Low Molecular Inhibitors Research Articles

Safety and efficacy of apixaban vs. enoxaparin in thromboprophylaxis after spinal stenosis and degenerative spine surgery

IntroductionDegenerative spine surgeries often require postoperative immobilization or reduced mobility, predisposing patients to the formation of thrombosis and higher risk of thromboembolic complications. Despite the significance of this issue, there remains a lack of consensus on the optimal anticoagulant agent for postoperative thromboprophylaxis in spinal stenosis and degenerative spine surgeries. Low molecular weight heparins and direct Xa inhibitors represent two anticoagulant groups with high chemoprophylactic potential. MethodsThis study included a prospective cohort of patients undergoing posterior decompressive surgery with or without instrumentation for degenerative spine disease and/or spinal stenosis. Patients receiving postoperative prophylactic Enoxaparin and Apixaban were selected to evaluate the rate of complications, as assessed by Clavien-Dindo classification, thromboembolic events, and 30-day mortality, readmission, and reoperation rate between the two anticoagulants. Results130 patients were included in the analysis. 65 patients received Apixaban and Enoxaparin in each group. Mean age of the participants was 57.6±11.0. 83.1% underwent laminectomy and posterior spinal fusion, while 22 patients underwent decompressive surgery only. The incidence of venous thromboembolism (P-value=0.403), deep vein thrombosis (p-value=0.999), hematoma formation (p-value=0.403), surgical site infection (p-value=0.901), readmission (p-value=0.545), reoperation (p=0.510), mortality (p=0.648), and complications rate (p-value=0.232) were not statistically different between Enoxaparin and Apixaban. DiscussionBoth Apixaban and Enoxaparin may be viable options for postoperative thromboprophylaxis in spine surgeries with comparable efficacy and safety profile. Future research endeavors should investigate the efficacy of these agents in comparison to placebo in a randomized setting.

Targeted therapy for <i>МЕТ</i>-positive non-small cell lung cancer

Opportunities in the treatment of patients with metastatic non-small cell lung cancer (NSCLC) are expanding every year. New targets are em erging for molecular-directed antitumor therapy, the so-called targeted therapy. One of such promising targets is damage to the MET gene. Taking into account the large number of active targets in NSCLC, the time factor and the limited amount of tumor material, conducting extensive genomic testing using NGS is preferable to routine diagnostic methods.Mutation in the form of omission of the 14 exon of MET (METex14) occurs with a frequency of 3–4%, amplification of the MET gene – in 2–4% of cases. There is evidence that these disorders correlate with a poor prognosis. At the same time, the METex14 mutation and a high level of copyness are potential predictor markers for the response to capmatinib. For molecular genetic testing, the next-generation sequencing method is optimal, which makes it possible to detect multiple, including rare disorders. Capmatinib is a low molecular weight selective reversible MET inhibitor. In preclinical studies, the drug proved effective against various types of activation of the MET signaling pathway. Clinical studies have confirmed its high antitumor activity. In the GEOMETRY mono1 study, the objective response (OR) in patients with the METex14 mutation as the first line was among 68%, in pretreated patients – 41%, with a median response duration of 12.6 months and 9.7 months, respectively. The drug demonstrated high intracranial activity, regardless of whether radiation therapy was previously performed or not. Objective antitumor response and clinical improvement to targeted therapy with capmatinib are realized fairly quickly. The results obtained during the clinical trial were reproduced in routine practice. The drug has an acceptable toxicity profile. Capmatinib is the first and so far the only drug in the Russian Federation approved for the treatment of patients with a mutation of the MET gene.

Nanoparticle-inhibited neutrophil elastase prevents neutrophil extracellular trap and alleviates rheumatoid arthritis in C57BL/6 mice

