People survive owing to low amounts of the SMN protein produced from the SMN2 gene. Nusinersen modulates alternative splicing of the SMN2 gene, functionally converting it into SMN1 gene, thus increasing the level of SMN protein in the CNS.The drug distributes to CNS and peripheral tissues.The half-life is estimated to be 135 to 177 days in cerebrospinal fluid (CSF) and 63 to 87 days in blood plasma. The drug is metabolized via exonuclease (3′- and 5′)-mediated hydrolysis and does not interact with CYP450 enzymes. The primary route of elimination is likely by urinary excretion for nusinersen and its metabolites. Chemistry
Nusinersen is an antisense oligonucleotide in which the 2-hydroxy groups of the ribofuranosyl rings are replaced with 2-O-2-methoxyethyl groups and the phosphate linkages are replaced with phosphorothioate linkages. History
Nusinersen was developed in a collaboration between Adrian Krainer at Cold Spring Harbor Laboratory and Ionis Pharmaceuticals (formerly called Isis Pharmaceuticals). Initial work of target discovery of nusinersen was done by Dr. Ravindra Singh and co-workers at the University of Massachusetts Medical School funded by Cure SMA.Starting in 2012, Ionis partnered with Biogen on development and, in 2015, Biogen acquired an exclusive license to the drug for a US$75 million license fee, milestone payments up to US$150 million, and tiered royalties thereafter; Biogen also paid the costs of development subsequent to taking the license.
Norepinephrine, also known as noradrenaline, is a medication used to treat people with very low blood pressure. It is the typical medication used in sepsis if low blood pressure does not improve following intravenous fluids. It is the same molecule as the hormone and neurotransmitter norepinephrine. It is given by slow injection into a vein.Common side effects include headache, slow heart rate, and anxiety. Other side effects include an irregular heartbeat. If it leaks out of the vein at the site it is being given, norepinephrine can result in limb ischemia. If leakage occurs the use of phentolamine in the area affected may improve outcomes. Norepinephrine works by binding and activating alpha adrenergic receptors.Norepinephrine was discovered in 1946 and was approved for medical use in the United States in 1950. It is available as a generic medication. Medical uses
Norepinephrine is used mainly as a sympathomimetic drug to treat people in vasodilatory shock states such as septic shock and neurogenic shock, while showing fewer adverse side-effects compared to dopamine treatment. Mechanism of action
It stimulates α1 and α2 adrenergic receptors to cause blood vessel contraction, thus increases peripheral vascular resistance and resulted in increased blood pressure. This effect also reduces the blood supply to gastrointestinal tract and kidneys. Norepinephrine acts on beta-1 adrenergic receptors, causing increase in heart rate and cardiac output. However, the elevation in heart rate is only transient, as baroreceptor response to the rise in blood pressure as well as enhanced vagal tone ultimately result in a sustained decrease in heart rate.