1. Crambescins are guanidine alkaloids from the sponge Crambe crambe. Crambescine C induces metallothionein genes and nitric oxide is one of the triggers. We assayed in silico, in vitro and, in vivo the effect in comparison with two analogs: crambescine A, and homo-crambescine C 2. HepG2 gene expression was analyzed using microarrays and additionally assays used isolated rat aortic rings. The targets of crambescines were studied in silico. In vivo vasodilation in rats was done by direct measurement. 3. Crambescines C and homo-crambescine C, but not crambescine A, induced metallothioneins transcripts. HepG2 cells with crambescine C increased nitric oxide production. Vasodilation was observed in aortic ring and in vivo after injection in rats. In silico analysis points to eNOS and iNOS as targets of crambescin C and source of nitric oxide increment. 4. Crambescin C effect is mediated through crambescing binding to the active site of eNOS and iNOS. In isolated rat aortic rings CC and HCC induced an endothelium-dependent relaxation related to eNOS activation and an endothelium-independent relaxation related to iNOS activation, hence both compounds increase NO and reduce vascular tone. 5. Crambescin C1 docking studies in iNOS and eNOS active site revealed hydrogen bonding of the hydroxylated chain with residues Glu377 and Glu361, involved in the substrate recognition, and explains its higher binding affinity than Crambescin A1. The later interaction and the extra polar contacts with its pyrimidine moiety, absent in the endogenous substrate, explain its role as exogenous substrate of NOSs and NO production.

Aim The aim of the study was to define and compare persistence of infliximab and adalimumab according to the treatment line. The secondary objectives were to identify factors that influence persistence. Methods We performed an observational, retrospective, single-center study with adult patients diagnosed with Crohn’s disease between November 2001 and May 2020. A total of 309 patients were included. Survival analysis and Cox regression were used. The following factors were studied: gender, body mass index, use of concomitant immunosuppressants, time from diagnosis to the beginning of the biological, trough drug levels on target, year where the anti-TNFα began and initial patient characteristics at the beginning of the treatment. Results The median persistence associated with the first-line of anti-TNFα treatment showed a statistically significant difference with respect to the second-line (7.0 vs 5.2, p= 0.0082). Differences between infliximab and adalimumab were not statistically significant (7.8 vs 6.5, p= 0.91). The multivariate Cox analysis shows that only drug concentrations on target and year of initiation of anti-TNFα were associated with higher persistence in first-line treatment (p= 0.04). In the second-line the difference between the infliximab and adalimumab subgroups was not statistically significant (5.1 vs 5.2, p= 0.5). Only the year of initiation of treatment showed an influence on persistence. Conclusion Persistence was greater in the first-line. No differences in persistence were observed between infliximab and adalimumab. The most important influencing factors were the year of initiation of treatment and target drug concentrations.

Since the publication of the American Gastroenterological Association’s (AGA) recommendations in 2017, there have been no significant changes in the biological monitoring recommendations. Lack of evidence on proactive therapeutic drug monitoring (pTDM) over the reactive therapeutic drug monitoring (rTDM) and the absence of recommendations on the individualized dosage methods have been limiting. The aims of this review were to identify updates on TDM strategies and in individualized dosing methods. For the analysis of the TDM strategies and individualized dosing method, a search was carried out in PubMed and Cochrane Central. In TDM case, since 2017. A total of 263 publications were found. Only 7 related to pTDM. Two of them were clinical trials and one systematic review. Of the 8 studies analyzed, 7 found benefit from pTDM over rTDM and one found no difference. Only one study was prospective. Regarding the individualized dosing method, 229 results were found. Population pharmacokinetics was the most widely used technique to explore and develop individual dosage models. It has been used to analyze the influence of factors on drug concentrations (serum albumin, weight… etc. We have not found major changes in TDM strategies. The available evidence is limited and of low quality. Retrospective designs and low power of the studies are the main problems. Population pharmacokinetics methods are the most widely used. But are more used to identify factors that affect drug concentrations than for dosage individualization.