoxin antibodies, was identified from the human plasma as the long-sought sodium pump inhibitor. However, it is yet to be determined whether sodium pump inhibitory activity in the circulation results from one substance or several. Some researchers still insist on the possible physiological roles of digoxin-like immunoreactivity which may or may not be related to the regulation of sodium pump. These issues are critically reviewed in this article.

Animals↗
PubMed1993

The mechanism of the verapamil-digoxin interaction in renal tubular cells (LLC-PK1).

Verapamil, usually given as a racemic mixture, decreases in vivo and in vitro digoxin renal tubular secretion, which is suggested to be mediated by P-glycoprotein, an ATP-dependent multidrug efflux pump. Importantly, the two enantiomers of verapamil have been reported to similarly inhibit P-glycoprotein-mediated transport of chemotherapeutic agents. In this study, we examined effects of enantiomers of verapamil on digoxin transport across an LLC-PK1 cell monolayer, a model of proximal renal tubular cells. The results indicate that verapamil inhibition of digoxin transport is non-stereospecific. Furthermore, the verapamil-digoxin interaction is not competitive. The two drugs may not share a common initial step in the P-glycoprotein-mediated transport.

Animals↗
PubMed1996

Purification and characterization of endogenous digoxin-like immunoreactive factors in chicken blood.

Studies have been performed to determine whether an endogenous material capable of binding to digoxin antibodies is present in the chicken plasma. In the blood of 12 chickens without feed control, endogenous digoxin-like immunoreactive factors (DLIF) binding of digoxin antibodies in enzyme immunoassays amounted to 866 / 302 pg digoxin equivalents/mL of plasma (mean +/- SEM). Immunoreactivity of DLIF increased to 1848***331 pg/mL with a double value of control after boiling and acid pretreating the plasma. The major purification steps employed in this report were gel filtration column chromatography, high performance liquid chromatography (HPLC) and isoelectric focusing (IEF). Using HPLC for the separation, at least 10 chicken DLIFs with different molecular weight (MW) have been found. The MW of the smallest is 300 daltons (Da) while the largest is 100 kDa. The value of the isoelectric point of the most abundant type of DLIF from untreated chicken plasma is 6.3 as determined by IEF. The partially purified DLIF inhibits Na+, K(+)-ATPase from a porcine cerebral cortex as well as three human red blood cell membrane preparations in a dose-response fashion.

Animals↗
PubMed1994

Effects of digoxin on the anabolic response to clenbuterol.

The possible involvement of increased cation exchange in the anabolic response to the beta 2-selective adrenergic agonist clenbuterol was investigated using dietary admixtures of clenbuterol and the Na,K-adenosine triphosphatase (ATPase) inhibitor digoxin. In a rat feeding trial to assess the effects on body composition, it was found that the higher of two levels (5 and 30 mg/kg diet) of digoxin had an inhibitory effect on the repartitioning effects (ie, increased body weight and fat-free mass) of clenbuterol (2 mg/kg diet). In two further experiments using 30 and 60 mg digoxin/kg diet, it was found that the anabolic effects of clenbuterol on gastrocnemius muscle protein deposition were inhibited by digoxin, but the effects of clenbuterol on soleus muscle protein were more resistant to inhibition. Given the observed dose-dependent inhibition by digoxin of gastrocnemius muscle protein deposition in the three experiments, it was concluded that at least part of clenbuterol's anabolic actions on skeletal muscle may depend on increased Na,K-ATPase activity. However, different mechanisms or a different time course of Na,K-ATPase activation may occur in different muscle fiber types.

Analysis of Variance↗
PubMedDate not supplied

Maternal and fetal digoxin-like immunoreactive factor in elective cesarean sections and spontaneous vaginal delivery.