Rheumatoid arthritis (RA) is characterized by inflammation outbreak and joint destruction. As the main culprit of RA, neutrophils firstly migrated to inflamed joints and aggravate inflammatory reaction by release excess neutrophil extracellular traps (NETs). However, it remains unsatisfactory efficiency to prevent NETs formation. Emerging evidence indicated that inhibition of neutrophil elastase (NE) could prevent NETs production. Here, we established a method in which sivelestat (ST, a low molecular specific inhibitor of NE)–conjugated bovine serum albumin nanoparticles (BTST NPs) could specifically target inflamed neutrophils for delivery of ST, which could selectively inhibit NE and prevent NETs production. Moreover, BTST NPs were also loaded with dexamethasone palmitate (DP), a classic glucocorticoid drug for RA, to deliver DP to the inflammatory site to achieve synergistically treatment of RA. It was identified that activated neutrophil could selectively internalize DP/BTST NPs. The release of ST and DP were depending on ROS environments in neutrophils at inflamed joints, subsequently could hinder NETs generation. In collagen-induced arthritis (CIA) models, DP/BTST NPs significantly improved targeting effect, alleviated RA symptoms, and enhanced prominent biological safety. We pioneer proved that this novel ST-conjugated BSA NPs holds a promising approach to improve treatment of RA and various NET-mediated inflammatory diseases.

Melanoma Cell Lines As a Basis for Vasculogenic Mimicry Model Development

In tumors, traditional angiogenesis is observed in addition to vascular channels that lack endothelial cell lining. It is assumed that the network of such channels compensates for the insufficiently development of the blood circulatory system in the tumor and prevents early necrosis inside the tumor. A strong statistical correlation established between the presence of vascular channels in the tumor and the low survival rate of patients confirms this hypothesis. In the light of these data, the search for a low-molecular inhibitor of vascular channels formation in a tumor becomes extremely relevant. This review discusses the functional and prognostic significance of vasculogenic mimicry. Particular attention is paid to the optimization of the in vitro vasculogenic mimicry model based on the analysis of 11 melanoma cell lines obtained from metastases of patients with disseminated melanoma. In addition, the development of an in vivo vasculogenic mimicry model is being discussed.

Virtual Screening and Biological Evaluation of Novel Low Molecular Weight Protein Tyrosine Phosphatase Inhibitor for the Treatment of Insulin Resistance.

Protein tyrosine phosphatases (PTPs) play an essential way in diseases including cancer, obesity, diabetes and autoimmune disorders. As a member of PTPs, low molecular weight PTP (LMPTP) has been a well-recognized anti-insulin resistance target in obesity. However, the number of reported LMPTP inhibitors is limited. Our research aims to discover a novel LMPTP inhibitor and evaluate its biological activity against insulin resistance. A virtual screening pipeline based on the X-ray co-crystal complex of LMPTP was constructed. Enzyme inhibition assay and cellular bioassay were used to evaluate the activity of screened compounds. The screening pipeline rendered 15 potential hits from Specs chemical library. Enzyme inhibition assay identified compound F9 (AN-465/41163730) as a potential LMPTP inhibitor with a K i value of 21.5 ± 7.3 μM. Cellular bioassay showed F9 could effectively increase the glucose consumption of HepG2 cells as a result of releasing insulin resistance by regulating PI3K-Akt pathway. In summary, this study presents a versatile virtual screening pipeline for potential LMPTP inhibitor discovery and provides a novel-scaffold lead compound that is worthy of further modification to get more potent LMPTP inhibitors.

Glycosylation increases the anti-QS as well as anti-biofilm and anti-adhesion ability of the cyclo (L-Trp-L-Ser) against Pseudomonas aeruginosa

Pseudomonas aeruginosa infections pose a huge threat to cystic fibrosis patients, as well as those suffering from immunodeficiency. Antimicrobial resistance, especially multi-drug resistance, due to its ability to aggregate the compact biofilm, makes it more inefficient to treat this pathogen with traditional antibiotics. Biofilm and quorum sensing (QS) have become the alternative targets for treating P. aeruginosa infections. Previously, a cyclic dipeptide cyclo(L-Trp-L-Ser) has been identified as a QS inhibitor of P. aeruginosa. On the other hand, some monosaccharides have been proved lectin-targeting behavior and to mediate biofilm formation and adhesion of P. aeruginosa. We constructed novel cyclic dipeptide-carbohydrate conjugates as a low molecular weight dual-functional QS inhibitor, which can not only enhance its anti-QS activity but also enable good anti-biofilm and anti-adhesion ability. The IC50 of galactosylated c(WS) on biofilm formation and glass adhesion was 1/6 and 1/4 of that of the unmodified cyclic dipeptide, respectively. And the ability to eliminate the preformed biofilm was increased 10-fold. Furthermore, the carbohydrate conjugates can increase the germicidal efficiency of clinical antibiotic azithromycin when used synergistically. Our results provide a novel scaffold for developing anti-virulence adjuvants when taken with clinical antibiotics.

