The Influence of Inhibitors of Plasmin and Plasminogen Activation on the Streptokinase-Induced Fibrinolytic State

SummaryThe influence of the inhibitors of plasminogen activation by streptokinase, urokinase and tissue activator and of the two antiplasmins i.e. α1 antitrypsin and α2-macroglobulin, upon the formation and clearance of streptokinase-activator in vivo was investigated in 22 subjects. No influence of the above mentioned inhibitors on the formation of the streptokinase-activator could be found, whereas the clearance of the activator seems to be a function of the α2-macroglobulin level before streptokinase administration. The clearance rate of the streptokinase-activator differed significantly from the clearance rate of 131I labelled streptokinase caused by antigen-antibody complex formation [Fletcher et al. (10)], and was similar to the clearance rate of the histamine or nicotinic acid induced plasminogen activator. The possibility of a common clearing mechanism of fibrinolytic activators is discussed.The existence of 3 different inhibitors activities on plasminogen activation as tested in vitro i. e. inhibitor of streptokinase, urokinase and tissue activator, was demonstrated. These inhibitory activities are probably not the properties of 3 different serum proteins but rather the result of the action of α1antitrypsin and α2-macroglobulin. The degree of inhibition, however, of each of the 2 proteins on each of the 3 plasminogen activators (streptokinase, urokinase and tissue activator) seems to be different. This difference may be caused by a different inhibitory effect of α1 antitrypsin or α2-macroglobulin on each of the plasminogen activators.The plasmin formed after the streptokinase infusion is rapidly bound by the α2macroglobulin and this plasmin-antiplasmin complex is immediately removed from the blood, causing a decrease of the α2-macroglobulin level. This decrease of α2-macroglobulin is correlated with the initial level of α2-macroglobulin. This finding demonstrates the concentration depending formation of the plasmin-antiplasmin complex also in vivo.

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Distinction of Plasma Inhibitor of Activator-Induced Clot Lysis from Antiplasmins

10.1055/s-0039-1689178 ◽

1975 ◽

Author(s):

N. Aoki ◽

M. Matsuda ◽

M. Moroi ◽

N. Yoshida

Keyword(s):

Affinity Chromatography ◽

Human Plasma ◽

Gel Filtration ◽

Plasminogen Activators ◽

Inhibitory Effect ◽

Clot Lysis ◽

Plasminogen Activation ◽

Lysis Time ◽

Α2 Macroglobulin ◽

Clot Lysis Time

A fraction of human plasma prolongs the activator-induced clot lysis time and inhibits plasminogen activation by the plasminogen activators derived from various sources (urine and tissues). This fraction, designated as antiactivator fraction, was separatid from antiplasmin fractions (α2-macroglobulin and α1-antitrypsin) by gel filtration and affinity chromatography on Sepharose coupled with IgG of antiserum to α1-antitrypsin. Anti-activator fraction thus obtained exerted little antiplasmin activity but inhibited strongly activator-induced clot lysis.Inhibitory effect of plasma on urokinase-induced clot lysis (antiactivator activity) was assayed in various diseases and compared with antiplasmin activity. No correlation was found between the two activities, and it was concluded that the two activities are independent and are ascribed to two different entities.

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A Comparative Ex Vivo Study of Plasminogen Activators and Proteases for Fibrinolytic Activity and Side Effects in Rabbits

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649213 ◽

1977 ◽

Vol 37 (01) ◽

pp. 154-161 ◽

Cited By ~ 1

Author(s):

B. A Janik ◽

S. E Papaioannou

Keyword(s):

Side Effects ◽

Effective Dose ◽

Fibrinolytic Activity ◽

Ex Vivo ◽

Plasminogen Activators ◽

Assay System ◽

Coagulation Parameters ◽

Ex Vivo Assay

SummaryUrokinase, streptokinase, Brinase, trypsin, and SN 687, a bacterial exoprotease, have been evaluated in an ex vivo assay system. These enzymes were injected into rabbits and the fibrinolytic activity as well as other coagulation parameters were measured by in vitro techniques. Dose-response correlations have been made using the euglobulin lysis time as a measure of fibrinolytic activity and the 50% effective dose has been determined for each enzyme. Loading doses, equal to four times the 50% effective dose, were administered to monitor potential toxicity revealing that Brinase, trypsin, and SN 687 were very toxic at this concentration.Having established the 50% effective dose for each enzyme, further testing was conducted where relevant fibrinolytic and coagulation parameters were measured for up to two days following a 50% effective dose bolus injection of each enzyme. Our results have demonstrated that urokinase and streptokinase are plasminogen activators specifically activating the rabbit fibrinolytic system while Brinase, trypsin and SN 687 increase the general proteolytic activity in vivo.The advantages of this ex vivo assay system for evaluating relative fibrinolytic potencies and side effects for plasminogen activators and fibrinolytic proteases have been discussed.

