PubMed · 1777075
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J P Mumford, P J Lewis. 1991. Vigabatrin.. https://pubmed.ncbi.nlm.nih.gov/1777075/
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Prourokinase-induced plasminogen activation is complex and involves three distinct reactions: (1) plasminogen activation by the intrinsic activity of prourokinase; (2) prourokinase activation by plasmin; (3) plasminogen activation by urokinase. To further understand some of the mechanisms involved, the effects of epsilon-aminocaproic acid (EACA), a lysine analogue, on these reactions were studied. At a low range of concentrations (10-50 microM), EACA significantly inhibited prourokinase-induced (Glu-/Lys-) plasminogen activation, prourokinase activation by Lys-plasmin, and (Glu-/Lys-) plasminogen activation by urokinase. However, no inhibition of plasminogen activation by Ala158-prourokinase (a plasmin-resistant mutant) occurred. Therefore, the overall inhibition of EACA on prourokinase-induced plasminogen activation was mainly due to inhibition of reactions 2 and 3, by blocking the high-affinity lysine binding interaction between plasmin and prourokinase, as well as between plasminogen and urokinase. These findings were consistent with kinetic studies which suggested that binding of kringle 1-4 of plasmin to the N-terminal region of prourokinase significantly promotes prourokinase activation, and that binding of kringle 1-4 of plasminogen to the C-terminal lysine158 of urokinase significantly promotes plasminogen activation. In conclusion, EACA was found to inhibit, rather than promote, prourokinase-induced plasminogen activation due to its blocking of the high-affinity lysine binding sites on plasmin(ogen).
OBJECTIVES: Pericardial effusion occurs frequently after orthotopic heart transplantation, but the causes of this complication have not been well described. This study was designed to identify factors predisposing toward the development of significant postoperative pericardial effusions in a large, single-institution population of orthotopic heart transplant recipients. METHODS: A retrospective review of more than 90 preoperative, intraoperative, and postoperative variables was conducted for 241 patients undergoing orthotopic heart transplantation from September 1988 to December 1999. Patients who had significant postoperative pericardial effusions develop were identified from postoperative echocardiograms by standard criteria. Factors associated with the development of significant pericardial effusions were determined by multivariate logistic regression analysis. RESULTS: Echocardiographic data were available for 203 of 241 transplant recipients. Forty-two patients (21%) had significant effusions develop. According to multivariate analysis, pericardial effusions were less likely to occur in recipients with a history of previous cardiac surgery (odds ratio 0.13, 95% confidence interval 0.05-0.36, P <.0001) and with greater weight (odds ratio 0.96, 95% confidence interval 0.94-0.99, P <.0048). Pericardial effusions were more likely to occur in patients who had received aminocaproic acid during the operation (odds ratio 5.92, 95% confidence interval 2.23-15.72, P <.0008). Patient survival and hospital length of stay did not differ between patients with and without postoperative pericardial effusions. CONCLUSIONS: Postoperative pericardial effusions develop in approximately 20% of patients undergoing orthotopic cardiac transplantation. On the basis of the risk factors identified in this study, prevention may prove difficult, although avoidance of the intraoperative use of aminocaproic acid may be helpful.
In the synthesis of peptidomimetics containing alpha-hydroxy-beta-amino acid, the coupling of this N(beta)-protected beta-amino acid with amine components was generally performed without the protection of its alpha-hydroxyl group. However, the formation of dipeptides in low yield was often observed when sterically hindered amine components were used. Boc-Apns-OH [Apns: (2S,3S)-3-amino-2-hydroxy-4-phenylbutanoic acid, allophenylnorstatine] (6), which is one of such beta-amino acid derivatives, is intensively employed as a core structure in the development of HIV-1 protease inhibitors. There have been no precise studies, to date, that have examined amide bond formation with alpha-hydroxy-beta-amino acid derivatives as an acyl component. To determine the cause of this low-yield reaction, we studied the amide bond formation focusing on the activation step of N(beta)-protected alpha-hydroxy-beta-amino acid by using a model coupling reaction between 6 and H-Dmt-OR [Dmt: (R)-5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid] (7). A significant amount of homobislactone 9 was formed through the activation of the carboxyl group of 6 to the benzotriazole-type active esters such as OBt and OAt. In addition, this homobislactone formation was markedly increased in the presence of a catalytic amount of a base, which exhibited good correlation with the low yield of the amide bond formation, suggesting that homobislactone formation is one major reason for the low yield of the amide bond formation. Moreover, homobislactones were also formed in other derivatives of the N(beta)-protected alpha-hydroxy-beta-amino acid, suggesting a common feature of this type of amino acids. The use of a strong activation method like EDC--HOAt without base addition enhanced amide bond formation, although a small amount of homobislactone may be formed during the coupling reaction.