Long-term Outcome of Irish Wolfhound Dogs with Preclinical Cardiomyopathy, Atrial Fibrillation, or Both Treated with Pimobendan, Benazepril Hydrochloride, or Methyldigoxin Monotherapy.

BACKGROUND: Dilated cardiomyopathy (DCM) is a common cause of morbidity and mortality in the Irish Wolfhound (IW). However, the benefit of medical treatment in IW dogs with preclinical DCM, atrial fibrillation (AF), or both has not been demonstrated. OBJECTIVES: Compare the time to develop congestive heart failure (CHF) or sudden death in IW dogs with preclinical DCM, AF, or both receiving monotherapy with pimobendan, methyldigoxin, or benazepril hydrochloride. ANIMALS: Seventy-five client-owned IW dogs. METHODS: Irish Wolfhound dogs were prospectively randomized to receive pimobendan (Vetmedin®), benazepril HCl (Fortekor®), or methyldigoxin (Lanitop®) monotherapy in a 1:1:1 ratio in a blinded clinical trial. The prospectively defined composite primary endpoint was onset of CHF or sudden death. To assure stringent evaluation of treatment effect, data from dogs complying with the study protocol were analyzed. RESULTS: Sixty-six IW fulfilling the study protocol included 39 males, 27 females; median (interquartile range) age, 4.0 years (3.0-5.0 years) and weight, 70.0 kg (63.0-75.0 kg). Primary endpoint was reached in 5 of 23 (21.7%) IW receiving pimobendan, 11 of 22 (50.0%) receiving benazepril HCl, and 9 of 21 (42.9%) receiving methyldigoxin. Median time to primary endpoint was significantly longer for pimobendan (1,991 days; 65.4 months) compared to methyldigoxin (1,263 days; 41.5 months; P = .031) or benazepril HCl-(997 days; 32.8 months; P = .008) treated dogs. CONCLUSIONS AND CLINICAL IMPORTANCE: In IW dogs with preclinical DCM, AF or both, pimobendan monotherapy significantly prolonged time to onset of CHF or sudden death than did monotherapy with benazepril HCl or methyldigoxin.

Impact of ABCB1 (MDR1) gene polymorphism and P-glycoprotein inhibitors on digoxin serum concentration in congestive heart failure patients.

Digoxin, a drug of narrow therapeutic index, is a substrate for common transmembrane transporter, P-glycoprotein, encoded by ABCB1 ( MDR1 ) gene. It has been suggested that ABCB1 polymorphism, as well as co-administration of P-glycoprotein inhibitors, may influence digoxin bioavailability. The aim of the present study was to evaluate the effects of ABCB1 gene polymorphism and P-gp inhibitor co-administration on steady-state digoxin serum concentration in congestive heart failure patients. Digoxin concentrations as well as 3435C > T and 2677G > A,T ABCB1 single nucleotide polymorphisms, were determined in 77 patients administered digoxin (0.25 mg daily) and methyldigoxin (0.50 mg daily), some of them co-medicated with known P-glycoprotein (Pgp) inhibitors. Significant differences were noted in digoxin serum concentrations (C(min,ss)) between patients co-administered and not co-administered P-gp inhibitors: 0.868 +/- 0.348 and 0.524 +/- 0.281 for digoxin (p < 0.002), as well as 1.280 +/- 0.524 and 0.908 +/- 0.358 for methyldigoxin (p < 0.02), respectively. No influence of ABCB1 2677G > A,T and C3435C > T polymorphisms on digoxin concentration was noted. Although some of the previous studies have shown that digoxin pharmacokinetics might be affected by ABCB1 genetic polymorphism, those modest changes are probably clinically irrelevant, and digoxin dose adjustment should include P-gp inhibitor co-administration rather than ABCB1 genotyping.

[Isolated non-compaction of the left ventricular myocardium in a neonate--a case report]. / Kardiomiopatia gabczasta u noworodka.

We describe a case of a neonate who developed cardiogenic shock 24 days after birth. Echocardiography revealed congenital anomaly--isolated non-compaction of the left ventricular myocardium. Medical treatment was effective. The whole clinical presentation suggests the Barth syndrome. The diagnosis and treatment of this condition are discussed.

[Digoxin-like immunoreactivity in newborn infants--a pitfall of digoxin therapy?]. / Digoxin-ähnliche Immunoreaktivität bei Neugeborenen--eine Falle bei der Digoxintherapie?