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The Effect of Barbituric Acid Derivatives on Platelet Function in Vitro and in Vivo

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649080 ◽

1973 ◽

Vol 30 (02) ◽

pp. 315-326

Author(s):

J. Heinz Joist ◽

Jean-Pierre Cazenave ◽

J. Fraser Mustard

Keyword(s):

Platelet Aggregation ◽

Platelet Function ◽

Barbituric Acid ◽

Platelet Rich Plasma ◽

Inhibitory Effect ◽

Primary Response ◽

Sodium Pentobarbital ◽

Barbituric Acid Derivatives

SummarySodium pentobarbital (SPB) and three other barbituric acid derivatives were found to inhibit platelet function in vitro. SPB had no effect on the primary response to ADP of platelets in platelet-rich plasma (PRP) or washed platelets but inhibited secondary aggregation induced by ADP in human PRP. The drug inhibited both phases of aggregation induced by epinephrine. SPB suppressed aggregation and the release reaction induced by collagen or low concentrations of thrombin, and platelet adherence to collagen-coated glass tubes. The inhibition by SPB of platelet aggregation was readily reversible and isotopically labeled SPB did not become firmly bound to platelets. No inhibitory effect on platelet aggregation induced by ADP, collagen, or thrombin could be detected in PRP obtained from rabbits after induction of SPB-anesthesia.

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Inhibition of Human and Animal Platelet Adhesiveness to Glass Bead Columns by Adenosine, Dipyridamole, Chlorpromazine and Acetylsalicylic Acid

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648055 ◽

1976 ◽

Vol 36 (02) ◽

pp. 401-410 ◽

Cited By ~ 6

Author(s):

Buichi Fujttani ◽

Toshimichi Tsuboi ◽

Kazuko Takeno ◽

Kouichi Yoshida ◽

Masanao Shimizu

Keyword(s):

Guinea Pig ◽

Acetylsalicylic Acid ◽

Guinea Pigs ◽

Glass Bead ◽

Animal Species ◽

Inhibitory Effect ◽

Rabbit Platelet ◽

Platelet Adhesiveness

SummaryThe differences among human, rabbit and guinea-pig platelet adhesiveness as for inhibitions by adenosine, dipyridamole, chlorpromazine and acetylsalicylic acid are described, and the influence of measurement conditions on platelet adhesiveness is also reported. Platelet adhesiveness of human and animal species decreased with an increase of heparin concentrations and an increase of flow rate of blood passing through a glass bead column. Human and rabbit platelet adhesiveness was inhibited in vitro by adenosine, dipyridamole and chlorpromazine, but not by acetylsalicylic acid. On the other hand, guinea-pig platelet adhesiveness was inhibited by the four drugs including acetylsalicylic acid. In in vivo study, adenosine, dipyridamole and chlorpromazine inhibited platelet adhesiveness in rabbits and guinea-pigs. Acetylsalicylic acid showed the inhibitory effect in guinea-pigs, but not in rabbits.

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Inhibition of the Activities of α2-Plasmin inhibitor (PI) and CI inhibitor (CI-Inh) by the Synthetic Fibrinolytic Agent, 3-Hydroxypropyl Flufenamide (Flu-HPA)

10.1055/s-0038-1665785 ◽

1979 ◽

Author(s):

L Miles ◽

J Burnier ◽

M Verlander ◽

M Goodman ◽

A Kleiss ◽

...

Keyword(s):