Preparation of Ammonium Oleic Acid Salts and Their Evaluation as Shale Swelling Inhibitors in Water-Based Drilling Fluid

Abstract In this paper, ammonium oleic acid salts (AOS) were prepared from oleic acid and amines and investigated as low molecular weight shale swelling inhibitors. First, the inhibitory effect of AOS was investigated using the linear expansion test of bentonite. The results show that the inhibitor prepared from oleic acid and tetraethylene pentamine with a molar ratio of 1:2 (AOS-8) has an excellent inhibitory effect on the hydration expansion of bentonite. The inhibitory effect of AOS-8 on bentonite was further investigated in subsequent work steps using various methods, including the linear swelling test of clay and particle distribution measurement. The results show that AOS-8 has superior performance in inhibiting hydration swelling and dispersion of bentonite. With 0.5% AOS-8, the swelling rate was reduced to 37.7%, and the particle size of bentonite in water could be controlled with AOS-8. Finally, the inhibition mechanism of AOS-8 was determined in detail by scanning electron microscopy (SEM) and thermogravimetric analysis (TGA). In water-based drilling fluid, AOS-8 is compatible with conventional additives. It can also significantly improve the lubricating capacity of the mud cake after ageing at 120°C.

Calcium-Phosphate Nanoparticles — a System for Drug Delivery to the Anterior Eye Chamber

Purpose: to prepare and characterize calcium-phosphate nanoparticles loaded with compounds of different nature: low-molecular inhibitor of angiotensin-converting enzyme lisinopril, and high-molecular enzyme superoxide dismutase 1. To estimate the possibility of enhancing the biological efficacy of these compounds via incorporation to the nanoparticles.Material and methods. To increase the stability of calcium-phosphate nanoparticles coating with β-D-cellobiose was used. The size, surface charge (ζ-potential) of the particles and efficacy of including of the selected compounds to the particles were measured. Comparative assessment of the efficacy of lisinopril solution and lisinopril in nanoparticles was made via the estimation of their ocular hypotensive effect in normotensive rabbits. To compare the efficacy of the superoxide dismutase 1 solution and superoxide dismutase 1 in nanoparticles the rabbit model of immunogenic uveitis was used. We estimated the clinical score for several signs of uveitis, protein level, and antioxidant activity in aqueous humor.Results. Calcium-phosphate nanoparticles containing lisinopril had average hydrodynamic radius of 170–300 nm and negative ζ-potential of –17 mV. Particles containing superoxide dismutase 1 had average hydrodynamic radius of 220–450 nm and negative ζ-potential of –4 mV. Lisinopril in nanoparticles caused a significantly greater decrease of intraocular pressure than lisinopril solution. Superoxide dismutase 1 in calcium-phosphate nanoparticles more efficiently decreased the clinical manifestations of uveitis and normalized the biochemical processes in aqueous humor than the enzyme in buffer solution.Conclusion. Incorporation of both low-molecular and high-molecular drugs to the calcium-phosphate nanoparticles enhance their bioavailability and therapeutic efficiency. The data obtained give evidence of the prospectively of the using of these nanoparticles as vehicles for the ophthalmic drugs used in eyedrops.

