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PubMed2003

Hypothalamic digoxin, hemispheric dominance, and family bonding behavior.

The isoprenoid pathway produces endogenous digoxin, a substance that can regulate neurotransmitter and amino acid transport. Digoxin synthesis and neurotransmitter patterns were assessed in individuals with differing family bonding patterns. The family bonding patterns were assessed by the FACES scale--family adaptability and cohesiveness evaluation scale. The criteria given in the handbook for the 16 PF--16 personality factors questionnaire by Cattell, Eber, and Tatsouke--was also chosen for assessing the individual personality aspect of family bonding after suitable modification. The patterns were compared in those with right hemispheric and left hemispheric dominance. Digoxin synthesis was increased with upregulated tryptophan catabolism (increased levels of serotonin, strychnine, and nicotine) and downregulated tyrosine catabolism (decreased levels of dopamine, noradrenaline, and morphine) in those with reduced family bonding and right hemispheric dominance. Digoxin synthesis was reduced with downregulated tryptophan catabolism (decreased levels of serotonin, strychnine, and nicotine) and upregulated tyrosine catabolism (increased levels of dopamine, noradrenaline, and morphine) in those with increased family bonding and left hemispheric chemical dominance. Hypothalamic digoxin plays a central role in the regulation of family bonding behavior. Hemispheric chemical dominance in relation to digoxin status is also crucial in this respect.

Adult↗
PubMed2003

A hypothalamic digoxin-mediated model for autism.

The isoprenoid pathway and its metabolites--digoxin, dolichol, and ubiquinone--were assessed in autism. The isoprenoid pathway and digoxin status was also studied for comparison in individuals of differing hemispheric dominance to determine the role of cerebral dominance in the genesis of autism. There was an upregulation of the isoprenoid pathway as evidenced by elevated HMG CoA reductase activity in autism. Digoxin, an endogenous Na+-K+ ATPase inhibitor secreted by the hypothalamus, was found to be elevated and RBC membrane Na+-K+ ATPase activity was found to be reduced in autism. Membrane Na+-K+ ATPase inhibition can result in increased intracellular Ca2+ and reduced magnesium levels. Hypothalamic digoxin can modulate conscious and subliminal perception and its dysfunction may lead to autism. Digoxin can also preferentially upregulate tryptophan transport over tyrosine resulting in increased levels of depolarizing tryptophan catabolites--serotonin, quinolinic acid (NMDA agonist), strychnine (blocks glycinergic inhibitory transmission), and nicotine (promotes dopamine release) and decreased levels of hyperpolarizing tyrosine catabolites--dopamine, noradrenaline, and morphine--contributing to membrane Na+-K+ ATPase inhibition. Increased nicotine levels can produce increased dopaminergic transmission in the presence of low dopamine levels. NMDA excitotoxicity could result from hypomagnesemia induced by membrane Na+-K+ ATPase inhibition and quinolinic acid, an NMDA agonist acting on the NMDA receptor. Hypomagnesemia and increased dolichol level can affect glycoconjugate metabolism and membranogenesis leading on to disordered synaptic connectivity in the limbic allocortex and defective presentation of viral antigens and neuronal antigens contributing to autoimmunity and viral persistence important in the pathogenesis. Membrane Na+-K+ ATPase inhibition can produce immune activation, a component of autoimmunity. Mitochondrial dysfunction consequent to altered calcium/magnesium ratios and reduced ubiquinone levels can result in increased free radical generation and reduced free radical scavenging and defective apoptosis leading to abnormal synaptogenesis. Autism can thus be considered a syndrome of hypothalamic digoxin hypersecretion consequent to an upregulated isoprenoid pathway. The biochemical patterns including hyperdigoxinemia observed in autism correlated with those obtained in right hemispheric chemical dominance. Right hemispheric chemical dominance is a predisposing factor for autism.

Adolescent↗
PubMed2006

The influence of potassium ion (K+) on digoxin-induced inhibition of porcine cerebral cortex Na+ / K+-ATPase.

