Aminocaproic Acid Research Articles

PHARMACOLOGICAL INTERVENTIONS FOR THE PREVENTION OF BLEEDING IN PEOPLE UNDERGOING ELECTIVE HIP OR KNEE SURGERY: A COCHRANE SYSTEMATIC REVIEW AND NETWORK META-ANALYSIS

Preoperative anaemia and intraoperative blood loss result in ∼90% of individuals being anaemic following hip and knee arthroplasty. Reducing blood loss offers the opportunity to improve outcomes and reduce the risk of transfusion and costs. This review's aim was to determine the effectiveness of drugs for preventing blood loss, and identify optimal dose, route, and timing of administration.Cochrane network meta-analysis of randomised controlled trials was conducted. Inclusion criteria: adults undergoing primary or revision elective hip or knee arthroplasty. Drugs studied: tranexamic acid (TXA), aprotinin, epsilon-aminocaproic acid, desmopressin, factor VIIa and XIII, fibrinogen, fibrin sealants, and non-fibrin sealants. Primary outcomes: need for allogenic blood transfusion, all• cause mortality (within 30 days). Secondary outcomes: mean number of transfusion episodes, re-operation, length of hospital stay and adverse events (DVT, PE, CVA, MI).102 studies with 8418 participants. Trials included more women (63%). 47 studies (4398 participants) were included within the blood transfusion NMA. TXA given intra-articularly and orally at a total dose of greater than 3g pre-incision, intraoperatively and postoperatively ranked the highest, with anticipated absolute effect of 147 fewer transfusions per 1000 (53% chance ranking 1st) (relative risk(RR) 0.02, 95% credible interval(CrI) 0–0.31); moderate-certainty). Aprotinin (RR 0.59, 95%:CrI 0.36–0.86; low certainty evidence), fibrin (RR 0.86, CrI 0.25–2.93; very-low certainty) and EACA (RR 0.60, 95%:CrI 0.29–1.27; very-low certainty) were not shown to be as effective as TXA.TXA was the most effective drug for preventing bleeding in lower limb arthroplasty. Aprotinin and EACA were not as effective. Currently, the optimal dose, route and timing of administration of TXA is unclear. However, TXA given at higher doses and via mixed routes ranked higher in the treatment hierarchy. Oral TXA may be as effective as intavenous. There was no evidence of harm associated with higher doses of TXA.

Efficacy and utility of antifibrinolytics in pediatric spine surgery: a systematic review and network meta-analysis.

Antifibrinolytics have gained increasing attention in minimizing blood loss and mitigating the risks associated with massive transfusions, including infection and coagulopathy in pediatric patients undergoing spine surgery. Nevertheless, the selection of optimal agent is still a matter of debate. We aim to review the utility of these agents and compare the efficacy of antifibrinolytics in pediatric and adolescent spine surgeries. A comprehensive search was performed in Scopus, Web of Science, and MEDLINE databases for relevant works. Studies providing quantitative data on predefined outcomes were included. Primary outcome was perioperative bleeding between the groups. Secondary outcomes included transfusion volume, rate of complications, and operation time. Twenty-eight studies were included in the meta-analysis incorporating 2553 patients. The use of Tranexamic acid (RoM: 0.71, 95%CI: [0.62-0.81], p < 0.001, I2 = 88%), Aprotinin (RoM: 0.54, 95%CI: [0.46-0.64], p < 0.001, I2 = 0%), and Epsilon-aminocaproic acid (RoM: 0.71, 95%CI: [0.62-0.81], p < 0.001, I2 = 60%) led to a 29%, 46%, and 29% reduction in perioperative blood loss, respectively. Network meta-analysis revealed higher probability of efficacy with Tranexamic acid compared to Epsilon-aminocaproic acid (P score: 0.924 vs. 0.571). The rate of complications was not statistically different between each two antifibrinolytic agent or antifibrinolytics compared to placebo or standard of care. Our network meta-analysis suggests a superior efficacy of all antifibrinolytics compared to standard of care/placebo in reducing blood loss and transfusion rate. Further adequately-powered randomized clinical trials are recommended to reach definite conclusion on comparative performance of these agents and to also provide robust objective assessments and standardized outcome data and safety profile on antifibrinolytics in pediatric and adolescent pediatric surgeries.

Splenic hematoma and hemoperitoneum in a Thoroughbred racehorse after racing.

