Using positron emission tomography imaging, we determined the hepatic concentrations and hepatobiliary transport of [11C]rosuvastatin (RSV; i.v. injection) in the absence (n = 6) and presence (n = 4 of 6) of cyclosporin A (CsA; i.v. infusion) following a therapeutic dose of unlabeled RSV (5 mg, p.o.) in healthy human volunteers. The sinusoidal uptake, sinusoidal efflux, and biliary efflux clearance (CL; mL/minute) of [11C]RSV, estimated through compartment modeling were 1,205.6 ± 384.8, 16.2 ± 11.2, and 5.1 ± 1.8, respectively (n = 6). CsA (blood concentration: 2.77 ± 0.24 μM), an organic‐anion‐transporting polypeptide, Na+‐taurocholate cotransporting polypeptide, and breast cancer resistance protein inhibitor increased [11C]RSV systemic blood exposure (45%; P < 0.05), reduced its biliary efflux CL (52%; P < 0.05) and hepatic uptake (25%; P > 0.05) but did not affect its distribution into the kidneys. CsA increased plasma concentrations of coproporphyrin I and III and total bilirubin by 297 ± 69%, 384 ± 102%, and 81 ± 39%, respectively (P < 0.05). These data can be used in the future to verify predictions of hepatic concentrations and hepatobiliary transport of RSV.
BackgroundThe magnitude of risk of serious infections due to available medical therapies of inflammatory bowel disease (IBD) remains controversial. We conducted a systematic review and network meta-analysis of the existing IBD literature to estimate the risk of serious infection in adult IBD patients associated with available medical therapies.MethodsStudies were identified by a literature search of PubMed, Cochrane Library, Medline, Web of Science, Scopus, EMBASE, and ProQuest Dissertations and Theses. Randomized controlled trials comparing IBD medical therapies with no restrictions on language, country of origin, or publication date were included. A network meta-analysis was used to pool direct between treatment comparisons with indirect trial evidence while preserving randomization.ResultsThirty-nine articles fulfilled the inclusion criteria; one study was excluded from the analysis due to disconnectedness. We found no evidence of increased odds of serious infection in comparisons of the different treatment strategies against each other, including combination therapy with a biologic and immunomodulator compared to biologic monotherapy. Similar results were seen in the comparisons between the newer biologics (e.g. vedolizumab) and the anti-tumor necrosis factor agents.ConclusionsNo treatment strategy was found to confer a higher risk of serious infection than another, although wide confidence intervals indicate that a clinically significant difference cannot be excluded. These findings provide a better understanding of the risk of serious infection from IBD pharmacotherapy in the adult population.Prospero registrationThe protocol for this systematic review was registered on PROSPERO (CRD42014013497).Electronic supplementary materialThe online version of this article (doi:10.1186/s12876-017-0602-0) contains supplementary material, which is available to authorized users.
Background Combining biologics and small molecules could potentially overcome the plateau of drug efficacy in inflammatory bowel disease (IBD). We conducted a systematic review and meta-analysis to assess the safety and effectiveness of dual biologic therapy (DBT), or small molecule combined with a biologic therapy (SBT) in IBD patients. Methods We searched MEDLINE, EMBASE, Scopus, Web of Science, Cochrane Database of Systematic Reviews and Clinical trials.gov until Nov 3, 2020, including studies with two or more IBD patients on DBT or SBT. Main outcome was safety assessed as pooled rates of adverse events (AEs) and serious AEs (SAEs) for each combination. Effectiveness was reported as pooled rates of clinical, endoscopic and/or radiographic response and remission. The certainty of evidence was rated according to the Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) framework. Results Of the 3,688 publications identified, 13 studies (1 clinical trial, 12 observational studies) involving 266 patients on seven different combinations were included. Median number of prior biologics ranged from 0-4, and median duration of follow-up was 16-68 weeks. Most common DBT and SBT were vedolizumab (VDZ) with anti-Tumor Necrosis Factor (aTNF, n=56) or tofacitinib (Tofa, n=57), respectively. Pooled rates of SAE for these were 9.6% (95% CI, 1.5–21.4) for VDZ-aTNF and 1.0% (95% CI, 0.0–7.6) for Tofa-VDZ. The overall certainty of evidence was very low due to the observational nature of the studies, and very serious imprecision and inconsistency. Conclusions DBT or SBT appears to be generally safe and may be effective in IBD patients, but the evidence is very uncertain.
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