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US 2006/0134106A1 Adair (43) Pub US 2006O1341 06A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0134106A1 Adair (43) Pub. Date: Jun. 22, 2006 (54) ANTIBODY COMPOSITION AND PASSIVE Publication Classification MMUNIZATION AGAINST PREGNANCY-INDUCED HYPERTENSION (51) Int. Cl. (76) Inventor: Charles David Adair, Signal Mountain, A 6LX 39/395 (2006.01) TN (US) (52) U.S. Cl. ..................................... 424/133.1; 424/178.1 Correspondence Address: (57) ABSTRACT HUSCH & EPPENBERGER, LLC 190 CARONDELET PLAZA A composition is provided to prevent, limit the effects of SUTE 6OO delay the onset of, or treat one or more of the causes, ST. LOUIS, MO 63105-3441 (US) symptoms or complications of gestational hypertension, preeclampsia, eclampsia and/or intrauterine growth restric (21) Appl. No.: 11/317,378 tion. The composition comprises a therapeutically effective amount of an antibody that reacts immunologically with or (22) Filed: Dec. 23, 2005 binds digoxin and has a high dose of digoxin binding Related U.S. Application Data capacity as the active ingredient. There is also provided a method of preventing, limiting the effects of delaying the (63) Continuation-in-part of application No. 10/202,957, onset of, or treating a cause, symptom or complication of filed on Jul. 25, 2002. gestational hypertension, preeclampsia, eclampsia or intrau Continuation-in-part of application No. 10/292.338, terine growth restriction, comprising the step of administer filed on Nov. 12, 2002. ing to a mammal a composition comprising a therapeutically effective amount of an antibody that reacts immunologically (60) Provisional application No. 60/681,693, filed on May with or binds digoxin and has a high dose of digoxin binding 17, 2005. capacity. Patent Application Publication Jun. 22, 2006 Sheet 1 of 6 US 2006/01341 06 A1 Fig. 1 Evaluate Patient for (a) Diagnostic Indications or Risk Factors for OR (b) Clinical symptoms or complications of Gestational Hypertension Preeclampsia Eclampsia IUGR Select a "high dose" digoxin antibody composition Administer the digoxin antibody composition Monitor patient response Repeat administration of a "high dose" digoxin antibody composition, as indicated or determined by clinical judgment Patent Application Publication Jun. 22, 2006 Sheet 2 of 6 US 2006/01341 06 A1 Figure 2 Patent Application Publication Jun. 22, 2006 Sheet 3 of 6 US 2006/01341 06 A1 Figure 3 Patent Application Publication Jun. 22, 2006 Sheet 4 of 6 US 2006/01341 06 A1 Figure 4a S/D = 4.84 (nl 4.35, 95%ile) RI 0.79 Umbilical artery flow before administration of a high dose digoxin antibody composition. Patent Application Publication Jun. 22, 2006 Sheet 5 of 6 US 2006/01341 06 A1 Figure 4b 20 hrs post infusion: S/D = 2.87 (nl 3.03, 50%ile) RI 0.65 Umbilical artery flow 20 hours after administration of a high dose digoxin antibody composition. Patent Application Publication Jun. 22, 2006 Sheet 6 of 6 US 2006/01341 06 A1 Fig. 5a Example of Cardenolide Aglycone Fig 5b Example of Bufadienolide Aglycone US 2006/01341 06 A1 Jun. 22, 2006 ANTIBODY COMPOSITION AND PASSIVE erate the endometrial cavity. The only cavity that remains in MMUNIZATION AGAINST the uterus is the amniotic cavity, containing amniotic fluid PREGNANCY-INDUCED HYPERTENSION and the fetus. CROSS-REFERENCE TO RELATED 0009 Placentation begins at about 10 days gestation, APPLICATIONS when the trophoblasts invade the endometrium and its blood vessels (spiral arterioles). As early as day 11 or 12, branch 0001. This application is related to and is a continuation like cell formations (villi) begin to form on the chorionic in part of co-pending U.S. application Ser. No. 10/202,957, Surface. Invasion of the maternal spiral arterioles causes filed Jul. 25, 2002, and U.S. application Ser. No. 10/292.338, maternal blood to leak into spaces between the villi, pro filed Nov. 12, 2002, and provisional U.S. Application No. viding nourishment to the developing embryo. At about 12 60/681,693, filed May 17, 2005, each of which applications weeks' gestation, the placenta begins to form as a distinct, is incorporated herein by this reference. disk-shaped organ. The placenta is attached by the villi to the decidua directly overlying maternal spiral arterioles. The STATEMENT REGARDING FEDERALLY maternal spiral arterioles empty maternal blood into the SPONSORED RESEARCH OR DEVELOPMENT intervillous space so that the blood circulates around and 0002) Not Applicable. through the latticework of villi. Nutrients are transferred from maternal blood in the intervillous space, across tro phoblast cells, through the fibrous core of the villus, and APPENDIX through the endothelial cells of the fetal capillaries to the 0003) Not Applicable. fetal blood. Fetal wastes move in the opposite direction. The placenta reaches its final development at approximately 18 BACKGROUND OF THE INVENTION to 20 weeks of pregnancy. 