The in vitro influence of potassium ion modulations, in the concentration range 2 mM-500 mM, on digoxin-induced inhibition of porcine cerebral cortex Na+ / K+-ATPase activity was studied. The response of enzymatic activity in the presence of various K+ concentrations to digoxin was biphasic, thereby, indicating the existence of two Na+ / K+-ATPase isoforms, differing in the affinity towards the tested drug. Both isoforms showed higher sensitivity to digoxin in the presence of K+ ions below 20 mM in the medium assay. The IC50 values for high/low isoforms 2.77 x 10(-6) M / 8.56 x 10(-5) M and 7.06 x 10(-7) M / 1.87 x 10(-5) M were obtained in the presence of optimal (20 mM) and 2 mM K+, respectively. However, preincubation in the presence of elevated K+ concentration (50-500 mM) in the medium assay prior to Na+ / K+-ATPase exposure to digoxin did not prevent the inhibition, i.e. IC50 values for both isoforms was the same as in the presence of the optimal K+ concentration. On the contrary, addition of 200 mM K+ into the medium assay after 10 minutes exposure of Na+ / K+-ATPase to digoxin, showed a time-dependent recovery effect on the inhibited enzymatic activity. Kinetic analysis showed that digoxin inhibited Na+ / K+-ATPase by reducing maximum enzymatic velocity (Vmax) and Km, implying an uncompetitive mode of interaction.

Adenosine Triphosphatases↗
PubMed2001

Morning-evening administration time differences in digoxin kinetics in healthy young subjects.

Digoxin, frequently used in the treatment of congestive heart failure, has a very narrow therapeutic index. We studied the differences in digoxin pharmacokinetics when ingested in the morning versus evening. A single digoxin (0.25 mg) dose was given orally to the same group of 10 diurnally active healthy (6 male and 4 female) volunteers in the morning at 08:00 and evening at 20:00 in separate experiments scheduled 2 weeks apart. Blood samples were collected at specific times for 48h after each timed dose; digoxin was determined by radioimmunoassay (RIA). Maximum plasma concentration Cmax; Tmax, the time to reach Cmax; area under plasma concentration curve AUC; and elimination half-time T1/2 of digoxin were determined. Tmax was statistically significantly shorter (54 min) following 08:00 dosing com pared to 20:00 dosing (96 min). Although the Cmax was higher after morning than evening dosing, it was not significantly so. No other parameter of digoxin pharmacokinetics except Tmax exhibited administration time dependency.

Adult↗
PubMed1990

Generation of monoclonal anti-digoxin antibodies.

Anti-digoxin monoclonal antibodies are a useful model for basic immunochemical studies, for investigation of endogenous digoxin-like substances and in immunoassay for cardiac glycosides. The complete phenotypic characterization is a requisite for the selection of antibodies with desired binding parameters for different purposes. Twenty-two high-affinity monoclonal antibodies specific for digoxin were obtained in two fusion experiments. Treatment of antigen-antibody complex with potassium thiocyanate (KSCN) and absorption ELISA were used for the selection of high-affinity antibodies at the earliest stages of hybridoma growth. The true affinity constants of selected antibodies were determined in ELISA. They had proven to vary between 10(-7) and 10(-10) M. The fine specificity of 21 anti-digoxin monoclonal antibodies was determined by cross-reactivity experiments with 25 structurally related compounds. Cardiac glycosides, digoxin metabolites, endogenous steroids and spironolactone were used in the elucidation of the antigenic recognition pattern of antibodies. The elucidation of the binding characteristics of anti-digoxin monoclonal antibodies makes possible the selection of antibodies possessing binding characteristics appropriate for a wide range of designations.

Animals↗
PubMed1984

Effect of chronic digoxin treatment on cardiac function, electrolytes and ATPase in failing heart due to pressure overload.

