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  • For each woman who dies during pregnancy, 30 women suffer complications. Initiatives should include: Family planning Management of complications of abortion Management of complications of pregnancy and childbirth
  • For each woman who dies during pregnancy, 30 women suffer complications. Initiatives should include: Family planning Management of complications of abortion Management of complications of pregnancy and childbirth

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  • 1.  First described in 1979 as a potent relaxant of peripheral vascular smooth muscle.  Used by the body as a signaling molecule.  Serves different functions depending on body system. i.e. neurotransmitter, vasodilator, bactericide.
  • 2.  Nitric oxide is a diatomic free radical consisting of one atom of nitrogen and one atom of oxygen  Lipid soluble and very small for easy passage between cell membranes  Short lived, usually degraded or reacted within a few seconds  The natural form is a gas N O
  • 3.  Nitric oxide is synthesized from L-arginine  This reaction is catalyzed by nitric oxide synthase, a 1,294 aa enzyme COO- C (CH2)3 NH C H2N H NH2+ +H3N Arginine NOS NADPH + O2 NAD+ COO- C (CH2)3 NH C H+H3N N + H2N H OH N-w-Hydroxyarginine COO- C (CH2)3 NH H+H3N + NO NOS C O NH2 Citrulline
  • 4.  L-arginine is a chemical building block known as an amino acid.  Amino acids form the molecular foundation of proteins.  Arginine is a precursor for the synthesis of nitric oxide (NO), which causes blood vessels to relax, and it reduces the healing time of injuries.  Arginine has multiple health applications that pregnant women can benefit from.
  • 5.  L-arginine is a semi-essential amino acid. This means that your body produces most of the arginine it needs independent of consumption.  Under certain conditions, however, arginine must also come from your diet.  Dietary sources of arginine include meat, seafood, dairy, granola, oatmeal, nuts, seeds and soybeans.
  • 6.  Glutamate neurotransmitter binds to NMDA receptors  Ca++ channels open causing Ca influx into cell  Activation of calmodulin, which activates NOS  Mechanism for start of synthesis dependent on body system  NO synthesis takes place in endothelial cells, lung cells, and neuronal cells
  • 7. Http://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-06.htm
  • 8.  NOS I  Central and peripheral neuronal cells  Ca+2 dependent, used for neuronal communication  NOS II  Most nucleated cells, particularly macrophages  Independent of intracellular Ca+2  Inducible in presence of inflammatory cytokines  NOS III  Vascular endothelial cells  Ca+2 dependent  Vascular regulation
  • 9.  NO serves as a vasodilator  Released in response to high blood flow rate and signaling molecules (Ach and bradykinin)  Highly localized and effects are brief  If NO synthesis is inhibited, blood pressure skyrockets  (Diagram of vasodilation mechanism after muscular system)  NO aids in gas exchange between hemoglobin and cells  Hemoglobin is a vasoconstrictor, Fe scavenges NO  NO is protected by cysteine group when O2 binds to hemoglobin  During O2 delivery, NO locally dilates blood vessels to aid in gas exchange  Excess NO is picked up by HGB with CO2
  • 10. Http://www.kumc.edu/research/medicine/biochemistry/bioc800/sig02-11.htm
  • 11.  Produced by the endothelial cell linings along 100,000 miles of blood vessels and capillaries in the human body  Keeps blood vessels open, elastic and functioning properly
  • 12.  Nitric oxide (NO), a potent endothelial-derived vasodilator, implicated in gestational vasodilation.  It is actually detectable in healthy placenta and is localized to the endothelium of the umbilical cord and placenta (chorionic plate, and stem villous vessels)  Besides, NO is localized in villous cytotrophoblasts, the specialized epithelial cells that aggregate into cell columns and invade the uterine interstitium and vasculature, anchoring the fetus to the mother and establishing blood flow to the placenta.  Reduced formation of NO could account for abnormal placental perfusion in preeclampsia
  • 13. L-Arginine depletion in pre-eclampsia promotes poor placental perfusion and microvascular damage. eNOS, endothelial nitric oxide synthase; Flt1, Fms-like tyrosine kinase 1; L-Arg, L-arginine; NO, nitric oxide; O2 –, superoxide anion; ONOO–, peroxynitrite; PlGF, placental growth factor; sFlt1, soluble Fms-like tyrosine kinase 1; VEGF, vascular endothelial growth factor.
