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Biomedical subjects

J Malinowski

Publications and source records attributed to J Malinowski.

At least 19 recordsLinked to original sources
PubMed2002

Effect of anticoagulants and antiplatelet agents on platelet-mediated thrombin generation.

The present study was designed to determine the mechanism by which and extent to which antagonists of glycoprotein IIbIIIa (GPIIbIIIa or alpha beta ) or activated factor X (FXa) activity block tissue factor-initiated thrombin generation by prothrombinase complexes assembled on the surface of activated platelets. In the presence of high concentrations of GPIIbIIIa antagonists, which eliminate platelet aggregation but not activation, there is still a substantial amount of thrombin produced. In contrast, specific antagonists of the coagulation cascade lead to abolition of both thrombin generation and platelet aggregation. In addition, inhibitors with similar inhibitory activity (Ki) against purified human FXa require a much broader range of concentrations (a variation of 10 000-fold or more) to reduce the amount of thrombin produced in a platelet-rich plasma assay. At the doses tested, inhibitors with greater potency in prevention of thrombin production in the platelet-rich plasma assay were effective in vivo antithrombotics in an animal model system, whereas a lower potency compound did not reduce thrombus mass. Therefore, inhibition of FXa within platelet bound prothrombinase rather than inhibition of purified FXa in solution may be a better predictor of antithrombotic efficacy. In addition, all the studied anticoagulants fared better than the antiplatelet agents in reducing thrombin generation.

Animals↗
PubMed2001

Design and synthesis of glycolic and mandelic acid derivatives as factor Xa inhibitors.

A series of glycolic and mandelic acid derivatives was synthesized and investigated for their factor Xa inhibitory activity. These analogues are highly potent and selective inhibitors against fXa. In a rabbit deep vein thrombosis model, compound 26 showed significant antithrombotic effects (81% inhibition of thrombus formation) at 1.1 microM plasma concentration following intravenous administration.

Acetanilides↗
PubMed2001

[Activity of aminopeptidase and inter-alpha-trypsin inhibitor in serum of women in physiological labor].

Aminopeptidase activity was measured towards L-alanine and L-leucine naphtylamides in the blood serum obtained from the non-pregnant women and from women during the stages of the physiological delivery. In the same samples the concentration of inter-alpha-trypsin inhibitor (alpha ITI) was measured. The highest aminopeptidase activity was observed in the stage II, and it was statistically significant comparing to the stage I, whereas the statistically significant increase in the alpha ITI concentration was noticed in stage I in primiparae and in stage I in multiparae.

Adult↗
PubMed2000

Antithrombotic and hemostatic capacity of factor Xa versus thrombin inhibitors in models of venous and arteriovenous thrombosis.

Thrombin plays a central role in venous and arterial thrombosis. We utilized two different rabbit models of in vivo thrombosis to investigate the effect of inhibitors of thrombin generation and thrombin activity. The agents tested were specific inhibitors of factor Xa (fXa) [N2-[(phenylmethyl)sulfonyl]-D-arginyl-N-[(1S)-4-[(aminoiminomethyl++ +)a mino]-1-(2-thiazolylcarbonyl)butyl]-glycinamide (C921-78)] and thrombin [D-phenylalanyl-N-[4-[(aminoiminomethyl)amino]-1-(chloroacetyl)but yl]-L-prolinamide (PPACK)], as well as drugs that affect both thrombin and fXa, unfractionated and low molecular weight (enoxaparin) heparin. The agents administered as constant intravenous infusion were evaluated for antithrombotic efficacy in anesthetized rabbits. All four agents were capable of dose dependent inhibition of thrombosis in venous and arteriovenous thrombosis models. However, due to the more aggressive nature of thrombotic stimulation in the arteriovenous shunt model, complete cessation of thrombus growth was not achieved for any of the agents at the doses tested. Comparison between the agents focused on the differences in extension of coagulation parameters (activated partial thromboplastin time, prothrombin time, thrombin clotting time), changes in hematological parameters, and extension of rabbit cuticle bleeding time at doses required to produce maximum inhibition in the thrombosis models. In the venous thrombosis model at the maximally effective dose, C921-78 had minimal extension of ex vivo clotting parameters, while enoxaparin and unfractionated heparin demonstrated a two to sevenfold increase in activated partial thromboplastin times, and PPACK had a threefold extension of thrombin clotting times. In addition, unlike the other three agents, which exhibited no significant changes in hematological parameters, PPACK demonstrated dose dependent thrombocytopenia. A standardized cuticle bleeding time was used as a measure of perturbation of hemostasis. The agents were evaluated for significant increases in bleeding time at doses up to eight times that needed to completely inhibit venous thrombus formation. Unfractionated heparin displayed a significant bleeding time effect at the dose required to inhibit venous thrombosis (100 u/kg+2 u/kg/min). Enoxaparin and PPACK caused significant bleeding time extensions at four times the fully efficacious venous dose (800 u/kg+8 u/kg/min and 30 microg/kg/min). By contrast, C921-78 did not significantly increase bleeding time even at eight times the maximally effective dose (240 microg/kg+7.2 microg/kg/min). Our results demonstrate that specific inhibition of fXa can be utilized to derive potent antithrombotic activity without disrupting extravascular hemostasis.

