Inducers result in levels of isavuconazole that are too low and wont work, and inhibitors can cause high levels of isavuconazole which will in turn cause increased adverse events and toxicity. Likewise isavuconazonium can interfere with appropriate dosing of other drugs that are substrates for those enzymes.In addition, isavuconazole induces CYP2B6 and can decrease the amount of drugs that are metabolized by the enzyme. Isavuconazole inhibits P-glycoprotein (P-gp), BCRP, SLC22A2, and uridine diphosphate-glucuronosyltransferases, each of which remove drugs from circulation; isavuconazonium will increase the amount of drugs that are affected by those proteins and may increase their toxicities. Pharmacology
After oral or intravenous (IV) administration, isavuconazonium is rapidly hydrolysed by esterases in blood or the gastrointestinal tract to the active form, isavuconazole.Isavuconazole works by inhibition of lanosterol 14α-demethylase, the enzyme responsible for converting lanosterol to ergosterol by demethylation. The resulting depletion of ergosterol and buildup of lanosterol compromise the structure of the fungal cell membrane. Mammalian cells are resistant to demethylation inhibition by azoles, making the drug effects specific to fungi. Chemistry
Isavuconazonium comprises an N-(3-acetoxypropyl)-N-methylamino-carboxymethyl group linked through an ester moiety to the triazole nitrogen in isavuconazole. History
Isavuconazole and isavuconazonium were discovered in Japan by researchers at Roches research center in Kamakura. Basilea Pharmaceutica, which had been spun out of Roche to develop antimicrobial assets, developed isavuconazonium through Phase II clinical trials. In February 2010, Basilea partnered with Astellas Pharma to complete Phase III trials, obtain regulatory approvals, and market the drug.
Other causes include Mallory-Weiss tears, cancer, and angiodysplasia.A number of medications are found to cause upper GI bleeds. NSAIDs or COX-2 inhibitors increase the risk about fourfold. SSRIs, corticosteroids, and anticoagulants may also increase the risk. The risk with dabigatran is 30% greater than that with warfarin. Lower gastrointestinal
Lower gastrointestinal bleeding is typically from the colon, rectum or anus. Common causes of lower gastrointestinal bleeding include hemorrhoids, cancer, angiodysplasia, ulcerative colitis, Crohns disease, and aortoenteric fistula. It may be indicated by the passage of fresh red blood rectally, especially in the absence of bloody vomiting. Lower gastrointestinal bleeding could also lead to melena if the bleeding occurs in the small intestine or proximal colon. Signs and symptoms
Gastrointestinal bleeding can range from small non-visible amounts, which are only detected by laboratory testing, to massive bleeding where bright red blood is passed and shock develops. Rapid bleeding may cause syncope. The presence of bright red blood in stool, known as hematochezia, typically indicates lower gastrointestinal bleeding. Digested blood from the upper gastrointestinal tract may appear black rather than red, resulting in "coffee ground" vomit or melena. Other signs and symptoms include feeling tired, dizziness, and pale skin color.A number of foods and medications can turn the stool either red or black in the absence of bleeding. Bismuth found in many antacids may turn stools black as may activated charcoal. Blood from the vagina or urinary tract may also be confused with blood in the stool.