Digoxin Immune Fab Treatment for Severe Preeclampsia

C. David Adair; Vardaman M Buckalew; Steven W Graves; Garrett K Lam; Donna D Johnson; George Saade; David F Lewis; Christopher Robinson; Theodore M Danoff; Nikhil Chauhan; Moana Hopoate-Sitake; Kathy B Porter; Rachel G Humphrey; Kenneth F Trofatter; Erol Amon; Suzanne Ward; Lizbeth Kennedy; Lorrie Mason; J. Andrew Johnston

doi:10.1055/s-0030-1249762

American Journal of Perinatology, Table of Contents

Am J Perinatol 2010; 27(8): 655-662
DOI: 10.1055/s-0030-1249762

Digoxin Immune Fab Treatment for Severe Preeclampsia

C. David Adair¹ ^, ² , Vardaman M. Buckalew³ , Steven W. Graves⁴ , Garrett K. Lam⁵ , Donna D. Johnson⁶ , George Saade⁷ , David F. Lewis⁸ , Christopher Robinson⁶ , Theodore M. Danoff⁹ , Nikhil Chauhan¹⁰ , Moana Hopoate-Sitake⁴ , Kathy B. Porter¹¹ , Rachel G. Humphrey¹² , Kenneth F. Trofatter¹³ , Erol Amon¹⁴ , Suzanne Ward¹⁵ , Lizbeth Kennedy¹⁶ , Lorrie Mason¹⁷ , J. Andrew Johnston²

¹University of Tennessee, Chattanooga, Tennessee
²Glenveigh Research, Chattanooga, Tennessee
³Wake Forest University School of Medicine, Winston-Salem, North Carolina
⁴Brigham Young University, Provo, Utah
⁵Phoenix Perinatal Associates, Phoenix, Arizona
⁶Medical University of South Carolina, Charleston, South Carolina
⁷University of Texas Medical Branch, Galveston, Texas
⁸Louisiana State University Medical Center, Shreveport, Louisiana
⁹GlaxoSmithKline, King of Prussia, Pennsylvania
¹⁰Protherics, London, United Kingdom
¹¹University of South Alabama, Mobile, Alabama
¹²Winnie Palmer Hospital, Orlando Florida
¹³Greenville Hospital System, Greenville, South Carolina
¹⁴St. Louis University, St. Louis, Missouri
¹⁵Protherics, Nashville, Tennessee
¹⁶Regional Neonatal Specialists, Chattanooga, Tennessee
¹⁷Regional Obstetrical Consultatns, Chattanooga, Tennessee

Abstract

ABSTRACT

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.

KEYWORDS

Digoxin immune Fab - endogenous digitalis-like factors - preeclampsia - sodium pump

