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Levophed

Norepinephrine (INN) or noradrenaline (BAN) is a catecholamine and a phenethylamine with chemical formula C8H11NO3. It is released from the adrenal glands as a hormone into the blood, but it is also a neurotransmitter in the nervous system where it is released from noradrenergic neurons during synaptic transmission. As a stress hormone, it affects parts of the human brain where attention and impulsivity are controlled. more...

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Along with epinephrine, this compound effects the fight-or-flight response, activating the sympathetic nervous system to directly increase heart rate, release energy from fat, and increase muscle readiness.

The host of physiological changes activated by a stressful event are unleashed in part by activation of a nucleus in the brain stem called the locus ceruleus. This nucleus is the origin of most norepinephrine pathways in the brain. Neurons using norepinephrine as their neurotransmitter project bilaterally from the locus ceruleus along distinct pathways to the cerebral cortex, limbic system, and the spinal cord, among other projections.

At synapses it acts on both alpha and beta adrenoreceptors.

Antidepressants

Changes in the norepinephrine system are implicated in depression. Serotonin-norepinephrine reuptake inhibitors (SNRIs) treat depression by increasing the amount of serotonin and norepinephrine available to postsynaptic cells in the brain. There is some recent evidence showing that the norepinephrine transporter also normally transports some dopamine as well, implying that SNRIs may also increase dopamine transmission. This is because SNRIs work by preventing the serotonin and norepinephrine transporter from taking their respective neurotransmitters back to their storage vesicles for later use. If the norepinephrine transporter normally recycles some dopamine too, then SNRIs will also enhance dopaminergic transmission. Therefore, the antidepressant effects associated with increasing norepinephrine levels may also be partly or largely due to the concurrent increase in dopamine (particularly in the prefrontal cortex).

Some other antidepressants (for example some tricyclic antidepressants (TCAs)) affect norepinephrine as well, in some cases without affecting other neurotransmitters (at least not directly).

Role in attention

Norepinephrine, along with dopamine, has come to be recognized as playing a large role in attention and focus. In response, Eli Lilly Pharmaceuticals has released Strattera (atomoxetine), a selective norephinephrine reuptake inhibitor, for the treatment of ADHD in adults and children. Strattera is unique in medications specifically indicated for ADHD, as, unlike the psychostimulants (methylphenidate, dextroamphetamine, Adderall (a racemic mixture of amphetamine salts)), it affects norephinephrine, rather than dopamine. As a result, Strattera has a very low abuse potential and can act 24 hours-per-day. (It should be noted that some antidepressants, including SNRIs, have been used off-label for treatment of ADHD.)

Clinical use

Norepinephrine (commonly referred to by the brand name Levophed) is also a powerful medicine used in critically-ill patients as a vasopressor. It is given intravenously and acts on both alpha-1 and beta-1 adrenergic receptors to cause vasoconstriction. Norepinephrine is mainly used to treat patients in septic shock.

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Association Of Il-10 Gene Polymorphism And Mortality Following Coronary Artery Bypass Graft Surgery - CABG - interleukin-10 - Abstract
From CHEST, 10/1/00 by Sachin Yende

Sachin Yende, MBBS(*); Michael Quasney, MD PhD; Sarah Lambert, RN; Qing Zhang, BS and Richard G Wunderink, MD FCCP. Methodist Lebonheur Healthcare, Memphis, TN and Methodist-Lebonheur Healthcare and University of Tennessee, Memphis, TN.

PURPOSE: During CABG, exposure of blood to the foreign surface of bypass circuit, complement activation, ischemia-reperfusion injury and endotoxin release from the gastrointestinal tract stimulate release of pro-inflammatory and anti-inflammatory mediators. IL-10 is an important anti-inflammatory cytokine and regulates the inflammatory cascade. The G[right arrow]--A transition at the -1082 site within the IL-10 gene is associated with lower IL-10 levels. We therefore attempted to study effects of this polymorphism on outcomes of CABG.

METHODS: A prospective observational study of all patients undergoing conventional and off-pump CABG (OPCAB). Patients were weaned by standardized respiratory protocol and assessed at 8, 24 and 48 hours for failure to wean. Duration of inotropes (dopamine, dobutamine, levophed, amrinone, milrinone and epinephrine) and need for blood products including packed red cells (PRBC), fresh frozen plasma (FFP), cryoprecipitate (Cryo) and platelets within the first 48 hours were recorded. Pre-collected blood was used for gene analysis using polymerase chain reaction and restriction enzyme digestion. Primary end-points include duration of mechanical ventilation, need for inotrope support and blood product transfusion within 48 hours after surgery. Secondary end-points include length of stay, need for rehabilition after surgery and 30 day mortality.

RESULTS: 246 patients were enrolled. 40.8% and 8.6% of patients failed to wean at 8 and 24 hours respectively. 17 (6.9%) patients were lost to follow up after hospital discharge. Patients homozygous for A allele (AA) were compared to heterozygous (GA) and those homozygous for G allele (GG). The mean duration of mechanical ventilation, inotrope and blood products used were similar in all three groups. The gene polymorphism failed to affect length of stay and need for discharge to rehabilitation facility (table). The A allele is associated with lower mortality (2.7%) compared to G allele (7.4%). The odds ratio for mortality was 2.9 (95% CI = 1.2-7.6). The mortality was lowest amongst patients with AA.

CONCLUSION: The AA genotype at the -1082 site within the IL-10 gene is associated with lower mortality compared to GA and GG. The polymorphism however does not affect respiratory, cardiovascular or hematologic complications after CABG.

CLINICAL IMPLICATIONS: Pre-operative genotyping of IL-10 gene may improve risk stratification of patients prior to CABG.

GRANT SUPPORT: This study is funded by the Methodist-Lebonheur Healthcare and Crippled Children's Foundation.

COPYRIGHT 2000 American College of Chest Physicians
COPYRIGHT 2001 Gale Group

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