Endogenous digoxin-like immunoreactive substances (DLIS) show crossreactions with different immunoassays used for digoxin drug monitoring. In 61 blood samples of 47 eutrophic healthy newborns with jaundice, digoxin serum concentrations were measured during examination of serum bilirubin using a digoxin polarisation immunoassay. Although there was no digoxin therapy in any case, we found positive serum digoxin immunoreactivity (> or = 0.2 ng/ml) in 86% of serum samples. The mean DLIS-concentration was 0.43 +/- 0.19 ng/ml with a maximum of 0.9 ng/ml. We found a significant indirect correlation (rs = -0.34; p = 0.05) between age and serum DLIS concentration. A case report demonstrates the possibility of DLIS interference on digoxin drug monitoring.

[Analysis of the use of digitalis in a sample of the geriatric population]. / Analiza primjene digitalisa u uzorku gerijatrijske populacije.

Rationality of digitalis use in 20 elderly patients in long term-care institution was analysed using the method of correlation of the past medical history, clinical examination and basic laboratory findings. After consultation of clinical pharmacologist, general practitioner and medical biochemist it was possible to stop the digoxin therapy in 6 (30%) of the patients. Four (20%) patients were hypersaturated with digoxin. Lack of indication was the reason for stopping the digitalis in one of them. Therapy was modified in 3 patients. Use of digitalis was rational in 10 (50%) of the patients. The results suggest that digitalis was prescribed too often in this sample of the elderly patients.

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

Concentrations of serum digoxin were measured by the polarized immunofluorescence Abbot TDx11 method in 59 samples from 53 children under treatment with mean beta methyl digoxin doses of 8.9 +/- 2.0 micrograms.kg.day. The therapeutic range for serum digoxin concentration was estimated to be 0.9 to 2.25 ng/ml. Simultaneous Na, K and creatine serum concentrations were measured. In 36 samples mean serum digoxin level was 1.52 +/- 0.45 ng/ml -within therapeutic range- and in only one of these cases clinical evidence of toxicity was apparent. In 15 samples digoxin level was above the therapeutic range and 11 patients of this group (73%) showed clinical signs of toxicity, consisting in arrythmias (six cases: supraventricular in 5 patients, ventricular in one child) and gastrointestinal symptoms (eight patients). Six patients with digoxin levels over therapeutic range and signs of digitalis toxicity had coincidental acute renal failure, which in 4 cases was subclinical--in 2 of these late it was pre-renal- and, in spite of this, all were inadvertently given the usual dosage of beta methyl digoxin. Almost invariably there was clinical evidence of toxicity when digoxin serum levels were above 2.4 ng/ml, so established maximal therapeutic level at 2.25 ng/ml seems adequate. Signs of digitalis toxicity must be looked on systematically in children treated with such drugs. In the critically ill or in children with acute renal failure it is necessary to monitor serum digoxin concentration. Among the clinical signs of toxicity, gastrointestinal symptoms are more frequent in children. An oral dose from 7 to 10 micrograms.kg.day of beta methyl digoxin in recommended.

Beta-methyl digoxin: a better absorbable digoxin.

Since Megges and Repke [1961] showed that acetylation of the hydroxyl groups in the aglycone or the sugar side chain of the digitalis molecule results in a derivative with enhanced and more complete absorption from the gastrointestinal tract, several new compounds resulting from acetylation or methylation of digoxin molecule have been developed. Beta-methyl digoxin (beta-methyl digoxin) is a methyl derivative (methyl group in position 4 of the digitoxose residue) of digoxin. Enhanced and more complete gastrointestinal absorption of tritium labeled beta-methyl digoxin [Rennekamp et al. 1972] has been confirmed. Weiss et al. [1975], based on the serum levels following oral administration, calculated that to achieve comparable levels, digoxin dose would have to be increased by 1.55 times compared to that of beta-methyl digoxin. These and other studies supported an earlier notion that beta-methyl digoxin was a better and desirable cardiotropic agent than the digoxin. Comparison of cardiac effects using equivalent doses of the two compounds however, showed no difference [Das et al. 1977]. Following oral administration, the serum glycoside levels to beta-methyl digoxin indeed were significantly greater than those with digoxin. However, these differences in serum levels were not of sufficient magnitude to influence detectable cardiac inotropic effects, hence, the search for a better digoxin should continue.

