A Phase 2b/3a, Multi-Center, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study of the Efficacy and Safety of AMAG-423, a Digoxin Immune Fab, in Antepartum Subjects With Severe Preeclampsia

This study evaluates the use of AMAG-423 (Digoxin Immune Fab) in addition to expectant management in the treatment of severe preeclampsia as compared to placebo.

Start Date12 Apr 2017

Sponsor / Collaborator

AMAG Pharmaceuticals, Inc.

JPRN-UMIN000003252 / RecruitingPhase 2IIT

Phase II trial of DIF drug as adjuvant therapy after curative resection of colon cancer - Investigation of risk facter for colon cancer- - Phase II trial of DIF drug as adjuvant therapy after curative resection of colon cancer

Start Date01 Jul 2008

Sponsor / Collaborator-

NCT00281021 / TerminatedPhase 2IIT

Phase II Trial of Second Line Erlotinib + Digoxin in Patients With Non-Small Cell Lung Cancer

The purpose of this study is to determine the potential benefit of adding Digoxin to erlotinib (Tarceva) treatment for patients with non-small cell lung cancer.

Start Date01 Feb 2006

Sponsor / Collaborator

University of Louisville

[+1]

100 Clinical Results associated with digoxin

100 Translational Medicine associated with digoxin

0 Patents (Medical) associated with digoxin

Literatures (Medical) associated with digoxin

01 Oct 2008·Biochemical PharmacologyQ2 · MEDICINE

Induction of P-glycoprotein expression and function in human intestinal epithelial cells (T84)

Q2 · MEDICINE

Article

Author: Iain S. Haslam ; T. Coleman ; N.L. Simmons ; K. Jones

Intestinal induction of Pgp is known to limit the oral availability of certain drug compounds and give rise to detrimental drug-drug interactions. We have investigated the induction of P-glycoprotein (Pgp; MDR1) activity in a human intestinal epithelial cell line (T84) following pre-exposure to a panel of drug compounds, reported to be Pgp substrates, inhibitors or inducers. Human MDR1-transfected MDCKII epithelial monolayers were used to assess Pgp substrate interactions and inhibition of digoxin secretion by the selected drug compounds. The T84 cell line was used to assess induction of Pgp-mediated digoxin secretion following pre-exposure to the same compounds. Changes in gene expression (MDR1, MRP2, PXR and CAR) were determined by quantitative RT-PCR. Net transepithelial digoxin secretion was increased (1.3 fold, n=6, P<0.05) following pre-exposure to the PXR activator hyperforin (100nM, 72h), as was MDR1 mRNA expression (3.0 fold, n=4, P<0.05). A number of Pgp substrates (quinidine, amprenavir, irinotecan, topotecan, atorvastatin and erythromycin) induced net digoxin secretion, as did the non-Pgp substrate artemisinin. Various non-Pgp substrates demonstrated inhibition of digoxin secretion (verapamil, mifepristone, clotrimazole, mevastatin, diltiazem and isradipine) but did not induce Pgp-mediated digoxin secretion. Of the compounds that increased Pgp secretion, quinidine, topotecan, atorvastatin and amprenavir pre-exposure also elevated MDR1 mRNA levels, whereas erythromycin, irinotecan and artemisinin displayed no change in transcript levels. This indicates possible post-translational regulation of digoxin secretion. Finally, a strong correlation between drug modulation of MRP2 and PXR mRNA expression levels was evident.

01 May 2005·European Journal of PharmacologyQ3 · MEDICINE

Mechanism-based modeling of reduced inotropic responsiveness to digoxin in endotoxemic rat hearts

Q3 · MEDICINE

Article

Author: Michael Weiss ; Myoungki Baek

The mechanisms by which endotoxemia affects myocardial contractility and responsiveness to inotropic drugs are not well understood. We examined the positive inotropic effect of digoxin in single-pass Langendorff-perfused hearts from rats after in vivo pretreatment with lipopolysaccharide (LPS, 4 mg/kg, i.p., 4 h before heart isolation). Using a mathematical modeling approach that allows differentiation between effects elicited at the receptor and postreceptor level, we studied uptake, receptor binding and effectuation kinetics after three consecutive digoxin doses (15, 30, and 45 microg) in the absence and presence of the reverse mode Na(+)/Ca(2+) exchange (NCX) inhibitor KB-R7943 (0.1 microM) in perfusate. LPS significantly depressed baseline contractility and the inotropic response to digoxin without affecting its uptake mechanism. Compared with the control group, the slope of the functional receptor occupancy (stimulus)-to-response relationship was reduced by 44% in the LPS group. Model analysis revealed a significant correlation between changes in digoxin action and LPS-induced febrile response: digoxin receptor affinity increased and the response/stimulus ratio decreased with rise in body temperature, respectively. In contrast, the diminished responsiveness to digoxin observed after NCX inhibition in the control group was not further attenuated in the LPS group. These results support the hypothesis that postreceptor events may be responsible for the diminished contractile response to digoxin during endotoxemia.

09 Mar 2004·Proceedings of the National Academy of SciencesQ1 · CROSS-FIELD

Isolation and characterization of a digoxin transporter and its rat homologue expressed in the kidney

Q1 · CROSS-FIELD

Article

Author: Tsuyoshi Mikkaichi ; Takaaki Abe ; Satohiro Masuda ; Fumitoshi Satoh ; Sadayoshi Ito ; Hiroya Mizutamari ; Tatsuji Chaki ; Nobuaki Eto ; Masayuki Tanemoto ; Michiaki Unno ; Takehiro Suzuki ; Ken Ichi Inui ; Junichi Goto ; Taro Tokui ; Masahiro Okada ; Takanori Hishinuma ; Tohru Onogawa ; Michiaki Abe

Digoxin, which is one of the most commonly prescribed drugs for the treatment of heart failure, is mainly eliminated from the circulation by the kidney. P-glycoprotein is well characterized as a digoxin pump at the apical membrane of the nephron. However, little is known about the transport mechanism at the basolateral membrane. We have isolated an organic anion transporter (OATP4C1) from human kidney. Human OATP4C1 is the first member of the organic anion transporting polypeptide (OATP) family expressed in human kidney. The isolated cDNA encodes a polypeptide of 724 aa with 12 transmembrane domains. The genomic organization consists of 13 exons located on chromosome 5q21. Its rat counterpart, Oatp4c1, is also isolated from rat kidney. Human OATP4C1 transports cardiac glycosides (digoxin, Km = 7.8 μM and ouabain, Km = 0.38 μM), thyroid hormone (triiodothyronine, Km = 5.9 μM and thyroxine), cAMP, and methotrexate in a sodium-independent manner. Rat Oatp4c1 also transports digoxin ( Km = 8.0 μM) and triiodothyronine ( Km = 1.9 μM). Immunohistochemical analysis reveals that rat Oatp4c1 protein is localized at the basolateral membrane of the proximal tubule cell in the kidney. These data suggest that human OATP4C1/rat Oatp4c1 might be a first step of the transport pathway of digoxin and various compounds into urine in the kidney.

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