Digitálicos: os resultados do DIG no século XXI / Digoxin: the results of the DIG study in the XXI century / Digitálicos: los resultados del DIG en el siglo XXI

Depois da divulgação de que não houve significância estatística na mortalidade geral do estudo DIG, a indicação dos digitálicos nos esquemas de tratamento da insuficiência cardíaca congestiva (ICC) reduziu drasticamente. Estudos post hoc, que reavaliaram os dados do DIG, indicaram que um aspecto não considerado neste ensaio multicêntrico exerce influência decisiva no prognóstico dos pacientes: a concentração sérica da digoxina. Em relação àqueles que receberam placebo, a mortalidade geral e a hospitalização foram reduzidas em pacientes com concentração de digoxina inferior a 0,9 ng/ml. No primeiro trabalho que avaliou a influência dos digitálicos em modelo experimental de ICC, verificamos em nosso laboratório que ratas com síndrome congestiva secundária a infarto do miocárdio têm a sobrevida prolongada sob tratamento com digitoxina. As informações atuais recomendam que os méritos dos digitálicos continuem a ser analisados para estabelecer adequadamente sua importância no tratamento da ICC.

After the report that there was no statistical significance in the general mortality of the DIG study, the indication of digoxin in the treatment regimens for congestive heart failure (CHF) drastically decreased. Post hoc studies that reassessed the DIG study data, indicated that an aspect that was not considered in this multicenter study has a critical influence on the prognosis of patients: the serum levels of digoxin. Regarding those that received a placebo, the general mortality and hospitalization were decreased in patients with a digoxin level < 0.9 ng/ml. At the first study that assessed the influence of digitalis in an experimental model of CHF, we verified in our lab that female rats with congestive syndrome secondary to myocardial infarction have a prolonged survival when undergoing treatment with digitoxin. The current information recommends that the merits of digoxin continue to be analyzed in order to adequately establish its importance in the treatment of CHF.

Después de la divulgación de que no hubo significancia estadística en la mortalidad general del estudio DIG, la indicación de los digitálicos en los esquemas de tratamiento de la insuficiencia cardíaca congestiva (ICC) se redujo drásticamente. Estudios post hoc, que reevaluaron los datos del DIG, indicaron que un aspecto no considerado en este ensayo multicéntrico ejerce influencia decisiva en el pronóstico de los pacientes: la concentración sérica de la digoxina. En relación a aquellos que recibieron placebo, la mortalidad general y la hospitalización fueron reducidas en pacientes con concentración de digoxina inferior a 0,9 ng/ml. En el primer trabajo que evaluó la influencia de los digitálicos en modelo experimental de ICC, verificamos en nuestro laboratorio que ratas con síndrome congestivo secundario a infarto de miocardio tienen la sobrevida prolongada bajo tratamiento con digitoxina. Las informaciones actuales recomiendan que los méritos de los digitálicos continúen a ser analizados para establecer adecuadamente su importancia en el tratamiento de la ICC.

Digoxin serum levels in patients with Chagas' cardiomyopathy and heart failure / Níveis séricos de digoxina em pacientes com insuficiência cardíaca secundária à cardiomiopatia da doença de Chagas

INTRODUCTION: The purpose of this study was to determine digoxin serum concentrations in patients with Chagas' cardiomyopathy with chronic heart failure, because little is known concerning this laboratory test in patients with this condition. METHODS: This study focuses on 29 (29 percent) out of 101 patients with chronic heart failure secondary to Chagas' cardiomyopathy receiving digoxin therapy. Digoxin was measured by the immune-enzymatic method. RESULTS: New York Heart Association Functional Class III/IV was noted in 13 (45 percent) patients. The mean potassium serum level was 4.3± 0.5mEq/L, mean creatinine serum levels 1.4± 0.3dg/100ml, and left ventricular ejection fraction 34.7± 13.8 percent. The median digoxin serum level was 1.27 (0.55; 1.79)ng/ml. Sixteen (55 percent) patients had digoxin serum levels higher than 1.0ng/ml. Abnormal digoxin serum levels were verified in 13 (45 percent) patients. Digoxin serum levels correlated moderately with creatinine serum levels (r = 0.39; p< 0.03) and negatively with sodium serum levels (r= -0.38; p= 0.03). CONCLUSIONS: Digoxin serum concentration should be measured in patients with Chagas' cardiomyopathy with chronic heart failure receiving digoxin therapy due to the potential for digoxin toxicity.

