Introduction
Increasing evidence suggests surgical patients are at risk for developing new, persistent opioid use (NPOU) following surgery. This risk may be heightened for patients undergoing ...bariatric surgery. Few studies have evaluated this important long-term outcome and little is known about the rate of NPOU, or factors associated with NPOU for bariatric surgery patients.
Methods and procedure
We conducted a systematic review of MEDLINE, Embase, Scopus, Web of Science, and Cochrane databases in August 2021. Studies were reviewed and data extracted independently by two reviewers following MOOSE guidelines. Studies evaluating bariatric surgery patients reporting NPOU, defined as new opioid use > 90 days after surgery, were included. Abstracts, non-English, animal,
n
< 5, and pediatric studies were excluded. Primary outcome was NPOU prevalence, and secondary outcomes were patient and surgical factors associated with NPOU. Factors associated with NPOU are reported from findings of individual studies; meta-analysis could not be completed due to heterogeneity of reporting.
Results
We retrieved a total of 2113 studies with 8 meeting inclusion criteria. In studies reporting NPOU rates (
n
= 4 studies), pooled prevalence was 6.0% (95% CI 4.0–7.0%). Patient characteristics reported by studies to be associated with NPOU included prior substance use (tobacco, alcohol, other prescription analgesics), preoperative mental health disorder (anxiety, mood disorders, eating disorders), and public health insurance. Surgical factors associated with NPOU included severe post-operative complications and in-hospital opioid use (peri- or post operatively).
Conclusions
NPOU is an uncommon but important complication following bariatric surgery, with patient factors including prior substance abuse, mental health disorders, and use of public health insurance placing patients at increased risk, and surgical factors being complications and peri-operative opioid use. Studies evaluating techniques to reduce NPOU in these high-risk populations are needed.
Myeloperoxidase (MPO) is a heme peroxidase that catalyzes the production of hypochlorous acid. Clinical evidence suggests a causal role for MPO in various autoimmune and inflammatory disorders ...including vasculitis and cardiovascular and Parkinson’s diseases, implying that MPO inhibitors may represent a therapeutic treatment option. Herein, we present the design, synthesis, and preclinical evaluation of N1-substituted-6-arylthiouracils as potent and selective inhibitors of MPO. Inhibition proceeded in a time-dependent manner by a covalent, irreversible mechanism, which was dependent upon MPO catalysis, consistent with mechanism-based inactivation. N1-Substituted-6-arylthiouracils exhibited low partition ratios and high selectivity for MPO over thyroid peroxidase and cytochrome P450 isoforms. N1-Substituted-6-arylthiouracils also demonstrated inhibition of MPO activity in lipopolysaccharide-stimulated human whole blood. Robust inhibition of plasma MPO activity was demonstrated with the lead compound 2-(6-(5-chloro-2-methoxyphenyl)-4-oxo-2-thioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamide (PF-06282999, 8) upon oral administration to lipopolysaccharide-treated cynomolgus monkeys. On the basis of its pharmacological and pharmacokinetic profile, PF-06282999 has been advanced to first-in-human pharmacokinetic and safety studies.
The melanocortin-4 receptor (MC4R) is a centrally expressed, class A GPCR that plays a key role in the regulation of appetite and food intake. Deficiencies in MC4R signaling result in hyperphagia and ...increased body mass in humans. Antagonism of MC4R signaling has the potential to mitigate decreased appetite and body weight loss in the setting of anorexia or cachexia due to underlying disease. Herein, we report on the identification of a series of orally bioavailable, small-molecule MC4R antagonists using a focused hit identification effort and the optimization of these antagonists to provide clinical candidate 23. Introduction of a spirocyclic conformational constraint allowed for simultaneous optimization of MC4R potency and ADME attributes while avoiding the production of hERG active metabolites observed in early series leads. Compound 23 is a potent and selective MC4R antagonist with robust efficacy in an aged rat model of cachexia and has progressed into clinical trials.
Purpose
Single anastomosis duodeno-ileal bypass with sleeve gastrectomy (SADI-S) offers a novel bariatric procedure. This systematic review and meta-analysis evaluates observational and comparative ...studies evaluating SADI-S, with meta-analysis comparing outcomes to other malabsorptive procedures (MPs).
