Opioid exit plans for tapering postoperative pain control in noncancer patients: a systematic review.

BACKGROUND: A growing number of countries have reported sharp increases in the use and harm of opioid analgesics. High rates of new opioid initiation are observed in postoperative patients. In response, various tertiary care institutions have developed opioid exit plans (OEPs) to curb potential opioid-related harm. METHODS: PubMed and Embase were systematically searched to identify, summarize, and compare the interventional elements of OEPs for postoperative patient populations published from January 1, 2000, to June 4, 2024. Two researchers independently screened the articles for eligibility following the PRISMA 2020 guidelines, extracted the data, and assessed the study quality and risk of bias. Data synthesis was performed for study characteristics, intervention details, efficacy, and development. RESULTS: A total of 2,585 articles were screened, eight of which met the eligibility criteria. All studies were conducted in North America and focused on orthopedic surgery patients following total hip or knee arthroplasty (n = 5) or neurosurgery (n = 3). Most studies (n = 7) included a pre-post (n = 4) or randomized clinical design (n = 3). Three studies were of good quality, and none had a low risk of bias. The interventions varied and ranged from educational sessions (n = 1) to individualized tapering protocols (n = 4) or a combination of the two (n = 2). Key elements were instructions on how to anticipate patients' postoperative need for opioid analgesics and tapering strategies based on 24-h predischarge opioid consumption. Six studies included efficacy as an endpoint in their analysis, of which four assessed statistical significance, with all four identifying that the OEPs were successful in reducing postoperative opioid use. CONCLUSION: Despite differences in design and implementation, the identified OEPs suggest that they are efficacious in reducing outpatient opioid consumption. They provide a robust estimate of postoperative analgesic requirements and a rationale for tapering duration and rate. However, more rigorous studies are needed to evaluate their real-world effectiveness.

An alternative broad-specificity pathway for glycan breakdown in bacteria.

The vast majority of glycosidases characterized to date follow one of the variations of the 'Koshland' mechanisms1 to hydrolyse glycosidic bonds through substitution reactions. Here we describe a large-scale screen of a human gut microbiome metagenomic library using an assay that selectively identifies non-Koshland glycosidase activities2. Using this, we identify a cluster of enzymes with extremely broad substrate specificities and thoroughly characterize these, mechanistically and structurally. These enzymes not only break glycosidic linkages of both α and ß stereochemistry and multiple connectivities, but also cleave substrates that are not hydrolysed by standard glycosidases. These include thioglycosides, such as the glucosinolates from plants, and pseudoglycosidic bonds of pharmaceuticals such as acarbose. This is achieved through a distinct mechanism of hydrolysis that involves oxidation/reduction and elimination/hydration steps, each catalysed by enzyme modules that are in many cases interchangeable between organisms and substrate classes. Homologues of these enzymes occur in both Gram-positive and Gram-negative bacteria associated with the gut microbiome and other body parts, as well as other environments, such as soil and sea. Such alternative step-wise mechanisms appear to constitute largely unrecognized but abundant pathways for glycan degradation as part of the metabolism of carbohydrates in bacteria.

Total Synthesis of Isoxeniolide A.

Isoxeniolide A is a highly strained xenicane diterpenoid of marine origin. This natural product is representative for a subfamily of xenicanes incorporating an allylic hydroxy group in the nine-membered ring; members of this xenicane subfamily so far have not been targeted by total synthesis. Herein, we describe the first asymmetric total synthesis of isoxeniolide A. Key to forming the challenging E-configured cyclononene ring was a diastereoselective intramolecular Nozaki-Hiyama-Kishi reaction. Other important transformations include an enzymatic desymmetrization for absolute stereocontrol, a diastereoselective cuprate addition and the use of a bifunctional vinyl silane building block. Our strategy also permits access to the enantiomer of the natural product and holds potential to access a multitude of xenicane natural products and analogs for structure-activity relationship studies.

A Mechanism-Based Approach to Screening Metagenomic Libraries for Discovery of Unconventional Glycosidases.

Functional metagenomics has opened new opportunities for enzyme discovery. To exploit the full potential of this new tool, the design of selective screens is essential, especially when searching for rare enzymes. To identify novel glycosidases that employ cleavage strategies other than the conventional Koshland mechanisms, a suitable screen was needed. Focusing on the unsaturated glucuronidases (UGLs), it was found that use of simple aryl glycoside substrates did not allow sufficient discrimination against ß-glucuronidases, which are widespread in bacteria. While conventional glycosidases cannot generally hydrolyze thioglycosides efficiently, UGLs follow a distinct mechanism that allows them to do so. Thus, fluorogenic thioglycoside substrates featuring thiol-based self-immolative linkers were synthesized and assessed as selective substrates. The generality of the approach was validated with another family of unconventional glycosidases, the GH4 enzymes. Finally, the utility of these substrates was tested by screening a small metagenomic library.

Xenicane Natural Products: Biological Activity and Total Synthesis.

The xenicanes are a large class of mostly bicyclic marine diterpenoids featuring a cyclononane ring as a common structural denominator. After a brief introduction into the characteristic structural features of xenicanes and some biogenetic considerations, the major focus of this review will be on the various biological activities that have been reported for xenicanes and on efforts towards the total synthesis of these structures. Several xenicanes have been shown to be potent antiproliferative agents in vitro, but activities have also been reported in relation to inflammatory processes. However, so far, data on the possible in vivo activity of xenicanes are lacking. The major challenge in the total synthesis of xenicanes is the construction of the nine-membered ring. Different strategies have been pursued to establish this crucial substructure, including Grob fragmentation, ring-closing olefin metathesis, or Suzuki cross coupling as the enabling transformations.

Total synthesis of (-)-zampanolide and structure-activity relationship studies on (-)-dactylolide derivatives.

A new total synthesis of the marine macrolide (-)-zampanolide (1) and the structurally and stereochemically related non-natural levorotatory enantiomer of (+)-dactylolide (2), that is, ent-2, has been developed. The synthesis features a high-yielding, selective intramolecular Horner-Wadsworth-Emmons (HWE) reaction to close the 20-membered macrolactone ring of 1 and ent-2. The ß-keto phosphonate/aldehyde precursor for the ring-closure reaction was obtained by esterification of a ω-diethylphosphono carboxylic acid fragment and a secondary alcohol fragment incorporating the THP ring that is embedded in the macrocyclic core structure of 1 and ent-2. THP ring formation was accomplished through a segment coupling Prins-type cyclization. Employing the same overall strategy, 13-desmethylene-ent-2 as well as the monocyclic desTHP derivatives of 1 and ent-2 were prepared. Synthetic 1 inhibited human cancer cell growth in vitro with nM IC(50) values, while ent-2, which lacks the diene-containing hemiaminal-linked side chain of 1, is 25- to 260-fold less active. 13-Desmethylene-ent-2 as well as the reduced versions of ent-2 and 13-desmethylene-ent-2 all showed similar cellular activity as ent-2 itself. The same activity level was attained by the monocyclic desTHP derivative of 1. Oxidation of the aldehyde functionality of ent-2 gave a carboxylic acid that was converted into the corresponding N-hexyl amide. The latter showed only µM antiproliferative activity, thus being several hundred-fold less potent than 1.