Full Text

References

REFERENCES

1 Wallis A B, Saftlas A F, Hsia J, Atrash H K. Secular trends in the rates of preeclampsia, eclampsia, and gestational hypertension, United States, 1987–2004. Am J Hypertens. 2008; 21 521-526
2 Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol. 2000; 183 S1-S22
3 Buchbinder A, Sibai B M, Caritis S National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units et al. Adverse perinatal outcomes are significantly higher in severe gestational hypertension than in mild preeclampsia. Am J Obstet Gynecol. 2002; 186 66-71
4 Hladunewich M, Karumanchi S A, Lafayette R. Pathophysiology of the clinical manifestations of preeclampsia. Clin J Am Soc Nephrol. 2007; 2 543-549
5 Bagrov A Y, Shapiro J I, Fedorova O V. Endogenous cardiotonic steroids: physiology, pharmacology, and novel therapeutic targets. Pharmacol Rev. 2009; 61 9-38
6 Gusdon Jr J P, Buckalew Jr V M, Hennessy J F. A digoxin-like immunoreactive substance in preeclampsia. Am J Obstet Gynecol. 1984; 150 83-85
7 Beyers A D, Odendaal H J, Spruyt L L, Parkin D P. The possible role of endogenous digitalis-like substance in the causation of pre-eclampsia. S Afr Med J. 1984; 65 883-885
8 Graves S W. The possible role of digitalislike factors in pregnancy-induced hypertension. Hypertension. 1987; 10(5 Pt 2) I84-I86
9 Averina I V, Tapilskaya N I, Reznik V A et al.. Endogenous Na/K-ATPase inhibitors in patients with preeclampsia. Cell Mol Biol (Noisy-le-grand). 2006; 52 19-23
10 Ujhelyi M R, Robert S. Pharmacokinetic aspects of digoxin-specific Fab therapy in the management of digitalis toxicity. Clin Pharmacokinet. 1995; 28 483-493
11 Agunanne E, Horvat D, Uddin M N, Puschett J. The treatment of preeclampsia in a rat model employing Digibind(R). Am J Perinatol. 2009; Available at: https://www.thieme-connect.com/ejournals/html/ajp/doi/10.1055/s-0029-1241739 , Accessed Oct 12, 2009
12 Adair C D, Luper A, Rose J C, Russell G, Veille J C, Buckalew V M. The hemodynamic effects of intravenous digoxin-binding Fab immunoglobulin in severe preeclampsia: a double-blind, randomized, clinical trial. J Perinatol. 2009; 29 284-289
13 Goodlin R C. Antidigoxin antibodies in eclampsia. N Engl J Med. 1988; 318 518-519
14 Adair C D, Buckalew V, Taylor K et al.. Elevated endoxin-like factor complicating a multifetal second trimester pregnancy: treatment with digoxin-binding immunoglobulin. Am J Nephrol. 1996; 16 529-531
15 Adair C D, Buckalew V M, Kipikasa J, Torres C, Stallings S P, Briery C M. Repeated dosing of digoxin-fragmented antibody in preterm eclampsia. J Perinatol. 2009; 29 163-165
16 Committee on Technical Bulletins of the American College of Obstetricians and Gynecologists . ACOG technical bulletin. Hypertension in pregnancy. Number 219—January 1996 (replaces no. 91, February 1986). Int J Gynaecol Obstet. 1996; 53 175-183
17 Zhen Y, Franz K B, Graves S W. A novel assay of cell rubidium uptake using graphite furnace atomic absorption: application to rats on a magnesium-deficient diet. J Nutr Biochem. 2005; 16 291-296
18 Miller K J, Bowsher R R, Celniker A et al.. Workshop on bioanalytical methods validation for macromolecules: summary report. Pharm Res. 2001; 18 1373-1383
19 DeSilva B, Smith W, Weiner R et al.. Recommendations for the bioanalytical method validation of ligand-binding assays to support pharmacokinetic assessments of macromolecules. Pharm Res. 2003; 20 1885-1900
20 Alper A B, Yi Y, Webber L S et al.. Estimation of glomerular filtration rate in preeclamptic patients. Am J Perinatol. 2007; 24 569-574
21 Moodley J, Gangaram R, Khanyile R, Ojwang P J. Serum cystatin C for assessment of glomerular filtration rate in hypertensive disorders of pregnancy. Hypertens Pregnancy. 2004; 23 309-317
22 Shannon J A. Glomerular filtration and urea excretion in relation to urine flow in the dog. Am J Physiol. 1936; 117 206-225
23 Lindheimer M D, Weston P V. Effect of hypotonic expansion on sodium, water, and urea excretion in late pregnancy: the influence of posture on these results. J Clin Invest. 1969; 48 947-956
24 Moran P, Lindheimer M D, Davison J M. The renal response to preeclampsia. Semin Nephrol. 2004; 24 588-595
25 Moran P, Baylis P H, Lindheimer M D, Davison J M. Glomerular ultrafiltration in normal and preeclamptic pregnancy. J Am Soc Nephrol. 2003; 14 648-652
26 Hauth J C, Ewell M G, Levine R J Calcium for Preeclampsia Prevention Study Group et al. Pregnancy outcomes in healthy nulliparas who developed hypertension. Obstet Gynecol. 2000; 95 24-28
27 Haddad B, Sibai B M. Expectant management in pregnancies with severe pre-eclampsia. Semin Perinatol. 2009; 33 143-151
28 Haddad B, Deis S, Goffinet F, Paniel B J, Cabrol D, Siba B M. Maternal and perinatal outcomes during expectant management of 239 severe preeclamptic women between 24 and 33 weeks’ gestation. Am J Obstet Gynecol. 2004; 190 1590-1595 discussion 1595-1597
29 Vigil-De Gracia P, Montufar-Rueda C, Ruiz J. Expectant management of severe preeclampsia and preeclampsia superimposed on chronic hypertension between 24 and 34 weeks’ gestation. Eur J Obstet Gynecol Reprod Biol. 2003; 107 24-27
30 Brown M A, Hague W M, Higgins J Austalasian Society of the Study of Hypertension in Pregnancy et al. The detection, investigation and management of hypertension in pregnancy: full consensus statement. Aust N Z J Obstet Gynaecol. 2000; 40 139-155
31 Mirza F G, Cleary K L. Pre-eclampsia and the kidney. Semin Perinatol. 2009; 33 173-178
32 Bar J, Kaplan B, Wittenberg C et al.. Microalbuminuria after pregnancy complicated by pre-eclampsia. Nephrol Dial Transplant. 1999; 14 1129-1132
33 Vikse B E, Irgens L M, Leivestad T, Skjaerven R, Iversen B M. Preeclampsia and the risk of end-stage renal disease. N Engl J Med. 2008; 359 800-809
34 Morris J F, Poston L, Wolfe C D, Hilton P J. A comparison of endogenous digoxin-like immunoreactivity and sodium transport inhibitory activity in umbilical arterial and venous serum. Clin Sci (Lond). 1988; 75 577-579
35 Hilton P J, White R W, Lord G A et al.. An inhibitor of the sodium pump obtained from human placenta. Lancet. 1996; 348 303-305
36 Adair C D, Haupert Jr G T, Koh H P, Wang Y, Veille J C, Buckalew V. Erythrocyte sodium/potassium ATPase activity in severe preeclampsia. J Perinatol. 2009; 29 280-283

C David Adair M.D.

Professor, University of Tennessee, Chairman, Glenveigh Research

401 Chestnut Street, Suite 230, Chattanooga, TN 37402

Email: David.Adair@Glenveigh.com