Abstract TMP98: A New Class of Precision Oral Anticoagulants (proacs) That Mostly Preserves Platelet Activity in vitro and in vivo

Stroke ◽  
2019 ◽  
Vol 50 (Suppl_1) ◽  
Author(s):  
Mohanram Sivaraja ◽  
Daniel Clemens ◽  
Sivan Sizikov ◽  
Chengpei Xu ◽  
Bo Yang ◽  
...  
Keyword(s):  
Oral Anticoagulants ◽  
Platelet Activity ◽  
New Class

Conjugates of Classical DNA/RNA Binder with Nucleobase: Chemical, Biochemical and Biomedical Applications

2019 ◽  
Vol 26 (30) ◽  
pp. 5609-5624
Author(s):  
Dijana Saftić ◽  
Željka Ban ◽  
Josipa Matić ◽  
Lidija-Marija Tumirv ◽  
Ivo Piantanida
Keyword(s):  
Molecular Weight ◽  
Small Molecules ◽  
Biomedical Applications ◽  
Protein Targets ◽  
New Class ◽  
Rna Targets ◽  
Covalently Linked ◽  
Structural Aspects

: Among the most intensively studied classes of small molecules (molecular weight < 650) in biomedical research are small molecules that non-covalently bind to DNA/RNA, and another intensively studied class is nucleobase derivatives. Both classes have been intensively elaborated in many books and reviews. However, conjugates consisting of DNA/RNA binder covalently linked to nucleobase are much less studied and have not been reviewed in the last two decades. Therefore, this review summarized reports on the design of classical DNA/RNA binder – nucleobase conjugates, as well as data about their interactions with various DNA or RNA targets, and even in some cases protein targets are involved. According to these data, the most important structural aspects of selective or even specific recognition between small molecule and target are proposed, and where possible related biochemical and biomedical aspects were discussed. The general conclusion is that this, rather new class of molecules showed an amazing set of recognition tools for numerous DNA or RNA targets in the last two decades, as well as few intriguing in vitro and in vivo selectivities. Several lead research lines show promising advancements toward either novel, highly selective markers or bioactive, potentially druggable molecules.

scholarly journals ROLE OF NITRIC OXIDE (NO) IN CAPSAICIN MEDIATED ANTI-PLATELET ACTIVITY IN IN VITRO, IN VIVO, EX-VIVO MODEL OF PLATELET AGGREGATION ASSAY AND ARTERIAL THROMBOSIS IN RAT: POTENTIAL THERAPEUTIC TARGET?

2018 ◽  
Vol 10 (4) ◽  
pp. 44
Author(s):  
Mihir K Patel ◽  
Kiranj K. Chaudagar ◽  
Anita A. Mehta
Keyword(s):  
Platelet Aggregation ◽  
Arterial Thrombosis ◽  
Ex Vivo ◽  
Platelet Activity ◽  
Aggregation Assay ◽  
Thrombosis Model ◽  
Platelet Aggregation Assay