A decrease in the cardiac function and intracellular calcium, and an increase in the cardiac sarcolemmal ATPase have been reported in aortic stenosis of 6 to 9 months duration in dogs. The present investigation deals with the effect of 3 months of digoxin treatment on cardiac function, electrolytes and ATPase in dogs with 3 months of aortic stenosis in order to determine whether digoxin treatment gives only haemodynamic improvement or if it also improves the condition of the myocardium in terms of contractility and biochemical changes. There were no significant changes in any of the haemodynamic parameters of left and right ventricles except the left ventricular end-diastolic pressure which increased significantly at 3 months of aortic stenosis. All the hearts developed left ventricular hypertrophy. Concomitant with these changes, there was a tendency for a decrease in the total tissue Ca2+, intracellular Ca2+ and K+, and a tendency for an increase in the sarcolemmal ATPase. There were no significant differences in any of the haemodynamic parameters between the aortic stenotic and digoxin treated aortic stenotic dogs indicating that digoxin was at least maintaining the haemodynamics close to the pretreatment level. Although digoxin treatment prevented the changes in the sarcolemmal ATPase and extracellular space, it did not prevent the further decrease in the total or intracellular Ca2+. The total and intracellular Ca2+ was still significantly higher than previously observed after 6 to 9 months of aortic stenosis. These results suggest that digoxin treatment not only tended to prevent further deterioration of cardiac function but also tended to prevent further changes in the sarcolemmal ATPase and electrolytes.

Adenosine Triphosphatases↗
PubMed1997

Intravenous digoxin in acute atrial fibrillation. Results of a randomized, placebo-controlled multicentre trial in 239 patients. The Digitalis in Acute Atrial Fibrillation (DAAF) Trial Group.

AIMS: The DAAF Trial was designed to investigate whether digoxin, within 16 h of its use, increases the rate of conversion to sinus rhythm in patients with acute atrial fibrillation. METHODS AND RESULTS: In a randomized, double-blind multicentre trial the effects of intravenous digoxin and placebo, (mean dose 0.88 +/- 0.35 mg and 0.96 +/- 0.37 mg) were compared in 239 patients with a mean age of 66.2 +/- 13.0 years and atrial fibrillation of, at most, 7 days' duration. The mean arrhythmia duration was 21.7 +/- 30.4 h and baseline heart rate 122.0 +/- 23.0 beats.min-1. At 16 h, 46% of the placebo group and 51% of the digoxin group had converted to sinus rhythm, (ns). Time to sinus rhythm was shorter in the digoxin group, but the difference was not significant. Digoxin had a pronounced and rapid effect on heart rate, which was already significant at 2 h; 104.6 +/- 20.9 beats.min-1 vs 116.8 +/- 22.5 beats.min-1 (P = 0.0001). CONCLUSION: Acute intravenous treatment with digoxin does not increase the rate of conversion to sinus rhythm, but has a fast acting and clinically significant effect on heart rate and should remain an alternative in haemodynamically stable patients.

Acute Disease↗
PubMed1983

The effects of oral digoxin therapy in primary mitral leaflet prolapse.

The effects of oral digoxin on symptoms, arrhythmias, exercise tolerance and echocardiographic function in primary mitral leaflet prolapse were studied in 23 patients using a double-blind crossover protocol. Digoxin reduced the incidence and severity of chest pain compared with both the control (P = 0.0002) and placebo (P = 0.0005) periods. We found a high (83%) incidence of predominantly minor arrhythmias on continuous ambulatory monitoring. Digoxin favourably affected the incidence of frequent supraventricular ectopic beats and supraventricular tachycardia but was associated with a significant number (P less than 0.0025) of asymptomatic bradyarrhythmias. In patients with frequent ventricular ectopics, digoxin had no consistent effect. No difference in exercise tolerance between treatment periods was found on maximal treadmill stress testing, but digoxin administration resulted in an increase in echocardiographic mean circumferential fibre shortening velocity (P less than 0.01) and fractional shortening percent (P less than 0.01). This study demonstrates the efficacy of oral digoxin therapy in ameliorating chest pain in patients with primary mitral leaflet prolapse and suggests a favourable effect on supraventricular arrhythmias in such patients.

Administration, Oral↗
PubMed1997

Update on digoxin and other oral positive inotropic agents for chronic heart failure.