To describe the clinical presentation of a Thoroughbred filly with acute hemoperitoneum from a splenic source immediately after racing. A 3-year-old Thoroughbred filly used for racing and that had raced shortly before presentation to the hospital. On presentation, the filly was quiet, alert, and responsive with a heart rate of 76 beats/min, pale mucous membranes, and absent borborygmi. All other physical examination parameters were within normal limits. Abdominal ultrasound was performed and revealed echogenic free abdominal fluid and a splenic hematoma. Abdominocentesis yielded sanguinous fluid with a PCV of 35%. The next day, repeat ultrasound revealed the splenic hematoma with capsular separation. The filly was treated overnight with isotonic crystalloid fluids and aminocaproic acid (40 mg/kg, IV, slow bolus over 30 minutes followed by 20 mg/kg, IV, q 6 h), potassium penicillin (22,000 IU/kg, IV, q 6 h), gentamicin (6.6 mg/kg, IV, q 24 h), and omeprazole (4 mg/kg, PO, q 24 h). The lowest PCV obtained from the filly was 36 hours after presentation. The filly stabilized with medical treatment and was discharged to a farm for further recuperation. There are no published reports detailing hemoperitoneum of splenic origin in Thoroughbreds immediately after racing. Hemoperitoneum of splenic origin is not common in horses, with most cases of hemoperitoneum being secondary to acute trauma, neoplasia, parturition, or postoperative complications. While uncommon, this case raises awareness to another differential for a colicky horse immediately after racing.

Consensus of the Brazilian association of hematology, hemotherapy and cellular therapy on patient blood management: Antifibrinolytics

The use of strategies to reduce blood loss and transfusions is essential in the treatment of surgical patients, including in complex cardiac surgeries and those that use cardiopulmonary bypass. Antifibrinolytics, such as epsilon-aminocaproic acid (EACA) and tranexamic acid (TXA), are widely used in these procedures, as well as in other types of surgeries. These medicines are included in the World Health Organization (WHO) list of ‘essential medicines’. Scientific evidence demonstrates the effectiveness of EACA in reducing bleeding and the need for transfusions in heart surgery. EACA is highly recommended for use in heart surgery by the American Society of Anesthesiology Task Force on Perioperative Blood Management. Regarding the safety of EACA, there is no robust evidence of any significant thrombotic potential. TXA has also been shown to be effective in reducing the use of blood transfusions in cardiac and non-cardiac surgeries and is considered safer than other antifibrinolytic agents. There is no evidence of any increased risk of thromboembolic events with TXA, but doses greater than 2 g per day have been associated with an increased risk of seizures. It is also important to adjust the dose in patients with renal impairment. In conclusion, antifibrinolytics, such as EACA and TXA, are effective in reducing blood loss and transfusion use in cardiac and non-cardiac surgeries, without causing serious adverse effects.

Guanidine dicycloamine-based analogs: green chemistry synthesis, biological investigation, and molecular docking studies as promising antibacterial and antiglycation leads.

Dicyandiamide (DCD) reacted with amino acids 1a-f to produce biguanides 2 and 4 and guanidine pyrazolones 3, 5, 6, 7, and 8, according to the reaction. DCD exhibited the following reactions: imidodicarbonimidicdiamide 9, diazocan-2-ylguanidine 10, methyl biguanidylthion 11, N-carbamothioylimidodicarbonimidicdiamide 12, 2-guanidinebenzoimidazole 13a, 2-guanidinylbenzoxazole 13b, and 2-guanidinylbenzothiazol 13c. These reactions were triggered by 6-amino caproic acid, thioacetamide, thiourea, o-aminophenol, o-aminothiophenol, and anthranilic acid, respectively. Compound 2 had the least antimicrobial activity, while compound 13c demonstrated the most antibacterial impact against all bacterial strains. Furthermore, in terms of antiglycation efficacy (AGEs), 12, 11, and 7 were the most effective AGE cross-linking inhibitors. Eight and ten, which showed a considerable inhibition on cross-linking AGEs, come next. Compounds 4 and 6 on the other hand have shown the least suppression of AGE production. The most promising antiglycation scaffolds 8, 11, and 12 in the Human serum albumin (HAS) active site were shown to be able to adopt crucial binding interactions with important amino acids based on the results of in silico molecular docking. The most promising antiglycation compounds 8, 11, and 12 were also shown to have better hydrophilicity, acceptable lipophilicity, gastrointestinal tract absorption (GIT), and blood-brain barrier penetration qualities when their physicochemical properties were examined using the egg-boiled method.

Development of a Thermodynamically Favorable Multi-enzyme Cascade Reaction for Efficient Sustainable Production of ω-Amino Fatty Acids and α,ω-Diamines.