INTRODUÇÃO: O propósito deste trabalho foi o de determinar a concentração sérica de digoxina em pacientes com insuficiência cardíaca crônica secundária à cardiomiopatia da doença de Chagas porque pouco se conhece sobre os níveis séricos desse fármaco em pacientes com tal condição clínica. MÉTODOS: Foram recrutados 29 (29 por cento) de 101 pacientes com insuficiência cardíaca crônica secundária à cardiomiopatia da doença de Chagas, os quais estavam sendo tratados com digoxina. Essa droga foi medida no soro desses pacientes pelo método imunoenzimático. RESULTADOS: Treze (45 por cento) pacientes estavam no grau III/ IV da Sociedade Nova-Iorquina de Cardiologia. Os níveis séricos de potássio médio foram 4,3± 0,5 mEq/L, a creatinina sérica média 1,4± 0,3dg/100ml, e a fração de ejeção do ventrículo esquerdo 34.7± 13. 8 por cento. Os níveis séricos médios de digoxina foram 1,27 (0,55; 1,79)ng/ml. Dezesseis (55 por cento) pacientes apresentaram níveis séricos de digoxina > 1,0ng/ml. Níveis séricos anormais de digoxina foram observados em 13 (45 por cento) pacientes. Os níveis séricos de digoxina correlacionaram moderadamente com os de creatinina (r= 0,39; p< 0,03) e negativamente com os de sodium (r= -0,38; p= 0,03). CONCLUSÕES: Os níveis séricos de digoxina devem ser medidos em pacientes com insuficiência cardíaca crônica secundária à cardiomiopatia da doença de Chagas por causa do potencial para ocorrer toxicidade pela digoxina.

Comparison of target concentration intervention strategy with conventional dosing of digoxin.

Digoxin is a widely used drug in patients with congestive heart failure. The present study compared the quality of life of congestive heart failure patients on one year follow-up period with two different dosing of digoxin (5/7 therapy and 7/7 therapy in whom the target serum digoxin concentration is maintained). Quality of life significantly improved in intervention group thus emphasizing the need for continuous dosing of digoxin based on target concentration.

Pharmacokinetics of digoxin in patients with atrial fibrillation: role of the classic co-variables

This work was performed to study the pharmacokinetics of digoxin in patients suffering from atrial fibrillation [AF] after optimization of all the known classic factors contributing to inter-patient variability in serum digoxin levels, to detect if any variability in serum digoxin levels still exists or this variability is only a function of the classic co-variables so that their optimization will diminish or eliminate it. Twenty male patients suffering from AF, were selected from the Critical Care Medicine Department, Cairo University Hospitals to be enrolled in the study. A patient is initially considered to be a candidate for this study when digoxin therapy was indicated. Patients were selected to have non-significant variations in their demographics and pretreatment clinical data. Blood samples were drawn from each patient at specified intervals and the serum fractions were separated and assayed for digoxin, using digoxin enzyme multiple immunoassay technique [Emit 2000]. The results revealed unpredictable variability in serum digoxin levels among patients at each sampling time and a marked inter-patient variability in mean serum digoxin levels among individuals throughout the twenty four hours, [P value: 0.0001].Considerable inter-patient variability was also evident in digoxin pharmacokinetics. Digoxin was rapidly absorbed after dosage administration, with C[max] occurring at 0.5 to 1.0 hour in all patients. Mean T[max] was 0.575 +/- 0.18 hr. Digoxin C[max] varied from 0.86 to 6.72 ng/ml with a mean value of 3.99 +/- 1.91 ng/ml. AUC also varied greatly among patients [from 6.16 ng hr/ml to 112.14 ng hr/ml] with a mean value of 49.47 +/- 30.344 ng/hr/ml. The elimination half-life [t[1/2]] varied from 0.86 days to 7.16 days with a mean value of 2.66 +/- 1.45 days. The overall mean oral clearance also showed a great variability among patients with a mean of 9.3 +/- 8.7 ml/hr/kg [CV: 92.9%]. In conclusion: variability in serum digoxin concentrations and digoxin pharmacokinetics existed in spite of careful patient selection and optimization of all the classic co-variables known to affect digoxin concentrations, suggesting the presence of other unstudied factors; the recently evolving genetic factors might contribute to this variability

Familial hypodigoxinemic membrane Na(+)-K(+) ATPase upregulatory syndrome - relation between digoxin status and cerebral dominance.

