Effects of plasma lipid levels on blood distribution and pharmacokinetics of cyclosporin A.

The present study attempted to characterize the distribution of cyclosporin A (CsA) among the lipoprotein fractions, very-low-, intermediate-, low-, and high-density (VLDL, IDL, LDL, and HDL, respectively) in the plasma of patients awaiting heart transplantation and the influence of plasma lipid constituents on the pharmacokinetics of CsA. Major fractions of a therapeutic concentration of CsA were found in HDL and in LDL. In addition, plasma lipid concentrations (total cholesterol, triglycerides, phospholipids, VLDL-cholesterol--TC, TG, PL, VLDLc, respectively) are positively correlated with the CsA distribution within the LDL fraction, and negatively correlated with the CsA distribution within the HDL fraction. Thus, the percentage of CsA in each type of lipoproteins was shown to vary with the lipid levels among individuals. A significant negative correlation was found between apparent distribution volume at steady state (Vss) in plasma and TC, PL, and LDLc and between the area under the curve measured in blood (AUCB) for whole blood and PL.

Temperature-dependent immunoreactive assay to screen for digoxin-like immunoreactive factor(s).

Endogenous circulating digoxin-like immunoreactive factors (DLIF) are known to cross-react with antibodies to digoxin and to inhibit Na+/K(+)-transporting ATPase (Na+K+ATPase; EC 3.6.1.37). Moreover, increasing the immunoassay temperature from 4 to 37 degrees C markedly decreases DLIF from human cord serum. We tested several compounds, including hormonal steroids, bile salts, lipids, and methionine-enkephalin, for their ability to cross-react with two commercially available 125I digoxin RIAs, to inhibit porcine Na+K+ATPase, and to see whether they present the same incubation temperature dependence as human cord serum. Except for methionine-enkephalin, all compounds were inhibitors of Na+K+ATPase in the range of 1-10 mmol/L. Progesterone exhibited the highest cross-reactivity in the two RIAs. The apparent digoxin immunoreactivity for the majority of the cross-reacting steroids, bile salts, and linoleic acid was markedly decreased by increasing the incubation temperature from 4 to 37 degrees C, whereas estriol, pregnanediol, and nonspecific compounds (e.g., ethanol, human serum albumin) did not appear to be temperature-sensitive. Both lysophosphatidyl lipids gave an increased apparent digoxin concentration with increasing incubation temperature. Our data suggest that numerous weakly cross-reactive compounds can parallel the response of human cord serum. However, the temperature-dependent effect could be an additional criterion for identifying DLIF.

Existence of a digitalis-like compound in the human fetus.

Digoxin-like inhibitors of Na+,K(+)-ATPase have been implicated in several pathophysiological problems in the perinatal period. Aqueous endogenous digoxin-like immunoreactive substance (DLIS) was extracted from 9 different organs of a 24-week-old human fetus whose mother died after paraquat poisoning. The results indicate that this endogenous DLIS has a wide distribution in fetal tissues. The highest levels were found in gut and adrenals, and there was a correlation between these high levels and the inhibition of Na+,K(+)-ATPase. The hypothesis that DLIS originated in the fetus is of particular relevance.

[Prenatal diagnosis and treatment of auricular flutter. Apropos of a case and review of the literature]. / Diagnostic et traitement anténatal d'un flutter auriculaire. A propos d'un cas, revue de la littérature.

In newborns, atrial flutter is a rare, but severe condition. Late diagnosis was usual and based on fetal ECG. Now, fetal ultrasonography can differentiate in utero atrial flutter and other supra ventricular tachycardias; so it can be treated before development of cardiac failure. Among numerous and various available drugs, digoxin is universally recommended, but the delayed effect and the maternal serum levels to obtain effective fetal concentration of digoxin are not well known. Furthermore, endogenous "digoxin-like" substances have been found in maternal blood in late pregnancy; this finding raises the problem of the validity of monitoring the treatment only by serum digoxin levels. A case of atrial flutter, diagnosed in utero by ultrasonography and treated by digoxin before development of cardiac failure is reported. Neonatal echocardiography showed an aneurysm of the atrial septum, which needed simple monitoring. Its responsibility in the pathogenesis of the arrhythmia is unclear. Numerous cases of aneurysm of the atrial septum have been reported in healthy adults without atrial arrhythmias.

Endogenous digitalis-like immunoreactive substances in cord serum characterized by anti-digitoxin and anti-digoxin antibodies. Effect of modulated incubation conditions.

Digoxin-like immunoreactive substances (DLIS) have been extensively described in biological fluids of pregnant women, neonates and renal impaired patients, by the use of several digoxin immunoassays. In this paper a similar interference with anti-digitoxin antibodies is reported by investigating 20 cord sera. By increasing both the time and the temperature of the incubation, the levels of digitalis-like immunoreactive substances may be modulated and decreased to zero. Digitoxin- and digoxin-like immunoreactive substances have been successfully extracted with methanol and concentrated from cord serum. Our data suggest the competitive nature of DTLIS and DLIS interactions with digitalis antibodies. They also show a means of minimizing these interferences in routine digitalis immunoassays.

[Endogenous digitalis-like substances in umbilical cord blood: analytical interference or new hormones?]. / Composés digitaliques endogènes dans le sérum de cordon: interférences analytiques ou nouvelles hormones?

Endogenous substances with a digitalis-like action have been found in the newborn and in women in the first three months of pregnancy. These substances have three properties that are characteristic of cardiotonic heterosides: a positive inotropic effect; inhibition of Na+, K+-ATPase and binding with anti-digoxin antibodies. The result of this last property, when immunological methods are used to calculate the levels of digoxin, is that significant concentrations of "apparent digoxin" seem to be present although neither the mother nor the newborn child have received any digoxin. We describe the existence of concentrations of the "apparent digoxin" found in 37 cord sera using two radioimmunological methods. In the one, the concentrations were 0.88 +/- 0.20 nmol/L, and in the other 0.17 +/- 0.10 nmol/L. These results emphasize the significant differences obtained when the two methods are used for calculating levels (p less than 0.01). There was no significant variation as far as the geographical origin, the sex of the infant and associated therapy carried out at the delivery. The nature of the interference is not yet known. It could be due to natriuretic hormones or steroids. Its existence gives rise to numerous problems: the physiological role, the validity of pharmacokinetic studies and the control of treatment with digoxin in pregnant women and in the newborn.

Specific interaction between antidigoxin antibodies and digoxin-like immunoreactive substances in cord serum.

Digoxin-like immunoreactive substances (DLIS) have been quantified by two different digoxin radioimmunoassays (RIA) in 47 cord sera. The mean DLIS value (in digoxin equivalents) ranged from 0.960 (SD 0.184) to 0.181 (SD 0.104) nmol/L between the two different kits and different lot numbers of the reagents. One of the RIA methods showed an obvious lot-to-lot effect. The use of a longer incubation interval and a higher incubation temperature markedly decreased cross reactions with DLIS. The effect of modifying the incubation conditions in RIA is similar to that described for assays of steroids because the dissociation rates of the immunocomplex play a critical role. Data suggest a specific interaction between DLIS and digoxin antibodies. Control of the incubation conditions is recommended, to decrease or increase the amount of the DLIS in cord serum specimens.