MODL-14. SMALL MOLECULE TARGETING OF ONCOGENIC FGF2-FGFR SIGNALING IN BRAIN TUMORS

FGF2, the ligand of FGF receptors (FGFRs), is expressed in the developing and adult brain. FGF2-FGFR1 signaling causes the induction and maintenance of cancer stem cells through ERK-dependent up-regulation of ZEB1 and Olig2 in glioblastoma. In SHH medulloblastoma, Olig2 triggers tumor initiation from GCPs, maintains quiescent stem-like cells during the disease and contributes to tumor outgrowth at recurrence. We found that FGF2-FGFR signaling causes increased growth and tissue invasion through the FGFR adaptor protein FRS2 in SHH and group-3 medulloblastoma 1. Thus, targeting of FGFR-FRS2 signaling could abrogate brain tumor growth and spread by repressing tumor-promoting functions that are induced by microenvironmental FGF2. Using virtual screening combined with functional validation, we identified protein-protein interaction inhibitors (F2i) that bind FRS2 and abrogate FGFR signaling to the MAP-ERK pathway. Consistent with the requirement of FRS2 for pro-invasive signaling downstream of FGFR1 in medulloblastoma, F2i also efficiently block FGF2-induced migration and invasion in medulloblastoma-derived cells. Selected F2i display excellent binding kinetics with a similar Kd as the natural ligand domain of FGFR and cause steric alterations in the targeted protein domain. On-target activity was confirmed by thermal proteome profiling. Neither in silico screening nor empirical testing revealed significant off-target activity of the compounds. No toxicity of F2i was observed in cell-based models with confirmed functional activity on invasion and MAPK activation. Thus, we identified novel, low molecular weight pharmacological protein-protein interaction inhibitors with an excellent potential to specifically block FGFR functions relevant for brain tumor progression. 1. Santhana Kumar et al., CellReports23, 3798–3812.e8 (2018).

Prospects of Chemotherapy for Gastrointestential Stromal Colon Tumours

Gastrointetinal stromal tumours are the most common primary mesenchymal tumours of the gastrointestinal tract. According to statistical data, the annual incidence of this pathology in Russia comprises 13 patients per 1 million inhabitants, i.e. about 2,000 patients per year on average. In the United States, 3,000–4,000 cases are registered every year. This article discusses general and specific issues associated with morbidity and mortality from gastrointestinal stromal tumours, as well as reasons for the low efficacy of surgical and targeted therapies. Methods for combined treatment of patients with gastrointestinal stromal tumours are proposed. The treatment of such pathologies has evolved with the development of immunohystochemical analytical procedures and therapies against KIT/PDGFRA-specific protooncogenes, as well as the emergence of low-molecular kinase inhibitors. However, the probability of non-recurrence survival can only be increased by complete surgical removal of gastrointestinal stromal colon tumours. In the surgical treatment, three main approaches are defined: the initial stage of treatment, provided that the tumour is resectable and has a small size; surgical treatment after neoadjuvant therapy; symptomatic treatment, so-called ‘debulking surgery’. Adjuvant targeted therapy with Imatinib provides for a high objective response. The use of Imatinib chemotherapy determines the efficacy and radicality of surgical treatment in most cases. In general, the question of treating gastrointestinal stromal colon tumours is still relevant, requiring further research and objective evaluation of all technical and tactical approaches in the context of distant results.

Synthesis and Inhibitory Studies of Phosphonic Acid Analogues of Homophenylalanine and Phenylalanine towards Alanyl Aminopeptidases.

A library of novel phosphonic acid analogues of homophenylalanine and phenylalanine, containing fluorine and bromine atoms in the phenyl ring, have been synthesized. Their inhibitory properties against two important alanine aminopeptidases, of human (hAPN, CD13) and porcine (pAPN) origin, were evaluated. Enzymatic studies and comparison with literature data indicated the higher inhibitory potential of the homophenylalanine over phenylalanine derivatives towards both enzymes. Their inhibition constants were in the submicromolar range for hAPN and the micromolar range for pAPN, with 1-amino-3-(3-fluorophenyl) propylphosphonic acid (compound 15c) being one of the best low-molecular inhibitors of both enzymes. To the best of our knowledge, P1 homophenylalanine analogues are the most active inhibitors of the APN among phosphonic and phosphinic derivatives described in the literature. Therefore, they constitute interesting building blocks for the further design of chemically more complex inhibitors. Based on molecular modeling simulations and SAR (structure-activity relationship) analysis, the optimal architecture of enzyme-inhibitor complexes for hAPN and pAPN were determined.

Assessment of the antiviral activity of 2HCl*H-His-Rim compound compared to the anti-influenza drug Arbidol for influenza caused by A/duck/Novosibirsk/56/05 (H5N1) (Influenza A virus, Alphainfluenzavirus, Orthomyxoviridae).

