Potential antitumor agents. 19. Multiply substituted 4'-(9-acridinylamino)methanesulfonanilides

A series of 42 multiply substituted 4'-(9-acridinylamino)methanesulfonanilides has been prepared and evaluated in the L1210 system. In addition to biologic activity changes resulting from altered agent lipophilic-hydrophilic balance variants containing both acridine 4-CH3 and 3-NH2, NHCOCH3 or NO2 substituents have reduced activity. Variants 3,6-disubstituted, using functions of differing electronic character, have depressed activity, suggesting that there is limited site bulk tolerance. Asymmetric 3,5-disubstitution should then be the preferred pattern; the 3-ND-5CH-3'-OCH variant is the most dose potent (optimum dose qd 1-5, 1.25 mg/kg/day) of the high activity agents of this series so far prepared.     

Functional longevity of intraperioneal drains: an experimental evaluation

Various types of drains were inserted into the peritoneal cavity of twenty-eight dogs. After one to seven days, all drains failed to show the presence of 200 cc of colored fluid injected intraperitoneally. On autopsy, all tubes were surrounded and occluded by omentum.     

A combination of a common splice site mutation and a frameshift mutation in the COL7A1 gene: absence of functional collagen VII in keratinocytes and skin

Musk xylene (2,4,6-trinitro-1-t-butylxylene; MX) is a synthetic nitromusk perfume ingredient that induces and inhibits mouse cytochrome P4502B (CYP2B) enzymes in vivo. The purpose of the present work was to determine whether amine metabolites of MX contributed to the enzyme inhibition and, if so, to define the nature and kinetics of this inhibition. When dosed orally to phenobarbital (PB)-treated mice, MX (200 mg/kg) inhibited > 90% of the PB-induced O-dealkylation of 7-pentoxyresorufin (PROD), and [14C]MX equivalents bound covalently to microsomal proteins. However, when this experiment was repeated in mice pretreated with antibiotics to eliminate the gastrointestinal flora, no decrease in PB-induced PROD activity and no covalent binding to microsomal proteins were observed. Thus, the ability of antibiotic treatment to eliminate the enzyme inhibition and covalent binding implicated amine metabolites of MX formed by nitroreduction in anaerobic intestinal flora as obligatory for these effects. Two monoamine metabolites of MX were synthesized to study enzyme inhibition directly. These metabolites were 2-amino-4,6-dinitro-1-t-butyl-xylene and 4-amino-2,6-dinitro-1-t-butylxylene, referred to as o-NH2-MX and p-NH2-MX, respectively, reflecting the position of the amine substitution relative to the t-butyl function. In the in vitro studies with PB-induced mouse liver microsomes, both amines inhibited PROD activity when preincubated in the absence of NADPH. However, only p-NH2-MX caused a time- and NADPH-dependent loss of PROD activity, and the inactivation rate was a pseudo-first-order process that displayed saturation kinetics. These results indicate that p-NH2-MX is a mechanism-based inactivator of mouse CYP2B enzymes. From kinetic analyses, the Ki was calculated to be 10.5 microM and the Kinact was 1.2 min-1. As final confirmation of the inhibitory effects of p-NH2-MX on mouse CYP2B enzymes, the amine (0.67 mmol/kg) was dosed orally to PB-induced mice. At 2 hr after dosing, p-NH2-MX inhibited essentially all of the PB-induced PROD activity, whereas an equimolar dosage of parent MX had no effect at this early time. Thus, although MX is an inducer of mouse CYP2B enzymes, an amine metabolite of MX is a mechanism-based inactivator of mouse CYP2B10. Furthermore, it is likely that the amine is responsible for the lack of functional CYP2B enzyme activity associated with induction of this enzyme by MX.     

Effects of dilute acetic acid on the cervical smear

BACKGROUND: Mesothelial integrity is essential for the prevention of pericardial adhesions. This study was performed to determine the effect of physical protection of the pericardium on mesothelial integrity. METHODS: A pericardial biopsy specimen was obtained at the time of pericardiotomy (0 minutes) in 10 patients undergoing a cardiac operation for the first time. The left free edge of the pericardiotomy was plicated inward to protect the mesothelium. Biopsy specimens were obtained from the protected and unprotected pericardium at 45 and 90 minutes after the start of extracorporeal circulation. Mesothelial integrity and the local inflammatory response were then assessed and graded histologically. RESULTS: The mesothelium was found to be present in the protected specimens at 0, 45, and 90 minutes, but it was found to be denuded in the unprotected specimens (p = 0.003 at 45 minutes; p = 0.004 at 90 minutes). Local inflammation was totally established in both the protected and unprotected specimens at 45 minutes. CONCLUSIONS: Physical agents appear to be the main factor that is damaging to the pericardial mesothelium, and this is an important concept to be taken into consideration when designing a method to prevent pericardial adhesions.     

Accumulation of pyrraline-modified albumin in phagocytes due to reduced degradation by lysosomal enzymes

Previous studies suggested that the interaction between proteins modified by advanced glycation end products (AGEs) and cells, such as macrophages, may be involved in diabetic angiopathy. Pyrraline is one of the AGEs and known to be elevated in plasma of diabetic rats and humans, and is present in vascular lesions of diabetic and elderly subjects. We examined whether modification of albumin by pyrraline influences its degradation by macrophage-like cell line, P388D1 cells. Degradation of pyrraline-modified albumin by these cells was diminished, causing accumulation of the albumin in these cells. The susceptibility of pyrraline-modified albumin to lysosomal proteolytic enzymes was reduced by approximately 40% in vitro, while lysosomal activity in the cells per se was not affected. This phenomenon was also observed when human monocytes were used instead of P388D1 cells. Our results suggest that accumulation of pyrraline-modified albumin in P388D1 cells is due to the reduced susceptibility of the protein to lysosomal enzymatic degradation. Such alterations in the interaction between AGEs-modified protein and phagocytes may contribute to angiopathy in elderly subjects and patients with diabetes.