Plasminogen Activators ◽

Inhibitory Effect ◽

Mechanisms Of Action ◽

Flufenamic Acid ◽

Clot Lysis ◽

Factor Xiia ◽

Dependent Inhibition ◽

Normal Human ◽

Plasmin Inhibitor

Flu-HPA is one of a series of flufenamic acid derivations that enhances plasminogen-dependent clot lysis in vitro. Studies of possible mechanisms of action of Flu-HPA were undertaken. The influence of Flu-HPA on the inhibition of purified plasmin by purified PI was studied. PI activity was assessed by its inhibition of the clevage of the tripeptide S-2251 (H-D-Val-Leu-Lys-pNA) by plasmin. Flu-HPA was dissolved in DMF or in methonol and preincubated with PI before addition of plasmin. At Flu-HPA concentrations greater than 1mM and up to 60mM, the inhibitory activity of PI was totally lost. The inhibitory effect of normal human plasma on plasmin was also completely abolished at concentrations of Flu-HPA between 2.5 and 40mM. The effect of Flu-HPA on the inhibition of purified plasma kallikrein by purified CI-Inh was also studied. CI-Inh activity was measured by its inhibition of cleavage of the tripeptide Bz-Pro-Phe-Arg-pNA by kallikrein. When Flu-HPA, dissolved in DMF or in methonol, was preincubated with CI-Inh, a concentration dependent inhibition of CI-Inh activity was observed. CI-Inh activity was abolished by concentrations of Flu-HPA greater than 1mM. Flu-HPA also inhibited the activity of CI-Inh on purified Factor XIIa. These observations suggest that this flufenamic acid derivative may enhance fibrinolysis not only by inhibiting PI activity but also by decreasing the inactivation of plasminogen activators by CI-Inh.

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Phenolic Acids Exert Anticholinesterase and Cognition-Improving Effects

Current Alzheimer Research ◽

10.2174/1567205014666171128102557 ◽

2018 ◽

Vol 15 (6) ◽

pp. 531-543 ◽

Cited By ~ 4

Author(s):

Dominik Szwajgier ◽

Ewa Baranowska-Wojcik ◽

Kamila Borowiec

Keyword(s):

Phenolic Acids ◽

Ex Vivo ◽

Amyloid Β ◽

Inhibitory Effect ◽

In Vivo Studies ◽

Amyloid Β Peptide ◽

Beneficial Effects ◽

Aβ Fibrils

Numerous authors have provided evidence regarding the beneficial effects of phenolic acids and their derivatives against Alzheimer's disease (AD). In this review, the role of phenolic acids as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is discussed, including the structure-activity relationship. In addition, the inhibitory effect of phenolic acids on the formation of amyloid β-peptide (Aβ) fibrils is presented. We also cover the in vitro, ex vivo, and in vivo studies concerning the prevention and treatment of the cognitive enhancement.

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Stage-dependent effect of deferoxamine on growth of Plasmodium falciparum in vitro

Blood ◽

10.1182/blood.v76.6.1250.1250 ◽

1990 ◽

Vol 76 (6) ◽

pp. 1250-1255 ◽

Cited By ~ 36

Author(s):

S Whitehead ◽

TE Peto

Keyword(s):

Plasmodium Falciparum ◽

Growth Inhibition ◽

Antimalarial Activity ◽

Clinical Malaria ◽

Inhibitory Effect ◽

Parasite Development ◽

And Control ◽

Speed Of Onset

Abstract Deferoxamine (DF) has antimalarial activity that can be demonstrated in vitro and in vivo. This study is designed to examine the speed of onset and stage dependency of growth inhibition by DF and to determine whether its antimalarial activity is cytostatic or cytocidal. Growth inhibition was assessed by suppression of hypoxanthine incorporation and differences in morphologic appearance between treated and control parasites. Using synchronized in vitro cultures of Plasmodium falciparum, growth inhibition by DF was detected within a single parasite cycle. Ring and nonpigmented trophozoite stages were sensitive to the inhibitory effect of DF but cytostatic antimalarial activity was suggested by evidence of parasite recovery in later cycles. However, profound growth inhibition, with no evidence of subsequent recovery, occurred when pigmented trophozoites and early schizonts were exposed to DF. At this stage in parasite development, the activity of DF was cytocidal and furthermore, the critical period of exposure may be as short as 6 hours. These observations suggest that iron chelators may have a role in the treatment of clinical malaria.

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A Peptide Found in Human Serum, Derived from the C-Terminus of Albumin, Shows Antifungal Activity In Vitro and In Vivo

Microorganisms ◽

10.3390/microorganisms8101627 ◽

2020 ◽

Vol 8 (10) ◽

pp. 1627

Author(s):

Tecla Ciociola ◽

Pier Paolo Zanello ◽

Tiziana D’Adda ◽

Serena Galati ◽

Stefania Conti ◽

...