The emergence of influenza virus strains with drug resistance to antiviral drugs requires finding new compounds, potential direct-acting inhibitors. Аdamantane compounds drugs used since the 1960s have lost their activity the resulting due to resistance. Only neuraminidase inhibitors such as zanamivir and oseltamivir have been approved by WHO for influenza treatment. The Russian pharmaceutical drug Arbidol (Umifenovirum) is actively used in Russia. This drug is used to treat influenza in Russia, China and most post-Soviet republics. This work presents a new derivative of aminoadamantane - dichlorohydrate L-histidyl-1-adamantayl ethylamine (2HCl*H-His-Rim), which showed a high level of inhibition of strains of influenza virus A in vitro. Comparison of antiviral properties of the new synthetic low-molecular inhibitor of influenza A virus replication and Arbidol drug pharmacy. The compound 2HCl*H-His-Rim was obtained by classical peptide synthesis methods. It was identified by methods of mass spectrometry, infrared spectroscopy (IR) and nuclear magnetic resonance spectroscopy (NMR). Its antiviral properties have been studied in vitro for monolayer of cells Vero-E6 infected with a high-virulent strain of A/duck/Novosibirsk/56/06 (H5N1) influenza virus at various injection schemes of the investigated compounds. The antiviral activity of the 2HCl*H-His-Rim compound against the highly pathogenic strain of the influenza A/H5N1 virus was slightly higher than for the known pharmacy drug arbidol. The difference in antiviral activity of these two compounds is explained by different mechanisms of action on the viral particle. The 2HCl*H-His-Rim compound can be recommended as a candidate for preclinical and clinical trials in order to obtain an etiotropic antiviral drug based on it, due to its high efficacy and economic and synthetic availability. The synthetic compound 2HCl*H-His-Rim acts on influenza A virus variants resistant to Rimantadine and Amantadine.

An Investigation on the Function of Mud Cakes on the Inhibition of Low Molecular Inhibitor for Water-Based Drilling Fluids

The major low molecular inhibitors showed inhibition in the hydration of clay in the laboratory for water-based drilling fluids, according to the principle of intercalation adsorption. However, inhibitors have failed and caused serious engineering accidents in drilling oil and natural gas. This paper investigated the transmission of several of drilling fluids to indicate whether low molecular inhibitor for drilling can effectively inhibit the wellbore hydration. The inhibition of drilling fluid with the plugging of mud cakes, was significantly weakened based on the hydration expansion of cores and cutting recoveries. The residual contents of inhibitors were determined with the precolumn derivation of high-performance liquid chromatography (HPLC) analysis and were chartered with Fourier transform infrared spectroscopy (FTIR) and nuclear magnetic resonance (NMR) analysis in the structure of the derivative. The clogging behavior of the mud cake was described by environmental scanning electron microscopy (ESEM). Experiments show that 40 wt% to 90 wt% by weight of the corrosion inhibitor cannot pass through the mud cake in the dynamic filtration of the drilling fluid. The mud cake can be further divided into a nanostructure layer, a homogeneous layer and an anisotropic layer with different permeability. Most inhibitors should be limited to the nanostructure layer and the homogeneous layer.

Inhibtion of Mineralization of Urinary Stone Forming Minerals by Some Low Molecular Weight Natural Urinary Inhibitors under Different Chemical Miliew

Inhibtion of Mineralization of Urinary Stone Forming Minerals by Some Low Molecular Weight Natural Urinary Inhibitors under Different Chemical Miliew

Inhibitor of pro-apoptotic PERK-dependent signalling pathway as a novel treatment strategy in Alzheimer’s disease treatment

Objectives. The newest data reported that Alzheimer’s disease (AD) pathogenesis and progression are correlated with excessive activation of Endoplasmic Reticulum (ER) stress conditions and, as a result, pro-apoptotic branch of the protein kinase RNA-like ER kinase (PERK)-dependent Unfolded Protein Response (UPR) signalling pathway, in which the major apoptotic marker constitutes C/EBP homologous protein (CHOP). The aims of the study were the evaluation of LDN-0060609 in terms of its inhibitory activity towards pro-apoptotic branch of the PERK-dependent UPR signalling pathway as well as evaluation of LDN-0060609 cytotoxicity. Material and methods. Research was conducted on mouse neurons CATH.a. Cells were incubated with LDN-0060609 at the concentration range and with thapsigargin as an activator of ER stress. Evaluation of CHOP protein level was performed by Western Blot technique; apoptosis analysis – by flow cytometry; whereas evaluation of LDN-0060609 cytotoxicity – by XTT assay. Results. The results of the study showed that inhibitor LDN-0060609 at 25μM concentration evokes 80% decrease in the CHOP protein level as compared to untreated control cells. Additionally, at 25μM, LDN-0060609 effectively inhibits apoptosis in cells with activated ER stress. Only 5.6% less viable cells were shown as compared to control cells incubated with 0.01% DMSO. LDN-0060609 did not evoke a cytotoxic effect at any used concentrations and incubation times. Conclusions. The results of our own research showed that LDN-0060609 inhibitor effectively inhibits apoptosis-mediated neuronal cell death and does not evoke a cytotoxic effect. Thus, low-molecular inhibitors of pro-apoptotic branch of PERK-dependent UPR signalling pathway may constitute an innovative therapeutic strategy for AD treatment.

