Cardiovascular effects, pharmacokinetics and cross-reactivity in digitalis glycoside immunoassays of an antidiarrheal uzara root extract.

Uzara glycosides (UG) extracted from Xysmalobium undulatum are used for treating non-specific diarrhea.Cross-reactivity has been described for UG in digitalis glycoside assays but digitalis-like cardiac effects are controversially discussed. Therefore, we performed a randomized, singleblind cross-over study in 18 healthy volunteers receiving a commercially available Uzara product (Uzara® Lösung N, Stada AG, Bad Vilbel, Germany (ULN)), digoxin (1 mg, i.v., positive control) and placebo in double-dummy technique. Pharmacodynamic effects were quantified by means of ECG and impedance cardiography (ICG). After oral administration of ULN, main metabolites were determined using HPLC-MS/MS and digitalis-like serum levels (DLSL) were measured in two digitoxin and digoxin assays, respectively. In comparison to placebo, ULN did not change significantly any PD parameters whereas digoxin altered significantly area under the effect curve of several ECG and ICG parameters, respectively. Since some serum levels of three ULN ingredients (uzarin, uzarigenin and xysmalorin) were below LLQ, PK analyses could only be performed for allouzarigenin and revealed a marked inter-individual variability. Therefore, median values (min; max) were calculated as follows: Cmax = 0.39 (0.15; 1.81) ng/ml, tmax = 7.0 (3.0; 36.0) h, T1/2 = 5.2 (0.8; 23.6) h, AUC0-36h = 4.2 (0.8; 11.1) ng/ml×h, AUC0-∞ = 5.8 (1.8; 13.1) ng/ml×h. DLSL reached Cmax of 28 ng/ml and 1,980 ng/ml for digoxin and digitoxin, respectively. We could not observe significant cardiovascular pharmacodynamic effects after oral administration of the recommended single dose of Uzara extract to healthy volunteers. However, considerable DLSL could be detected, proving cross-reactivity of uzara components with the conventional digitalis assays used. However, none of the metabolites we had suspected to be the cause for the crossreactivity could be identified in reasonable quantities.

The measurement of digitoxin in human serum by radioimmunoassay.

A sensitive, specific, and relatively simple immunoassay permitting measurement of pharmacological levels of digitoxin in human serum has been developed. The assay involves binding of (125)I-labeled tyrosine-digitoxigenin (specific activity > 400 mc/mg) by rabbit antibody to digitoxin. Antibody-bound radioactivity is precipitated by addition of a second antibody (goat anti-rabbit gamma globulin), and precipitate radioactivity is measured. Unlabeled digitoxin can be determined by the extent to which it competes with (125)I-labeled digitoxigenin and thus reduces precipitation of radioactivity. Before the assay, unlabeled digitoxin is extracted from serum with chloroform, and the chloroform solution is evaporated to dryness. Quantitation is accomplished by reference to a standard curve in which known amounts of digitoxin are added to normal serum. As little as 1 mmug of digitoxin per ml of serum produces significant reduction in precipitate radioactivity. The sera of 5 patients were analyzed before and after digitalization. A highly significant reduction in precipitate counts in the postdigitalization sera was observed (P < 0.001). Serum digitalis levels were measured in 19 patients receiving no digitalis and in 19 patients taking digitoxin or digitalis leaf. Little of no digitalis-like activity was detected in control sera, whereas serum levels averaged 27 mmug/ml in those on digitalis (range 4-60 mmug/ml, P < 0.001). Patients judged clinically to show digitals toxicity in general had higher levels than those without signs of toxicity. Patients receiving digoxin had little or no detectable digitalis in their serum with this method. In addition to the assay itself, other potential uses of the antidigitalis antibody include treatment of digitalis toxicity and studies on the tissue localization of digitalis.

Effects of digitalis on mortality in a large cohort of implantable cardioverter defibrillator recipients: results of a long-term follow-up study in 1020 patients.

