Digoxin immune fab treatment for severe preeclampsia.

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.

Increasing evidence for and regulation of a human placental endogenous digitalis-like factor.

Endogenous digitalis-like factors (EDLFs) appear to be hypertensiogenic and increased in the serum and placenta of women with preeclampsia (PE), a complication of pregnancy. Digibind, an anti-digoxin antibody Fab fragment, reverses in vitro effects of EDLF and in vivo features of PE. We used Digibind in a radioimmunoassay to measure EDLF and compared this to a bio-functional assay of EDLF with good agreement. These methods confirmed that human placenta was a source of EDLF, synthesizing and releasing EDLF into the media of cultured human placental tissue. Ketoconazole, a steroid synthesis inhibitor, and 17-OH progesterone, a possible substrate of steroid synthesis, were shown to inhibit or increase EDLF release respectively, suggesting overlap of synthetic pathways. Abnormalities of PE such as placental hypoxia, increased reactive oxygen species and increased pro-inflammatory cytokines were demonstrated to increase placental EDLF release. These findings strongly support placental production of EDLF with increased release due to features of PE.

Digibind reverses inhibition of cellular rb+ uptake caused by endogenous sodium pump inhibitors present in serum and placenta of women with preeclampsia.

INTRODUCTION: Mechanisms mediating preeclampsia (PE) are unclear. Endogenous digitalis-like factors (EDLFs) are sodium pump (SP) inhibitors implicated in essential hypertension, but not fully explored in PE. This study asks whether EDLFs are present and increased in PE and considers their source. METHODS: EDLF in sera and placentas from third trimester women with uncomplicated pregnancies or PE was assessed by a Rb(+) uptake assay. A digoxin antibody Fab fragment (Digibind) known to inactivate EDLFs was also used to assess EDLFs. RESULTS: PE serum caused significantly more SP inhibition than serum from uncomplicated pregnancies. This inhibition was concentration-dependent and reversed by Digibind. Serum from uncomplicated pregnancies showed no concentration-dependence or reversal with Digibind. Placental homogenates from control women showed little SP inhibition, but homogenates from PE women showed marked SP inhibition reversed by Digibind. CONCLUSION: These studies evidence EDLF in PE serum. Additionally, PE placentas have high EDLF and may represent a source.