Amino Acid Chloromethyl Ketones↗
PubMed2000

[Aminopeptidases activity in the amniotic fluid in women in labor with EPH-gestosis].

The thesis of this work was to compare the aminopeptidases activity in the amniotic fluid obtained during the physiological labor and during the labor of pregnant with EPH-gestosis, in presence of the beta-naphtlamidic L-amino-acids (alanine, leucine, phenylalanine, tyrosine, histidine, cysteine) chromogenic substrates. It was assumed the 3-7 times increase in the aminopeptidases activity counted to the proteins from the labored with EPH-gestosis comparing to the labored in physiological labor. Among the used substrates the highest activity in both groups of labored women was measured in presence of substrates with exact amino-acids in this order: L-Ala > L-Leu > L-Phe > L-Tyr > L-His > L-Cys.

2-Naphthylamine↗
PubMed1998

[Calcification of allogenic aortic heart valves].

The material used for the studies consisted of allogenic aortic valves (AAV) collected from 14 individuals. The necessity of AAV replacement arose from growing circulation insufficiency and AAV dysfunction. The aim the study was the determination of the elemental composition and crystallographic structure of the inorganic deposits in AAV. Moreover, the results of the physicochemical investigations were correlated with clinical data (age of the patient, time between valve replacement surgeries, endomyocarditis, number of infections during last 12 months, arterial hypertension and disturbance of the lipid balance) and with echocardiographic examinations (cusp mineralization and perforation, vegetation, systolic and diastolic dimensions of the left ventricle, maximal and average gradient through allograft valve as well as range of the recoil wave to left ventricle). It was found that mineralization of the AAV cusps was a time-dependent process and took place predominantly at the surface of the cusp. The elemental composition and crystallographic data revealed that the inorganic deposits in AAV were composed of hydroxyapatite crystals. However, the presence of other calcium salts was also found. The development of the mineralization process in AAV does not correlate with endomyocarditis, arterial hypertension and the disturbance of the lipid balance. Probably, endomyocarditis and arterial hypertension induce the pathologic alternations of AAV independently from the mineralization process. The echocardiographic estimations of the pathomorphologic changes of the aortic valve cups are not always consistent with the results of the physicochemical studies.

Adult↗
PubMed1996

Effects of Plasmodium vinckei hemozoin on the production of oxygen radicals and nitrogen oxides in murine macrophages.

When murine peritoneal macrophages were loaded in vitro with Plasmodium vinckei hemozoin and stimulated with opsonized zymosan for 90 min or with lipopolysaccharide and/or murine interferon-gamma for 24 hr, significant decreases in the production of oxygen radicals and nitrogen oxides, respectively, could be detected by comparison with macrophages without hemozoin. Moreover, nonradioactive in situ hybridization and immunohistologic analysis in liver sections of P. vinckei-infected mice with more than 60% parasitemia showed that liver cells were still expressing considerable levels of inducible nitric oxide synthase in the late phase of murine malaria, but most of the liver macrophages presenting accumulation of malaria pigment were negative in this analysis. These results further indicate that malaria pigment accumulation may be responsible for toxicity and impairment of macrophage functions during murine malaria.

Animals↗
PubMed1995

Effect of systemic treatment with cholesterol-lowering drugs on the skin barrier function in humans.

The intercellular lipids of stratum corneum are predominantly formed by cholesterol, ceramides and free fatty acids. Cholesterol synthesis is inhibited by statins, cholesterol-lowering drugs (lovastatin, pravastatin, simvastatin). The present study was undertaken to examine the effect of these drugs on skin barrier function. Knowledge about the effect on epidermis of systemic inhibition of cholesterol synthesis may improve our understanding of the skin barrier function. Seventeen statin-treated subjects were compared to controls. All were patch-tested with sodium lauryl sulphate (SLS), and the skin was evaluated after 24 h and after 7 days by measurement of transepidermal water loss (TEWL), erythema and visual scoring. After 24 h as well as after one week erythema was significantly less pronounced in the statin-treated group than in controls (p < 0.001). No significant differences in TEWL were found between the groups at any time. The results imply a decreased bioavailability of SLS in the statin-treated group, while no evidence for an altered permeability barrier to water was found.

Adult↗
PubMed1994

[Stab wound of the right atrium of the heart].

A case is presented of heart wound treated surgically as emergency with positive result. The attention is paid to the necessity of introduction of therapeutic management in the hospital to which the patient was admitted.

Adult↗
PubMed1990

Isolation and studies of the mutagenic activity in the Ames test of flavonoids naturally occurring in medical herbs.