AIMS: The effects of digitalis on mortality in patients with structural heart disease are controversially discussed. We aimed to assess the effects of digitalis administration in implantable cardioverter defibrillator (ICD) recipients. METHODS AND RESULTS: This retrospective analysis comprises 1020 consecutive patients who received an ICD at our institution and who were followed for up to 10 years (median 37 months). A total of 438 patients were receiving digitalis at the time of ICD implantation and 582 did not. Patients on digitalis were more often in atrial fibrillation and had more often a prolonged QRS duration of ≥120 ms, a severely impaired left ventricular ejection fraction, and higher New York Heart Association (NYHA) classification heart failure. Crude Kaplan-Meier analysis demonstrated significantly higher mortality in patients on digitalis (HR = 2.47; 95% CI 1.87-3.25; P = 0.001). After adjustment for patient characteristics found statistically significant in adjusted Cox regression analysis (age, gender, NYHA classification, and QRS duration of ≥120 ms), a HR of 1.65 remained (95% CI 1.14-2.39; P = 0.01). Patients on digitalis died more often from cardiac arrhythmic and cardiac non-arrhythmic causes than patients not on digitalis (P = 0.04). There was no difference in mortality between patients receiving digitoxin and those receiving digoxin (HR = 1.55; 95% CI 0.74-3.25; P = 0.25). CONCLUSION: In this large ICD patient population, digitalis use at baseline was independently associated with increased mortality even after careful adjustment for possible confounders. Digitalis should be used with great caution in this population.

Antibodies and digitalis: the modern revolution in the use of an ancient drug.

Although digitalis glycosides have been widely used in clinical medicine since the classic description by William Withering in 1785, it was not until the advent of a specific immunoassay that their clinical pharmacology could be examined intensively under a wide variety of circumstances. The insights gained into the relations among dosage, plasma concentration, bioavailability, distribution, metabolism, excretion and interactions with other drugs and the manifestations of toxicity certainly have reduced the frequency of adverse reactions to this highly toxic but useful group of drugs. More recently, antibodies have also been utilized as specific antidotes for digitalis toxicity, with dramatic life-saving effect.

Plasma digitalislike activity in essential hypertension or end-stage renal disease.

Plasma extracts from 119 subjects showed a digitalislike activity, as evidenced by the ability of these extracts to inhibit ouabain binding to the Na+-K+ pump. High levels of the digitalislike compound were found in 18 of 54 untreated hypertensive subjects, 7 of 21 normotensive subjects with a family history of hypertension, and 10 of 14 patients with end-stage renal failure. Dialysis significantly reduced the activity of this compound. These results suggest 1) that endogenous digitalislike factor is not directly linked to hypertension but rather is related to sodium balance and 2) that it neither originates nor is activated by renal tissue, as it was present in four of six anephric patients.

Digitalis intoxication misdiagnosed as depression by primary care physicians.

Three cases are described in which digitalis intoxication was misdiagnosed as depression by primary care physicians. The authors discuss the potentially life-threatening consequences of such a misdiagnosis, guidelines for an accurate diagnosis, and the implications for medical education.

Digitalis toxicity: epidemiology and clinical use of serum concentration measurements.

Despite continuing advances in understanding of the basic pharmacology of the cardiac glycosides, digitalis intoxication remains a common clinical problem. Physician education programs and increasing use of serum or plasma concentration data have, however, been shown to be capable of substantially reducing the incidence of digitalis toxicity. Methodologic progress and availability of commercial radioimmunoassay kits have placed measurement of clinically relevant serum or plasma cardiac glycoside concentrations within the capability of most well equipped clinical laboratories. Extensive experience with serum digitalis levels now provides a basis for ongoing examination of the role of these measurements in clinical practice. Results of studies to date demonstrate that mean serum digoxin and digitoxin levels are significantly higher in patients with electrocardiographic evidence of toxicity compared with patients without such evidence. It must be emphasized, however, that because of overlap in serum digitalis levels between these two groups, sole dependence on these levels for established of a diagnosis of digitalis toxicity is not warranted. Multiple factors influence individual responses to cardiac glycosides, and serum concentration data must be interpreted in the over-all clinical context. Type and extent of underlying heart disease are important determinants of the clinical response to any given dose or concentration of cardiac glycoside. Knowledge of the serum digitalis concentration is likely to be helpful in the setting of suspected digitalis intoxication in the absence of an adequate history, or in the presence of fluctuating renal function, overt or suspected malabsorption, or uncertain bioavailability. More generally, such measurements may prove useful whenever an unanticipated response to digitalis is encountered, whether it be suspected toxicity or the absence of an expected therapeutic effect.

Digitalis-like activity in human plasma: relation to blood pressure and sodium balance.

