Kallikreins inhibitors

Factor Xlla converts prekallikrein to kallikrein and kallikrein cleaves HK to generate bradykinin. There is also an important positive feedback in the system in which the kallikrein generated rapidly converts unactivated factor XII to activated factor XII, and the rate of this reaction is hundreds of times faster than the rate of autoactivation [11]. Therefore, much of the unactivated factor XII can be cleaved and activated by kallikrein. Cl inhibitor inhibits all functions of factor Xlla and it is one of two major plasma kallikrein inhibitors. Thus all functions of kallikrein are also inhibited, including the feedback activation of factor XII, the cleavage of HK, and the activation of plasma pro-urokinase [66] to lead to plasmin formation. Cl inhibitor also inhibits the fibrinolytic enzyme plasmin, although it is a relatively minor inhibitor compared to a2-antiplasmin or a2-macroglobulin. 

Bacterial products such as lipopolysaccharides (endotoxins) and cytokines (IL-2) are able to activate the contact system in vitro and in vivo (D9, H4, H7, M41). Immediately after severe trauma or after surgical intervention and particularly during sepsis, a reduction of plasma contact system proteins has been found (C10, K1, N9). Gel filtration studies of plasma demonstrated that plasma PK after activation becomes complexed with a2-M and Cl-Inh (W4). These complexes are rapidly eliminated from the circulation in vivo. In experimental studies in which pulmonary insufficiency was induced in dogs, a significant reduction of plasma kallikrein inhibitors was observed together with reduced HMK. Analysis of the relation be-... 

The synthesis of kinins can be inhibited with the kallikrein inhibitor aprotinin. Actions of kinins mediated by prostaglandin generation can be blocked nonspecifically with inhibitors of prostaglandin synthesis such as aspirin. Conversely, the actions of kinins can be enhanced with ACE inhibitors, which block the degradation of the peptides. Indeed, as noted above, inhibition of bradykinin metabolism by ACE inhibitors contributes significantly to their antihypertensive action. 

Wolf WC, Evans DM, Chao L, Chao J. A synthetic tissue kallikrein inhibitor suppresses cancer cell invasiveness. Am J Pathol 2001 159 1797-1805. 

The effectiveness of lidocaine in preventing pain on injection has been confirmed, and a concentration of 0.1% was optimal (24). The kallikrein inhibitor nafamo-stat mesilate was as effective as lidocaine. 

Assays for plasma prekaUikrein have been available for over 10 years. Since the immunologic assays fail to distinguish between prekallikrein, kallikrein, and kallikrein-inhibitor complexes, a functional assay (clot-endpoint or synthetic substrate), is preferred to monitor the patient status (F4). Functional assays of prekallikrein, however, have encountered technical problems. To measure prekallikrein in plasma, it must be quantitatively converted to kalUkrein. As stated above, this transformation is dependent on the... 

POTENTIAL THERAPEUTIC USES Bradykinin contributes to many of the effects of the ACE inhibitors (Eigure 24-2). Aprotinin, a kallikrein inhibitor, is administered to patients undergoing coronary bypass to minimize bleeding and blood requirements (see below). Kinin agonists potentially may increase the delivery of chemotherapeutic agents past the blood-brain barrier. Based on some of the actions outlined earlier, kinin antagonists are being tested in inflammatory conditions. 

Snail epidermis contains at least six trypsin-kallikrein inhibitors with molecular weights ranging from 6431 to 6591 (70-72). The soybean contains two basic types of protease inhibitors, the Kunitz inhibitor of 21,500 daltons (73) and the Bowman-Birk inhibitor of 7975 daltons (74). The two are quite different proteins as shown in Figure 6. The Great Northern bean (Phaseolus vulgaris) has at least three trypsin isoinhibitors ranging in molecular weight from 8086 to 8884 (15). There are four and possibly six isoinhibitors of trypsin in lima bean (Phaseolus lunatus)(75). 

Sharma JN, Amrah SS, Noor AR. Suppression of hypotensive responses of captopril and enalapril by the kallikrein inhibitor aprotinin in spontaneously hypertensive rats. Pharmacology (1995) 50,363-9. 

Thrombin, factor Xa, XII, XI, IX, kallikrein inhibitor Heparin accelerates the activity of AT III GV qualitative and quantitative... 

Trypsin-Kallikrein-Inhibitors K aus Weinbergschnecken (Helix pomatia). Thermische Denaturierung und thermolysinolyti sche Inaktivierung. Hoppe-Seyler s Z. Physiol. Chem. 357, 139-145. 

Fig. 4, have demonstrated the presence and specific cellular localization of kallikrein, kininogen, and kallikrein inhibitor in such diverse tissues as the pancreas, salivary glands, small intestine, tongue, and kidney. Localization of kallikrein and kallikrein tissue inhibitor in the parotid gland of the dog are seen in microphotographs. Fig. 5a, b. Furthermore, our observation... 

Figure 5b. Localization of tissue kallikrein inhibitor in the parotid gland of the dog (450 x).

Figure 1 Generation of phage-encoded combinatorial chemical libraries and an isolated molecule, (a) A phage-encoded peptide with three cysteine residues is tethered to the trifunctional compound TBMB in a nucleophilic substitution reaction (see refs. 18-20 for the chemical reaction). The resulting chemical entities could optionally be further modified through enzymatic reactions such as proteolysis, (b) Chemical structure of a macrocyclic plasma kallikrein inhibitor isolated by phage display (PK15).

Affinity maturation of human plasma kallikrein inhibitors... 

Katori M, Nishiyama K, Iguchi Y, Majima M, Yao K. Reduction by a kallikrein inhibitor of the increased nasal airway resistance of allergic patients after antigen challenge. Immunopharmacology 1996 33 308-310. 

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