A family with coexistence of hypotension, recurrent respiratory infection, motor tics, obsessive compulsive disorder, major depressive disorder, early onset osteoporosis, low body mass index, bulimia nervosa and healthy aging with longevity is described. The family members had hyposexual behavior, less tendency for spirituality, had no insomnia but a tendency towards increased somnolence, no addictive behaviour, had more bonding and affectionate behavior and were less creative with an average IQ. There was no vascular thrombosis, systemic neoplasm and neuronal degeneration in the index family. All members of the family were left hemispheric dominant. The level of serum digoxin, HMG CoA reductase activity and dolichol was found to be decreased in all with a corresponding increase in RBC Na(+)-K(+) ATPase activity and serum ubiquinone magnesium level. There was increase in tyrosine catabolites and a reduction in tryptophan catabolites in serum. Total and individual glycosaminoglycan fractions, carbohydrate residues of glycoproteins, glycolipids, activity of GAG degrading enzymes and glycohydrolases were decreased in serum. The concentration of RBC membrane total GAG and carbohydrate residues of glycoproteins increased while cholesterol : phospholipid ratio of membrane decreased. The activity of free radical scavenging enzymes were increased while the concentration of free radicals decreased significantly. The same biochemical patterns were observed in left hemispheric dominance as opposed to right hemispheric dominance. The significance of these findings in the pathogenesis of these disorders is discussed.

Digoxin toxicity in Thai medical patients: clinical manifestations and an appropriate diagnostic serum level.

This study considers the clinical manifestations and risk factors of digoxin toxicity and establishes an appropriate cut-off serum level for the diagnosis of toxicity. A retrospectivestudy of 125 hospitalized patients whose serum digoxin was assayed in 1998 was conducted. Of the 125 subjects, 42 (33.6%) were classified as having definite digoxin toxicity, 9 (7.2%) were classified as having probable digoxin toxicity, and 74 (59.2%) were classified as non-toxicated. Of the patients with definite digoxin toxicity, 24 (57.1%) had cardiac manifestations, seven (16.7%) had non-cardiac manifestations, and 11 had manifestations of both types. The commonest manifestation was atrial fibrillation with block. Average daily doses of digoxin in the patients with definite digoxin toxicity and those without intoxication varied from 0.125 to 0.5 ng/ml. There was no significant statistical difference in digoxin dosage between those with and those without digoxin toxicity. Seven univariate factors of digoxin toxicity were examined: logistic regression analysis showed that, serum BUN and serum chloride were independent associated factors of digoxin toxicity: the finding suggests that renal impairment and volume contraction are strong determinants of digoxin toxicity. Mean (SD) serum digoxin levels among the patients with and without toxicity were 2.28 (1.3) and 1.05 (0.6) ng/ml respectively (p = 0.000). The best cut-off level determined by Receiver Operating Characteristic (ROC) analysis was 1.97 ng/ml. However, a low sensitivity and a high specificity make serum digoxin levels a diagnostic rather than a screening tool. The manifestations of digoxin toxicity among Thai inpatients are no different from those of other populations. The best cut-off level of serum digoxin for the diagnosis of toxicity is 2 ng/ml.

Inhibition of membrane Na+-K+ ATPase activity: a common pathway in central nervous system disorders.