  • 14.  Thus placentation involves remodelling of the maternal blood vessels to provide the fetus with sufficient nutrients from the mother's blood supply.
  • 15.  Pathogenesis of Preeclampsia: A Syndrome of Theories Consensus  The placenta is the major culprit  Defects in trophoblast invasion and vascular remodeling  Endothelial cell dysfunction Debate  A problem of immunology/chronic systemic inflammation  A genetic problem  A vascular endothelial problem  An oxidative stress problem  A nutritional problem  A metabolism problem  
  • 16. PLACENTA: the real cause!!!!!PLACENTA: the real cause!!!!!
  • 17. Abnormal placentation (stage 1), particularly lack of dilatation of the uterine spiral arterioles, is the common starting point in the genesis of pre-eclampsia, which compromises blood flow to the maternal–fetal interface. Maternal syndrome (stage 2) is a function of the circulatory disturbance
  • 18. Normal function of placenta is of utmost importance for intrauterine fetal development and growth. Abnormal placentation leads to preclampsia and is associated with intrauterine fetal growth restriction (IUGR).
  • 19. Hence L-Arginine holds a promising value
  • 20. • L-Arginine: a vital amino acid that plays a role in a number of physiological functions in the body, but is best known for its cardiovascular benefits. • L-Arginine is converted to nitric oxide, which relaxes the blood vessels and regulates blood vessel tone and flexibility. This reduces stress on the heart, improves circulation, and lowers blood pressure. • L-Arginine provides the base upon which can be stacked a literal powerhouse of building block health supplements.
  • 21.  Nitric oxide Generated by a  CONSTITUTIVE ENZYME ▪ Very small quantities  Substrate Dependent  The more arginine, the more vasodilation  Better Organ Perfusion  More tolerance to low flow states - SHOCK
  • 22. Circulating NOx was Increased
  • 23. P<0.05 P<0.01 Nitric oxide production measured by chemiluminescence – microdialysis Flap viability using vital dyes
  • 24.  L-Arginine is considered a semi-essential amino acid: it becomes essential in growing children, during pregnancy or after injury.  A Western diet provides about 4-6 g/day of which 40-50% is absorbed.
  • 25. •The liver produces considerable amounts of arginine during the urea cycle, but little is available for synthesis. • The intestines produce citrulline which is converted by other tissues (kidney, 80%) into L-arginine which is then made available to other tissues.
  • 26. •L-arginine is methylated while a component of proteins by: •PRMT (type I): occurs in nucleus, many substrates forms ADMA and NMA •PRMT (type II) : specific for myelin basic protein, forms SDMA and NMA •The methylated analogues are released by hydrolysis during normal protein turnover
  • 27. • The methylated analogues are removed by renal excretion or catabolism •DDAH type I associated with neural NOS •DDAH type II associated with endothelial NOS •Neither DDAH is active on SDMA •DPT (a minor pathway) acts on all three analogues •The enzymes are particularly active in kidney
  • 28. 30 Protein PRMT (types I and II) Modified Protein Containing ADMA+ SDMA+ NMA Hydrolysis ADMA +SDMA +NMA Acetylated Products α-keto acid products Citrulline + Methylamines DDAH (types I and II) Renal Excretion PRMT: Protein arginine methyltransferase ADMA: Asymmetrical dimethylarginine SDMA: Symmetrical dimethylarginine NMA: N-monomethylarginine DDAH: Dimethylaminohydrolase DPT: Dimethylarginine pyruvate transferase DPT
  • 29.  Endothelium dependent relaxation of the thoracic aortae elicited by acetylcholine was reduced in cholesterol-fed animals and the response was significantly ameliorated by L-arginine.  L-arginine also significantly reduced the lesion surface area in the descending thoracic aorta elicited by cholesterol diets (intima thickness also reduced)
  • 30.  Study Population: Pregnant women with hypertension prior to 20 weeks gestation  Primary outcome: Hypertension and proteinuria  Intervention: Daily anti-oxidant vitamins and 6.6 gm L- arginine, anti-oxidant vitamins, or placebo starting at 20 weeks gestation
  • 31. Study Group N Preeclampsia Placebo 175 53 L-Arginine + Vitamins 174 14* Vitamins 170 31** * OR vs. placebo: 0.203 (C.I. 0.16, 0.52), p<0.001 (80% reduction) ** OR vs. placebo: 0.49 (C.I. 0.28, 0.71) 7, p <0.007 (50% reduction)