PURPOSE: On the assumption that renal tubular cells are more important as the target cells for a natriuretic factor than blood cells, we used a well-characterized cultured renal tubular cell line, Madin-Darby canine kidney (MDCK), cells to monitor the circulating digitalis-like factor in human plasma and examine its role in the regulation of blood pressure and sodium balance. SUBJECTS AND METHODS: We investigated the effects of plasma on binding of radioactive ouabain to monolayered MDCK cells in order to determine the level of a circulating digitalis-like factor. First, we measured specific 3H-ouabain binding to MDCK cells in the presence of plasma from 71 outpatients (34 normotensive subjects and 37 hypertensive patients) after incubation for 4 hours. Second, we measured specific 3H-ouabain binding after incubation of cells with plasma from 16 hospitalized subjects (eight normotensive subjects and eight hypertensive patients) receiving low and high sodium diets. RESULTS: In Study 1, ouabain binding was lower by 30% with plasma from hypertensive patients than with plasma from normotensive subjects (p less than 0.01). There was a significant negative correlation between individual subject's systolic or mean blood pressure and ouabain binding (r = -0.34, p less than 0.01 or r = -0.29, p less than 0.01). In Study 2, ouabain binding was also significantly reduced by 25% in the presence of plasma from hypertensive subjects as compared with plasma from normotensive subjects irrespective of sodium intake (p less than 0.01). A significant negative correlation was also found for all subjects between either systolic, diastolic, or mean blood pressure and ouabain binding (r = -0.58, p less than 0.01, r = -0.51, p less than 0.01, or r = -0.55, p less than 0.01, respectively). With the changes from low to high sodium intake, there was a corresponding decrease in ouabain binding (p less than 0.01) and an increase in sodium excretion (p less than 0.01). A significant negative correlation was observed between these two parameters (r = -0.47, p less than 0.05). CONCLUSIONS: These findings suggest that a circulating digitalis-like factor, which may act on renal tubular cells as the ouabain-displacing compound, is increased in patients with essential hypertension and also demonstrate that plasma levels may be influenced by changes in dietary sodium intake.

Serum digitalis measurements in the assessment of digitalis resistance and sensitivity.

Antibodies to digitalis glycosides have been elicited in experimental animals and have been utilized in the development of rapid, sensitive, specific and convenient radioimmunoassay methods for the clinical measurement of digoxin and other cardiac glycosides in man. The use of these assay methods has supplemented earlier studies with radiolabeled digitalis preparations and has made it possible to obtain much new information concerning factors which may contribute to the well known patient to patient variability in digitalis dosage requirements and in sensitivity to the toxic effects of cardiac glycosides. In some patients with a poor clinical response to digitalis, the finding of a serum concentration which is relatively low for the dose prescribed may suggest that true digitalis resistance is not present and may raise questions of poor patient compliance, tablet inadequacies, intestinal malabsorption, increased metabolic degradation or hyperthyroidism; if the cause of the low serum level cannot be identified or corrected, serial serum measurements should enable safe and rational upward adjustment of dosage. In some patients with digitalis toxicity, the finding of a serum level which is relativity high for the dose prescribed may suggest that the patient is not sensitive to digitalis but rather is excreting it slowly; in such instances in elderly patients (with decreased glomerular filtration rates) and in patients with renal disease, serial digitalis measurements are useful adjuncts to clinical observation in determining optimal digitalis dosage schedules. A knowledge of serum digitalis concentrations should enable us to develop sound principles for a more rational approach to the clinical administration of cardiac glycosides, especially in patients with unusually high dosage requirements or with unusual sensitivity to relatively small doses of digitalis.

Incidence of hospitalization for digitalis toxicity among elderly Americans.

OBJECTIVE: To document the prevalence of digitalis use and the incidence of hospitalization caused by digitalis toxicity. DESIGN: Observational cohort followed for 6 years. SETTING: Urban community. PARTICIPANTS: Persons were eligible if they were (1) enrolled in the Yale Health and Aging Project and (2) using digitalis when interviewed in 1982 or 1985. The Project comprises a sample of noninstitutionalized persons aged 65 years and over living in New Haven, Connecticut. METHODS: Between 1982 and 1988 when a Project participant was hospitalized in New Haven, a researcher reviewed the medical record and coded up to 16 International Classification of Diseases-Class 9 (ICD-9) diagnoses. To identify hospitalizations caused by digitalis, we reexamined records with ICD-9 codes suggesting toxicity. We confirmed the admission illness was an adverse drug reaction with a decision algorithm. RESULTS: The prevalence of digitalis use was 13% in 1982 and 12% in 1985. The incidence of hospitalization caused by definite or probable toxicity was 4.2% (95% confidence interval = 0.3% to 8.1%) over 6 years. Manifestations of toxicity were malaise or gastrointestinal symptoms (two patients) and heart block plus malaise or gastrointestinal symptoms (six patients). Use of quinidine was associated (P < .05) with toxicity. CONCLUSION: Knowledge about the incidence of severe, morbid toxicity may help clinicians estimate and compare the risks and benefits of digitalis and alternate therapies.