Objective: Although recent advances in the treatment of congestive heart disease, mortality among patients’ remains a questionable remark. Therefore, we evaluated the role of capsaicin on in vitro and ex vivo platelet aggregation induced by Adenosine Di-Phosphate (ADP) as well as in in vivo thrombosis models and role of NO, KATP was also identified in the capsaicin-induced anti-platelet animal model as well as in vivo model of arterial thrombosis.Methods: According to body weight wistar rats were divided into five groups. Group I and Group II was treated with saline and capsaicin (3 mg/kg, i. v), while animals from Group III were treated with N(ω)-nitro-L-arginine methyl ester (L-NAME) (30 mg/kg, i. v) 30 min before administration of capsaicin (3 mg/kg, i. v). Group IV animals were treated with glibenclamide (10 mg/kg,i. v) 30 min before administration of capsaicin (3 mg/kg, i. v). Group V was considered as a positive control and administered clopidogrel (30 mg/kg, p. o). Animals were subjected for in vitro, ex-vivo platelet aggregation assay. ADP (30µM) was utilized as an aggregating agent in these experiments. After these assays; animals of each group were subjected for subaqueous tail bleeding time in a rat model and FeCl3-induced arterial thrombosis model in rats.Results: In ADP-induced in vitro platelet aggregation, a significant reduction in % platelet aggregation was observed at 50µM (64.35±4.641) and 100µM (52.72±4.192) concentration of capsaicin as compared to vehicle control (85.82±3.716). Capsaicin (3 mg/kg, i. v) also showed a significant reduction (49.53±4.075) in ex-vivo ADP-induced platelet aggregation as compared to vehicle control (89.38±2.057). In FeCl3 induced arterial thrombosis model, Capsaicin (3 mg/kg, i. v) exhibited an increase in time to occlusion in this rodent model and presence of the L-NAME and glibenclamide had inhibited the activity of capsaicin.Conclusion: In our study, capsaicin (50 µM, 100µM) exhibited potent anti-platelet activity in ADP-induced platelet aggregation, similarly capsaicin exhibited significant anti-platelet action in the ex-vivo study. Moreover, the presence of L-NAME and glibenclamide inhibited the anti-thrombotic and anti-platelet action of capsaicin. Therefore, it was concluded that NO and KATP may be involved in the anti-thrombotic action of capsaicin.

scholarly journals Development of Optically-Controlled “Living Electrodes” with Long-Projecting Axon Tracts for a Synaptic Brain-Machine Interface

2018 ◽  
Author(s):  
Dayo O. Adewole ◽  
Laura A. Struzyna ◽  
James P. Harris ◽  
Ashley D. Nemes ◽  
Justin C. Burrell ◽  
...  
Keyword(s):  
Brain Activity ◽  
Optical Recording ◽  
Neural Interfaces ◽  
New Class ◽  
Brain Surface ◽  
Long Term Performance ◽  
Term Performance ◽  
The Brain

AbstractAchievements in intracortical neural interfaces are compromised by limitations in specificity and long-term performance. A biological intermediary between devices and the brain may offer improved specificity and longevity through natural synaptic integration with deep neural circuitry, while being accessible on the brain surface for optical read-out/control. Accordingly, we have developed the first “living electrodes” comprised of implantable axonal tracts protected within soft hydrogel cylinders for the biologically-mediated monitoring/modulation of brain activity. Here we demonstrate the controlled fabrication, rapid axonal outgrowth, reproducible cytoarchitecture, and simultaneous optical stimulation and recording of neuronal activity within these engineered constructs in vitro. We also present their transplantation, survival, integration, and optical recording in rat cortex in vivo as a proof-of-concept for this neural interface paradigm. The creation and functional validation of these preformed, axon-based “living electrodes” is a critical step towards developing a new class of biohybrid neural interfaces to probe and modulate native circuitry.

scholarly journals Non-Toxic Virucidal Macromolecules Show High Efficacy Against Influenza Virus Ex Vivo and In Vivo

2020 ◽  
Author(s):  
Ozgun Kocabiyik ◽  
Valeria Cagno ◽  
Paulo Jacob Silva ◽  
Yong Zhu ◽  
Laura Sedano ◽  
...  
Keyword(s):  
Broad Spectrum ◽  
Viral Infections ◽  
Ex Vivo ◽  
Public Health Problem ◽  
Major Public Health Problem ◽  
New Class ◽  
Influenza Strain ◽  
Low Toxicity

AbstractInfluenza is one of the most widespread viral infections worldwide and represents a major public health problem. The risk that one of the next pandemics is caused by an influenza strain is very high. It is very important to develop broad-spectrum influenza antivirals to be ready for any possible vaccine shortcomings. Anti-influenza drugs are available but they are far from ideal. Arguably, an ideal antiviral should target conserved viral domains and be virucidal, i.e. irreversibly inhibit viral infectivity. Here, we describe a new class of broad-spectrum anti-influenza macromolecules that meets these criteria and displays exceedingly low toxicity. These compounds are based on a cyclodextrin core modified on its primary face with long hydrophobic linkers terminated in 6’sialyl-N-acetyllactosamine (6’SLN) or 3’SLN. SLN enables nanomolar inhibition of the viruses while the hydrophobic linkers confer irreversibility to the inhibition. The combination of these two properties allows for efficacy in vitro against several human or avian influenza strains, as well as against a 2009 pandemic influenza strain ex vivo. Importantly, we show that, in mice, the compounds provide therapeutic efficacy when administered 24h post-infection allowing 90% survival as opposed to no survival for the placebo and oseltamivir..

