However, Minot, Murphy, and Whipple received the joint Nobel Prize for discovering a cure for a previously fatal disease of unknown cause in 1934, becoming the first Americans to be awarded the Nobel Prize in Physiology and Medicine.It is not easy to eat uncooked liver, and extracts were developed as a concentrate of liver juice for intramuscular injection. In 1928, chemist  Edwin Cohn prepared an extract that was 50 to 100 times stronger than obtained from raw liver. This became part of the standard management of pernicious anemia until the 1950s. The active ingredient in the liver remained unknown until 1948. The anti-pernicious anemia factor was only isolated from the liver by Smith, Rex and others. The substance was cobalamin, which the discoverers called "vitamin B12". They showed that giving a few micrograms could prevent relapse in the disease. Dorothy Hodgkin and co-workers went on to use X-ray crystallography to elucidate the structure of cobalamin for which she, too, was awarded a Nobel Prize.Understanding of the pathogenesis of pernicious anaemia increased over subsequent decades. It had long been known that the disease was associated with defects in the gastrointestinal tract: patients had chronic gastritis and lack of acid secretion (achlorhydria). It is known that transport of physiological amounts of vitamin B12 depends on the combined actions of gastric, ileal and pancreatic components. The gastric moiety was discovered and named intrinsic factor by William Castle in 1930.
The thickened mucus can lead to inflammation, respiratory infections, and clogged ducts. Mechanism of action
Elexacaftor/tezacaftor/ivacaftor is a tridrug treatment in which the medications work together to increase the transport of chloride and sodium ions, and reducing thick mucus production. CFTR channel potentiator
Ivacaftor is a selective small-molecule potentiator of the CFTR protein that increases the proteins ability to open chloride channels. Its effectiveness is highly dependent on the amount of CFTR protein at the cell surface and the responsiveness of the mutant CFTR protein. Ivacaftors primary target is to treat class III CFTR gating mutations like G551D as well as other less common mutations. In the crystalline figure, you can see ivacaftor, shown as a gray ball and stick model on the bottom-right, bound to CFTR docked in a cleft formed by transmembrane helices at the protein-lipid interface. CFTR correctors
Elexacaftor and Tezacaftor act as CFTR correctors to repair F508del processing by binding to the CFTR protein to increase the availability of CFTR protein on the cell surface. They work by modulating the position of the CFTR protein into the right position on the cell surface.The combination of increased CFTR protein in the correct position on the cell surface with ivacaftors potentiation of chloride channel opening results in increased transport of chloride and thinned mucus secretions. Pharmacokinetics
Elexacaftor/tezacaftor/ivacaftor is primarily metabolized by CYP3A4 /5. This medication should be taken with a high fat meal to improve absorption through the gut. It is excreted as metabolites or unchanged mainly through feces and to a smaller extent urine.