OBJECTIVES: The study was conducted to assess the role of hypothalamic digoxin in neuropsychiatric and systemic disorders. A hypothesis regarding the central role of hypothalamic digoxin in neuroimmunoendocrine integration is proposed. METHODOLOGY: Blood samples from patients of CNS glioma, multiple sclerosis, systemic lupus erythematosis, subacute sclerosing panencephalitis, primary generalized epilepsy, Parkinson's disease, Down syndrome, AIDS dementia with neuropsychiatric features, syndrome X with multiple lacunar state, senile dementia, familial group (a family with familial coexistence of schizophrenia, Parkinson's disease, primary generalized epilepsy, malignant neoplasia, rheumatoid arthritis and syndrome X over three generations), schizophrenia and manic depressive psychosis were analysed for RBC membrane Na+-K+ ATPase, levels of digoxin and Mg++. RESULTS: Inhibition of RBC membrane Na+-K+ ATPase activity was observed in most cases along with increase in the levels of serum digoxin and decrease in the level of serum Mg++. CONCLUSION: The decreased Na+-K+ ATPase activity can be due to increased digoxin, which is a potent inhibitor of this enzyme. The inhibition of Na+-K+ ATPase can contribute to increase in intracellular calcium and decrease in magnesium, which can result in 1) defective neurotransmitter transport mechanism, 2) neuronal degeneration and apoptosis, 3) mitochondrial dysfunction, 4) defective golgi body function and protein processing dysfunction, 5) immune dysfunction and oncogenesis. The mechanism of how increased intracellular calcium and decreased magnesium can contribute to the above effects is discussed.

Serum and tissue glycoconjugates, digoxin and magnesium levels in chronic calcific pancreatitis.

BACKGROUND: Endogenous or exogenous digoxin can lead to membrane Na+,K+-ATPase inhibition and hypomagnesemia. Low magnesium levels can lead to increased glycosaminoglycans (GAG) concentration in many organs. Aim: To measure the serum levels of pancreatic GAG and glycoproteins, two major components of the extracellular matrix, in patients with chronic calcific pancreatitis (CCP). Serum levels of magnesium and digoxin were also assessed. METHODS: Patients with CCP and age- and sex-matched healthy control subjects (15 each) were studied. Serum GAG, Mg and digoxin levels were measured. RBC membrane Na+,K+-ATPase activity was also assessed. Pancreatic tissue obtained at autopsy from seven patients with CCP and sex- and age-matched healthy subjects who had died in accidents were also tested for GAG and glycoproteins. RESULTS: Total GAG levels were significantly increased in the serum and pancreas of patients with CCP. This was associated with lower serum Mg levels, increased serum digoxin levels and decreased RBC membrane Na+,K+-ATPase activity. CONCLUSION: Exogenous or endogenous digoxin-induced hypomagnesemia and the consequent altered glycoconjugate metabolism may be important in the pathogenesis of CCP.

Hypothalamic digoxin and irritable bowel syndrome.

BACKGROUND: The hypothalamus produces an endogenous membrane Na+-K+ ATPase inhibitor digoxin that can modulate neurotransmitter transport and may play a role in hemispheric dominance. It can also modulate glycoconjugate synthesis and thus affect synaptic connectivity in the bowel wall. Digoxin could play a role in the genesis of irritable bowel syndrome (IBS). AIM: To study digoxin status in IBS and to correlate it with hemispheric dominance. METHODS: The isoprenoid pathway, tryptophan/tyrosine catabolic patterns and glycoconjugate metabolism were assessed in patients with IBS and in right hemispheric dominant/left hemispheric dominant/bihemispheric dominant individuals. RESULTS: The isoprenoid pathway was upregulated in IBS, with increased HMG CoA reductase activity (0.8 [0.07] vs 0.4 [0.06] in controls; p<0.01), serum digoxin (14.8 [1.0] vs 29.0 [1.2] ng/dL; p<0.01) and dolichol levels (63.8 [3.0] vs 120.3 [3.6] mg/dL; p<0.01). RBC membrane Na+-K+ ATPase activity (3.0 [0.2] vs 1.0 [0.1] microg/p/mg protein; p<0.01), serum magnesium (1.7 [0.1] vs 1.0 [0.1] mg/dL; p<0.01) and ubiquinone (86.4 [5.9] vs 39.8 [1.2] microg/dL; p<0.01) were reduced. There was increase in tryptophan catabolites and reduction in tyrosine catabolites. Serum total glycosaminoglycan and carbohydrate component of glycoproteins were increased in IBS. The activity of glycosaminoglycan degrading enzymes and glycohydrolases were increased. This pattern correlated with those obtained in right hemispheric chemical dominance. CONCLUSION: Hypothalamic digoxin and right hemispheric dominance could play a role in the genesis of irritable bowel syndrome.

