Interactions
Only in vitro interaction studies are available. In these, trifluridine used the concentrative nucleoside transporter 1 (CNT1) and equilibrative nucleoside transporters 1 (ENT1) and 2 (ENT2), and tipiracil was transported by the solute carrier proteins SLC22A2 and SLC47A1. Drugs that interact with these transporters could influence blood plasma concentrations of trifluridine and tipiracil. Trifluridine, being a thymidine phosphorylase inhibitor, could also interact with substrates of this enzyme such as zidovudine. Pharmacology
Mechanism of action
The drug consists of the cytotoxin trifluridine and the thymidine phosphorylase inhibitor (TPI) tipiracil. Trifluridine is incorporated into DNA during DNA synthesis and inhibits tumor cell growth. Trifluridine (TFT) is incorporated into DNA by phosphorylation by thymidylate kinase (TK) to TF-TMP;  TF-TMP then covalently binds to tyrosine 146 of the active site of thymidylate synthase (TS) inhibiting the enzymes activity. TS is vital to the synthesis of DNA because it is an enzyme involved in the synthesis of the deoxynucleotide, thymidine triphosphate (dTTP). Inhibition of TS depletes the cell of dTTP and causes accumulation of deoxyuridine monophosphate (dUMP), which increases the likelihood that uracil gets misincorporated into the DNA. Also, subsequent phosphorylations of TF-TMP cause an increased level of TF-TTP within the cell, which results in it being incorporated into DNA. Even though the exact mechanism of how TFT causes DNA damage is not completely understood, it is hypothesized that the incorporation TF-TTP in DNA leads to DNA strand break formation.Tipiracil prevents the degradation of trifluridine via thymidine phosphorylase (TP) when taken orally and also has antiangiogenic properties.
Non-occlusive disease (NOD) or Non-occlusive mesenteric ischaemia (NOMI) is a life-threatening condition including all types of mesenteric ischemia without mesenteric obstruction. It affects mainly elderly patients above 50 years of age who suffer from cardiovascular disease (myocardial infarction, congestive heart failure or aortic regurgitation), hepatic, chronic kidney disease or diabetes mellitus. It can be triggered also by a previous cardiac surgery with a consequent heart shock. It represents around 20% of cases of acute mesenteric ischaemia. Pathophysiology
Non-occlusive mesenteric ischemia occurs due to severe vasoconstriction of mesenteric vessels supplying the intestine. Acute abdominal pain is the only early acute symptom in those patients, which makes early diagnosis difficult. Diagnosis
CT angiography would be helpful in differentiating occlusive from non-occlusive causes of mesenteric ischaemia. Prognosis
Non-occlusive disease has a poor prognosis with survival rate between 40-50%. == References ==