Digoxin is a cardiac glycoside used for patients in congestive heart failure
to increase the circulation. It is also used in patients with atrial fibrillation
and flutter to slow the ventricular rate.
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CHARACTERIZATION |
Neutralization of Free Digoxin-like Immunoreactive Components of Oriental Medicines Dan Shen and Lu-Shen-Wan by the Fab Fragment of Antidigoxin Antibody (Digibind)
Amitava Dasgupta, PhD, and Kathleen A. Szelei-Stevens, MD |
Am J Clin Pathol 2004;121:276-281 Abstract quote
Dan Shen and Lu-Shen-Wan, traditional Chinese medicines used as remedies for heart diseases, demonstrate digoxin-like immunoreactivity. The digoxin-like immunoreactive components of Lu-Shen-Wan show approximately 55% protein binding, while Dan Shen demonstrates concentration-dependent protein binding (68% bound at lower concentrations but only 25% bound at higher concentrations). Because Dan Shen and Lu-Shen-Wan can cause substantial toxic effects in patients, we studied the potential use of Digibind (Fab fragment of polyclonal antidigoxin antibody; Burroughs Wellcome, Research Triangle Park, NC) for neutralizing the pharmacologically active free fractions of Dan Shen and Lu-Shen-Wan.
Drug-free serum pools were supplemented with Dan Shen or Lu-Shen-Wan to achieve apparent digoxin concentrations expected in severe overdoses. Aliquots of supplemented serum pools were supplemented further with aqueous Digibind solution to achieve final Digibind concentrations between 5 and 20 µg/mL (expected in vivo range in patients overdosed with digoxin and being treated with Digibind).
We observed complete removal of the free apparent digoxin in the presence of Digibind for Dan Shen and Lu-Shen-Wan. Digibind binds free digoxin-like immunoreactive components of Dan Shen and Lu-Shen-Wan in vitro. |
Effect of Asian and Siberian ginseng on serum digoxin measurement by
five digoxin immunoassays. Significant variation in digoxin-like immunoreactivity
among commercial ginsengs.
Dasgupta A, Wu S, Actor J, Olsen M, Wells A, Datta P.
Department of Pathology and Laboratory Medicine, University
of Texas-Houston Medical School, 6431 Fannin, MSB 2.292, Houston, TX
77030, USA.
|
Am J Clin Pathol 2003 Feb;119(2):298-303 Abstract quote
Asian and Siberian ginsengs contain glycosides with structural similarities
to digoxin.
We studied potential interference of ginseng in 5 digoxin immunoassays
in 3 Asian (2 liquid extracts, 1 capsule) and 3 Siberian ginseng preparations
(1 liquid extract, 2 capsules). With the fluorescence polarization immunoassay
(FPIA), we observed apparent digoxin activity in 1 Asian liquid preparation
and in the liquid extract and 1 capsule form of Siberian ginseng. In
mice fed ginseng, we observed digoxin activities in the serum (Asian,
0.48-0.68 ng/mL [0.6-0.9 nmol/L]; Siberian, 0.20-0.47 ng/mL [0.3-0.6
nmol/L]), indicating that such interferences also occur in vivo.
Serum pools prepared from samples from patients receiving digoxin and
then supplemented with Asian or Siberian ginseng showed falsely increased
digoxin values using the FPIA (e.g., for Asian ginseng, 1.54 ng/mL [2.0
nmol/L] vs control value, 1.10 ng/mL [1.4 nmol/L]) and falsely decreased
values using the microparticle enzyme immunoassay (MEIA; 0.73 ng/mL
[0.9 nmol/L] vs control value, 1.04 ng/mL [1.3 nmol/L]).
Digoxin-like immunoreactive substances (DLISs) showed synergistic
effects with ginsengs in interfering with the FPIA and MEIA for digoxin.
No interference was observed with 3 other digoxin assays, even in the
presence of elevated DLISs. |
| Seven different digoxin immunoassay kits compared
with respect to interference by a digoxin-like immunoreactive substance
in serum from premature and full-term infants.
Pudek MR, Seccombe DW, Jacobson BE, Whitfield MF. |
Clin Chem 1983 Nov;29(11):1972-4 Abstract quote
Seven different digoxin immunoassay kits showed cross reactivity with
an endogenous digoxin-like immunoreactive substance consistently present
in serum of neonates, whether premature or full-term.
The degree of interference, in decreasing order was: NML greater than
New England Nuclear greater than Bio-Rad greater than Clinical Assays
greater than Becton Dickinson greater than Serono greater than Syva
(EMIT). More recently purchased NML kits showed less sensitivity to
the substance, evidently reflecting lot-to-lot differences in antibody.
A single baseline determination of the substance before digoxin is administered
inadequately compensates for this interference, because the interferent
concentrations can differ from day to day, with evidence that it may
be most concentrated on the fourth to sixth postnatal day.
Its concentration in the serum of neonates is unrelated to the concentration
of dehydroepiandrostenedione sulfate, an indicator of fetal adrenal-cortical
activity. |
| Digoxin-like substance in amniotic fluid--fact or
artifact?
Greenway DC, Nanji AA. |
Gynecol Obstet Invest 1986;22(2):108-9 Abstract quote
A digoxin-like immunoreactive substance (DLIS) has been reported in
the amniotic fluid. Since radioimmunoassay kits are standardized using
serum-based standards, we hypothesized that measurement of DLIS may
be an artifact related to the low protein content of amniotic fluid.
