This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Purpose This study aimed to develop and demonstrate the in vivo feasibility of a 3D stack‐of‐spiral balanced steady‐state free precession(3D‐bSSFP) urea sequence, interleaved with a metabolite‐specific gradient echo (GRE) sequence for pyruvate and metabolic products, for improving the SNR and spatial resolution of the first hyperpolarized 13C‐MRI human study with injection of co‐hyperpolarized [1‐13C]pyruvate and [13C,15N2]urea. Methods A metabolite‐specific bSSFP urea imaging sequence was designed using a urea‐specific excitation pulse, optimized TR, and 3D stack‐of‐spiral readouts. Simulations and phantom studies were performed to validate the spectral response of the sequence. The image quality of urea data acquired by the 3D‐bSSFP sequence and the 2D‐GRE sequence was evaluated with 2 identical injections of co‐hyperpolarized [1‐13C]pyruvate and [13C,15N2]urea formula in a rat. Subsequently, the feasibility of the acquisition strategy was validated in a prostate cancer patient. Results Simulations and phantom studies demonstrated that 3D‐bSSFP sequence achieved urea‐only excitation, while minimally perturbing other metabolites (<1%). An animal study demonstrated that compared to GRE, bSSFP sequence provided an ∼2.5‐fold improvement in SNR without perturbing urea or pyruvate kinetics, and bSSFP approach with a shorter spiral readout reduced blurring artifacts caused by J‐coupling of [13C,15N2]urea. The human study demonstrated the in vivo feasibility and data quality of the acquisition strategy. Conclusion The 3D‐bSSFP urea sequence with a stack‐of‐spiral acquisition demonstrated significantly increased SNR and image quality for [13C,15N2]urea in co‐hyperpolarized [1‐13C]pyruvate and [13C,15N2]urea imaging studies. This work lays the foundation for future human studies to achieve high‐quality and high‐SNR metabolism and perfusion images.

Background. Constipation is frequent in critically ill adults receiving opioids. Naloxegol (N), a peripherally acting mu-receptor antagonist (PAMORA), may reduce constipation. The objective of this trial was to evaluate the efficacy and safety of N to prevent constipation in ICU adults receiving opioids. Methods and Patients. In this single-center, double-blind, randomized trial, adults admitted to a medical ICU receiving IV opioids (≥100 mcg fentanyl/day), and not having any of 17 exclusion criteria, were randomized to N (25 mg) or placebo (P) daily randomized to receive N (25mg) or placebo (P) and docusate 100 mg twice daily until ICU discharge, 10 days, or diarrhea (≥3 spontaneous bowel movement (SBM)/24 hours) or a serious adverse event related to study medication. A 4-step laxative protocol was initiated when there was no SBM ≥3 days. Results. Only 318 (20.6%) of the 1542 screened adults during the 1/17–10/19 enrolment period met all inclusion criteria. Of these, only 19/381 (4.9%) met all eligibility criteria. After 7 consent refusals, 12 patients were randomized. The study was stopped early due to enrolment futility. The N (n = 6) and P (n = 6) groups were similar. The time to first SBM (N 41.4 ± 31.7 vs. P 32.5 ± 25.4 hours, P  = 0.56) was similar. The maximal daily abdominal pressure was significantly lower in the N group (N 10 ± 4 vs. P 13 ± 5, P  = 0.002). The median (IQR) daily SOFA scores were higher in N (N 7 (4, 8) vs. P 4 (3, 5), P  < 0.001). Laxative protocol use was similar (N 83.3% vs. P 66.6%; P  = 0.51). Diarrhea prevalence was high but similar (N 66.6% vs. P 66.6%; P  = 1.0). No patient experienced opioid withdrawal. Conclusions. Important recruitment challenges exist for ICU trials evaluating the use of PAMORAs for constipation prevention. Despite being underpowered, our results suggest time to first SBM with naloxegol, if different than P, may be small. The effect of naloxegol on abdominal pressure, SOFA, and the interaction between the two requires further research.

The ATP‐binding cassette transporter P‐glycoprotein (P‐gp) limits the oral bioavailability of many drugs. Although P‐gp has been well studied in humans and mice, little is known about the substrate specificities of many of its species orthologs. To address this, we performed in vitro analysis of P‐gp transporter function using HEK293 cells stably expressing human, ovine, porcine, canine, and feline P‐gp. We also employed a human physiologically based pharmacokinetic (PBPK) model to assess variations in digoxin exposure resulting from altered P‐gp function. Compared to human P‐gp, sheep P‐gp had significantly less digoxin efflux (2.3‐fold ±0.04 vs. 1.8‐fold ±0.03, p < .0001) and all species orthologs had significantly less quinidine efflux compared with human P‐gp (p < .05). Human P‐gp also had significantly greater efflux of talinolol compared to sheep and dog P‐gp (1.9‐fold ±0.04 vs. 1.6‐fold ±0.06, p = .003 and 1.6‐fold ±0.05, p = .0002, respectively). P‐gp expression protected all lines against paclitaxel‐induced toxicity, with sheep P‐gp being significantly less protective. The inhibitor verapamil demonstrated dose‐dependent inhibition of all P‐gp orthologs. Finally, a PBPK model showed digoxin exposure was sensitive to altered P‐gp activity. Overall, our study found that species differences in this major drug transporter exist and that the appropriate species ortholog of P‐gp should be evaluated during veterinary drug development.