The benefit of digoxin in chronic heart failure has been debated fervently for decades. In the 1970s, the use of digoxin was challenged due to the high incidences of digitalis toxicity and the lack of data on the effects of digoxin in patients with chronic heart failure. In the 1980s, interest in digoxin was renewed after several trials with oral inotropic agents demonstrated increased mortality. Recently, several trials have studied the hemodynamic, neurohormonal, and clinical effects of digoxin, providing further insights into the possible mechanisms for its beneficial effects in patients with chronic heart failure. In an effort to find new pharmacologic therapies for the treatment of this patient population, studies of newer oral inotropic agents such as vesnarinone, pimobendan, and ibopamine have been disappointing. This paper reviews data published or presented in 1995 and 1996 examining the effects of digoxin and other oral inotropic agents in patients with chronic heart failure.

Cardiotonic Agents↗
PubMedDate not supplied

Comparisons of the inotropic effects of the beta 1-adrenoceptor partial agonists SL 75.177.10 and ICI 118,587 with digoxin on the intact canine heart.

The effects of the beta 1-adrenoceptor partial agonists ICI 118,587 (xamoterol) and SL 75.177.10 on the left ventricular inotropic state and relaxation rate were compared with those of digoxin in open-chest dogs. These agents were administered to three separate groups of dogs (5, 6, and 7 dogs, respectively). In each animal, the inotropic effects were assessed at fixed heart rate (atrial pacing) and at similar end-diastolic left ventricular diameter. Under these controlled conditions, ICI 118,587 (200 micrograms/kg) increased peak (+) dP/dt by 3176 +/- 363 mm Hg/s (p less than 0.005) and the slope of the end-systolic pressure/end-systolic diameter relation rose by 190% above the control value (p less than 0.01). These changes were significantly greater than after digoxin (100 micrograms/kg) which increased these indexes, respectively, by 2132 +/- 248 mm Hg/s (p less than 0.003) and by 31 +/- 4% (p less than 0.05). SL 75.177.10 (200 micrograms/kg) also increased dP/dt, but significantly less than did digoxin or ICI 118,587 (+428 +/- 105 mm Hg/s; p less than 0.007); the increase in end-systolic pressure/diameter slope was not different from that observed after digoxin. In contrast to ICI 118,587 which accelerated isovolumic relaxation (-7.6 ms in time constant of isovolumic pressure fall; p less than 0.01), neither SL 75.177.10 nor digoxin modified this phase of the cardiac cycle. Finally, at the dose used in the study, digoxin induced ventricular arrhythmias in all animals, a side effect which was never observed after ICI 118,587 or SL 75.177.10.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗
PubMedDate not supplied

Inhibition of platelet aggregation by oral digoxin and reversal with nifedipine.

To study the effect of cardiac glycosides on platelet function, we obtained serial blood samples from 18 normal male volunteers before and 3, 5, and 7 weeks after beginning digoxin therapy (0.375 mg daily). The combined effect of digoxin and nifedipine (mean dose, 57 mg/day) was assessed during the 5th week. Spontaneous platelet aggregation and platelet response to adenosine diphosphate (ADP) were measured in whole blood by electronic particle sizing. Digoxin (mean serum concentration, 0.9 ng/ml) caused significant reduction in total volume and mean size of platelet aggregates formed in response to ADP. However, with addition of nifedipine, the volume and mean size of aggregates returned to baseline measurements. In vitro administration of digoxin to whole blood failed to inhibit ADP-induced platelet aggregation. The volume of spontaneously induced aggregates decreased with digoxin; however, the decrease was not statistically significant. These data indicate that digoxin given in vivo for several weeks inhibits platelet response to ADP; this effect is reversed by the addition of nifedipine.

Adenosine Diphosphate↗
PubMed1984

Simple method to predict digoxin serum concentration.