The effect of mode of delivery on maternal and newborn plasma levels of total digoxin-like immunoreactive factor was evaluated. 32 healthy at term parturients with normal fetuses were studied. The cord blood level of digoxin-like immunoreactive factor of the 16 vaginally delivered infants was significantly higher than in the 16 matched controlled newborns delivered by an elective Cesarean section (1381 +/- 334 versus 1104 +/- 338 pg/ml, p less than 0.02). No differences were found between the maternal venous blood levels of digoxin-like immunoreactive factor of both study groups. The cord blood levels of this factor in the vaginal as well as the Cesarean section groups were significantly higher than the concentration in the corresponding maternal blood (p less than 0.001 and p less than 0.01, respectively). It is suggested that the changes in digoxin-like immunoreactive factor in the cord blood may reflect the stress of vaginal delivery on the fetus.

Adult↗
PubMed1995

Digoxin dialdehyde reductive aminations. Structure proof of the perhydro-1,4-oxazepine product.

Digoxin dialdehyde reportedly undergoes reductive amination with primary amines to form a perhydro-1,4-oxazepine; however, no structural proof has been published to substantiate this belief. A digoxin perhydro-1,4-oxazepine derivative has been isolated from the reductive amination of digoxin dialdehyde and its structure determined by mass spectroscopy and NMR measurements. Comparison of the NMR, mass spectroscopy, and HPLC of two compounds obtained from the degradation of the digoxin reductive amination product with synthesized perhydro-1,4-oxazepine diastereomers showed them to be identical. We conclude that, under appropriate conditions, reductive amination products can be obtained, but caution that other products may be produced as well, especially under the conditions of bioconjugation to proteins.

Amines↗
PubMed1993

Characterization of an anti-digoxin antibody binding site by site-directed in vitro mutagenesis.

In vitro mutagenesis and immunoglobulin gene transfection were used to investigate the binding site of a monoclonal antibody, 2610, that binds to digoxin, a cardiac glycoside. A computer model was generated in order to select sites in the complementarity determining regions (CDR) that would participate in binding. Residues in the CDR segments were chosen that possess high solvent exposure and were located in a putative cleft. The cloned heavy and light chain variable regions were subjected to in vitro mutagenesis at these sites. The mutated variable regions in M13 were then subcloned into expression vectors and transfected. The affinities and specificity binding properties of the resultant expressed antibodies were measured. Many of the mutants of the putative contact residues showed significant but not major alterations of binding properties. Since most of the residues in the binding site are non-polar and aromatic and since many of the mutations resulted in only modest binding changes, we theorize that much of the high affinity binding (> 10(9)/M) is the cumulation of many weak interactions, arising from dispersion forces and hydrophobic effects in the pocket. Preliminary mutagenesis of two L chain positions proposed to bind to the lactone end of digoxin have larger binding effects. Specificity studies show that the mutants more frequently possess altered binding to the lactone ring of digoxin that altered binding to other digoxin moieties. The data are most suggestive of a model in which lactone is at the bottom of a binding pocket, followed by the steroid nucleus and then by the sugar moiety extruding out of the pocket. The binding information may be useful in understanding the immune response to large, hydrophobic haptens.

Amino Acid Sequence↗
PubMed1989

Digoxin-like immunoreactive substance: monoclonal and polyclonal RIA and FPIA compared.

Digoxin-like immunoreactive substance (DLIS) was measured in 34 samples obtained from subjects not receiving digoxin: 10 uremic, 10 third trimester pregnancy, seven cord blood and seven normal. DLIS concentration was measured by four commercial polyclonal radioimmunoassay (RIA) systems: Clinical Assay (CA), Corning Immophase (CI), Diagnostic Products Double Antibody (DP), Kallestad Quantitope (KK), a monoclonal antibody (MA) assay and a Fluorescence Polarization Immunoassay (FPIA). In general, the cord blood samples were richer in DLIS. Digoxin immunoassays, MA and DP showed minimal interference by DLIS in all samples, whereas FPIA and CA exhibited the maximal cross-reactivity with DLIS. In cord blood samples, mean +/- SD DLIS concentration ranged from 0.41 +/- 0.13 (by CA) to 0.034 +/- 0.02 ng ml-1 as measured by MA assay. In uremics, the mean DLIS concentration was below the detection limit of all RIA assays. The FPIA method showed a higher degree of cross-reactivity to DLIS, especially in the cord and pregnancy samples (0.42 +/- 0.13 and 0.4 +/- 0.14 ng ml-1, respectively). DLIS in uremics was below the FPIA detection limit of 0.2 ng ml-1. Overall, the degree of interference by DLIS in decreasing order was FPIA greater than CA greater than CI greater than or equal to KQ greater than DP greater than or equal to MA. The cord blood samples were re-analysed by FPIA (Digoxin-II assay) 4 months later, resulting in 2-4-fold higher DLIS concentrations for these samples. This appears to be due to the substitution of 5-sulphosalicylic acid as a protein precipitating reagent and this effect may have been accentuated by freeze-thaw cycles.