Efficacy and tolerance of selective and non-selective factor Xa inhibitors in the prevention of thrombosis in kidney disease in patients with systemic lupus erythematosus and antiphospholipid syndrome

The use of factor Xa inhibitors is justified in the therapy of thrombosis in antiphospholipid syndrome (APS) and active lupus nephritis (LN). To monitor the efficacy and safety of these drugs, plasma anti-Xa (aXa) activity is determined. Objective : to assess the aXa activity of selective and non-selective factor Xa inhibitors in patients with systemic lupus erythematosus (SLE) and APS depending on how they affect the kidneys. Patients and methods. Clinical and laboratory findings were prospectively analyzed in SLE and APS patients who long received low molecular weight heparins (LMWHs) and selective Xa inhibitors, such as fondaparinux and rivaroxaban. The investigation enrolled 70 patients (54 females and 16 males) aged 39 years (range, 31 to 43 years) with SLE (n=15 (21%)), primary APS (PAPS) (n=10 (14%)), and SLE + APS (n=45 (65%)). Results . Kidney disease was diagnosed in 33 (47%) of the 70 patients. LN was detected in 15 (25%) of the 60 patients: 10 and 5 patients with SLE and SLE + APS, respectively. APS nephropathy (APSN) was manifested by elevated creatinine and urea levels with normal urine sediment and no history of glomerulonephritis and was observed in 18 (33%) of the 55 patients: in 16 with SLE + APS and 2 with PAPS. The therapeutic aXa range of 0.1—1.5 IU/ml was found in 43 (61%) of the 70 patients, low and high aXa activities were seen in 14 (20%) and 13 (19%) patients, respectively. In patients with APSN, the creatinine clearance (CC) depended on aXa levels: the highest CC was noted in patients with aXa >1.5 IU/mL, the lowest CC was in those with aXa <0.9 IU/ mL (p=0.046). The levels of aXa above the therapeutic range were more common in patients taking fondaparinux (9 (31%) out of the 29 patients) than in those using nadroparin (2 (7%) out of the 29 patients) (odds ratio (OR) 1.92; 95% confidence interval (CI), 1.25—2.97; p=0.04). In the fondaparinux group, high aXa was more frequently observed in patients with high SLE activity (7 (47%) out of the 15 patients) than in those with moderate or mild SLE activity (none out of the 7 patients) (OR 1.88; 95% CI, 1.17—3.01; p=0.037) and was unassociated with LN. The highest aXa level with no signs of hemorrhage was 2.08 IU/mL. Conclusion. The level of aXa is a qualitative laboratory marker for the efficacy and safety of LMWHs and fondaparinux. In patients with APS, the enhanced aXa activity of LMWHs and fondaparinux was associated with elevated CC and was not accompanied by hemorrhage. Fondaparinux is an effective and safe anticoagulant for the treatment and prevention of thrombosis in SLE and APS. The therapeutic window for aXa should be extended in these patients.