Quercetin, rhamnetin, isohamnetin, apigenin and luteolin were isolated from medicinal herbs: Erigeron canadensis L., Anthyllis vulneraria L. and Pyrola chloranta L. The mutagenicity of these naturally occurring flavonoids was tested by the Ames method with S. typhimurium strains TA1535, TA1538, TA97, TA98, TA100 and TA102 in the presence and absence of metabolic activation. Of the above flavonoids only quercetin and rhamnetin revealed mutagenic activity in the Ames test. Quercetin induced point mutations in strains TA97, TA98, TA100 and TA102 of S. typhimurium. The presence of S9 rat liver microsome fraction markedly enhanced the mutagenic activity of quercetin in these strains. Rhamnetin appeared to be a much weaker mutagen in the Ames test. The compound induced mutations in strains TA97, TA98 and TA100 of S. typhimurium but only in the presence of metabolic activation. Comparison of the structure of the studied flavonoids with their mutagenic activity indicates that the mutagenicity of flavonoids is dependent on the presence of hydroxyl groups in the 3' and 4' positions of the B ring, and that the presence of a free hydroxy or methoxy group in the 7 position of the A ring also probably contributes to the appearance of mutagenic activity of flavonoids in the Ames test. It also appeared that the presence of methoxy groups, particularly in the B ring of the flavonoid molecule, markedly decreases the mutagenic activity of the compound.

Animals↗
PubMed1989

Characterization and autoprocessing of precursor and mature forms of human immunodeficiency virus type 1 (HIV 1) protease purified from Escherichia coli.

A recombinant plasmid encompassing the human immunodeficiency virus type 1 (HIV 1) protease coding sequence and flanking regions (Ala-13 to Gly-185 of the pol open reading frame) has been expressed in two distinct strains of Escherichia coli, AR58 and AR68. In the first strain, AR58, the primary translation product, a 25 kilodalton (kDa) precursor protein, is short-lived and rapidly processes itself to the 11 kDa mature protease in vivo. In the second strain, AR68, the 25 kDa species is only partially processed, and it, a 13 kDa intermediate, and the mature 11 kDa enzyme accumulate at a ratio of 3:4.5:2.5, respectively. The 11 kDa mature protease from AR58 and the 25 kDa precursor from AR68 have been purified to homogeneity. The yield of 11 kDa enzyme from AR58 is approximately 0.02 mg/g wet weight of E. coli cell pellet. The protease has both the expected NH2- and COOH-terminal sequences. The yield of 25 kDa enzyme from AR68 is approximately 0.1 mg/g wet weight of E. coli cell pellet. In vitro, the 25 kDa precursor enzyme rapidly (t1/2 approximately equal to 9 min) processes itself into a species with a mass of approximately 13 kDa and a species with a mass of approximately 11 kDa. Both of these latter species can be separated by RP-HPLC, have the NH2-terminal sequence expected for the mature protease, and are active. The 11 kDa enzyme from AR58 comigrates with the 11 kDa enzyme from AR68 on RP-HPLC and SDS polyacrylamide gel electrophoresis. On extended incubation at 4 degrees C at either neutral or acidic pH all species of the protein exhibit further autodegradation at defined sequences. The availability of the mature, 11 kDa enzyme and the 25 kDa precursor will allow biochemical and physical studies on this critical viral enzyme.

Amino Acid Sequence↗
PubMed1988

UV-induced photoproducts of 5-methylcytosine in a DNA sequence context.

In order to detect possible m5C photoproducts, highly purified rat liver DNA-cytosine methyltransferase was used to specifically generate m5C with a radioactive methyl group. When these DNAs were subjected to a large dose (10 kJ/m2) of 254 nm or 302 nm ultraviolet light (UVB) to enhance the yield, two labeled photoproducts were detected and isolated by reverse phase HPLC after formic acid hydrolysis. Further studies using acetone as a triplet state sensitizer and UVB irradiation suggested that photoproduct II was activated via a triplet state while the more polar photoproduct I was not. Photoreversion of the purified photoproducts with 10 kJ/m2 254 nm light demonstrated the following reactions: Photoproduct I regenerated m5C, while photoproduct II is split and regenerated m5C and photoproduct I. These results suggest that photoproduct I is monomeric while photoproduct II dimeric, and from the latter's elution position possibly a cyclobutyl type dimer arising from a reaction with an adjacent cytosine. Using d[TTG] and d[Cm5CG] as models of typical sequences, irradiation with 10 kJ/m2 254 nm or 302 nm, respectively, gave rise to a small component having altered mobility in sequencing gels. The altered mobility trinucleotides were resistant to degradation by PI and micrococcal nucleases as expected from photodimerization of the pyrimidine bases. Furthermore, oligonucleotide substrates containing m5C were synthesized and shown to be susceptible to T4 endonuclease v action at locations consistent with d[Cm5C] photodimer formation when irradiated in the UVB range.

5-Methylcytosine↗