Antibodies↗
PubMed1993

Digoxin in heart failure: implications of recent trials.

Although supported by 2 centuries of anecdotal clinical evidence, the safety and efficacy of the cardiac glycosides for the treatment of congestive heart failure due to systolic ventricular dysfunction had never been rigorously examined by prospective clinical trials until the past decade. A reevaluation of the appropriate role of these drugs in modern cardiovascular pharmacology was prompted by the introduction in the 1970s of new classes of drugs for the treatment of congestive heart failure and supraventricular arrhythmias. Concurrently, several reports appeared, questioning the routine prescription of digoxin for the treatment of heart failure, particularly in patients in sinus rhythm. The majority of clinical trials published since 1980, most of which examined patients with New York Heart Association class II and III congestive heart failure, indicate that digoxin with or without concomitant administration of a vasodilator lessens symptoms and reduces the morbidity associated with congestive heart failure, particularly in patients with more advanced symptoms and ventricular dysfunction. The data on efficacy are less clear in support of the routine prescription of digoxin in the treatment of mild (class I and II) congestive heart failure. Although most recent trials attest to the relative safety and efficacy of digoxin in patients with congestive heart failure whose serum levels are maintained between 1 and 2 ng/ml, there is no conclusive evidence as yet that cardiac glycosides improve survival, as has been documented for vasodilators and, in particular, angiotensin-converting enzyme inhibitors. The National Institutes of Health-sponsored Digitalis Investigators Group (DIG) trial now underway should provide an answer to this question within the next few years.

Clinical Trials as Topic↗
PubMed2006

[Digoxin-Josamycin: a dangerous drug interaction in children].

Digitalis intoxication is usually accidental in children. We report the case of a young infant with congenital heart disease in whom the coadministration of digoxin and josamycin led to a 50% increase in the digoxin concentration, generating sinoatrial block and cardiac failure. Clinical and electrocardiographic symptoms very quickly resolved following immunotherapy with antidigitalis Fab fragments. Digoxin concentrations must be carefully monitored in patients concomitantly receiving macrolides to ensure that the digoxin dose can be readjusted if necessary.

Anti-Bacterial Agents↗
PubMed2005

Relationship of serum digoxin concentration to mortality and morbidity in women in the digitalis investigation group trial: a retrospective analysis.

OBJECTIVES: The purpose of this study was to investigate the relationship of serum digoxin concentration (SDC) and outcomes in women with heart failure (HF). BACKGROUND: Controversy continues concerning the clinical utility of digoxin in women with HF. METHODS: Our analysis was retrospective with data from the Digitalis Investigation Group (DIG) trial. The principal study analysis reviewed 4,944 patients with HF due to systolic dysfunction who survived for at least 4 weeks (all 3,366 patients randomized to placebo and the 1,578 of 3,372 patients randomized to digoxin who had serum concentration measured 6 to 30 h [inclusive] after the last dose of study drug at 4 weeks). RESULTS: Continuous multivariable analysis demonstrated a significant linear relationship between SDC and mortality in women (p = 0.008) and men (p = 0.002, p = 0.766 for gender interaction). Averaging hazard ratios (HRs) across serum concentrations from 0.5 to 0.9 ng/ml in women produced a HR for death of 0.8 (95% confidence interval [CI] 0.62 to 1.13, p = 0.245) and for death or hospital stay for worsening HF of 0.73 (95% CI 0.58 to 0.93, p = 0.011). In contrast, SDCs from 1.2 to 2.0 ng/ml were associated with a HR for death for women of 1.33 (95% CI 1.001 to 1.76, p = 0.049). CONCLUSIONS: Retrospective analysis of data from the DIG trial indicates a beneficial effect of digoxin on morbidity and no excess mortality in women at serum concentrations from 0.5 to 0.9 ng/ml, whereas serum concentrations > or =1.2 ng/ml seem harmful.