Hypothalamic digoxin and neural regulation of blood pressure and vascular thrombosis.

The isoprenoid pathway produces three key metabolites--digoxin (membrane sodium-potassium ATPase inhibitor and regulator of neurotransmitter/aminoacid transport), dolichol (regulates N-glycosylation of proteins) and ubiquinone (free radical scavenger). This was assessed in patients with essential hypertension, familial hypotension, acute coronary artery disease and acute thrombotic strokes. The pathway was also assessed in patients with right hemispheric, left hemispheric and bihemispheric dominance for comparison. In patients with acute coronary artery disease, acute thrombotic stroke, essential hypertension and right hemispheric dominance, there was elevated digoxin synthesis, increased dolichol and glycoconjugate levels and low ubiquinone and high free radical levels. There was also an increase in tryptophan catabolites, reduction in tyrosine catabolites, increase in cholesterol-phospholipid ratio and a reduction in glycoconjugate level of RBC membrane in this group of patients as well as in those with right hemispheric dominance. In patients with familial hypotension and left hemispheric dominance, the patterns were reversed. The role of a dysfunctional isoprenoid pathway and endogenous digoxin in the pathogenesis of essential hypertension and familial hypotension and in thrombotic vascular disease in relation to hemispheric dominance is discussed.

Digoxina: ¿tratamiento continuo o discontinuo? / Digoxin: continuous or discontinuous treatment?

En nuestro país los pacientes con insuficiencia cardíaca (IC) que reciben tratamiento crónico con digoxina, habitualmente lo suspenden dos días consecutivos a la semana por indicación médica. Probablemente el objetivo sea disminuir la toxicidad digitálica. Conociendo la farmacocinética de la droga, esta suspensión reduciría su concentración plasmáatica alrededor del 40 al 50 por ciento, quedando debajo de los niveles considerados terapéuticos (0.8 mug/l a 2 mug/l). Los objetivos del trabajo fueron: 1) analizar la disminución de los nivels plasmáticos de digoxina luego de interrumpir la droga durante dos días consecutivos 2) comparar las concentraciones plasmáticas de digoxina entre pacientes que reciben la droga en forma continua y aquellos que realizan tratamiento discontinuo. Se efectuó un ensayo clínico randomizado, con ciego simple. Se incluyeron 36 pacientes con insuficiencia cardíaca por disfunción sistólica con ritmo sinusal o fibrilación auricular. El grupo 1 (19 pacientes) recibió tratamiento continuo y el grupo 2 (17 pacientes) tratamiento discontinuo de lunes a viernes. En el grupo continuo los valores del lunes (1.06 + 0.55 mug/l) no mostraron diferencias estadísticamente significativas con los del viernes (1.1 + 0.57 mug/l). En el grupo discontinuo los niveles del lunes (0.611 + 0.396 mug/l) disminuyeron significativamente con la suspensión de la droga con respecto a los del viernes (1.04 + 0.58 mug/l) siendo la p =0.000002. Se concluye que el régimen con suspensión semanal durante dos días consecutivos disminuye significativamente los niveles séricos de digoxina a concentraciones consideradas subterapéuticas. El régimen de tratamiento continuo demostró que mantiene la digoxinemia constante y en rango útil. Ajustando la dosis de digoxina según el clearance de creatinina los nivels séricos promedio de la droga son adecuados (alrededor de 1 mug/l). Estos resultados sugieren que la intoxicación digitálica se podría prevenir ajustando la dosis diaria de la droga de acuerdo a la función renal del paciente, más que interrumpiendo el tratameiento como es habitual en nuestro país.

Cardiac surgery and plasma digoxin levels.