Diverse effects of stress and additional adrenocorticotropic hormone on digitalis-like compounds in normal and nude mice.

Digitalis-like compounds (DLC) are steroidal hormones that are synthesized in, and released from, the adrenal gland, whose regulation may be directed by the hypothalamic-pituitary-adrenal (HPA) axis. Increasing evidence points to antitumour properties of these compounds and we hypothesized that the establishment of tumours in athymic nude mice may be facilitated by an abnormal synthesis or secretion of DLC. To explore this hypothesis, DLC concentrations were determined in the plasma, and in adrenal and hypothalamic tissues of nude compared to normal mice under basal conditions, and 30 min after a stress stimulus (i.p. injection of 100 micro l saline) with or without additional adrenocorticotropic hormone (ACTH) 1 micro g/per animal. Simultaneously, plasma corticosterone and serum adrenocorticotropic hormone (ACTH) concentrations were analysed. The basal DLC concentrations were similar in the plasma and the hypothalamus of both strains, whereas the basal adrenal DLC concentration was significantly lower in the nude mice compared to normal mice. The stress stimulus induced in normal mice a significant increase in DLC concentrations in the adrenal gland, the plasma and the hypothalamus. However, in nude mice, it caused an increase only in the adrenal gland and the hypothalamus, whereas the plasma DLC concentration was not affected. In both strains, the administration of ACTH in addition to injection stress did not provoke a further increase in DLC concentrations while inducing a significant increase in plasma corticosterone concentration. Regardless of the applied stimulus, the nude mice expressed significant lower DLC concentrations in the adrenal gland and the plasma compared to normal mice. The low basal adrenal DLC concentration in nude mice and their impaired DLC response towards stress- and ACTH stimulation both support an involvement of DLC in tumorigenesis.

New advances in the assessment and treatment of digitalis toxicity.

The narrow margin between the therapeutic and toxic doses and serum levels of cardiac glycosides results in a high incidence of digitalis toxicity. This common problem has led to the development of methods for determining serum glycosides concentrations. It is clear that overlap of serum digoxin levels occurs between groups of patients with and without evidence of toxicity. In spite of these difficulties, use of serum digoxin measurement has been reported to be associated with a lower incidence of digitalis intoxication in clinical practice. When digitalis toxicity does develop, it is generally of two types: disturbances of impulse formation and disturbances of conduction. Therapeutic interventions may include antiarrhythmic drugs, pacemaker placement, and, in the most severe cases, administration of cardiac glycosides-specific antibodies. Recent studies have shown that monoclonal digoxin-specific antibodies and Fab fragments obtained by somatic cell fusion are effective in reversing advanced and otherwise lethal digoxin intoxication. The homogeneity of this antibody offers attractive possibilities for improving our ability to treat advanced digitalis intoxication safely and effectively.

Increase in plasma digitalis-like activity during percutaneous transluminal coronary angioplasty in patients with coronary stenosis.

Despite the fact that numerous studies have been published regarding the possible presence in plasma of an endogenous Na-K pump inhibitor with a digitalis-like structure in essential hypertension, very little is known about this factor in heart disease in general, and in situations characterized by low cardiac output. We measured the ability of plasma obtained from the femoral vein to inhibit a human renal Na(+)-K+ ATPase before and immediately after percutaneous transluminal coronary angioplasty (PTCA) in 6 patients suffering from angina pectoris and severe coronary stenosis. Intraerythrocyte sodium and potassium concentrations were also measured simultaneously. Na(+)-K+ ATPase inhibition proved significantly greater after angioplasty as compared to basal activity (percentage inhibition: 31.5 +/- 7.8 vs 16.1 +/- 12.2). No significant changes in intraerythrocyte sodium and potassium were detected. Though we are not in a position to define the mechanism underlying the increase in the digitalis-like factor, a plausible hypothesis may be that the reduction in cardiac output during PTCA by raising cardiac pressures may stimulate the production of a factor of compensatory inotropic significance.