Keyword(s):

Antifungal Activity ◽

Human Serum ◽

Fungicidal Activity ◽

Galleria Mellonella ◽

Serum Proteins ◽

Morphological Alterations ◽

C Terminus ◽

Different Sources

The growing problem of antimicrobial resistance highlights the need for alternative strategies to combat infections. From this perspective, there is a considerable interest in natural molecules obtained from different sources, which are shown to be active against microorganisms, either alone or in association with conventional drugs. In this paper, peptides with the same sequence of fragments, found in human serum, derived from physiological proteins, were evaluated for their antifungal activity. A 13-residue peptide, representing the 597–609 fragment within the albumin C-terminus, was proved to exert a fungicidal activity in vitro against pathogenic yeasts and a therapeutic effect in vivo in the experimental model of candidal infection in Galleria mellonella. Studies by confocal microscopy and transmission and scanning electron microscopy demonstrated that the peptide penetrates and accumulates in Candida albicans cells, causing gross morphological alterations in cellular structure. These findings add albumin to the group of proteins, which already includes hemoglobin and antibodies, that could give rise to cryptic antimicrobial fragments, and could suggest their role in anti-infective homeostasis. The study of bioactive fragments from serum proteins could open interesting perspectives for the development of new antimicrobial molecules derived by natural sources.

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A novel BRD4 inhibitor suppresses osteoclastogenesis and ovariectomized osteoporosis by blocking RANKL-mediated MAPK and NF-κB pathways

Cell Death and Disease ◽

10.1038/s41419-021-03939-7 ◽

2021 ◽

Vol 12 (7) ◽

Author(s):

Ying Liu ◽

Wenjie Liu ◽

Ziqiang Yu ◽

Yan Zhang ◽

Yinghua Li ◽

...

Keyword(s):

Bone Loss ◽

Osteoporosis Treatment ◽

Inhibitory Effect ◽

Specific Gene ◽

Actin Ring ◽

Treatment Target ◽

Significant Inhibitory Effect ◽

Promising Treatment

AbstractBromodomain-containing protein 4 (BRD4) has emerged as a promising treatment target for bone-related disorders. (+)-JQ1, a thienotriazolodiazepine compound, has been shown to inhibit pro-osteoclastic activity in a BRD4-dependent approach and impede bone loss caused by ovariectomy (OVX) in vivo. However, clinical trials of (+)-JQ1 are limited because of its poor druggability. In this study, we synthesized a new (+)-JQ1 derivative differing in structure and chirality. One such derivative, (+)-ND, exhibited higher solubility and excellent inhibitory activity against BRD4 compared with its analogue (+)-JQ1. Interestingly, (-)-JQ1 and (-)-ND exhibited low anti-proliferative activity and had no significant inhibitory effect on RANKL-induced osteoclastogenesis as compared with (+)-JQ1 and (+)-ND, suggesting the importance of chirality in the biological activity of compounds. Among these compounds, (+)-ND displayed the most prominent inhibitory effect on RANKL-induced osteoclastogenesis. Moreover, (+)-ND could inhibit osteoclast-specific gene expression, F‐actin ring generation, and bone resorption in vitro and prevent bone loss in OVX mice. Collectively, these findings indicated that (+)-ND represses RANKL‐stimulated osteoclastogenesis and averts OVX-triggered osteoporosis by suppressing MAPK and NF-κB signalling cascades, suggesting that it may be a prospective candidate for osteoporosis treatment.

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Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer

Nature Communications ◽

10.1038/s41467-021-21396-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Hayato Mizuta ◽

Koutaroh Okada ◽

Mitsugu Araki ◽

Jun Adachi ◽

Ai Takemoto ◽

...

Keyword(s):

Gene Rearrangement ◽

Kinase Inhibitors ◽

Inhibitory Effect ◽

In Vivo Model ◽

Resistance Mutations ◽

Lung Cancer Patients ◽

Short Period ◽

Tki Resistance

AbstractALK gene rearrangement was observed in 3%–5% of non-small cell lung cancer patients, and multiple ALK-tyrosine kinase inhibitors (TKIs) have been sequentially used. Multiple ALK-TKI resistance mutations have been identified from the patients, and several compound mutations, such as I1171N + F1174I or I1171N + L1198H are resistant to all the approved ALK-TKIs. In this study, we found that gilteritinib has an inhibitory effect on ALK-TKI–resistant single mutants and I1171N compound mutants in vitro and in vivo. Surprisingly, EML4-ALK I1171N + F1174I compound mutant-expressing tumors were not completely shrunk but regrew within a short period of time after alectinib or lorlatinib treatment. However, the relapsed tumor was markedly shrunk after switching to the gilteritinib in vivo model. In addition, gilteritinib was effective against NTRK-rearranged cancers including entrectinib-resistant NTRK1 G667C-mutant and ROS1 fusion-positive cancer.

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