An inflammatory reaction could be an important source of intraindividual variability in cyclosporine pharmacokinetics, possibly through an inhibition of cytochrome P4503A-dependent enzyme activities by endogenous interleukin-6. Blood AM1 accumulation might be explained by a secondary metabolic step that is highly sensitive to the inhibitory effect of interleukin-6.

Tenofovir-related tubular damage, like all other recently reported cases, occurred in patients receiving the protease inhibitor (PI) ritonavir, often with lopinavir. Increased plasma concentrations of didanosine were also observed after the addition of tenofovir. It was suspected that tenofovir with PIs interacted with renal organic anion transporters, leading to nephrotoxic tubular concentrations of tenofovir and systemic accumulation of didanosine. Until there is a better understanding of these interactions, close monitoring is recommended for patients receiving tenofovir, PIs, and didanosine.

1 The toxic e ects of nonsteroidal anti-in¯ammatory drugs for the lower gastrointestinal tract share certain features with in¯ammatory processes, suggesting that the release of in¯ammation cytokines such as TNF-a may damage the intestine. 2 Rats received a s.c. injection of indomethacin. Then, jejunum-ileum was taken up for the quanti®cation of ulcerations, production of TNF-a, nitrites and PGE2 ex vivo and activity of calciumindependent NO synthase and myeloperoxydase. Activation of NO metabolism and myeloperoxydase were measured as potential e ectors of TNF-a. 3 Jejunum-ileum from rats having received indomethacin (10 mg kg 71 ) produced TNF-a ex vivo. Cytokine production was associated with the onset of macroscopic ulcerations of the small intestine, and preceded nitrite production and tissue activity of myeloperoxidase. 4 Similar intestinal ulcerations and upregulation of TNF-a were obtained with¯urbiprofen (30 mg kg 71 ), chemically unrelated to indomethacin. 5 TNF-a production was proportional to the indomethacin dose (from 3 ± 20 mg kg 71 ) and correlated with the surface area of ulcerations and nitrite production, 24 h after indomethacin administration. 6 Pretreatment of rats with RO 20-1724, a type-IV phosphodiesterase inhibitor which inhibits TNF-a synthesis, substantially reduced jejunum-ileum ulcerations, TNF-a and nitrite production and tissue enzyme activities. 7 These ®ndings provide evidence that TNF-a is increased in indomethacin-induced intestinal ulcerations and support suggestions that TNF-a is involved at an early stage of nonsteroidal antiin¯ammatory drug toxicity for the small intestine.

Cirrhotic patients with severe sepsis have decreased blood levels of zymogen forms of factors VII+X, V, and prothrombin, which may be due not only to the severity of cirrhosis but also, at least in part, to the consumption of these zymogens by the extrinsic coagulation pathway.

No abstract