Plasma volume expansion increases lysophosphatidylcholine and digitalis-like activity in rat plasma.

A circulating factor with digitalis-like activity has been proposed to play a role in the regulation of plasma volume. Lysophosphatidylcholine has been found to be active in many assays for digitalis-like activity. To examine the relationship between plasma digitalis-like activity and plasma lysophosphatidylcholine, the effect of plasma volume expansion with saline on the plasma levels of phospholipids and on the ability of delipidated extracts of plasma to displace tritiated ouabain from the digitalis receptor was determined. Lysophosphatidylcholine was elevated after 15, 30, and 120 minutes of volume expansion but was decreased at 60 minutes. Phosphatidylcholine was decreased at 15, 60, and 120 minutes. Plasma sphingomyelin was not altered at any time point. The ability of plasma to displace tritiated ouabain was increased only at the 60 minute time point. These results indicate that the increase in digitalis-like activity in volume expanded states is mediated by a combination of at least two factors, lysophosphatidylcholine and another factor whose digitalis-like activity is not related to the surfactant actions of a lipid.

A non-fatal case of intoxication with foxglove, documented by means of liquid chromatography-electrospray-mass spectrometry.

The non-fatal self-poisoning of a 36-year-old female patient, who ingested a concoction of foxglove (Digitalis Purpurea), is presented. On the admission, initial symptoms were nausea and vomiting, abdominal pain, and cardiovascular shock with sinus bradycardia. Blood and urine were assayed for 17 cardiotonic hetorosides, using a highly specific LC-MS procedure. Serum and urine specimens were collected over five days and analyzed by liquid chromatography-electrospray-mass spectrometry (LC-ES-MS). This accurate procedure allowed the determination of the digitalis glycosides and their metabolites in serum and urine. The serum concentrations of digitalis glycosides were maximum on the first day (gitoxin 13.1 ng/mL, digitoxin 112.6 ng/mL, digitoxigenin 3.3 ng/mL, and digitoxigenin mono-digitoxoside 8.9 ng/mL) and decreased over five days. We observed a peak gitaloxin level (112.6 ng/mL) on the fifth day only. After administration of atropine as well as dimeticone, alginic acid, and metoclopramide, health status improved. The peak urine concentrations were reached at hour 30 and were respectively 91.3 and 69.9 ng/mL for gitaloxin and digitoxin, while those of digitoxigenin, digitoxigenin mono-digoxoside and gitoxin were lower (respectively 0.7, 1, and 5.6 ng/mL). The patient was discharged on the fifth day when there were no residual symptoms.

[Genetic hypertension in the SHR rat and circulating digitalis compounds]. / Hypertension génétique du rat SHR et composés "digitaliques" circulants.

Circulating digitalis-like compounds have been found elevated in some experimental sodium--and volume--dependent hypertensions, as well as in human essential hypertension. As few studies have been undertaken to assess their enhancement in the genetic hypertension of Okamoto (SHR) we have investigated their presence in plasma using 4 criteria: their apparent immunoreactivity with antidigoxin antibodies, their competition with tritiated ouabain binding to the sodium pump of human red blood cells,-their ability to inhibit the Na+, K+ ATPase activity of rat kidney membranes, and the Na+ fluxes from rat red blood cells. When compared to ordinary Wistar (W) and Wistar Kyoto rats (WKY), SHR exhibited a markedly enhanced apparent immunoreactivity with antidigoxin-antibodies (138 +/- 8; 59 +/- 3; 61 +/- 4 pg/ml, n = 15, 6 et 15, p less than 0.001, and p less than 0.001 respectively). The inhibition of ouabain binding by plasma extracts of the three strains did not differ (10.3 +/- 1.6, 9.9 +/- 1.7 and 12.9 +/- 1.4 ng/ml, n = 9, 18 and 14 respectively). When compared to WKY, SHR plasma extracts inhibited the renal Na+, K+ ATPase activity (75.6 +/- 2.6 vs 89.3 +/- 2.4 mumoles Pi . mg-1 . h-1, n = 11 and 10, p less than 0.01, respectively). When incubated in SHR plasma for one hour, net sodium effluxes from Wistar erythrocytes were inhibited compared to that measured in the presence of W or WKY plasma: (5.91 +/- 0.20 vs 7.68 +/- 0.25 and 7.52 +/- 0.15 mmol/l cells, n = 5, 3 and 5, p less than 0.001, and p less than 0.001 respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

[An unusual case of "catecholamine necrosis" caused by accidental digitalis poisoning]. / Un raro caso di "necrosi catecolaminica" da intossicazione digitalica accidentale.

