Repeated dosing of digoxin-fragmented antibody in preterm eclampsia

Adair, Charles; Buckalew, Vardaman M.; Kipikasa, Joseph; Torres, Carlos; Briery, Christian

doi:10.1038/jp.2008.181

Cited by 10 publications

(12 citation statements)

References 13 publications

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“…Following individual case reports (15,16). Digibind has been reported to reduce blood pressure in cohort of subjects with postpartum PE (17). Data from a recent phase II B randomized, double blinded, placebo controlled clinical trial of Digibind in women with severe antepartum PE suggest that CTS-induced abnormalities could be reversed by Digibind (18).…”

Section: Discussionmentioning

confidence: 99%

DigiFab Interacts With Endogenous Cardiotonic Steroids and Reverses Preeclampsia-Induced Na/K-ATPase Inhibition

Ishkaraeva-Yakovleva¹,

Федорова

Солодовникова³

et al. 2012

Reprod. Sci.

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Elevated levels of endogenous Na/K-ATPase (NKA) inhibitors, cardiotonic steroids (CTS) including marinobufagenin (MBG), contribute to pathogenesis of preeclampsia (PE) and represent a target for immunoneutralization by Digibind (Ovine Digoxin Immune Antibody, Glaxo-Smith Kline). Because Digibind is no longer commercially available we studied whether DigiFab (BTG International Ltd, UK) can substitute Digibind for immunoneutralization of CTS in patients with PE. We compared DigiFab, Digibind and anti-MBG monoclonal antibody (mAb) with respect to their ability to interact with CTS in PE plasma and to restore NKA activity in erythrocytes from patients with PE. Using immunoassays based on DigiFab, Digibind, and anti-MBG mAb we studied the elution profile of CTS following HPLC-fractionation of PE plasma. Seven patients with mild PE (28±2 years; gestational age, 39±0.5 weeks; blood pressure 156±5/94±2 mmHg) and six normotensive pregnant subjects (28±1 years; gestational age, 39±0.4 weeks; blood pressure 111±2/73±2 mmHg) were enrolled. PE was associated with a substantial inhibition of erythrocyte NKA (1.47±0.17 vs. 2.65±0.16 μmol Pi/mL/hr in control group, P<0.001). Ex vivo, at concentration 10 μg/mL, which is consistent with the clinical dosing of Digibind administered previously in PE, DigiFab and Digibind as well as anti-MBG mAb (0.5 μg/mL) restored erythrocyte NKA activity. Following HPLC fractionation of pooled PE and control plasma, PE-associated increase in CTS material was detected by Digibind (176 vs. 75 pmoles), DigiFab (221 vs. 70 pmoles) and anti-MBG mAb (1056 vs. 421 pmoles). Therefore, because DigiFab interacts with CTS from PE plasma and reverses PE-induced NKA inhibition, it can substitute Digibind for immunoneutralization of CTS in patients with PE.

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Section: Discussionmentioning

confidence: 99%

DigiFab Interacts With Endogenous Cardiotonic Steroids and Reverses Preeclampsia-Induced Na/K-ATPase Inhibition

Ishkaraeva-Yakovleva¹,

Федорова

Солодовникова³

et al. 2012

Reprod. Sci.

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“…10 DIF has been shown to reduce blood pressure in an animal model of PE, 11 in a postpartum trial, and in anecdotal reports in women with severe PE. [12][13][14][15] Based on these reports, we conducted a double-blind, placebocontrolled, randomized trial to evaluate the effect of antepartum DIF administration on maternal and fetal outcomes in severe PE.…”

mentioning

confidence: 99%

Digoxin Immune Fab Treatment for Severe Preeclampsia

et al. 2010

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We evaluated the efficacy, safety, and biological mechanisms of digoxin immune Fab (DIF) treatment of severe preeclampsia. Fifty-one severe preeclamptic patients were randomized in double-blind fashion to DIF ( N = 24) or placebo ( N = 27) for 48 hours. Primary outcomes were change in creatinine clearance (CrCl) at 24 to 48 hours and antihypertensive drug use. Serum sodium pump inhibition, a sequela of endogenous digitalis-like factors (EDLF), was also assessed. CrCl in DIF subjects was essentially unchanged from baseline versus a decrease with placebo (-3 +/- 10 and -34 +/- 10 mL/min, respectively, P = 0.02). Antihypertensive use was similar between treatments (46 and 52%, respectively, P = 0.7). Serum sodium pump inhibition was decreased with DIF compared with placebo at 24 hours after treatment initiation (least squares mean difference, 19 percentage points, P = 0.03). DIF appeared to be well tolerated. These results suggest DIF prevents a decline in renal function in severe preeclampsia by neutralizing EDLF. Sodium pump inhibition was significantly improved. Further research is warranted.

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“…During pregnancy, maternal EDLF levels are increased in women with preeclampsia compared with those of normotensive pregnancies 1–3 . Although the reason for increased EDLFs in preeclampsia is not known, it is believed that elevated EDLF levels may contribute to increased vasoconstriction associated with maternal hypertension and reduced utero‐placental blood flow in preeclampsia 3–5 . Studies have also shown that digoxin immune Fab (DIF), a polyclonal DIF, may be beneficial to preeclampsia.…”

Section: Introductionmentioning

confidence: 99%

“…Studies have also shown that digoxin immune Fab (DIF), a polyclonal DIF, may be beneficial to preeclampsia. DIF has an antihypertensive effect to reduce maternal blood pressure and increase utero‐placental blood flow 4,5 . It could restore Na + /K + ATPase activity of red blood cells both in humans and in animals 6 .…”

Section: Introductionmentioning

confidence: 99%

Digoxin Immune Fab Protects Endothelial Cells from Ouabain‐Induced Barrier Injury

Wang

Fan

et al. 2011

American J Rep Immunol

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Problem Endogenous digitalis-like factors (EDLF) inhibit sodium pump Na+ / K+ATPase activity, and maternal EDLF levels are elevated in preeclampsia (PE). This study determined whether digoxin immune Fab (DIF) could protect endothelial cells (ECs) from EDLF-induced endothelial barrier dysfunction. Method of study ECs were treated with escalating doses of ouabain (a known EDLF) in the presence or absence of DIF. EC barrier integrity was examined by junction protein VE-cadherin and occludin expressions. EC permeability was determined by horseradish-peroxidase (HRP) leakage and transendothelial electrical resistance (TEER). Results EC junction protein VE-cadherin distribution was disrupted in cells treated with ouabain. DIF, but not control IgG Fab fragment, blocked ouabain-induced decreases in VE-cadherin and occludin expressions and prevented ouabain-induced HRP leakage and TEER changes. Conclusion DIF protects ECs from ouabain-induced barrier injury, providing evidence of beneficial effects of DIF on EC function and supporting that Na+ /K+ATPase might be a therapeutic target to ameliorate endothelial dysfunction.

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Repeated dosing of digoxin-fragmented antibody in preterm eclampsia

Cited by 10 publications

References 13 publications

DigiFab Interacts With Endogenous Cardiotonic Steroids and Reverses Preeclampsia-Induced Na/K-ATPase Inhibition

DigiFab Interacts With Endogenous Cardiotonic Steroids and Reverses Preeclampsia-Induced Na/K-ATPase Inhibition

Digoxin Immune Fab Treatment for Severe Preeclampsia

Digoxin Immune Fab Protects Endothelial Cells from Ouabain‐Induced Barrier Injury

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