  • 32. 34 • Intrauterine growth retardation (IUGR) occurs when the unborn baby is at or below the 10th weight percentile for his or her age (in weeks). The foetus is affected by a pathologic restriction in its ability to grow.  Low birth weight (LBW) means a babymeans a baby with a birth weight of less thanwith a birth weight of less than 2500Gms, which could be due to IUGR2500Gms, which could be due to IUGR or Prematurityor Prematurity
  • 33. Normal & IUGR Newborn babies The most frequent etiology for late onset fetal growth restriction is uteroplacental dysfunction which is due to inadequate supply of nutrients and oxygen to support normal growth of the fetus. Normal & IUGR Placentas
  • 34. Hence L-Arginine, holds a promising value
  • 35.  L-Arginine 3-5 gm sachets  Two trial Shows positive effects in IUGR  One recent trial show no positive result effects in IUGR (only in cases of severely established PIH)  DHA 500 mg (12% pure)  Only pre-clinical Trial
  • 36.  Use of arginine in intruterine growth retardation (IUGR)  The positive results suggest the prosecution of clinical studies in order to attempt the achievement of an effective pharmacological treatment of IUGR.  32 patients improved the clinical course of pregnancy: 19 recovered the whole retardation; 9 only one week; 4 had premature delivery after 36 weeks with foetal weight coincident with gestational age. Minerva Ginecol. 1997 Dec;49(12):577-81.
  • 37.  There was analyzed newborn weight also--in a treated group mean value was at 2823 g and in not treated group mean value was at 2495 g.  In the treated group number of the growth retarded newborns was at 29% and in the not treated group was at 73%.  There was found a significant difference comparing both newborns groups at p < 0.05. Ginekol Pol. 2004 Dec;75(12):913-8.
  • 38.  Preconception nutrition has a documented impact on pregnancy outcome  Awareness of and compliance with the best documented recommendations is far from perfect  Insufficient weight gain during pregnancy remains an issue in certain populations  There is increasing evidence for a life-long impact of intrauterine and post-natal nutritional status  Bottom line: simple interventions could/can have a large impact if universally adopted
  • 39. [Nan Fang Yi Ke Da Xue Xue Bao. 2007 Feb;27(2):198-200
  • 40. J Matern Fetal Neonatal Med. 2004 Jun;15(6):363-6
  • 41. Indication Trials Outcome IUGR Effect and mechanism of L-arginine therapy for fetal growth retardation due to pregnancy- induced hypertension. [Nan Fang Yi Ke Da Xue Xue Bao. 2007 Feb;27(2):198- 200] L-Arg promote intrauterine growth of the fetus by increasing NO production and improving the umbilical artery flow in pregnant women with pregnancy-induced hypertension and FGR Effect of L-arginine on the expression of Bcl-2 and Bax in the placenta of fetal growth restriction. [J Matern Fetal Neonatal Med. 2011 Jun;24(6):822-6] L-arginine could reduce the expression of Bax, and enhance the expression of bcl-2, which may be associated with reduced placental apoptosis and improved placental function and fetal development. Effects of oral L-arginine on the foetal condition and neonatal outcome in preeclampsia: a preliminary report. [Basic Clin Pharmacol Toxicol. 2006 Aug;99(2):146-52] Supplementary treatment with oral L- arginine seems to be promising in improving foetal well-being and neonatal outcome as well as in prolonging pregnancy complicated with preeclampsia. Ultrasound evaluation of intrauterine growth restriction therapy by a nitric oxide donor (L- arginine). [J Matern Fetal Neonatal Med. 2004 Jun;15(6):363-6.] There was an acceleration of fetal development in the L-arginine-treated group of pregnant women as compared with the untreated group. Pre term labor Effects of oral L-arginine on the pulsatility indices of umbilical artery and middle cerebral artery in preterm labor. [Eur J Obstet Gynecol Reprod Biol. 2008 May;138(1):23- 8.] Oral supplementation with low doses of L- arginine changed feto-placental blood flow distribution in patients with threatened preterm labor. IMPROVES PLACENTAL FUNCTION. PROMOTES INTRAUTERINE FETAL GROWTH AND DEVELOPMENT. IMPROVES FETO-PLACENTAL BLOOD FLOW.