Toxic manifestations of digitalis are one of the most prevalent adverse drug reactions encountered in clinical practice. The estimated incidence is about 20% in hospitalized patients in the USA. The authors describe a rare case of myocardial "catecholamine necrosis" (anteroseptal myocardial infarction) during accidental digitalis intoxication. A male patient, 75 years old, suffering from cirrhosis and ascites, take on by mistake a tablet of digoxin 0.25 mg. four times at day for eleven days. He hadn't heart disease in the past. At the eleventh day the patient showed a deep tiredness and so he was submitted to a clinical examination and electrocardiogram. The ECG demonstrated an anteroseptal myocardial infarction in the second-third electrical stage. The patient was hospitalized. The successive examination revealed: very high plasma digitalis concentrations; an increase of the serum levels of CPK and LDH; a significant increase of plasmatic and urinary catecholamine levels which return to normal values after fifteen days; apical akinesia at the echocardiographic examination; no signs of residual myocardial ischemia to the echo-dypiridamole stress test; normal coronary artery to the coronary arteriography and absence of coronary artery spasm to the ergonovine test. Furthermore the abdominal echography and the abdominal computerized tomography didn't reveal surrenal disease but showed an important liver disease. The patient was free from other cardiac events in the follow-up. Generally, during the digitalis intoxication we observe various rhythm and conduction disturbances. Instead in this case no serious arrhythmias were registered and the main expression of the drug toxicity was an anteroseptal myocardial infarction with undamaged coronary artery. Also the usual extracardiac symptoms and signs of the digitalis intoxication were absent in this case. All these observations can be explained with the pathological increase of the cathecholamine levels, indirectly induced by digitalis; with the direct toxic effect of the drug at the myocardic level; with the contemporary absence of ionic disturbances; with the concomitant liver disease. The direct toxic effect of the digitalis produced an increase in calcium ions availability for the electromechanical coupling and an increase of the intramyocardial pressure; the increase of the adrenergic activity determined contemporary an increase in the oxygen consumption of the myocardial cells, a rise of vascular tone and coronary artery tone and a reduction of the duration of the diastole. All these factors provoked a "primary and secondary" ischemia which evolved toward a real "cathecholamine necrosis" and produced a myocardial infarction. This hypothesis explains the myocardial infarction in absence of injury at the coronary arteriography and without coronary spasm at the ergonovine test; moreover it explains the transient increase in cathecholamine plasma levels observed in the acute phases an normalized after fifteen days. The "cathecholamine necrosis" is an anatomical definition, nevertheless in our opinion it gives account of the rare clinical situation observed.

[Specifying for the general physician. Digitalis therapy in elderly patients]. / Especificando para o generalista. A terapêutica digitálica no doente idoso.

The experimental and clinical evidence on the decreased efficacy of digitalis on old age are reviewed. The trials on the efficacy of digitalis on elderly in heart failure and sinus rythm, are analysed and we try to characterize the sub-group of responders. So we try to explain the criteria to choose the therapeutic dose, to avoid intoxication and to interpret the seric concentrations. We describe the pharmacocynetics of digitalis on old people on heart failure which can explain the susceptibility to intoxication. We reviewed the incidence of digitalis intoxication on old age and the difficulties on its recognition.

[Guidelines for prescription of the assay of digitalis glycosides by immunologic methods]. / Règles de prescription du dosage des digitaliques par méthodes immunologiques.

Digoxin, digitoxin and acetyldigitoxin are the most widely prescribed of cardiotonic glycosides. Analytical exploration can be performed by a single assay when only one compound is prescribed or by multiple assays in cases of imprecise prescription or when several glycosides are given concomitantly. In addition, the metabolic transformation of digitoxin into digoxin and the presence of endogenous "digitalis-like compounds" mean that a number of precautions must be taken during prescription. These examples underline the ambiguity of the so-called "digitalinaemia" prescriptions and the need for biologists to be supplied with maximum information by clinicians.