Cardiopulmonary bypass (CPB) can induce several haemodynamic alterations and therefore influence pharmacokinetics of various drugs. In order to assess the effect of CPB on plasma digoxin levels, these were monitored in patients undergoing open heart surgery involving CPB (n = 11), over a 24 hour period, starting just prior to commencement of surgery. For comparison, plasma digoxin was also monitored in a group of patients (n = 10) who underwent cardiac surgery not involving CPB. In 7 of the 11 patients in the CPB group, plasma digoxin levels (ng/ml) were significantly (p < 0.01) lower at the end of 24 hours (0.654 +/- 0.094) than basal levels (1.3114 +/- 0.2498). In contrast, in the non CPB group, 7 of 10 patients showed significantly higher (p < 0.001) plasma levels (ng/ml) at the end of 24 hours (0.477 +/- 0.125) as compared to basal levels (0.26 +/- 0.098). Thus, rather than the type of surgery, it appears that the pre-operative levels of plasma digoxin influence its pharmacokinetics.

Investigation into the possible mechanisms involved in altered digoxin levels in diabetic patients.

The present study was undertaken to investigate the possible factors which may contribute to the altered digoxin levels in diabetic patients. The digoxin levels were found to be significantly higher in diabetics (1.74 +/- 0.09 ng/ml) as compared to non-diabetics (0.76 +/- 0.07 ng /ml). There was a positive correlation between digoxin levels and glycosylated haemoglobin levels. All diabetic patients had serum creatinine, urea and potassium levels within normal limits. However, serum TSH levels were found to be significantly higher in diabetics as compared to controls. Serum tri-iodo-1-thyronine (T3) levels were found to be lower in diabetics as compared to non-diabetics. Our data suggests that diabetes-mellitus causes alteration of digoxin levels. One of the causes of this increase in digoxin levels may be a tendency towards mild hypothyroidism associated with diabetes mellitus.

La digoxina es efectiva en el tratamiento de pacientes con insuficiencia cardíaca y ritmo sinusal / Digoxin is effectiveness in the treatment of cardiac failure and sinus rhythm patients

Due to differences in treatment effect in studies on the effectiveness of digoxin in patients with congestive heart failure in sinus rhythm, a cross-over placebo-controlled randomized double blind clinical trial was performed. Thirty one patients, without previous treatment with digoxin, in New York Heart Association (NYHA) functional class II to IV, with a dilated left ventricle and/or ventricular systolic dysfunction were included. Patients received digoxin, adjusted for blood levels, or placebo, during an 8 week period, prior to crossing over to the other treatment for another 8 weeks. The order of tretments was randomly allocated. Outcome measurement were performed at the end of each 8 week period. Digoxin, compared with placebo, improved NYHA class, 6,9 por ciento vs 41.4 por ciento (p=0.013) and increased the treadmill exercise time, 406 ñ 204 s vs 484 ñ 185 s (p=0.003). During the digoxin treatment the left ventricular and systolic diameter was reduced from 52.9 ñ 8.9 to 50.1 ñ 9.7 mm (p=0.009). No significant difference was observed in the left ventricular end diastolic diameter (LVED) of the left ventricle and in a estimation of quality of life. In conclusion, digoxin treatment produced a significant improvement in functional capacity, exercise time and left ventricular performance

Does any correlation exist between a high plasma digoxin concentration and an electrocardiogram in younger and older patients.

In a group of 152 elderly patients (age range between 65 to 92 years) and 54 patients (aged 35 to 64 years) plasma digoxin level measuring 2.5-6.2 nmol/1 were correlated with the clinical symptoms and the electrocardiogram. The conduction disturbances and arrhythmias as well as the P-R interval, P-T-Q index and corrected Q-T interval in the ECG were analyzed. The clinical symptoms of hypersaturation with digitalis were present in 54.6% of the elderly and 35.2% of the younger patients. Conduction disturbances were found in 42% of the elderly and 22.2% of the younger patients, while arrhythmias appeared in 40.1% of the elderly and 31.5% of the younger ones. 17.8% of the elderly and 46.3% of the younger patients were without these changes. The correlation between P-R interval and high plasma digoxin level in the elderly (p < 0.01) and younger patients (p < 0.05), as well as between the P-T-Q index and high plasma digoxin level in the elderly (p < 0.01) was found. There was no correlation between the corrected Q-T interval and high plasma digoxin level in both groups. No correlation was found between a high plasma digoxin level and serum creatinine level in both groups, neither between a high plasma digoxin level and serum potassium level in both groups. The effect of digitalis has not been shown to be a cause of specific changes in an electrocardiogram neither in the elderly nor in younger patients. However, the association between prolonged P-R interval as well as changes in the P-T-Q index and high plasma digoxin level has been found more often in the elderly than in the younger patients.

