Roland Valdes

An Endogenous Digoxin-Like Substance in Patients with Renal Impairment

Digoxin concentrations were measured in serum samples from 102 patients with renal impairment who were receiving digoxin therapy. Many patients had values that differed widely on several currently available immunoassays, with differences as great as 2.9 ng/mL. In contrast, patients with normal renal function who were receiving digoxin had few discrepant results, with the largest difference being 0.5 ng/mL. We also assayed serum samples from 54 patients with renal impairment not on digoxin therapy and found that more than 60% of these digoxin-free patients had false-positive digoxin values on most assays. Our data suggest that a substance with digoxin-like immunoactivity is present in many patients with renal insufficiency. This substance may seriously compromise the accuracy and interpretation of digoxin concentration measurements.

Endogenous substance in newborn infants causingfalse positive digoxin measurements

We report the detection of a digoxin-like immunoequivalent substance in the plasma of neonates and infants and in amniotic fluid. Time-course studies in individual infants indicate that the substance probably is produced endogenously and is not exclusively retained by the infants from external sources. Digoxin recovery studies demonstrated that the presence of this material caused falsely elevated digoxin values. Our results cast considerable doubt on the reliability and clinical utility of digoxin radioimmunoassay measurements on the serum or plasma of neonatal and infant patients.

Infantile hypophosphatasia: Enzyme replacement therapy by intravenous infusion of alkaline phosphatase-rich plasma from patients with Paget bone disease

Enzyme replacement therapy for a severely affected 6-month-old girl with hypophosphatasia was attempted by repeated intravenous infusions of alkaline phosphatase-rich plasma, obtained by plasmapheresis, from two men with Paget bone disease. Circulating Paget AP activity was found to have a half-life (two days) similar to that reported in adults, which did not change during a five-week period of six AP infusions. Normalization of the patients serum AP activity was followed by better control of her hypercalcemia and hypercalciuria. Sequential radiographic studies revealed arrest of worsening rickets with slight remineralization of metaphyses, although urinary excretion of the AP substrates phosphoethanolamine and inorganic pyrophosphate was unaltered by therapy. Our findings suggest that the infantile form of hypophosphatasia results from defective production of AP rather than from accelerated destruction of circulating enzyme, and that hydrolysis of AP substrates like PEA and PPi occurs primarily in tissue rather than blood. Study of additional cases of hypophosphatasia will be necessary to assess the clinical efficacy of this form of enzyme replacement therapy.

Anomalous Serum Digoxin Concentrations in Uremia

Excerpt When digoxin therapy is discontinued, it is generally assumed that the patients serum concentration of the drug will decrease over time with a half-life dependent on the rate of digoxin el...

Estrogen and progesterone receptor assays on breast carcinoma from mastectomy specimens

To determine whether autolytic loss of estrogen (ER) and progesterone (PgR) receptors might affect results of assays performed on primary carcinoma samples taken from fresh mastectomy specimens rather than from biopsy specimens, a group of 71 cases were examined, in which both types of samples were assayed. The comparisons showed a small significant reduction in the proportion of positive ER assay results in mastectomy‐primary specimens compared with biopsy specimens, although the frequency of high‐binding ER results in the mastectomy‐primary specimens was not reduced. The number of positive PgR assays on mastectomy‐primary specimens was not reduced in comparison with biopsy specimens. Correlation coefficients for ER values in the paired data were = 0.836 for biopsy versus mastectomy, and r = 0.795 for primary versus nodal metastasis. For PgR biopsy versus mastectomy r = 0.664, and for PgR primary versus node r = 0.352. The mean quantitative ER and PgR values were significantly higher in axillary lymph nodal metastases than in primary carcinomas, and the higher nodal receptor levels were explained in part by significantly higher tumor cellularity. It is concluded that while loss of ER sufficient to cause a false‐negative interpretation may possibly occur in a few cases during the course of mastectomy, as a general rule, significant losses do not occur. The performance of assays on axillary metastases in mastectomy specimens is advantageous because of their high cellularity. Cancer 52:2139‐2143, 1983.

Endogenous digoxin-like immunoreactivity in blood is increased during prolonged strenuous exercise

Digoxin-like immunoreactive factors (DLIFs) in serum may represent endogenous cardiotropic agents. We determined if blood levels of these endogenous factors changed during prolonged strenuous exercise. Total and loosely protein-bound (LPB) DLIF were measured by radioimmunoassay in the serum of nine healthy subjects during prolonged exercise to exhaustion. Mean total and LPB serum levels of DLIF increased by 72% (580 to 945 pg/mL) and 63% (53 to 91 pg/mL) over baseline values in digoxin equivalents (p less than 0.01), respectively, after three hours of exercise at 70% of VO2max. The prevalent serum nonesterified fatty acids (arachidonic, linoleic, oleic, palmitic, and stearic acids) as well as hydrocortisone did not account for the observed elevations in DLIF. Percent left ventricular fractional shortening (%FS) and mean velocity of left ventricular circumferential fiber shortening (mVCF) measured echocardiographically were lower (-18.0% and -16.4%, respectively, p less than 0.05) after exercise as compared to prior to exercise. Cardiac left ventricular dysfunction as measured by %FS did correlate with blood levels of DLIF (r = -0.680, p less than 0.02). These observations may suggest a relationship between serum levels of DLIF and cardiac fatigue.

Criteria for identifying endogenous compounds as digoxin-like immunoreactive factors in humans

Endogenous digoxin-like immunoreactive factors (DLIF) are factors in plasma that interact with anti-digoxin antibodies. In this report we propose specific empirical criteria that must be satisfied by any group of endogenous compounds purported to account for DLIF activity in human plasma. These criteria include immunoreactive potency relative to existing physiologic concentrations as well as the biochemical and protein binding properties of these compounds. Recent studies have identified several congeners of fatty acids and phospholipids, hydrocortisone, and dehydroepiandrosterone-sulfate as compounds likely to account for DLIF activity in plasma. Using the above criteria we demonstrate that the highest reported plasma concentrations of these compounds combined account for less than 25% of DLIF reported in healthy adult subjects, less than 11% in newborns, less than 27% in pregnant women, and less than 39% in patients with renal failure. Human serum albumin at a concentration of 40 g/l completely abolished any detectable interaction of these compounds with both anti-digoxin antibodies or canine kidney Na/K-ATPase. The immunoreactive and physical properties of these compounds are also not consistent with those reported for DLIF. We conclude that these compounds do not account for the plasma DLIF concentrations measured in human subjects nor are they likely to play a role as specific endogenous regulators of Na/K-ATPase.

Progesterone receptor in granulosa cell tumor

Abstract A virilizing granulosa cell tumor of the ovary contained large amounts of testosterone and progesterone and small amounts of estrogens. Assays for progesterone receptor were positive, but estrogen receptor could not be detected. The presence of progesterone receptor in the tumor is consistent with recent evidence for a role of the receptor in the physiology of the Graafian follicle, and suggests the possibility that progestational therapy may be effective in advanced stage granulosa cell tumor.