Esterase inhibitors

Hereditary angioneurotic edema with Ci esterase inhibitor... 

Malbran A, Hammer C, Frank M. Fries L Acquired angioedema observations on the mechanism of action of autoanfibodies directed against C1 esterase inhibitor. J Allergy Clin Immunol 1988 81 1199-1204. 

History. This includes the severity grading of the clinical reaction, the time of administration and onset of symptoms, the concomitant use of other drugs, foods or compounds (latex), previous history of drug allergy, atopy in the personal or family history, other underlying conditions such as mastocytosis or Cl esterase inhibitor deficiency. The actual preparation in its galenic identity should be stored or at least listed. 

Fig. 2. The intrinsic and extinsic cascade coagulation systems. activation -I, inhibition HMK, high molecular kininogen Cl-inh., complement-1 esterase inhibitor AT-III, antithrombin HI a 1 -PI, alpha-1 protein inhibitor pf-3, platelet factor 3.

The alternative pathway may become activated by lipopolysaccharides, endotoxin (sepsis), virus, fungi, immunoglobulin A-antigen (IgA-Ag) immunocom-plexes, and foreign material. These activate C3, after which the common pathway of complement activation takes place (Fig. 4). There are also a number of inhibitors that regulate and control complement activation. The most important are the Cl-esterase inhibitor (Cl-Inh) and the membrane attack complex inhibitor factor (MACIF CD59). In sepsis a relative deficiency of Cl-Inh has been reported. Administration of Cl-Inh to patients with septic shock attenuates complement acti-... 

Fig. 4. The classical and alternative pathway cascade of complement activation. activation Cl-inh., Cl-esterase inhibitor MACIF, membrane attack complex inhibiting factor (—CD59).

H6. Hack, C. E., Ogilvie, A. C., Eisele, B., Jansen, P. M Wagstaff, J., and Thijs, L. G Initial studies on the administration of Cl-esterase inhibitor to patients with septic shock or with a vascular leak syndrome induced by interleukin-2 therapy. Prog. Clin. Biol. Res. 388, 335-357 (1994). 

Kallikrein, which activates prourokinase, is inhibited by complement I1 esterase inhibitor (C 1-INH). 

In thrombotic episodes accompanied by activation of complement, C, -esterase inhibitor is consumed by binding to the C,-esterase that is formed, leading to an increase in the C(-esterase inhibitor complex (93). 

Pontine cholinergic agonists and acetylcholine esterase inhibitors... 

In this connexion we will stress again that, although there is often a correspondence between toxic action of organo-phosphorus insecticides and anti-cholinesterase activity (p. 67), the relationship is not always simple. Thus parathion (p. 178), not itself an esterase inhibitor, is converted in vivo into an enzyme inhibitor.1 On the other hand, Aldridge2 has shown that the inhibitor paroxan can be hydrolysed enzymically to produce non-inhibitory substances. 

It was also found that paraoxon, an esterase inhibitor, substantially reduced formation of polar metabolite 1 from DEHP by trout liver microsomes with added NADPH. This suggests that polar metabolite 1 is formed via further metabolism of the monoester, the production of which was reduced by paraoxon. 

The mode of action of the isobutylamides is unknown, although Miyakado et al. found that several isobutylamides (i.e. pipercide and related compounds) caused repetitive discharge when the nerve cord of the cockroach, Periplaneta americana was stimulated. We found that fagaramide was inactive as an acetylcholine esterase inhibitor in an m vitro assay(unpublished dat a). 

SERINE DEHYDRATASE SERINE DEHYDRATASE SERINE DEHYDROGENASE Serine esterase inhibitor, irreversible, PHENYLMETHYLSULFONYL FLUORIDE SERINE HYDROXYMETHYLTRANSFERASE SERINE PALMITOYLTRANSFERASE Serine protease inhibitor, irreversible, PHENYLMETHYLSULFONYL FLUORIDE Serine proteinase inhibitor,... 

Another possibility to treat a poisoning with esterase inhibitors of the organophosphorous type are the so called esterase reactivators compounds with an oxime structure like obidoxime and prali-doxime. The oxime moiety has a very high affinity for the phosphorous atom and can thereby under certain circumstances hydrolyze the otherwise stable organophosphorous-enzyme complex. 

Since the therapy with esterase inhibitors is not without risk a poisoning with atropine or other parasympatholytic drugs is treated only symptomatically. 

Mechanism of Action A testosterone derivative that suppresses the pituitary-ovarian axis by inhibiting the output of pituitary gonadotropins. Causes atrophy of both normal and ectopic endometrial tissue in endometriosis. Follicle-stimulating hormone (FSH) and luteinizing hormone (LH) are depressed in fibrocystic breast disease. Inhibits steroid synthesis and binding of steroids to their receptors in breast tissues. Increases serum levels of esterase inhibitor. Therapeutic Effect Produces anovulation and amenorrhea, reduces the production of est rogen, corrects biochemical deficiency as seen in hereditary angioedema. 

Noradrenaline is used to treat shock-like conditions associated with peripheral vasodilatation, e.g. sepsis, systemic inflammatory response syndrome (SIRS), neurogenic shock. The rationale of its use in sepsis and SIRS is to counteract the vasodilatory effects of nitric oxide. Following the surgical removal of phaeochromocytoma and similar tumours, noradrenaline is often given to maintain blood pressure in the initial period. During and after cardiac surgery, it may be used to optimise haemodynamic parameters in combination with other drugs, such as phosphodi-esterase inhibitors. Dose... 

Pancreatic cholesterol esterase (3.1.1.3.) aids in transporting cholesterol to the enterocyte. By utilizing a selective and potent cholesterol esterase inhibitor 6-chloro-3-(l-ethyl-2-cyclohexyl)-2-pyrone, the absorption of cholesterol in hamsters could be reduced [71]. Wadkins et al. [72] synthesized novel sulfonamide derivatives, which demonstrated greater than 200-fold selectivity for human intestinal carboxylesterase compared with the human liver carboxylesterase hCEl, and none of them was an inhibitor of human acetylcholinesterase or butyrylcholinester-ase. Maybe these agents can serve as lead compounds for the development of effective, selective carboxylesterase inhibitors for clinical applications. Also the potent P-gp inhibitor verapamil [73] as well as S,S,S-tributylphosphortrithionate (DEF) [74] may exhibit carboxylesterase inhibitory properties. Various other inhibitors of human esterases are listed in Table 5.6. 

An extremely interesting area for bioassays is the group of acetylcholine-esterase inhibitors, the organophosphate and carbamate pesticides. First of all this is based on the need for rapid screening tests, allowing on-site testing of fruits and vegetables. Secondly there is the awareness that the cumulative effects... 

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