Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of these studies was to investigate different regimens of thrombolytic therapy and oral anticoagulation, and to evaluate the effects of streptokinase (SK), heparin and warfarin in the treatment of deep vein thrombosis (DVT). Low-dose SK, although controlled according to the fibrinogen levels, did not provide improved thrombolysis compared to conventional high-dose SK, and more postthrombotic changes were registered after an average of 3 years. Furthermore, serious hemorrhagic side-effects occurred, which makes this regimen inexpedient. Various regimens of local venous infusion of SK were tried, and with a dose of 4,000 IU/h for 72 h in combination with heparin a thrombolytic effect was achieved, albeit not greater than usually observed with conventional SK. Systemic hypofibrinogenemia and hemorrhage were not avoided. A hitherto not described side-effect with bullous dermatitis was reported. Venographic severity of calf vein thrombosis displayed a statistically significant correlation to long-term hemodynamic changes, as assessed with foot volumetry, after an average of 5 years. This correlation was stronger for the size of the thrombus after initial treatment than for the size at diagnosis. Thus it seems important to treat calf vein thrombosis with heparin in order to limit the extent of the thrombus, thereby reducing long-term sequelae. During heparin treatment, an average reduction of the thrombi of 17% was observed. This reduction was significantly correlated to a short duration of symptoms but not to parameters of heparin therapy or fibrinolytic components. However, patients with substantial thrombolysis had high plasmin-alpha 2-antiplasmin (PAP) levels, and those with high tissue plasminogen activator (t-PA) inhibitor levels and remarkably also those with high t-PA antigen levels had no lysis. The concentration of t-PA antigen showed a significant increase during heparin infusion, whereas that of PAP and t-PA inhibitor was not influenced. By applying more intensive initial oral anticoagulation, stable therapeutic prothrombin time (PT)-levels were achieved one day earlier and the duration of heparin infusion could be equally reduced compared to the conventional regimen (4.4-5 days vs 5.4-6 days). The activity of coagulation factors II, VII, IX and X had dropped to the same level with both regimens the day heparin was discontinued, observed. The effectiveness of oral anticoagulation after DVT was studied in 596 patients treated for a total of 4450 months.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Studies on the medical treatment of deep vein thrombosis. 391 82

Recombinant human gamma interferon was used to treat 10 atopic dermatitis patients. Recombinant gamma interferon was administered weekly for three consecutive days at 50 microg/M2 SQ for four weeks. All patients' dermatitis improved with recombinant gamma interferon therapy and plasma tumor necrosis factor-alpha levels rose with treatment. Recombinant gamma interferon treatment positively correlated with reduced total plasma fibrinolysis as measured by the fibrin lysis plate, plasmin-alpha2antiplasmin complexes, and tissue type plasminogen activator levels. Accordingly, plasminogen activator inhibitor levels increased. Treatment also was associated with a transient increase in thrombin-antithrombin III complexes. Recombinant gamma interferon resulted in a significant increase in C1 inhibitor antigen but not activity. Plasma prekallikrein, high molecular weight kininogen, and factor XII levels were not decreased. However, 5 of the 10 atopic dermatitis patients before therapy had circulating cleaved plasma high molecular weight kininogen detected on immunoblot, indicating prior kallikrein formation. The cleaved, circulating plasma high molecular weight kininogen disappeared in four out of the five original patients who were reexamined at one year after treatment. These combined data indicated that recombinant gamma interferon treatment reduced total plasma fibrinolysis. In untreated atopic dermatitis, circulating cleaved high molecular weight kininogen also may be a presenting manifestation.
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PMID:Gamma interferon administration to patients with atopic dermatitis inhibits fibrinolysis and elevates C1 inhibitor. 966 47

A library of compounds were prepared by reacting 2-(bromomethyl)-1, 2-benzisothiazol-3(2H)-one 1,1-dioxide (5) with commercially available carboxylic acids in the presence of potassium carbonate or a tertiary amine base. From this library, (1,1-dioxido-3-oxo-1, 2-benzisothiazol-2(3H)-yl)methyl N-[(phenylmethoxy)carbonyl]-beta-alanate (7b) emerged as a potent inhibitor of human mast cell tryptase (IC50 = 0.85 microM). Extension of the side chain of 7b by two carbons gave (1, 1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)methyl 5-[[(phenylmethoxy)carbonyl]amino]pentanoate (7d) which was an 8-fold more potent inhibitor (IC50 = 0.1 microM). Further modification of this series produced benzoic acid derivative (1, 1-dioxido-3-oxo-1,2-benzisothiazol-2(3H)-yl)methyl 4-[[(phenylmethoxy)carbonyl]amino]benzoate (7n) which is the most potent inhibitor identified in this series (IC50 = 0.064 microM). These compounds exhibit time-dependent inhibition consistent with mechanism-based inhibition. For 7b, the initial enzyme velocity is not a saturable function of the inhibitor concentration and the initial Ki could not be determined (Ki > 10 microM). The steady-state rate constant, Ki, was determined to be 396 nM. On the other hand, compounds 7d and 7n are time-dependent inhibitors with a saturable initial complex. From these studies, an initial rate constant, Ki, for 7d and 7n was found to be 345 and 465 nM, respectively. The steady-state inhibition constants, Ki, for 7d and 7n were calculated to be 60 and 52 nM, respectively. Compound 7n is a 13-fold more potent inhibitor than 7b, and these kinetic studies indicate that the increase in inhibitory activity is due to an increase in initial affinity toward the enzyme and not an increase in chemical reactivity. These inhibitors generally show high selectivity for tryptase, being 40-fold weaker inhibitors of elastase, being 100-fold weaker against trypsin, and showing no inhibition against thrombin. These compounds are not inhibitors of thrombin, plasmin t-PA, urokinase, and factor Xa (IC50 > 33 microM). In the delayed-type hypersensitivity (DTH) mouse model, a model of skin inflammation, a 5% solution of 7d reduced edema by 69% compared to control animals.
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PMID:1,2-Benzisothiazol-3-one 1,1-dioxide inhibitors of human mast cell tryptase. 982 54