0010. It is generally known that abnormal placentation 0004) 1. Field of the Invention and placental vascular insufficiency are central features of 0005 The present invention relates generally to the field certain pregnancy-related medical conditions, including, of medicine and, more particularly, to prevention and treat without limitation, preeclampsia and intrauterine growth ment of diseases or conditions associated with elevated restriction. Preeclampsia is a rapidly progressive condition, levels of endogenous sodium pump inhibitors, including, characterized by the occurrence of high blood pressure and without limitation, the pregnancy-related conditions known abnormal levels of protein in the urine (proteinuria). as gestational hypertension, preeclampsia, eclampsia and Eclampsia is a more severe form of preeclampsia that is also intrauterine growth restriction. characterized by seizures. Gestational hypertension is hyper tension in pregnancy without proteinuria, and it may be a 0006 2. Related Art less severe form of or a precursor to preeclampsia. Preec 0007 Conception results from the fertilization of an egg lampsia and gestational hypertension may be further classi by a sperm and the development of the resulting embryo into fied as mild or severe depending upon the severity of the a fetus. In order for pregnancy to be established and the clinical symptoms. These hypertension-related disorders are embryo to develop it must embed itself within the uterine collectively referred to herein as "pregnancy-induced hyper wall. At about 12 weeks' gestation a temporary disk-shaped tension or “PIH. organ forms (the placenta), enhancing the transfer of oxygen and nutrients to, and permitting the removal of waste prod 0011 Typically, clinical symptoms of PIH occur in the late second trimester or in the third trimester of pregnancy, ucts from, the fetus. The placenta is critical to fetal devel although symptoms may occur earlier in pregnancy. PIH opment, and improper placental formation is associated with may be Superimposed over other forms of hypertension, preeclampsia and intrauterine growth restriction. Such as essential and secondary hypertension, that exist prior 0008. Upon conception, the fertilized egg (embryo) to or develop early in pregnancy. An increased risk for PIH undergoes repeated cell division and cell migration to form is associated with first time pregnancies, when there is a a blastocyst, a single layer of cells Surrounding a central large interval between pregnancies, pregnant women under cavity. One area of the blastocyst wall that is three or four the age of 20 or over the age of 35, women of black race, cells thick, known as the embryonic pole, becomes recog multi-gestational pregnancies, women who have conceived nizable as the embryo and eventually develops into the fetus. through in vitro fertilization (IVF), women who have had The remaining blastocyst cells form a structure called the a prior pregnancy with PIH, women who have had a prior trophoblast. Pregnancy begins upon implantation of the pregnancy conceived with a different partner, women with a blastocyst. Implantation occurs when the trophoblasts pro family history of PIH or high blood pressure or diabetes, liferate and invade the uterine wall so that the blastocyst women who are of higher than normal weight or body mass burrows into the central layer of tissue (endometrium). The index prior to pregnancy, undernutrition, women with a trophoblasts then develop to form the chorion (outer mem personal history of polycystic ovarian syndrome, insulin brane) and amnion (inner membrane) Surrounding the resistence or diabetes, hypertension, renal (kidney) disease, embryo. The amniotic sac fills with fluid and expands to rheumatoid arthrisis, systemic lupus erythematosus or other envelop the embryo. The embryo continues to grow but is autoimmune diseases, or thrombophilia risk factors. The risk confined within one wall of the uterus until about the 12th of recurrent PIH in Subsequent pregnancies is approximately week of gestation. At that time, the endometrium tissue thirty-three percent (33%), and PIH is superimposed in overlying the embryo comes in Such close contact with the twenty-five percent (25%) of pregnancies in which chronic tissue of the opposite uterine wall that they fuse and oblit hypertension is present before pregnancy. US 2006/01341 06 A1 Jun. 22, 2006 0012. It is believed PIH occurs in five percent (5%) to ten calcium Supplementation, vitamin and antioxidant Supple percent (10%) of all human pregnancies. PIH disorders are mentation and aspirin therapy, have not proven to be suc a leading global cause of maternal and infant illness and cessful. death. PIH occurs in over six million births a year and is 0018 Depending upon the stage of the pregnancy and the responsible for 15 percent of all premature births. By severity of maternal and fetal conditions, gestational hyper conservative estimates, these disorders are responsible for tension, preeclampsia, eclampsia, and IUGR may be man 76,000 deaths each year. The risk of death for a pregnant aged in an attempt to prolong the pregnancy and advance the woman with severe preeclampsia is 0.5%, and the risk of gestational age to improve the fetal outcome.
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