The predictability of a method of determining serum digoxin concentration was assessed in a retrospective study of 35 hospitalized patients taking digoxin orally for maintenance therapy. Simple pharmacokinetic expressions were used to estimate digoxin concentration. Clinically, the mean measured digoxin concentration (1.35 ng/ml) was in close agreement with the mean predicted value (1.36 ng/ml). There was also a strong statistical correlation between measured and predicted values (r = .82). The predictability of serum digoxin concentration was statistically equivalent in men and women. Our results indicate that a reasonably accurate prediction of digoxin concentration is possible using simple mathematical formulas that require only routine clinical data.

Administration, Oral↗
PubMed1983

An audit of requests for therapeutic drug monitoring of digoxin: problems and pitfalls.

The use of serum digoxin measurements in a teaching hospital was audited. The reason for test requisition, the timing of blood samples, the recognition of results, and the action taken by house staff were assessed using formal criteria. In 200 consecutive requests for serum digoxin measurements, the reason for requesting the test could not be determined in 165 (82.5%). The timing of plasma samples with respect to duration of therapy and time since last dose was usually satisfactory. However, only 73 (36.5%) of results appear to have been adequately recognized, and approximately 1 result in 4 was followed by an inappropriate decision. High plasma concentrations were usually dealt with more promptly and more appropriately than low plasma concentrations, possibly because the biochemistry laboratory informed physicians directly of the high results. There is a clear need for physicians to better identify the reasons for measuring plasma concentrations of digoxin and to request serum digoxin measurements only when there is a pertinent problem. Indiscriminate requests for serum digoxin measurements are associated with apparent disregard for the results and a high likelihood of making an inappropriate decision regarding further digoxin prescription.

Adult↗
PubMed1984

Falsely increased digoxin concentrations in samples from neonates and infants.

Several previous studies have suggested the presence of a digoxin-like immunoreactive substance in the serum of infants. In this study we examined eight different immunoassay kits to confirm the presence of such a substance. The kits were evaluated using serum from newborns and infants who were not receiving digoxin. We investigated the relationship of this digoxin-like immunoreactive substance to substances that are present in unusual concentrations in newborn sera. These substances included fatty acids, cholesterol, triglycerides, bilirubin, protein, and albumin. No relationship could be established. Since serum steroid concentrations are known to be increased in the newborn and since digoxin is essentially a steroid derivative, we looked at steroids separately and collectively to see whether they mimicked the immunoreactivity of digoxin. We found that pooled steroids did indeed mimic digoxin and might be implicated as the immunoreactive substances.

Adult↗
PubMed1987

Lack of apparent effect of assay methodology on the pharmacokinetics of digoxin.

The purpose of this study was to determine if serum digoxin concentration data using three different automated immunoassay methods would produce similar pharmacokinetic values in normal volunteer subjects. Area under the curve (AUC), steady-state volume of distribution/bioavailability ratio (Vd/F), terminal elimination rate constant (beta), clearance/bioavailability ratio (CL/F), maximum digoxin concentration (Cmax), minimum digoxin concentration (Cmin), and time of peak (Tp) were evaluated. Ten healthy volunteers received digoxin capsules 0.2 mg daily for 10 days. On day 10, 16 serial blood samples were collected over a 24-h dosing interval and analyzed by radioimmunoassay (RIA) (Concept 4, Micromedic Systems), fluorescence polarization immunoassay (FPIA) (TDx, Abbott Laboratories), and affinity column-mediated immunoassay (ACMIA), (aca, duPont Instruments). When comparing RIA and FPIA, the mean of the percent differences for AUC, Vd/F, beta, and CL/F were 9, 4, 10, and 6%, respectively. The mean of the percent differences were 2, 3, 44, and 6%, respectively, when comparing RIA and ACMIA. However, none of these differences were statistically significant. Although a trend toward higher Cmax values by RIA was noted, there was no statistical difference in Cmax, Cmin, and Tp. Orthogonal regression of all serum digoxin concentrations showed that FPIA = 0.76 RIA + 0.19, r = 0.967 (p less than 0.001); and ACMIA = 0.92 RIA + 0.04, r = 0.943 (p less than 0.001). At serum digoxin concentrations less than 1 ng/ml, FPIA overestimated RIA results (p less than 0.005), while ACMIA was approximately equal to the RIA results.(ABSTRACT TRUNCATED AT 250 WORDS)

Blood Proteins↗
PubMed1990

A dry-strip immunometric assay for digoxin on the Ames Seralyzer.