[Use of beta-methyldigoxin preparations medilazine and bemecor in patients with congestive heart failure]. / Primenenie preparatov beta-metildigoksina medilazina i bemekora u bo'lnykh s zastoinoi serdechnoi nedostatochnos'tiu.

The two agents beta-methyldigoxin (medixin), a Soviet medilazide, and bemecor (digicor), a foreign analogue (LEK, Yugoslavia) were comparatively evaluated. An equal high (85%) clinical efficacy of the drugs was found in 81 patients with varying stages of heart failure. A positive therapeutic effect was accompanied by lower heart rate, higher diuresis and natri-and kaliuresis, decreased systolic and diastolic pressures in the pulmonary artery. The incidence of adverse reactions and the causes of their occurrence are analyzed.

[Individual glycoside therapy using serum concentration determination in heart insufficiency of horses]. / Individuelle Glykosidtherapie mittels Serumkonzentrationbestimmung bei der Herzinsuffizienz des Pferdes.

23 horses and one donkey with congestive heart failure are treated with a standardized methyldigoxin dose (0.0032 mg/kg of body weight). The therapy is controlled by the serum concentration of the cardiac glycoside. 4 horses have a higher and 13 horses a lower serum concentration as necessary for therapeutic approach. The influence of additional diseases and medications is demonstrated. Finally a rule for the evaluation of the individual therapeutic glycoside-dose is given.

Direct intrauterine fetal treatment of fetal tachyarrhythmia with severe hydrops fetalis by antiarrhythmic drugs.

In cases of non-immune hydrops fetalis caused by tachyarrhythmias, the transplacental passage of antiarrhythmic drugs may be hampered. When this is proven by fetal blood sampling in cases of tachyarrhythmia refractory to transplacental treatment, additional administration of antiarrhythmic drugs into the fetus is necessary and seems to improve the results. Although injections of antiarrhythmic agents in fetal ascites are also highly effective, intravascular administration by sonographic guidance is to be preferred. Then, simultaneous measurements of fetal and maternal drug levels are possible for the evaluation of pharmacokinetics and for monitoring the antiarrhythmic therapy.

[Determinants of plasma digoxin and digitoxin concentrations in elderly patients. A multivariate analysis]. / Determinanten von Digoxinund Digitoxinplasmakonzentrationen bei älteren patienten. Eine multivariate Analyse.

In 1063 patients (greater than or equal to 60 years, 531 men, 532 women) the plasma concentration during digitalis maintenance therapy (metildigoxin, n = 356, beta-acetyldigoxin, n = 359, and digitoxin, n = 348) was determined and related to sex, age, body weight, serum potassium, renal function and the prescribed daily maintenance dose. Classification of treatment groups according to renal function (Crea less than or equal to 1.3 mg/dl parallel greater than 1.3 mg/dl) did not show any difference of the mean maintenance doses. In multiple linear regression analyses only a weak relationship between plasma digitalis concentration and the studied variables was found, which could be equally attributed to dose, creatinine and serum potassium in the digoxin derivative groups, whereas for digitoxin only body weight had a significant effect on the plasma concentration. During a maintenance dose of 0.07 or 0.1 mg/die which was given to 87% of patients in the digitoxin group, 70% were found to have plasma levels within the therapeutic range.

Variances in pharmacokinetic parameters due to assay methods for beta-methyldigoxin.

A digoxin radioimmunoassay (RIA) or fluorescence polarization immunoassay (FPIA) kit is frequently used in routine therapeutic drug monitoring (TDM) of beta-methyldigoxin (MD) by applying a calibration curve made using the corresponding digoxin calibrators. The variances in the plasma levels (61 samples) and pharmacokinetics (5 patients) due to these two different assay methods for MD were examined in our patients with congestive heart failure. Although the plasma levels of MD measured by these methods were well correlated (r = 0.956, p less than 0.001) to each other over a wide range, RIA showed significantly lower values (p less than 0.01) in the subtherapeutic range (less than 0.80 ng/ml), but significantly higher values (p less than 0.002) in the therapeutic and toxic ranges (0.80-2.00 and 2.00 less than ng/ml), respectively than FPIA. This trend occurred with increasing concentrations. When MD samples, spiked in normal human plasma, were analyzed by these methods, RIA showed almost true MD values and gave larger values than FPIA with a mean ratio of FPIA to RIA of 0.83. In contrast, normal plasma samples, each spiked with a MD metabolite such as digoxigenin-bisdigitoxide or digoxigenin-monodigitoxide, showed higher values by 10 to 22% in FPIA. These observations are in good agreement with the findings obtained in a pharmacokinetic study that RIA gave significantly higher levels than FPIA, only in the early stage after MD administration, resulting in a smaller total volume of distribution and a larger beta value in the elimination phase, as compared with FPIA.(ABSTRACT TRUNCATED AT 250 WORDS)