Age Factors↗
PubMed2004

Simultaneous determination of digoxin and permeability markers in rat in situ intestinal perfusion samples by RP-HPLC.

A simple, sensitive and specific reversed-phase high performance liquid chromatographic (RP-HPLC) assay for simultaneous determination of digoxin and permeability markers, in samples obtained from intestinal in situ single-pass perfusion studies, was developed and validated. Chromatography was carried on C-18 column with mobile phase comprising of acetate buffer (pH 3.0), acetonitrile and methanol in the ratio of 50:25:25 (v/v/v), was pumped at a flow rate of 0.5 ml/min and UV detection was employed at 220 nm. The average retention times for phenolred, propranolol, frusemide and digoxin were 9.1, 10.7, 12.9 and 15.3 min, respectively. The calibration curves were linear (R(2) > 0.998) in the range for each analyte. The method is specific and sensitive with limit of quantification of 25 ng/ml for digoxin and frusemide and 10 ng/ml for phenolred and propranolol. The method is accurate and precise with recoveries of digoxin in the range of 95.2 and 103.2% and relative standard deviation (R.S.D.) <5%. We found that this method was simple and reliable in permeability determination and to estimate the contribution of P-glycoprotein in limiting intestinal absorption.

Animals↗
PubMed2004

Rapid loading of sotalol or amiodarone for management of recent onset symptomatic atrial fibrillation: a randomized, digoxin-controlled trial.

BACKGROUND: Amiodarone and sotalol are commonly used for the maintenance of sinus rhythm, but the efficacy of these agents administered as high-dose infusions for rapid conversion of atrial fibrillation is unknown. Use in this context would facilitate drug initiation in patients in whom ongoing prophylactic therapy is indicated. METHODS: We assessed the efficacy and safety of rapid high-dose intravenous infusions of amiodarone and sotalol for heart rate control and rapid reversion to sinus rhythm in patients who came to the emergency department with recent-onset symptomatic atrial fibrillation. Patients (n = 140) were randomized to receive 1.5mg/kg of sotalol infused in 10 minutes, 10mg/kg of amiodarone in 30 minutes, or 500 microg of digoxin in 20 minutes. Electrical cardioversion was attempted for patients not converting to sinus rhythm within 12 hours. RESULTS: The rapid infusion of sotalol or amiodarone resulted in more rapid rate control than digoxin. Each of the 3 trial strategies resulted in similar rates of pharmacological conversion to sinus rhythm (amiodarone, 51%; sotalol, 44%; digoxin, 50%; P = not significant). The overall rates of cardioversion after trial drug infusion and defibrillation were high for all groups (amiodarone, 94%; sotalol, 95%,; digoxin, 98%; P = not significant), but there was a trend toward a higher incidence of serious adverse reactions in the amiodarone group. CONCLUSION: The rapid infusion of sotalol or amiodarone in patients with symptomatic recent-onset atrial fibrillation results in rapid control of ventricular rate. Even with high-dose rapid infusions, all 3 agents are associated with a poor overall reversion rate within 12 hours. Almost all patients were returned to sinus rhythm with a combination of pharmacological therapy and electrical cardioversion.

Aged↗
PubMed2000

Effect of concomitant digoxin and carvedilol therapy on mortality and morbidity in patients with chronic heart failure.

We retrospectively performed stepwise logistic regression analysis on 1,509 patients with chronic heart failure in 4 multicenter United States studies and 1 Australia-New Zealand study to examine the effect of digoxin in patients randomized to carvedilol or placebo. Patients receiving digoxin had more advanced heart failure, the incidence of hospitalization for any cause and the combination of all-cause death and all-cause hospitalization were the same in the digoxin versus no-digoxin groups.

Adrenergic beta-Antagonists↗