We evaluated the Ames Seralyzer III with a new reagent and drystrip test for assay of digoxin. Assay precision was acceptable in the therapeutic range. Within-run imprecision (coefficient of variation, n = 20) was 7% at 0.9 ng/ml (1.2 nM) and 3.5% at 1.9 ng/ml (2.4 nM); run-to-run imprecision was 7.6% at 0.8 ng/ml (1.0 nM) and 5.7% at 2.1 ng/ml (2.7 nM). The method is very reproducible and is linear between 0.5 and 4.3 ng/ml (0.6-5.5 nM). The assay performed well with patient samples, with Abbott TDx used as the reference procedure. Bilirubin up to 16 mg/dl (273 microM) and hemoglobin up to 11 g/l do not cause interference. Digoxin-like immunoreactive factors cause minimal interference. Some digoxin metabolites such as monodigitoxoside, bis-digitoxoside, and digoxigenin cross-react with the digoxin antibody. Patients on spironolactone have falsely increased digoxin values. The new digoxin assay is easy to perform and uses 30 microliters serum; the result can be reported in 15-20 min.

Antibody Specificity↗
PubMed1990

Digoxin-like immunoreactivity in Chinese medicine.

Immunoreactive digoxin-like activity was observed in Chinese medicine, KYUSHIN tablet, taken popularly in Japan without prescription. The antibodies used in the assays of digoxin reacted with Chan-su, the major effective component of KYUSHIN, which contained cardiotonic steroids with similar chemical structure as digoxin. One tablet of KYUSHIN had digoxin-like immunoreactivity equivalent to 1.9, 1.5, and 72 micrograms of digoxin measured by three different commercial kits. These different equivalences may be attributed to differences in cross-reactivity of the antibody used in the immunoassays. Two healthy volunteers took two KYUSHIN tablets three times a day, a typical dose, and digoxin-like immunoreactivity reached almost 0.4 micrograms/L in 0.5 day. Therapeutic drug monitoring should be interpreted carefully in patients taking Chinese medicines, many of which contain the Chan-su component.

Cross Reactions↗
PubMed1992

An enzyme-labeled immunometric assay for quantitation of digoxin in serum or plasma.

A heterogeneous enzyme-labeled immunometric assay for quantifying digoxin in serum or plasma was developed. The sample's drug reacts with an excess of an antidigoxin Fab'-beta-galactosidase monoconjugate and then the free monoconjugate is removed by polyacrylamide digitoxigenin-coupled beads; the beta-galactosidase activity of the supernatant measured photometrically at 634 nm is directly proportional to the digoxin concentration in the sample. The assay shares the basic reagents for the immunological reaction with the Seralyzer dry-strip immunometric assay; the reagents for the indicator enzyme reaction were instead formulated in liquid form for use with common clinical analyzers. The test requires a two-point calibration (a 3.0 micrograms/L digoxin calibrator and a reagent blank). One sample can be assayed in approximately 20 min; the assay range is from 0.3 to 5.0 micrograms/L. Dilution tests showed an average found/expected ratio of 100.6%. Mean analytical recovery was 99.2%. Overall coefficients of variation (CVs) (three replicates for 12 runs over 15 days; daily calibration) ranged from 4.9 to 10.0% (Technicon RA-50) and from 2.5 to 10.0% (Cobas Fara) for samples with digoxin concentrations of 4.7 to 0.5 micrograms/L. No interference was found by high levels of common analytes (bilirubin, triglycerides, hemoglobin, total protein, uric acid) or anticoagulants. Cross-reactivity by digoxin metabolites and structurally-related compounds was investigated. Good correlations were found with radiommunoassay (RIA) (r = 0.986) and enzyme immunoassay (EIA) (r = 0.994). Thus, the assay is a specific, reliable, and convenient method for measuring digoxin in both small and large laboratories.

Colorimetry↗