We analyzed 12 amniotic fluid samples before and after supplementation
with lyophilized human serum. The means +/- SDs for DLIS (nmol/l) at
protein concentrations of 0, 32 and 63 g/l were 1.4 +/- 0.16, 0.6 +/-
0.09, and 0.4 +/- 0.09 nmol/l, respectively.
We, therefore, hypothesize that DLIS in amniotic fluid may in part
be explained by a technical artifact. |
| Interference of digoxin-like immunoreactive substances
with three digoxin immunoassays in patients with various degrees of
renal function.
Pleasants RA, Gadsden RH Sr, McCormack JP, Piveral K, Sawyer WT.
|
Clin Pharm 1986 Oct;5(10):810-6 Abstract quote
The effect of renal function and digoxin use in adult patients on interference
from digoxin-like immunoreactive substances (DLIS) with three digoxin
immunoassays was studied.
Hospital patients entered into the study were categorized into the
following groups according to renal function: group I (serum creatinine
less than 1.5 mg/dL), group II (serum creatinine 1.5-2.5 mg/dL), group
III (serum creatinine greater than 2.5 mg/dL, not on hemodialysis),
and group IV (serum creatinine greater than 2.5 mg/dL, on maintenance
hemodialysis). Medical records were reviewed to determine whether or
not patients were receiving digoxin. Excess sera for analysis of serum
digoxin concentrations (SDCs) was collected from routine laboratory
tests. Serum samples were assayed singly by fluorescence polarization
immunoassay (FPIA, Digoxin I, Abbott), radioimmunoassay (RIA, Micromedic),
and affinity-column-mediated immunoassay (ACMIA, aca, E.I. du Pont).
Correlation of SDCs obtained by RIA and ACMIA with FPIA results was
determined using linear-regression analysis. A total of 177 patients
met the study criteria; 98 were receiving digoxin.
In patients on digoxin, SDCs by RIA were significantly higher than
those obtained by FPIA in group II and III patients. SDCs obtained by
ACMIA correlated well with and were not significantly different from
those obtained by FPIA in any of the patient groups. Maximum differences
and mean absolute differences in SDCs obtained by RIA were greater than
those for ACMIA when compared with FPIA values in all patient groups.
Over 40% of patients with renal dysfunction not on digoxin had false-positive
SDCs by RIA; the highest of these values was seen in groups II and III. |
| Positive and Negative In Vitro Interference of Chinese
Medicine Dan Shen in Serum Digoxin Measurement Elimination of Interference
by Monitoring Free Digoxin Concentration
Amer Wahed, MD
Amitava Dasgupta, PhD |
Am J Clin Pathol 2001;116:403-408 Abstract quote
Dan Shen, a traditional Chinese medicine used in the management of
cardiovascular diseases, is now available without prescription in the
United States from Chinese herbal stores.
We demonstrated digoxin-like immunoreactivity of Dan Shen in vitro.
Because Dan Shen is used to treat cardiovascular disease, we studied
potential interference of Dan Shen with serum digoxin measurement. Addition
of microliter quantities of Dan Shen extract to digoxin pools prepared
from patients receiving digoxin resulted in falsely elevated serum digoxin
concentrations (positive interference) as measured by the fluorescence
polarization immunoassay for digoxin (Abbott Laboratories, Abbott Park,
IL). More interestingly, serum digoxin concentrations were falsely lowered
(negative interference) when measured by the microparticle enzyme immunoassay,
also marketed by Abbott Laboratories.
Taking advantage of poor protein binding of digoxin (25%) and high
protein binding of digoxin-like immunoreactive components of Dan Shen,
we further demonstrated that the positive and negative interference
of Dan Shen in serum digoxin measurement can be eliminated by monitoring
the free digoxin concentration. |
Endogenous and Exogenous Digoxin-like Immunoreactive
Substances
Impact on Therapeutic Drug Monitoring of Digoxin
Amitava Dasgupta, PhD
|
Am J Clin Pathol 2002;118:132-140 Abstract quote
Endogenous digoxin-like immunoreactive substance (DLIS) was first reported
in volume-expanded dogs.
Its presence has been confirmed in blood, urine, and other body fluids.
Elevated DLIS concentrations are encountered in patients with volume-expanded
conditions such as uremia, essential hypertension, liver disease, and
preeclampsia. DLISs cross-react with antidigoxin antibodies and falsely
elevate serum digoxin concentrations, interfering in interpretation
of results for therapeutic digoxin monitoring. Falsely lower digoxin
values due to the presence of DLISs have been reported. The association
of DLISs with volume expansion led to speculation that they could be
natriuretic hormones. Several structures have been proposed for DLISs,
including nonesterified fatty acid, phospholipid, lysophospholipid,
bile acid, bile salt, and steroid. Exogenous DLISs can be found in serum
after ingestion of various Chinese medicines and therapy with spironolactone,
canrenone, or potassium canrenoate. Like endogenous DLISs, exogenous
DLISs interfere with serum digoxin assays, complicating therapeutic
digoxin monitoring. However, most reported endogenous and exogenous
DLISs are strongly protein-bound while digoxin is weakly protein-bound.
Therefore, interference of both endogenous and exogenous DLISs in serum
digoxin measurement can be eliminated by monitoring digoxin concentrations
in the protein-free ultrafiltrates. |