Materials and Methods
Systematic search of MEDLINE, Embase, Scopus, and Web of Science was conducted in March 2021. The study followed PRISMA guidelines. Studies evaluating SADI-S with
n
> 5 were included. Primary outcome was diabetes (DM) remission, and secondary outcomes included perioperative outcomes, comorbidity resolution, and weight loss.
Results
We reviewed 2285 studies with 16 included evaluating 3319 patients and 1704 (51.3%) undergoing SADI-S. SADI-S patients had increased BMI (49.6 kg/m
2
vs 48.8 kg/m
2
) and weight (139.7 kg vs 137.1 kg), were more likely to have DM (46.3% vs 42.1%), and dyslipidemia (36.6% SADI-S vs 32.7%).
SADI-S had a shorter operative duration than MPs (MD − 36.74,
p
< 0.001), 0.85-day shorter post-operative stay (
p
< 0.001), and trended towards fewer complications (OR 0.69,
p
= 0.06). Rate of reoperation (OR 0.83,
p
= 0.59) was similar and DM remission was similar (OR 0.07,
p
= 0.1). Subgroup analysis suggested greater DM remission than Roux-en-Y gastric bypass (OR 4.42,
p
= 0.04). SADI-S had fewer malabsorptive complications, though follow-up was shorter. Weight loss was 37.3% compared to 35.6% total weight loss after SADI-S and MPs, respectively.
Conclusion
SADI-S demonstrates improved metabolic and weight loss outcomes with lower perioperative risks. SADI-S represents a promising bariatric procedure but long-term outcomes are needed to guide future uptake.
Graphical abstract
The synthesis of imidazole fused spirocyclic ketones as templates for acetyl-CoA carboxylase (ACC) inhibitors is reported. By completing the spirocyclic ring closure via divergent pathways, the ...synthesis of these regioisomers from common intermediates was developed. Through an aldehyde homologation/transmetalation strategy, one isomer was formed selectively. The second desired isomer was obtained via an intramolecular aromatic homolytic substitution reaction. Preparation of these isomeric spiroketones provided templates which, upon elaboration, led to key structure–activity relationship (SAR) points for delivery of potent ACC inhibitors.
Background
Several therapeutic modalities have been proposed for the management of choledocholithiasis (CDL) following Roux-en-Y gastric bypass (RYGB), yet debate exists regarding the optimal ...management. The purpose of our study was to review the current literature to compare the efficacy of various techniques in the management of CDL post-RYGB.
Methods
A comprehensive search of multiple databases was conducted. Studies reporting on the management of CDL in patients post-RYGB and including at least 5 patients were eligible for inclusion. The primary outcome was successful stone clearance. Secondary outcomes included procedure duration, length of hospital stay, and adverse events.
Results
Of 3259 identified studies, 53 studies involving 857 patients were included in the final analysis. The mean age was 54.4 years (SD 7.05), 78.8% were female (SD 13.6%), and the average BMI was 30.8 kg/m
2
(SD 6.85). Procedures described included laparoscopy-assisted ERCP (LAERCP), balloon-assisted enteroscopy (BAE), ultrasound-directed transgastric ERCP (EDGE), laparoscopic common bile duct exploration (LCBDE), EUS-guided intra-hepatic puncture with antegrade clearance (EGHAC), percutaneous trans-hepatic biliary drainage (PTHBD), and rendezvous guidewire-associated (RGA) ERCP. High rates of successful stone clearance were observed with LAERCP (1.00; 95% CI 0.99–1.00;
p
= 0.47), EDGE (0.97; 95% CI 0.9–1.00;
p
= 0.54), IGS ERCP (1.00; 95% CI 0.87–1.00), PTHBD (1.0; 95% CI 0.96–1.00), and LCBDE (0.99; 95% CI 0.93–1.00,
p
< 0.001). Lower rates of stone clearance were observed with BAE (61.5%; 95%CI 44.3–76.3,
p
= 0.188) and EGHAC (74.0%; 95% CI 42.9–91.5,
p
= 0.124). Relative to EDGE, LAERCP had a longer procedure duration (133.1 vs. 67.4 min) but lower complication rates (12.8% vs. 24.3%).
Conclusion
LAERCP and EDGE had high rates of success in the management of CDL post-RYGB. LAERCP had fewer complications but was associated with longer procedure times. BAE had lower success rates than both LAERCP and EDGE.
