A gut-restricted glutamate carboxypeptidase II inhibitor reduces monocytic inflammation and improves preclinical colitis.

There is an urgent need to develop therapeutics for inflammatory bowel disease (IBD) because up to 40% of patients with moderate-to-severe IBD are not adequately controlled with existing drugs. Glutamate carboxypeptidase II (GCPII) has emerged as a promising therapeutic target. This enzyme is minimally expressed in normal ileum and colon, but it is markedly up-regulated in biopsies from patients with IBD and preclinical colitis models. Here, we generated a class of GCPII inhibitors designed to be gut-restricted for oral administration, and we interrogated efficacy and mechanism using in vitro and in vivo models. The lead inhibitor, (S)-IBD3540, was potent (half maximal inhibitory concentration = 4 nanomolar), selective, gut-restricted (AUCcolon/plasma > 50 in mice with colitis), and efficacious in acute and chronic rodent colitis models. In dextran sulfate sodium-induced colitis, oral (S)-IBD3540 inhibited >75% of colon GCPII activity, dose-dependently improved gross and histologic disease, and markedly attenuated monocytic inflammation. In spontaneous colitis in interleukin-10 (IL-10) knockout mice, once-daily oral (S)-IBD3540 initiated after disease onset improved disease, normalized colon histology, and attenuated inflammation as evidenced by reduced fecal lipocalin 2 and colon pro-inflammatory cytokines/chemokines, including tumor necrosis factor-α and IL-17. Using primary human colon epithelial air-liquid interface monolayers to interrogate the mechanism, we further found that (S)-IBD3540 protected against submersion-induced oxidative stress injury by decreasing barrier permeability, normalizing tight junction protein expression, and reducing procaspase-3 activation. Together, this work demonstrated that local inhibition of dysregulated gastrointestinal GCPII using the gut-restricted, orally active, small-molecule (S)-IBD3540 is a promising approach for IBD treatment.

Variation in bony landmarks and predictors of success with sacral neuromodulation.

INTRODUCTION AND HYPOTHESIS: We assessed variations in sacral anatomy and lead placement as predictors of sacral neuromodulation (SNM) success. Based solely on bony landmarks, we also assessed the accuracy of the 9 and 2 protocol for locating S3. METHODS: This is a retrospective cohort study performed from October 2008 to December 2016 at the University of North Carolina at Chapel Hill. Fluoroscopic images were used to assess sacral anatomy and lead location. Success was defined as >50% symptom improvement after stage I and clinical response at most recent follow-up. RESULTS: Of 249 procedures, 209 were primary implants and 40 were revisions among 187 (89.5%) women and 22 (10.5%) men. Success rate was 83.3% for primary implants and 89.4% for revisions. Success was associated with shorter implant duration (21.3 ± 22.2 vs 33.6 ± 25.8 months), higher body mass index (30.3 ± 7.8 vs 27.6 ± 6.1 kg/m2), and straight vs curved lead (90.5% vs 80.5%) (all p = .05), but not with sacral anatomy or lead placement. In assessing the 9 and 2 protocol, mean distance from coccyx to S3 did not equal 9 cm: 7.4 ± 1.0 vs 7.2 ± 0.8 cm (p = .26), while mean distance from midline to S3 did equal 2 cm: 1.9 ± 0.4 vs 2.0 ± 0.7 cm (p = .37). CONCLUSIONS: Variations in sacral anatomy and lead placement did not predict SNM success. The 2-cm protocol was verified while the 9-cm protocol was not, although neither was predictive of success, which may obviate the need to mark bony landmarks prior to fluoroscopy.

Partner-Drug Resistance and Population Substructuring of Artemisinin-Resistant Plasmodium falciparum in Cambodia.

Plasmodium falciparum in western Cambodia has developed resistance to artemisinin and its partner drugs, causing frequent treatment failure. Understanding this evolution can inform the deployment of new therapies. We investigated the genetic architecture of 78 falciparum isolates using whole-genome sequencing, correlating results to in vivo and ex vivo drug resistance and exploring the relationship between population structure, demographic history, and partner drug resistance. Principle component analysis, network analysis and demographic inference identified a diverse central population with three clusters of clonally expanding parasite populations, each associated with specific K13 artemisinin resistance alleles and partner drug resistance profiles which were consistent with the sequential deployment of artemisinin combination therapies in the region. One cluster displayed ex vivo piperaquine resistance and mefloquine sensitivity with a high rate of in vivo failure of dihydroartemisinin-piperaquine. Another cluster displayed ex vivo mefloquine resistance and piperaquine sensitivity with high in vivo efficacy of dihydroartemisinin-piperaquine. The final cluster was clonal and displayed intermediate sensitivity to both drugs. Variations in recently described piperaquine resistance markers did not explain the difference in mean IC90 or clinical failures between the high and intermediate piperaquine resistance groups, suggesting additional loci may be involved in resistance. The results highlight an important role for partner drug resistance in shaping the P. falciparum genetic landscape in Southeast Asia and suggest that further work is needed to evaluate for other mutations that drive piperaquine resistance.