Novel azapeptide inhibitors of cathepsins B and K. Structural background to increased specificity for cathepsin B

Abstract: We have designed and synthesized a new series of azapeptides which act as potential inhibitors of cathepsin B and/or cathepsin K. Their structures are based upon the inhibitory sites of natural cysteine protease inhibitors, cystatins. For the synthesized azapeptides, the equilibrium constants for dissociation of inhibitor–enzyme complex, K_i, were determined. Comparison of these values indicated that all of the azainhibitors act much stronger toward cathepsin B. Z‐Arg‐Leu‐His‐Agly‐Ile‐Val‐OMe ( 7 ) proved to be approximately 500 times more potent for cathepsin B than for cathepsin K. To be able to explain the obtained experimental values we used the molecular dynamics procedures to analyze the interactions between cathepsin B and compound 7 . We also determined the structure of the most potent and selective cathepsin B azainhibitor by means of NMR studies and theoretical calculations. In this report, we describe SAR studies of azapeptide inhibitors indicating the influence of the conformational flexibility of the examined compounds on inhibition of cathepsins B and K.     

FM sonography in diffuse liver disease: prospective assessment and blinded analysis

FM sonography - a signal-processing technique that uses frequency and phase information as well as amplitude data - shows promise in evaluation of patients with diffuse liver disease. In a prospective blinded review of 37 patients with biopsy-proved liver disease and 42 healthy volunteers, FM sonography was clearly superior to traditional amplitude-based (AM) sonography in distinguishing healthy from diseased subjects. Statistically significant differences were seen in accuracy (FM, 98.7%; AM, 84.8%), sensitivity (FM, 97.3%; AM, 70.3%), and negative predictive value (FM, 97.7%; AM, 78.8%). Our data also suggest that current FM sonographic techniques cannot differentiate among histologic findings associated with different hepatic parenchymal abnormalities. It is unclear, therefore, whether FM imaging can reduce the numbers of patients who require biopsy for diagnosis or the frequency of biopsy procedures in patients with known disease.     

Laparoscopic Cholecystectomy for Acute Cholecystitis: Prospective Trial

p < 0.00001) and for hydrops (28.5%) and empyema of the gallbladder (28.5%) ( p = 0.004). The difference in conversion between the group with acute necrotizing (gangrenous) cholecystitis and the two groups with hydrops and empyema of the gallbladder was not statistically significant ( p = 0.07). The complication rates of acute cholecystitis, hydrops, empyema of the gallbladder, and gangrenous cholecystitis were 9.0%, 9.5%, 14.0%, and 20.0%, respectively ( p = NS). Patients with an operative delay of 96 hours or less from the onset of acute cholecystitis had a conversion rate of 23%, whereas a delay of more than 96 hours was associated with a conversion rate of 47% ( p = 0.022). The complication rate was 8.5% in the laparoscopic group and 27% in the converted group ( p = 0.013). Patients over 65 years of age, with a history of biliary disease, a nonpalpable gallbladder, WBC count over 13,000/cc, and acute gangrenous cholecystitis were independently associated with a high LC conversion rate; male patients, finding large bile stones, serum bilirubin over 0.8 mg/dl, and WBC count over 13,000/cc were independently associated with a high complication rate following laparoscopic surgery with or without conversion. Generally, LC can be performed safely for acute cholecystitis, with acceptably low conversion and complication rates. Different forms of cholecystitis carry various conversion and complication rates in selected cases. LC for acute cholecystitis should be performed within 96 hours of the onset of disease. Predictors of conversion and complications may be helpful when planning the laparoscopic approach to acute cholecystitis.      

Development of a new wound dressing with antimicrobial delivery capability

A bilaminar wound dressing composed of an outer membrane and an inner three-dimensional matrix of a fabric or a sponge may be considered to constitute an ideal structure that promotes wound healing: the outer membrane prevents body fluid loss, controls water evaporation, and protects the wound surface from bacterial invasion, and the inner matrix encourages adherence by tissue growth into the matrix. Using this concept, we developed a biosynthetic wound dressing with a drug delivery capability. This medicated wound dressing is composed of a spongy sheet of a chitosane derivative and collagen mixture that is laminated to an antimicrobial-impregnated polyurethane membrane. In this study, a gentamycin sulfate-impregnated wound dressing was prepared and evaluated. The antimicrobial efficacy of this wound dressing was examined on an agar plate seeded with Pseudomonas aeruginosa. Also, the cytotoxicity of an antimicrobial released from this wound dressing was examined in an in vitro system with cultured skin substitutes. Both in vitro tests have shown that this wound dressing is capable of suppressing bacterial growth and minimizing cellular damage. In addition, in the treatment of wounds inflicted on rats and rabbits, this wound dressing was shown to be efficacious in covering full-thickness and split-thickness skin defects. Finally, the efficacy of this wound dressing was evaluated in a nonrandomized open-label study of 31 clinical cases. In 31 cases treated with this wound dressing, good or excellent wound healing was achieved.