scholarly journals Su1819 – New Class of Anti-Inflammatory Therapeutics Based on Gold (III) Complexes in Intestinal Inflammation – Proof of Concept Based on in Vitro and in Vivo Studies

2019 ◽  
Vol 156 (6) ◽  
pp. S-623
Author(s):  
Julia B. Krajewska ◽  
Jakub Wlodarczyk ◽  
Przemyslaw Taciak ◽  
Remigiusz Szczepaniak ◽  
Jakub Fichna
Keyword(s):  
Intestinal Inflammation ◽  
In Vivo Studies ◽  
Proof Of Concept ◽  
New Class ◽  
Anti Inflammatory

scholarly journals Candida: Platelet Interaction and Platelet Activity in vitro

2018 ◽  
Vol 11 (1) ◽  
pp. 52-62 ◽  
Author(s):  
Claudia Eberl ◽  
Cornelia Speth ◽  
Ilse D. Jacobsen ◽  
Martin Hermann ◽  
Magdalena Hagleitner ◽  
...  
Keyword(s):  
Whole Blood ◽  
Candida Species ◽  
Platelet Rich Plasma ◽  
Yeast Cells ◽  
Small Subset ◽  
High Morbidity ◽  
Platelet Activity ◽  
Secretory Products

Over the last 2 decades, platelets have been recognized as versatile players of innate immunity. The interaction of platelets with fungal pathogens and subsequent processes may critically influence the clinical outcome of invasive mycoses. Since the role of platelets in Candida infections is poorly characterized and controversially discussed, we studied interactions of human platelets with yeast cells, (pseudo-)hyphae, biofilms and secretory products of human pathogenic Candida species applying platelet rich plasma and a whole blood model. Incubation of Candida with platelets resulted in moderate mutual interaction with some variation between different species. The rate of platelets binding to ­Candida (pseudo-) hyphae and candidal biofilm was comparably low as that to the yeast form. Candida-derived secretory products did not affect platelet activity – neither stimulatory nor inhibitory. The small subset of platelets that bound to Candida morphotypes was consequently activated. However, this did not result in reduced growth or viability of the different Candida species. A whole blood model simulating in vivo conditions confirmed platelet activation in the subpopulation of Candida-bound platelets. Thus, the inability of platelets to efficiently react on Candida presence might favor fungal survival in the blood and contribute to high morbidity of Candida sepsis.

Properties of an Inhibitor of Platelet Aggregation and Thromboxane Synthesis Isolated from Onion and Garlic

1979 ◽  
Author(s):  
A.N. Makheja ◽  
J.Y. Vanderhoek ◽  
J.M. Bailey
Keyword(s):  
Platelet Aggregation ◽  
Allium Sativum ◽  
Chloroform Extract ◽  
Complete Suppression ◽  
Inhibit Platelet Aggregation ◽  
Platelet Activity ◽  
Rabbit Platelets ◽  
Mild Acid

Onion (allium cepa) and garlic (allium sativum) inhibit platelet aggregation both in vitro and in vivo. An oily chloroform extract of onion was prepared and the anti-platelet activity was purified using standard chromatographic procedures. Inhibitory activity from onion is associated with a non-polar material not inactivated by mild acid or alkali and stable to heating. Similar inhibitory properties were observed with both onion oil and garlic oil (I50/ml PRP = 30-100 μg with different samples of human and rabbit platelets). Platelets incubated with onion inhibitor and 1-14C arachidonic acid showed striking changes in the pattern of radioactive metabolites formed. Most apparent was the almost complete suppression of thromboxane B2 synthesis and the appearance of a new metabolite identified as a product of the platelet lipoxygenase. Measurements of oxygen consumption of treated platelets indicate that these materials inhibit the platelet cyclooxygenase. Similar inhibition of sheep vesicular gland cyclooxygenase was observed with onion oil but not with garlic. Gas chromatographic and mass spectrometric analyses of active extracts of onion and garlic show differences in several major components which may relate to the observed differences in biological activity. The results indicate that two members of the allium family commonly used in the diet contain chemically similar compounds which inhibit platelet aggregation by blocking thromboxane synthesis.

