The Effect of Preoperative Education Prior to Hip or Knee Arthroplasty on Immediate Postoperative Outcomes.

There is ample research demonstrating improved patient outcomes when using an enhanced recovery program. However, the literature reporting the impact of preoperative education alone prior to hip and knee arthroplasty is conflicting. With the number of these surgical procedures expected to increase in the next few years, the identification of strategies that positively impact outcomes is important. The aim of this study was to evaluate immediate postoperative physical therapy (PT) performance following a total hip or knee arthroplasty in patients who attended a preoperative education class compared with those who did not. This study was a retrospective chart review of 707 hip and knee arthroplasty patients, comparing outcomes based on preoperative educational session attendance. Demographics, comorbidities, length of stay (LOS), discharge disposition, and PT performance were collected from the chart review. Patients who attended the preoperative education class had significantly greater ambulation distances (p < .001), greater degrees of knee flexion (p < .001), and greater degrees of hip flexion (p = .012) on postoperative Day 1. Both hip (p < .001) and knee (p < .001) patients who attended the class had a significantly shorter LOS. The cost benefit analysis indicated a savings of $921.57 in direct costs per knee arthroplasty in those who attended a class. Patients who received preoperative education had greater mobility in the immediate postoperative period and reduced LOS for both hip and knee arthroplasties. Based on this study's results, preoperative education is effective in improving outcomes and reducing the cost of hip and knee arthroplasties.

Small molecule inhibitors of the LEDGF site of human immunodeficiency virus integrase identified by fragment screening and structure based design.

A fragment-based screen against human immunodeficiency virus type 1 (HIV) integrase led to a number of compounds that bound to the lens epithelium derived growth factor (LEDGF) binding site of the integrase catalytic core domain. We determined the crystallographic structures of complexes of the HIV integrase catalytic core domain for 10 of these compounds and quantitated the binding by surface plasmon resonance. We demonstrate that the compounds inhibit the interaction of LEDGF with HIV integrase in a proximity AlphaScreen assay, an assay for the LEDGF enhancement of HIV integrase strand transfer and in a cell based assay. The compounds identified represent a potential framework for the development of a new series of HIV integrase inhibitors that do not bind to the catalytic site of the enzyme.

Structural basis for a new mechanism of inhibition of HIV-1 integrase identified by fragment screening and structure-based design.

BACKGROUND: HIV-1 integrase is a clinically validated therapeutic target for the treatment of HIV-1 infection, with one approved therapeutic currently on the market. This enzyme represents an attractive target for the development of new inhibitors to HIV-1 that are effective against the current resistance mutations. METHODS: A fragment-based screening method employing surface plasmon resonance and NMR was initially used to detect interactions between integrase and fragments. The binding sites of the fragments were elucidated by crystallography and the structural information used to design and synthesize improved ligands. RESULTS: The location of binding of fragments to the catalytic core of integrase was found to be in a previously undescribed binding site, adjacent to the mobile loop. Enzyme assays confirmed that formation of enzyme-fragment complexes inhibits the catalytic activity of integrase and the structural data was utilized to further develop these fragments into more potent novel enzyme inhibitors. CONCLUSIONS: We have defined a new site in integrase as a valid region for the structure-based design of allosteric integrase inhibitors. Using a structure-based design process we have improved the activity of the initial fragments 45-fold.

Antiviral agents 3. Discovery of a novel small molecule non-nucleoside inhibitor of hepatitis B virus (HBV).

The discovery of a small molecule non-nucleoside inhibitor of Hepatitis B Virus is described. During our work on conocurvone derived naphthoquinone 'trimers' for the treatment of HIV, we discovered a potent inhibitor 9 of Hepatitis B Virus in an antiviral screen. During attempts to resynthesis 9 for proof of concept studies, we altered the synthesis in order to attempt to reduced side reactions and difficult to remove by-products. As a result we discovered a small molecule 19 that also was a potent inhibitor of HBV. Importantly, this small molecule inhibitor of Hepatitis B Virus is also an inhibitor of Hepatitis B Virus resistant to 3TC, a bench mark of nucleoside analogues active in the treatment of Hepatitis B Virus. The development of 19 as an agent to treat HBV infections is discussed.

Design of a series of bicyclic HIV-1 integrase inhibitors. Part 1: selection of the scaffold.

HIV integrase inhibitors based on a novel bicyclic pyrimidinone core is presented. Nine variations of the core scaffold are evaluated leading to optimization of the 6:6 core giving compound 48 with an EC(50) of 3 nM against wild type HIV infected T-cells.

Design of a series of bicyclic HIV-1 integrase inhibitors. Part 2: azoles: effective metal chelators.

Synthesis of a diverse set of azoles and their utilizations as an amide isostere in the design of HIV integrase inhibitors is described. The Letter identified thiazole, oxazole, and imidazole as the most promising heterocycles. Initial SAR studies indicated that these novel series of integrase inhibitors are amenable to lead optimization. Several compounds with low nanomolar inhibitory potency are reported.

Discovery of potent HIV integrase inhibitors active against raltegravir resistant viruses.

A series of novel HIV integrase inhibitors active against rategravir resistant strains are reported. Initial SAR studies revealed that activities against wild-type virus were successfully maintained at single digit nanomolar level with a wide range of substitutions. However, inclusion of nitrogen-based cyclic substitutions was crucial for achieving potency against mutant viruses. Several compounds with excellent activities against wild-type virus as well as against the viruses with the mutations Q148H/G140S or N155H/E92Q were reported.

Antiviral agents 2. Synthesis of trimeric naphthoquinone analogues of conocurvone and their antiviral evaluation against HIV.

The synthesis of a new series of conocurvone analogues is presented that explores the importance of the pyran rings of conocurvone, their degree of unsaturation as well as the role of alkoxy functionalities as pyran ring replacements, for the inhibition of the HIV-1 integrase (IN) enzyme. Difficulties in synthesising a trimeric naphthoquinone where the central quinone bears a peri-dihydropyran ring was attributed to distortion of the electrophilic dihaloquinone successfully utilised in the past. Increased electron density could also be a factor in reducing reactivity. The desired central dihydropyran bearing trimeric naphthoquinone was successfully synthesised by using a more reactive bromo-tosyloxyquinone intermediate. A maleimide derivative, where the central quinone between the pendant hydroxyquinones was replaced, was successfully synthesised and although it exhibited comparable enzyme inhibitory activity it had negligible HIV inhibitory cellular activity. Compounds were assessed for activity in both in vitro assays using purified recombinant HIV-1 IN and demonstrated superior or comparable activity to conocurvone derivatives previously reported.

Microwave-promoted synthesis of 3-amino-substituted 1,2-benzisoxazoles.

BACKGROUND: 1,2-benzisoxazole derivatives have been the focus of numerous studies, due to their biological and chemical interest. RESULTS: We demonstrate an efficient synthesis of a series of 3-amino-substituted 1,2-benzisoxazoles from a 3-chloro-1,2-benzisoxazole by microwave-promoted nucleophilic aromatic substitution. The 3-amino-1,2-benzisoxazoles prepared were obtained in 1-6 h in good-to-high yields of 54-90%. The 3-chloro-1,2-benzisoxazoles were also prepared by heating with microwave irradiation in quantitative yields in 2 h, from the corresponding 3-hydroxy-1,2-benzisoxazoles. CONCLUSION: This efficient microwave-assisted pathway could be applied to a variety of substrates in the further development of substituted 1,2-benzisoxazoles.