ВЫСОКОАФФИННЫЙ ИНГИБИТОР БЕЛКА BCL-XАКТИВИРУЕТ ПРОТЕИНКИНАЗУ А В ТРОМБОЦИТАХ И БЛОКИРУЕТ ИХ АКТИВАЦИЮ, "Российский физиологический журнал им. И.М. Сеченова"

При лечении раковых заболеваний противоопухолевыми препаратами частыми побочными эффектами являются тромбоцитопения и нарушение активации тромбоцитов. Некоторые низкомолекулярные ингибиторы антиапоптотических BCL-2 белков могут вызывать апоптоз тромбоцитов и блокировать их активацию. Были исследованы пять ингибиторов (MIM-1, ABT-199, обатоклакс, госсипол и WEHI-539) и обнаружено, что обатоклакс и госсипол вызывали прокоагулянтное состояние тромбоцитов и блокировали их активацию. WEHI-539 индуцировал каспаз-зависимый апоптоз и вызывал блокирование активации тромбоцитов за счет активации протеинкиназы А (ПКА), которая не связана с увеличением количества циклического аденозинмонофосфата в тромбоцитах. Действие обатоклакса и госсипола не зависит от активации ПКА и обусловлено другими механизмами. Ингибиторы белков MCL-1 и BCL-2 (MIM1 и ABT-199 соответственно) не вызывали гибель тромбоцитов и не оказывали действия на их активацию.

‘Sailing in troubled waters’

Simply providing anticoagulation therapy is not as straightforward of a solution in cancer patients who have concurrent thrombocytopenia owing to the increased risk of bleeding complications. Currently, few guidelines are in place to assist clinicians in safely managing thrombocytopenic cancer patients on anticoagulation. The purpose of this review is to critically examine the available body of biomedical literature surrounding anticoagulant use against the backdrop of cancer-related thrombocytopenia in adult patients. Available evidence for the use of parenteral anticoagulants (low molecular weight heparins, unfractionated heparin, pentasaccharides, and direct thrombin inhibitors) and oral anticoagulants (vitamin K antagonists and novel oral anticoagulants) in thrombocytopenic cancer patients is described. The review revealed many inconsistencies between reports on this topic, which made it difficult to draw firm conclusions as to, for example, the ideal well tolerated anticoagulant dose in thrombocytopenic cancer patients? Intriguingly, critical clinical information including (but not limited) patient platelet nadirs, platelet counts during bleeding episodes, and platelet transfusion support was absent from a not-so-insignificant number of publications. Despite these shortcomings, the review sets out to formulate recommendations on the management of anticoagulation, at prophylactic or treatment doses, in adult cancer patients who also have concurrent thrombocytopenia. It also enlists a call for the medical community, by mapping select clinical guideposts, for further research in this setting. With the inclusion of these criteria in future studies, only then formal recommendations on the ideal safe dosage of anticoagulants in cancer patients, based on solid evidence, are conceived.

Estudio preliminar sobre factores inhibidores de enzimas proteolíticas en la harina de pejibaye ( Bactris gasipaes )

Signs of malnutrition were observed in mice fed raw pejibaye (Bactris gasipaes) meal as a substitute of corn in the feed. No problems appeared when the animals were fed the same mixtures previously autoclaved. An aqueous extract of pejibaye meal inhibited the caseinolytic action of porcine pancreatine. The inhibiting effect disappeared when boiling the extract for one hour upon dialysis. ApparentIy a relatively low molecular weight pro tease inhibitor is present in raw pejibaye meal.

Effect of Thrombin Inhibitors on Positive Feedback in the Coagulation Cascade.

The coagulation cascade is a series of sequential reactions of limited proteolysis of protein factors resulting in generation of thrombin. Thrombin mediates both positive and negative feedback in regulating this cascade by taking part in activation of several factors. Some thrombin inhibitors, by affecting positive feedback, inhibit generation of thrombin itself. In the current study, we used two thrombin inhibitors: argatroban, a low molecular weight reversible competitive inhibitor that binds to the active site, and bivalirudin, a bivalent oligopeptide that blocks the active site and binding center of protein substrates (exosite I). Appearance rate and total amount of thrombin were measured in a thrombin generation assay (TGA) using a fluorescent substrate. We found that argatroban slows the appearance of thrombin and lowers its amount. Bivalirudin also slows appearance of thrombin, but it does not decrease its amount, perhaps because the region being bound to the active site undergoes hydrolysis so that the inhibitor stops binding to thrombin. Many reactions of the coagulation cascade proceed on the surface of phospholipid micelles (PLMs). In the case of argatroban, PLMs do not affect the results of the TGA, whereas for bivalirudin they lower its inhibitory activity. It seems that PLMs stabilize protein complexes (wherein thrombin exosite I is hindered) mediating positive feedback in the coagulation cascade, e.g. complexes of thrombin with factorV and VIII.