A Global Phase I Clinical Study Comparing the Safety and Pharmacokinetics of Proposed Biosimilar BAT1706 and Bevacizumab (Avastin®) in Healthy Male Subjects.

OBJECTIVE: BAT1706 is a proposed biosimilar of bevacizumab (BEV). The objective of this phase I clinical trial was to establish pairwise similarity between BAT1706, US-sourced BEV (US-BEV), and EU-sourced BEV (EU-BEV) after a single intravenous (IV) infusion in healthy male subjects. METHODS: This phase I clinical trial was a randomized, double-blinded, three-arm study in 128 healthy adult male subjects. Every subject received a single IV infusion of 1 mg/kg of study drug and was subsequently monitored for 14 weeks. Pharmacokinetic, safety, and immunogenicity data were collected from each patient. The primary pharmacokinetic endpoint of this clinical study was area under the concentration curve from time zero to infinity (AUC0-inf). Biosimilarity of the study drugs was confirmed if the two-sided 90% confidence interval (CI) ratios of the geometric means for the three pairwise comparisons were contained within the range 80-125%. Other pharmacokinetic parameters including area under the concentration curve to time t (AUC0-t), maximum concentration of drug in plasma (Cmax), half-life (t½), and time to Cmax (tmax) were also measured. RESULTS: The pharmacokinetic parameters were comparable for the three drug products evaluated. The 90% CI for the AUC0-inf was 99-112% for BAT1706 versus EU-BEV, 97-110% for BAT1706 vs US-BEV and 92-104% for EU-BEV versus US-BEV comparisons, respectively, demonstrating biosimilarity. There were no significant adverse events attributable to BAT1706, as compared to EU-BEV and US-BEV. BAT1706 demonstrated a similar safety profile to EU-BEV and US-BEV. In addition, no anti-drug antibody positive result was reported for any subject included in the study. CONCLUSION: In this study, BAT1706, a proposed biosimilar of BEV, was shown to be highly similar to EU-BEV and US-BEV in terms of pharmacokinetic equivalence, safety, and immunogenicity in healthy subjects after a single IV infusion. TRIAL REGISTRATION: NCT03030430.

Azetidine-based inhibitors of dipeptidyl peptidase IV (DPP IV).

The structure-activity relationships of azetidine-based DPP IV inhibitors will be discussed in detail in the following review. The azetidine-based DPP IV inhibitors can be divided into three main subtypes, the 2-cyanoazetidines, 3-fluoroazetidines and 2-ketoazetidines. These subtypes have been explored and structure-activity relationships have been established by several groups. Several compounds within each of these subtypes display sub micromolar potency against DPP IV. The most potent cyanoazetidines and ketoazetidines have large, hydrophobic amino acid groups bound to the azetidine nitrogen and display activities below 100 nM. DPP IV inhibition is not sensitive to stereochemistry at the 2-position as both 2-(R)- and 2-(S)-cyano and -keto azetidines display similar inhibitory potencies. While these "warhead"-based cyano- and ketoazetidines have the potential for covalent, bond-forming inhibition, they can also react to internally cyclize into inactive ketopiperazines and dihydroketopyrazine. Thus, chemical instability was also explored for compounds in these two subtypes and certain members of the cyanoazetidine series display aqueous stability comparable to the closely related cyanopyrrolidines. Select 3-fluoroazetidines also display inhibitory potencies below 1 microM without the propensity for cyclization and chemical instability associated with the other subseries.

Leg-length discrepancy after total hip arthroplasty.

Leg-length discrepancy after total hip arthroplasty can pose a substantial problem for the orthopaedic surgeon. Such discrepancy has been associated with complications including nerve palsy, low back pain, and abnormal gait. Careful preoperative measurement and assessment, as well as preoperative and postoperative patient education, are important factors in achieving an acceptable result. However, after total hip arthroplasty, equal leg length should not be guaranteed. Rather, the patient should be given a realistic assessment of what can reasonably be expected.

Quinic acid derivatives as sialyl Lewis(x)-mimicking selectin inhibitors: design, synthesis, and crystal structure in complex with E-selectin.