  • 42. Results: L-arginine increases the amniotic fluid index in cases of oligohydramnios by 2.03±0.39 cm. Conclusions: L-arginine could be a potent treatment option for treatment of oligohydramnios. (However extensive long-term studies are required to demonstrate not only its efficacy but also effect on maternal and perinatal outcome) Conclusions: L-arginine could be a potent treatment option for treatment of oligohydramnios. (However extensive long-term studies are required to demonstrate not only its efficacy but also effect on maternal and perinatal outcome) Int J Reprod Contracept Obstet Gynecol. 2013 Mar;2(1):80-82
  • 43. Adjuvant L-arginine treatment for IVF in poor responders 􀁺 34 poor responders, divided into : I - GnRH-a + FSH II - GnRH-a + FSH + L-arginine (daily supplementation until hCG) Battaglia, C et al, Human Reproduction, 1999 Oral L Arginine supplementation may improve Ovarian response Endometrial receptivity Pregnancy rate. Modulation of endometrial vascularity by oral L Arginine supplementation may improve the pregnancy rate, especially in poor responder patients who normally present an impaired uterine perfusion.
  • 44. BMJ. 2011 May 19;342:d2901. doi: 10.1136/bmj.d2901
  • 45. J Matern Fetal Neonatal Med. 2010 Dec;23(12):1456-60.
  • 46. Indication Trials Outcome Pre- eclampsia /PIH Effect of supplementation during pregnancy with L-arginine and antioxidant vitamins in medical food on pre-eclampsia in high risk population: randomised controlled trial. [BMJ. 2011 May 19;342:d2901. doi: 10.1136/bmj.d2901] Supplementation during pregnancy with a medical food containing L-arginine and antioxidant vitamins reduced the incidence of pre-eclampsia in a population at high risk of the condition. L-arginine supplementation in women with chronic hypertension: impact on blood pressure and maternal and neonatal complications. [J Matern Fetal Neonatal Med. 2010 Dec;23(12):1456-60.] L-Arg supplementation in pregnant women with mild chronic hypertension does not significantly affect overall BP but is associated with less need for antihypertensive medications and a trend toward fewer maternal and neonatal complications. L-arginine supplementation in patients with gestational hypertension: a pilot study. [Hypertens Pregnancy. 2007;26(1):121-30.] The treatment with L-Arg seems promising in prolonging pregnancy and reducing blood pressure, particularly in patients with gestational hypertension and without proteinuria Effect of L-arginine on blood pressure in pregnancy-induced hypertension: a randomized placebo-controlled trial. [J Matern Fetal Neonatal Med. 2006 May;19(5):277-81.] data support the use of L-Arg as an antihypertensive agent for gestational hypertension especially in view of the other beneficial effects nitric oxide donors display in pregnancy. REDUCED INCIDENCE OF PRE-ECLAMPSIA. LESS NEED FOR ANTIHYPERTENSIVE MEDICATIONS.
  • 47.  L-arginine is a semi-essential amino acid that plays an important role in the production of Nitric oxide a potent endogenous vasodilator.  Reduced formation of NO could account for abnormal placental perfusion in preeclampsia.  Abnormal placentation leads to preclampsia and is associated with intrauterine fetal growth restriction (IUGR).
  • 48.  Arginine has multiple health applications that pregnant women can benefit like management of Pregnancy induced hypertension. Women at risk of developing PIH. Intrauterine growth retardation. Preterm labor. Poor responders in IVF therapy.
  • 49.  Arginine is NO donor  Arginine is metabolized in a completely different way in health and disease  Changes in arginine metabolism occur principally in the vascular system  Arginase depletes arginine & generates ornithine
  • 50.  Clinical Evidence  PIH is benefited by the use of arginine, omega 3 fatty acids, and nucleotides  Ideally used in second and third trimester ▪ Overall > 20 clinical Studies ▪ ↓ 40% in reduction rates ▪ Significant savings  Trauma Patients appear to benefit also ▪ Modest number of patients
  • 51.  Medical Critically Ill Patients are NOT benefited.  No clear evidence of Harm  Eclampsia Patients Controversial evidence  Some studies show Harm  Some studies show benefit