Introduction
Cameron lesions (CL) are an under-recognized cause of gastrointestinal bleeding. Diagnosis is often impaired by technical difficulty, and once diagnosed, management remains unclear.
...Typically, patients are medically managed with proton pump inhibitors (PPI). Small studies have demonstrated improved therapeutic success with surgical management, hypothesizing that reversing mechanical gastric trauma and ischemia allows CL healing. This systematic review and meta-analysis aim to compare therapeutic success of surgical versus medical management of Cameron lesions (CL).
Methods and procedures
A comprehensive search and systematic review selected manuscripts using the following inclusion criteria:
Endoscopically diagnosed CL
Treated surgically
Follow-up for resolution of anemia or CL
n
≥ 5
Excluding non-English, animal, and studies with patients < 18 years old
Meta-analysis was performed to compare resolution of CLs with medical and surgical therapy.
Results
Systematic search retrieved 1664 studies, of these, 14 were included (randomized controlled trial = 1; prospective = 2; retrospective = 11). Patients had a mean age of 61.2 years (range 24–91) and were more often female (59.3%). Follow-up was between 3 and 120 months, and 82.9% of patients had hernias > 5 cm.
Surgical management was associated with therapeutic success (OR 5.20, 1.83–14.77,
I
2
= 42%,
p
< 0.001) with 92% having resolution, compared to 67.2% for those treated with PPI. Surgical complications occurred in 42/109 (38.5%) of patients (48.1% for Open Hill Repair, 15.4% for laparoscopic fundoplication). 40.0% of patients underwent a laparoscopic Nissen or Collis fundoplication, 21.7% underwent open modified Hill repair, and 38.3% had unspecified operations. Hemoglobin improved from 8.85 g/dL pre-operatively to 13.60 g/dL post-operatively. In six studies, surgical patients previously failed medical management.
Conclusions
This is the first systematic review comparing surgical and medical treatment of CL. Surgical management significantly improved therapeutic success. Our study supports therapeutic benefit of surgery in these patients.
Graphic Abstract
Adenosine monophosphate-activated protein kinase (AMPK) is a protein kinase involved in maintaining energy homeostasis within cells. On the basis of human genetic association data, AMPK activators ...were pursued for the treatment of diabetic nephropathy. Identification of an indazole amide high throughput screening (HTS) hit followed by truncation to its minimal pharmacophore provided an indazole acid lead compound. Optimization of the core and aryl appendage improved oral absorption and culminated in the identification of indole acid, PF-06409577 (7). Compound 7 was advanced to first-in-human trials for the treatment of diabetic nephropathy.
Discovery efforts leading to the identification of ervogastat (PF-06865571), a systemically acting diacylglycerol acyltransferase (DGAT2) inhibitor that has advanced into clinical trials for the ...treatment of non-alcoholic steatohepatitis (NASH) with liver fibrosis, are described herein. Ervogastat is a first-in-class DGAT2 inhibitor that addressed potential development risks of the prototype liver-targeted DGAT2 inhibitor PF-06427878. Key design elements that culminated in the discovery of ervogastat are (1) replacement of the metabolically labile motif with a 3,5-disubstituted pyridine system, which addressed potential safety risks arising from a cytochrome P450-mediated O-dearylation of PF-06427878 to a reactive quinone metabolite precursor, and (2) modifications of the amide group to a 3-THF group, guided by metabolite identification studies coupled with property-based drug design.
Acetyl-CoA carboxylase (ACC) inhibitors offer significant potential for the treatment of type 2 diabetes mellitus (T2DM), hepatic steatosis, and cancer. However, the identification of tool compounds ...suitable to test the hypothesis in human trials has been challenging. An advanced series of spirocyclic ketone-containing ACC inhibitors recently reported by Pfizer were metabolized in vivo by ketone reduction, which complicated human pharmacology projections. We disclose that this metabolic reduction can be greatly attenuated through introduction of steric hindrance adjacent to the ketone carbonyl. Incorporation of weakly basic functionality improved solubility and led to the identification of 9 as a clinical candidate for the treatment of T2DM. Phase I clinical studies demonstrated dose-proportional increases in exposure, single-dose inhibition of de novo lipogenesis (DNL), and changes in indirect calorimetry consistent with increased whole-body fatty acid oxidation. This demonstration of target engagement validates the use of compound 9 to evaluate the role of DNL in human disease.
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