A search for noncarbohydrate sLe(x) mimics led to the development of quinic acid derivatives as selectin inhibitors. At Wyeth we solved the first cocrystal structure of a small molecule, quinic acid, with E-selectin. In the cocomplex two hydroxyls of quinic acid mimic the calcium-bound fucose of the tetrasaccharide sLe(x). The X-ray structure, together with structure based computational methods, was used to design quinic acid based libraries that were synthesized and evaluated for their ability to block the interaction of sLex with P-selectin. A large number of analogues were prepared using solution-phase parallel synthesis. Selected compounds showed decrease in leukocyte rolling in the IVM mouse model. Compound 2 inhibited neutrophil influx in the murine TIP model and demonstrated good plasma exposure.

Ketopyrrolidines and ketoazetidines as potent dipeptidyl peptidase IV (DPP IV) inhibitors.

In this paper, the synthesis and structure-activity relationships (SAR) of two classes of electrophile-based dipeptidyl peptidase IV (DPP IV) inhibitors, the ketopyrrolidines and ketoazetidines, is discussed. The SAR of these series demonstrate that the 2-thiazole, 2-benzothiazole, and 2-pyridylketones are optimal S1' binding groups for potency against DPP IV. In addition, both cyclohexyl glycine (CHG) and octahydroindole carboxylate (OIC) serve as the most potent S2 binding groups within each series. Stereochemistry at the alpha-position of the central ring is relevant to potency within the ketopyrrolidines series, but not in the ketoazetidine series. Finally, the ketoazetidines display enhanced stability over the corresponding ketopyrrolidines, while maintaining their potency. In fact, certain stabilized ketoazetidines can maintain their in vitro potency and inhibit DPP IV in the plasma for up to 6h.

Synthesis, molecular modeling and biological evaluation of aza-proline and aza-pipecolic derivatives as FKBP12 ligands and their in vivo neuroprotective effects.

Nonimmunosuppressant ligands, exemplified by GPI 1046 (1), for the peptidyl-prolyl isomerase FKBP12 have been found to unexpectedly possess powerful neuroprotective and neuroregenerative effects in vitro and in vivo. We have extensively explored the therapeutic utility of FKBP12 ligands based on analogues of proline and pipecolic acid. As part of our ongoing program to explore novel structural classes of FKBP12 ligands, we herein wish to report a new class of FKBP12 ligands containing aza-proline and aza-pipecolic acid analogues. Details of the synthetic studies, together with biological activity will be presented.

Synthesis and evaluation of chiral bicyclic proline FKBP12 ligands.

As part of our ongoing program to explore novel structural classes of FKBP12 ligands, we herein wish to report a new class of FKBP12 ligands containing chiral bicyclic proline analogues. Details of the synthetic routes, together with preliminary biological activity, will be presented.

Design and synthesis of poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors. Part 4: biological evaluation of imidazobenzodiazepines as potent PARP-1 inhibitors for treatment of ischemic injuries.

A class of poly(ADP-ribose) polymerase (PARP-1) inhibitors, the imidazobenzodiazepines, are presented in this text. Several derivatives were designed and synthesized with ionizable groups (i.e., tertiary amines) in order to promote the desired pharmaceutical characteristics for administration in ischemic injury. Within this series, several compounds have excellent in vitro potency and our computational models accurately justify the structure-activity relationships (SARs) and highlight essential hydrogen bonding residues and hydrophobic pockets within the catalytic domain of PARP-1. Administration of these compounds (5q, 17a and 17e) in the mouse model of streptozotocin-induced diabetes results in maintainance of glucose levels. Furthermore, one such inhibitor (5g, IC(50)=26 nM) demonstrated significant reduction of infarct volume in the rat model of permanent focal cerebral ischemia.

Comparison of multi-lineage cells from human adipose tissue and bone marrow.

Our laboratory has recently characterized a population of cells from adipose tissue, termed processed lipoaspirate (PLA) cells, which have multi-lineage potential similar to bone-marrow-derived mesenchymal stem cells (MSCs). This study is the first comparison of PLA cells and MSCs isolated from the same patient. No significant differences were observed for yield of adherent stromal cells, growth kinetics, cell senescence, multi-lineage differentiation capacity, and gene transduction efficiency. Adipose tissue is an abundant and easily procured source of PLA cells, which have a potential like MSCs for use in tissue-engineering applications and as gene delivery vehicles.

