L-Arginine in Pre-Eclampsia
Condition: Pre-Eclampsia
MeSH terms: Eclampsia; Pre-Eclampsia
Study type: Interventional
Phase: Phase 3

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.
    

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
      angiogenic/vasculogenic 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 placentation.In 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.
    

Intervention name(s): L-arginine
Intervention type(s): Drug
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Educational/Counseling/Training