[Clinical importance of determining the digoxin level in the serum in long-term beta-methyldigoxin treatment]. / Klinichno znachenie na opredelianeto na digoksinovoto nivo v seruma pri produlzhitelno lechenie s beta-metildigoksin.

The digoxin level was determined by radioimmunologic method in 54 patients with cardiac failure on constant maintaining glycoside treatment with beta-methyldigoxin in doses of 0.7-0.1, 4 mg weekly. The results showed that: Between the maintaining dose of Beta-Methyldigoxin and the serum digoxin level there is not always parallelism in cases of achieved cardiac compensation. In spite of that the achievement of cardiac compensation and its maintainance in more than 85% of the cases is possible with a mean dose of Lanitop 1.0 mg weekly and digoxin serum level between 1.0 and 2.0 ng/ml. Between the toxic manifestations observed and the doses applied there is not a strong correlation. But the high digoxin levels are always potentially toxic.

The heart rate slowing effect of pindolol in patients with digitalis resistant atrial fibrillation and heart failure.

Heart rate (HR) slowing action and the possible negative inotropic effect of pindolol (P) (daily dose +/- standard error of the means (SEM): 14.7 +/- 1.6 mg) were studied in 12 patients with heart failure and with rapid atrial fibrillation (AF) resistant to effective beta-methyl dioxin (BMD) doses (mean plasma digoxin concentration +/- SEM: 2.05 +/- 0.17 ng/ml). Mild bicycle ergometer exercise test with the same work load was performed under both BMD and combined BMD--P therapy. Rest exercise and 5 minute recovery HR were significantly lower under combined BMD--P therapy than under BMD alone (80.8 +/- 3 vs. 101 +/- 4.5 beats/min, 123.8 +/- 3.9 vs. 155.8 +/- 7.6 beats/min and 84.9 +/- 2.6 vs. 105.1 +/- 4.5 beats min respectively, p less than 0.001, paired t test). Differences in cardiac volume were not significant (1.131 +/- 76 vs. 1.116 +/- 92 ml). Although all patients were clinically improved under combined BMD--P therapy the 13 to 14% increase in cardiac volume noted in 3 cases could be related to some negative inotropic effect of P. It is concluded that in patients with heart failure and with rapid AF resistant to digitalis, the association of P to digitalis is effective in rest- and mild-exercise HR control without a clinically expressed negative inotropic effect.

[Pharmacological and clinical research on the interaction of digitalis and amiodarone in heart disease patients with varying degrees of cardiac insufficiency]. / Ricerca farmacologico-clinica sull'interazione digitale-amiodarone in pazienti cardiopatici con insufficienza cardiaca di vario grado.

The increasing use of amiodarone as antiarrhythmic drug has raised the possibilities of dangerous effects from amiodarone-digitalis interaction. We have studied twelve patients who were taking digitalis and to whom amiodarone was administered because of arrhythmias. We found a 75,42% increase of digitalis plasma levels (p less than 0,001) in the early days of amiodarone therapy, and a 52,1% increase (p less than 0,001) in the medium term. An inverse correlation was found (r = -0,65; p less than 0,05) between the plasma levels of digitalis during the steady-state control period and during the following 2-to-6 months evaluation. Acute episodes of cardiac failure caused in our patients an abrupt increase of digitalis plasma levels: in three patients digitalis toxicity occurred. Based on our experience, we recommend that the dose of digitalis be halved when the two drugs are given together in patients with various degree of cardiac failure; moreover digitalis plasma levels should be frequently monitored in these patients. On the other hand digitalis administered according to age, sex, weight, kidney function, together with amiodarone, can be given at full dosage in patients without cardiac failure.