Metformin inhibits basal secretion from the pituitary gland of growth hormone, adrenocorticotropic hormone, follicle stimulating hormone, and expression of proopiomelanocortin, which in part accounts for its insulin-sensitizing effect with multiple actions on tissues including the liver, skeletal muscle, endothelium, adipose tissue, and the ovaries. The average patient with type 2 diabetes has three times the normal rate of gluconeogenesis; metformin treatment reduces this by over one-third.Activation of AMPK was required for metformins inhibitory effect on liver glucose production. AMPK is an enzyme that plays an important role in insulin signalling, whole-body energy balance, and the metabolism of glucose and fats. AMPK activation was required for an increase in the expression of small heterodimer partner, which in turn inhibited the expression of the hepatic gluconeogenic genes phosphoenolpyruvate carboxykinase and glucose 6-phosphatase. Metformin is frequently used in research along with AICA ribonucleotide as an AMPK agonist. The mechanism by which biguanides increase the activity of AMPK remains uncertain: metformin increases the concentration of cytosolic adenosine monophosphate (AMP) (as opposed to a change in total AMP or total AMP/adenosine triphosphate) which could activate AMPK allosterically at high levels; a newer theory involves binding to PEN-2. Metformin inhibits cyclic AMP production, blocking the action of glucagon, and thereby reducing fasting glucose levels.
Decitabine/cedazuridine, sold under the brand name Inqovi, is a fixed-dose combination medication for the treatment of adults with myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). It is a combination of decitabine, a nucleoside metabolic inhibitor, and cedazuridine, a cytidine deaminase inhibitor.The most common side effects of decitabine/cedazuridine include fatigue, constipation, hemorrhage, muscle pain (myalgia), mucositis (mouth sores), arthralgia (joint pain), nausea, dyspnea, diarrhea, rash, dizziness, fever with low white blood cell count (febrile neutropenia), edema, headache, cough, decreased appetite, upper respiratory tract infection, pneumonia, and transaminase increased. The combination can cause fetal harm.Decitabine/cedazuridine was approved for medical use in the United States and in Canada in July 2020. Medical uses
Decitabine/cedazuridine is indicated for treatment of adults with myelodysplastic syndromes (MDS), including previously treated and untreated, de novo and secondary MDS with the following French American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, and chronic myelomonocytic leukemia [CMML]) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups.MDS is a type of blood cancer in which blood cells in the bone marrow are defective leading to a low number of one or more types of blood cells. History
Decitabine/cedazuridine was approved for medical use in the United States and in Canada in July 2020.The U.S. Food and Drug Administration (FDA) granted the application of decitabine combined with cedazuridine priority review and orphan drug designation.