Ignite Creation Date:
2024-05-05 @ 11:52 AM
Last Modification Date:
2024-10-26 @ 9:15 AM
Study NCT ID:
NCT00157521
Status:
COMPLETED
Last Update Posted:
2006-12-22
First Post:
2005-09-08
Brief Title:
L-Arginine in Pre-Eclampsia
Sponsor:
Mario Negri Institute for Pharmacological Research
Organization:
Mario Negri Institute for Pharmacological Research
Study Overview
Official Title:
A Double-Blind Randomized Pilot Study to Explore Whether Enhancing L-Arginine Bioavailability by Oral Supplementation Increases NO Production and Prevents Peroxynitrite Generation in the Pre-Eclamptic Placenta
Status:
COMPLETED
Status Verified Date:
2006-12
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Pre-eclampsia is a disorder unique to pregnancy affecting both the mother and the fetus Hypertension proteinuria and edema are the most common and well-known maternal clinical symptoms The incidence is approximately 6-8 Pre-eclampsia is one of the leading causes of maternal and fetal mortality and morbidity associated with pregnancy throughout the world The pathophysiology is unknown At present the most effective treatment is immediate delivery
The researchers studies contributed to the demonstration that the vasodilator nitric oxide NO is important for correct placentation and that less nitric oxide NO- dependent vasodilation and an excess formation of reactive oxygen species explain poor placenta perfusion in pre-eclampsia This reduced NO activity and increased oxidative stress in pre-eclamptic placenta is related to low bioavailability of L-arginine the NO precursor
In this pilot study the researchers want to evaluate whether the administration of L-arginine to women with a clinical diagnosis of preeclampsia might restore physiological NO production in the placenta and ameliorate the pregnancy outcome
The researchers studies contributed to the demonstration that the vasodilator nitric oxide NO is important for correct placentation and that less nitric oxide NO- dependent vasodilation and an excess formation of reactive oxygen species explain poor placenta perfusion in pre-eclampsia This reduced NO activity and increased oxidative stress in pre-eclamptic placenta is related to low bioavailability of L-arginine the NO precursor
In this pilot study the researchers want to evaluate whether the administration of L-arginine to women with a clinical diagnosis of preeclampsia might restore physiological NO production in the placenta and ameliorate the pregnancy outcome
Detailed Description:
INTRODUCTION
In the past few years evidence has accumulated strongly suggesting that nitric oxide NO a potent endothelial-derived vasodilator might be implicated in gestational vasodilatation NO is synthesized from the aminoacid L-arginine by a family of enzymes the NO synthases NOS The endothelial isoform of nitric oxide synthase ecNOS has been found in the human placenta and immunohistochemically localized to the endothelium of the umbilical cord chorionic plate and stem villous vessels Locally formed ecNOS-dependent NO may serve to maintain low vascular resistance besides attenuating the action of vasoconstrictors With its unique angiogenicvasculogenic properties NO can be instrumental for promoting cytotrophoblast endovascular invasion of uterine spiral arteries an essential feature of normal placentation Inadequate production of the vasodilator nitric oxide NO in the placenta has been recently suggested to explain the high resistance state and the ineffective placentation of pre-eclampsia however the results to date are conflicting We recently found that placental endothelial NO synthase ecNOS expression and activity were comparable in normal pregnancy and in pre-eclampsia but in pre-eclamptic placenta NO is degraded to peroxynitrite that is good candidate for mediating the oxidative damage of pre-eclampsia Concentration of the NO precursor L-arginine was lower in pre-eclampsia suggesting a defect in L-arginine bioavailability in the placentas These results provide a biochemical explanation for the defective NO synthesis in pre-eclamptic placenta since NO production by endothelial NO synthase ecNOS is strongly dependent on the availability of the substrate L-arginine so that low L-arginine availability induces NOS to synthesize peroxynitrite at the expense of NO
These results suggest that in the normal placenta adequate concentration of L-arginine selectively orients ecNOS toward NO which is vital for a normal placentationIn the pre-eclamptic placenta instead a lower than normal L-arginine concentration re-directs ecNOS toward peroxynitrite which is generated in exuberant amounts at the expense of NO This favors microvascular damage and impairs cytotrophoblast invasion
Thus whether increasing L-arginine bioavailability might restore physiological NO production in pre-eclamptic placenta is worth investigating in a pilot study that might represent the basis of a large multicenter trial aimed to explore the impact of the above treatment on pregnancy outcome
AIMS
Primary
To compare L-arginine and NO metabolite NO2-NO3- concentrations in systemic and umbilical cord blood and placental ecNOS nitrotyrosine and HNE-lysine staining and levels of conjugated dienes in ten pre-eclamptic women given L-Arginine supplementation and in ten pre-eclamptic women given placebo
To compare L-arginine transport activity in normal and pre-eclamptic placenta syncytiotrophoblasts in vitro To compare the mRNA expression of cationic aminoacid systems Y LAT CAT-2 and CAT-4 in normal and pre-eclamptic placenta
Secondary
To compare in pre-eclamptic women given L-Arginine supplementation and in pre-eclamptic women given placebo the following
Time from pre-eclampsia onset to delivery