The Effect of Erythropoietin on Platelet Function and Fibrinolysis in Chronic Renal Failure

1994 ◽  
Vol 17 (3) ◽  
pp. 141-145 ◽  
Author(s):  
D. Stenver ◽  
L. Jeppesen ◽  
B. Nielsen ◽  
J. Dalsgaard Nielsen ◽  
C. Hædersdal ◽  
...  
Keyword(s):  
Platelet Function ◽  
Clot Lysis ◽  
Platelet Activity ◽  
Platelet Factor ◽  
Human Erythropoietin ◽  
Lysis Time ◽  
Euglobulin Clot Lysis Time ◽  
Erythropoietin Treatment

The influence of erythropoietin therapy on platelet function and fibrinolysis was evaluated in 12 anemic hemodialysis patients. Six months of therapy with human erythropoietin (50 to 80 IU/kg initially) raised the hemoglobin level to 10.8 g/dl but did not increase platelet activity in vivo as measured by beta-thromboglobulin or platelet factor 4. There was no change in the platelet aggregation thresholds in vitro for ADP, adrenaline, thrombin or collagen during treatment. Platelet number and volume were also unaffected. Fibrinolytic activity intensified as erythropoietin treatment proceeded, with a fall of euglobulin clot lysis time and rise in the activity of t-PA. PAI-1 levels also showed a downward trend, without reaching significance. Thus erythropoietin treatment in modest doses does not seem to adversely influence the hemostatic system in patients on hemodialysis.

scholarly journals The ketolide antibiotics HMR 3647 and HMR 3004 are active against Toxoplasma gondii in vitro and in murine models of infection.

1997 ◽  
Vol 41 (10) ◽  
pp. 2137-2140 ◽  
Author(s):  
F G Araujo ◽  
A A Khan ◽  
T L Slifer ◽  
A Bryskier ◽  
J S Remington
Keyword(s):  
Toxoplasma Gondii ◽  
Protozoan Parasite ◽  
Host Cells ◽  
Resistant Bacteria ◽  
New Class ◽  
Human Foreskin Fibroblasts ◽  
Significant Toxicity ◽  
Different Strains

Ketolides are a new class of macrolide antibiotics that have been shown to be active against a variety of bacteria including macrolide-resistant bacteria and mycobacteria. We examined two ketolides, HMR 3647 and HMR 3004, for their in vitro and in vivo activities against the protozoan parasite Toxoplasma gondii. In vitro, both ketolides at concentrations as low as 0.05 microg/ml markedly inhibited replication of tachyzoites of the RH strain within human foreskin fibroblasts. HMR 3004 demonstrated some toxicity for host cells after they were exposed to 5 microg of the drug per ml for 72 h. In contrast, HMR 3647 did not show any significant toxicity even at concentrations as high as 25 microg/ml. In vivo, both ketolides provided remarkable protection against death in mice lethally infected intraperitoneally with tachyzoites of the RH strain or orally with tissue cysts of the C56 strain of T. gondii. A dosage of 100 mg of HMR 3647 per kg of body weight per day administered for 10 days protected 50% of mice infected with tachyzoites. The same dosage of HMR 3004 protected 100% of the mice. In mice infected with cysts, a dosage of 30 mg of HMR 3647 per kg per day protected 100% of the mice, whereas a dosage of 40 mg of HMR 3004 per kg per day protected 75% of the mice. These results demonstrate that HMR 3647 and HMR 3004 possess excellent activities against two different strains of T. gondii and may be useful for the treatment of toxoplasmosis in humans.

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