Pharmacophore-based molecular docking to account for ligand flexibility.

Rapid computational mining of large 3D molecular databases is central to generating new drug leads. Accurate virtual screening of large 3D molecular databases requires consideration of the conformational flexibility of the ligand molecules. Ligand flexibility can be included without prohibitively increasing the search time by docking ensembles of precomputed conformers from a conformationally expanded database. A pharmacophore-based docking method whereby conformers of the same or different molecules are overlaid by their largest 3D pharmacophore and simultaneously docked by partial matches to that pharmacophore is presented. The method is implemented in DOCK 4.0.

Patients' reasons for undergoing total hip arthroplasty can change over time.

The purpose of this study was to determine if a patient's reasons for undergoing a primary total hip arthroplasty (THA) changed at 1 year follow-up and, if the reasons did change, how does this change influence patient satisfaction with the procedure. Patients undergoing THA (101 patients) were evaluated with the McMaster Toronto Arthritis Patient Preference Disability (MACTAR) questionnaire and questions related to their expectations regarding the procedure. With the exception of pain and walking, most patients did not select the same preoperative and postoperative reasons for undergoing the procedure. In fact, 60% chose 2 new postoperative items. Patients whose expectations were not met were less likely to choose the same reasons for undergoing THA. Surgeons need to clarify patients' reasons for wanting a THA and attempt to identify new factors at follow-up that may influence patient satisfaction with the procedure.

Design and synthesis of sialyl Lewis(x) mimics as E- and P-selectin inhibitors.

The selectins are a family of cell-adhesion proteins that mediate the rolling of leukocytes on activated endothelial cells through the recognition of the carbohydrate epitope sialyl Lewis(x) (sLe(x)). Control of the leukocyte-endothelial cell adhesion process may prove useful in cases where excess recruitment of leukocytes can contribute to acute diseases such as stroke and reperfusion injury and chronic diseases such as psoriasis and rheumatoid arthritis. The development of molecules that block the interactions between sLe(x) and the selectins has become an active area of research. In this review, we will highlight the various approaches taken toward the development of sLe(x) mimetics as antagonists of E- and P-selectin, including the use of structural information about the selectins and their interactions with sLe(x) that have been revealed through the use of NMR, protein crystallography and molecular modeling.

Use of allograft for large Hill-Sachs lesion associated with anterior glenohumeral dislocation. A case report.

Though Hill-Sachs lesion is a common injury associated with anterior glenohumeral dislocation, there have been only few articles describing specific treatments for the humeral head defects. This paper described the case of an alternative treatment for large defect of the posterior-superior aspect of the humeral head using allograft. The patient was a 69-year-old male and the diagnosis was a chronic anterior dislocation of the right glenohumeral joint with a large impaction fracture of the posterior-superior aspect of the humeral head. The size of this defect was 4 cm by 2.5 cm in diameter with a 2 cm depth. To reduce the impaction fracture of the humeral head, a preserved frozen allograft of the femoral head was selected and configured to fit the defect. The graft was then impacted firmly down into the defect, and appeared to offer excellent stability even without adjuvant internal fixation. Two years after surgery, the patient was doing quite well with no complaints. Radiographs showed humeral head with incorporation of the graft and no evidence of collapse.

The impact of mixed components on polyethylene wear.

Wear rates were measured in 50 mixed and 71 matched total hip arthroplasties with > or = 3-year follow-up to determine whether implanting mixed hip components increased polyethylene wear. Average patient age was 61 years for the mixed group and 57 years for the matched group. Average radiographic follow-up was 5.8 years and 6.8 years, respectively. The average linear wear rate for the mixed and matched groups was 0.11 mm/y. Therefore, implanting same-size, total hip components from different manufacturers did not lead to large increases in polyethylene wear.

Beta-C-mannosides as selectin inhibitors.

Potential E- and P-selectin inhibitors were synthesized to explore a hydrophobic area on the E-selectin surface and the PSGL-1 protein binding site on the P-selectin surface that was recently defined by crystallography. Three series of mannose-based compounds (libraries A, B, and C) were synthesized using solution phase parallel synthesis. Biological evaluation of these compounds was done using two ELISA-based assays and transferred NOE (trNOE) experiments. Some of the compounds showed better activity than sLe(x) in the P-selectin assay.