Concentraciones séricas de digoxina en niños tratados con beta metil digoxina / Serum digoxin in children treated with ß methyl digoxin

Se midieron concentraciones séricas de digoxina con el método de inmunofluorescencia polarizada (TDxII System Abbot Diagnostic Inc.) en 59 muestras de sangre tomadas de 53 pacientes pediátricos en tratamiento de mantención oral con ß metildigoxina. Se consideró como margen terapéutico las concentraciones séricas entre 0,9 y 2,25 ng/ml plasma. Se midió, además, Na, K y cratinina plasmática. En 8 muestras la concentración sérica fue inferior mínimo terapéutico de 0,9 ng/ml, la dosis de mantención fluctuaba entre 1,3 y 8,6 *g*kg*día (promedio 5,6 ñ 2,8) y entre ellos no hubo casos de toxicidad. En 36 muestras la concentración sérica estaba dentro de los márgenes establecidos como terapéuticos, las dosis de mantención de metildigoxina habían variado entre 5 y 12,5 *g*kg*día (promedio de 8,9 ñ 2,0) y entre ellos se detectó un caso de toxicidad, con concentración sérica de 2,0 ng/ml. En 15 muestras la concentración sérica superó la máxima del margen terapéutico establecido y 11 de ellas (73%) coincidieron con signos de toxicidad cardíacos y, o, digestivos en los respectivos pacientes. En 6 de estos 11 casos había coincidentemente insuficiencia renal aguda, que en 4/6 era subclínica y en 2/4 prerrenal. En el total de los 12 casos que presentaron toxicidad a partir de concentración sérica de 2,4 ng/ml, por lo que el margen terapéutico escogido para ésta parece adecuado; en niños los signos de toxicidad deben buscarse siempre y en los casos críticos o si se sospecha la posibilidad de insuficiencia renal, en el curso del tratamiento, conviene determinar dicha concentración sérica. En la práctica clínica los signos de toxicidad son predominantemente digestivos. La dosis de mantención con metildigoxina entre 7 y 10 *g*kg*día es razonablemente segura

Concentraçöes séricas, período de meia-vida e efeito sobre o eletrocardiograma, após aplicaçäo única ou repetida de digoxina em cäes sadios / Serum concentrations, half-life and effect on the electrocardiogram after single or repeated digoxin administration in healthy dogs

As concentraçöes séricas (CS) de digoxina foram medidas com auxílio de um método enzimático, por um período de 72 h, após aplicaçäo única intravenosa (iv.) ou oral. Mediram-se também as concentraçöes na fase platô, após a aplicaçäo repetida do glicosídio. Nesta fase, realizaram-se traçados eletrocardiográficos no momento da obtençäo das amostras de sangue. As concentraçöes de digoxina no soro após aplicaçäo de doses iguais por via i.v. ou oral näo diferiram estatisticamente (P>0,05). A concentraçäo sérica média de digoxina na fase platô foi de 1,60 ng/ml, após tratamento oral com dose inicial de 0,04 mg/kg p.v./dia, durante 3 dias e com dose de manutençäo de 0,02 mg/kg p.v./dia, durante 12 dias. O período de meia-vida sérica da digoxina, a partir da fase platô de um tratamento com duraçäo de 15 dias, foi de 29,2 horas. Nos eletrocardiogramas observou-se que o intervalo PQ aumentou em 0,02 seg. ou mais, quando comparado aos valores iniciais. Registrou-se bloqueio atrioventricular de 1§ grau (PQ>0,14 seg.) em um dos cäes tratados, em relaçäo a concentraçäo sérica de digoxina de 1,95 ng/ml