Arterial blood pressure albuminuria proteinuria complete blood cell count including platelet count serum creatinine uric acid triglycerides cholesterol C3 GOT GPT GammaGT HDL LDL and LDH concentration at the time of delivery
Structural changes of the placenta
Newborn weight height and Apgar score
Gestational age at delivery
DESIGN
Ten women with clinical diagnosis of pre-eclampsia given oral L-arginine supplementation from the time of diagnosis cases and ten women with clinical diagnosis of pre-eclampsia on placebo controls matched with cases for age parity time of onset of pre-eclampsia and concomitant risk factors chronic hypertension diabetes renal disease multiple pregnancy will be selected for study participation Cases and controls will also receive conventional therapy antihypertensive drugs nifedipine alpha-methyldopa magnesium for prophylaxis of eclampsia betamethasone for fetus maturation for pre-eclampsia and will be homogenous for treatment Ten normotensive pregnant women normotensive pregnancy matched for gestational age and for type of delivery cesarean or vaginal will be also studied All subjects will provide a written informed consent according to the declaration of Helsinki Patients will enter the study as soon as diagnosis of pre-eclampsia will be done
In the past few years evidence has accumulated strongly suggesting that nitric oxide NO a potent endothelial-derived vasodilator might be implicated in gestational vasodilatation NO is synthesized from the aminoacid L-arginine by a family of enzymes the NO synthases NOS The endothelial isoform of nitric oxide synthase ecNOS has been found in the human placenta and immunohistochemically localized to the endothelium of the umbilical cord chorionic plate and stem villous vessels Locally formed ecNOS-dependent NO may serve to maintain low vascular resistance besides attenuating the action of vasoconstrictors With its unique angiogenicvasculogenic properties NO can be instrumental for promoting cytotrophoblast endovascular invasion of uterine spiral arteries an essential feature of normal placentation Inadequate production of the vasodilator nitric oxide NO in the placenta has been recently suggested to explain the high resistance state and the ineffective placentation of pre-eclampsia however the results to date are conflicting We recently found that placental endothelial NO synthase ecNOS expression and activity were comparable in normal pregnancy and in pre-eclampsia but in pre-eclamptic placenta NO is degraded to peroxynitrite that is good candidate for mediating the oxidative damage of pre-eclampsia Concentration of the NO precursor L-arginine was lower in pre-eclampsia suggesting a defect in L-arginine bioavailability in the placentas These results provide a biochemical explanation for the defective NO synthesis in pre-eclamptic placenta since NO production by endothelial NO synthase ecNOS is strongly dependent on the availability of the substrate L-arginine so that low L-arginine availability induces NOS to synthesize peroxynitrite at the expense of NO
These results suggest that in the normal placenta adequate concentration of L-arginine selectively orients ecNOS toward NO which is vital for a normal placentationIn the pre-eclamptic placenta instead a lower than normal L-arginine concentration re-directs ecNOS toward peroxynitrite which is generated in exuberant amounts at the expense of NO This favors microvascular damage and impairs cytotrophoblast invasion
Thus whether increasing L-arginine bioavailability might restore physiological NO production in pre-eclamptic placenta is worth investigating in a pilot study that might represent the basis of a large multicenter trial aimed to explore the impact of the above treatment on pregnancy outcome
AIMS
Primary
To compare L-arginine and NO metabolite NO2-NO3- concentrations in systemic and umbilical cord blood and placental ecNOS nitrotyrosine and HNE-lysine staining and levels of conjugated dienes in ten pre-eclamptic women given L-Arginine supplementation and in ten pre-eclamptic women given placebo
To compare L-arginine transport activity in normal and pre-eclamptic placenta syncytiotrophoblasts in vitro To compare the mRNA expression of cationic aminoacid systems Y LAT CAT-2 and CAT-4 in normal and pre-eclamptic placenta
Secondary
To compare in pre-eclamptic women given L-Arginine supplementation and in pre-eclamptic women given placebo the following
Time from pre-eclampsia onset to delivery
Arterial blood pressure albuminuria proteinuria complete blood cell count including platelet count serum creatinine uric acid triglycerides cholesterol C3 GOT GPT GammaGT HDL LDL and LDH concentration at the time of delivery
Structural changes of the placenta
Newborn weight height and Apgar score
Gestational age at delivery
DESIGN
Ten women with clinical diagnosis of pre-eclampsia given oral L-arginine supplementation from the time of diagnosis cases and ten women with clinical diagnosis of pre-eclampsia on placebo controls matched with cases for age parity time of onset of pre-eclampsia and concomitant risk factors chronic hypertension diabetes renal disease multiple pregnancy will be selected for study participation Cases and controls will also receive conventional therapy antihypertensive drugs nifedipine alpha-methyldopa magnesium for prophylaxis of eclampsia betamethasone for fetus maturation for pre-eclampsia and will be homogenous for treatment Ten normotensive pregnant women normotensive pregnancy matched for gestational age and for type of delivery cesarean or vaginal will be also studied All subjects will provide a written informed consent according to the declaration of Helsinki Patients will enter the study as soon as diagnosis of pre-eclampsia will be done
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None