Aliphatic ω-amino fatty acids (ω-AFAs) and α,ω-diamines (α,ω-DMs) are essential monomers for the production of nylons. Development of a sustainable biosynthesis route for ω-AFAs and α,ω-DMs is crucial in addressing the challenges posed by climate change. Herein, we constructed an unprecedented thermodynamically favorable multi-enzyme cascade (TherFavMEC) for the efficient sustainable biosynthesis of ω-AFAs and α,ω-DMs from cheap α,ω-dicarboxylic acids (α,ω-DAs). This TherFavMEC was developed by incorporating bioretrosynthesis analysis tools, reaction Gibbs free energy calculations, thermodynamic equilibrium shift strategies and cofactor (NADPH&ATP) regeneration systems. The molar yield of 6-aminohexanoic acid (6-ACA) from adipic acid (AA) was 92.3 %, while the molar yield from 6-ACA to 1,6-hexanediamine (1,6-HMD) was 96.1 %, which were significantly higher than those of previously reported routes. Furthermore, the biosynthesis of ω-AFAs and α,ω-DMs from 20.0 mM α,ω-DAs (C6-C9) was also performed, giving 11.2 mM 1,6-HMD (56.0 % yield), 14.8 mM 1,7-heptanediamine (74.0 % yield), 17.4 mM 1,8-octanediamine (87.0 % yield), and 19.7 mM 1,9-nonanediamine (98.5 % yield), respectively. The titers of 1,9-nonanediamine, 1,8-octanediamine, 1,7-heptanediamine and 1,6-HMD were improved by 328-fold, 1740-fold, 87-fold and 3.8-fold compared to previous work. Therefore, this work holds great potential for the bioproduction of ω-AFAs and α,ω-DMs.

Pharmacological interventions for the prevention of bleeding in people undergoing elective hip or knee surgery: a systematic review and network meta-analysis.

Hip and knee replacement surgery is a well-established means of improving quality of life, but is associated with a significant risk of bleeding. One-third of people are estimated to be anaemic before hip or knee replacement surgery; coupled with the blood lost during surgery, up to 90% of individuals are anaemic postoperatively. As a result, people undergoing orthopaedic surgery receive 3.9% of all packed red blood cell transfusions in the UK. Bleeding and the need for allogeneic blood transfusions has been shown to increase the risk of surgical site infection and mortality, and is associated with an increased duration of hospital stay and costs associated with surgery. Reducing blood loss during surgery may reduce the risk of allogeneic blood transfusion, reduce costs and improve outcomes following surgery. Several pharmacological interventions are available and currently employed as part of routine clinical care. To determine the relative efficacy of pharmacological interventions for preventing blood loss in elective primary or revision hip or knee replacement, and to identify optimal administration of interventions regarding timing, dose and route, using network meta-analysis (NMA) methodology. We searched the following databases for randomised controlled trials (RCTs) and systematic reviews, from inception to 18 October 2022: CENTRAL (the Cochrane Library), MEDLINE (Ovid), Embase (Ovid), CINAHL (EBSCOhost), Transfusion Evidence Library (Evidentia), ClinicalTrials.gov and WHO International Clinical Trials Registry Platform (ICTRP). We included RCTs of people undergoing elective hip or knee surgery only. We excluded non-elective or emergency procedures, and studies published since 2010 that had not been prospectively registered (Cochrane Injuries policy). There were no restrictions on gender, ethnicity or age (adults only). We excluded studies that used standard of care as the comparator. Eligible interventions included: antifibrinolytics (tranexamic acid (TXA), aprotinin, epsilon-aminocaproic acid (EACA)), desmopressin, factor VIIa and XIII, fibrinogen, fibrin sealants and non-fibrin sealants. We performed the review according to standard Cochrane methodology. Two authors independently assessed trial eligibility and risk of bias, and extracted data. We assessed the certainty of the evidence using CINeMA. We presented direct (pairwise) results using RevMan Web and performed the NMA using BUGSnet. We were interested in the following primary outcomes: need for allogenic blood transfusion (up to 30 days) and all-cause mortality (deaths occurring up to 30 days after the operation), and the following secondary outcomes: mean number of transfusion episodes per person (up to 30 days), re-operation due to bleeding (within seven days), length of hospital stay and adverse events related to the intervention received. We included a total of 102 studies. Twelve studies did not report the number of included participants; the other 90 studies included 8418 participants. Trials included more women (64%) than men (36%). In the NMA for allogeneic blood transfusion, we included 47 studies (4398 participants). Most studies examined TXA (58 arms, 56%). We found that TXA, given intra-articularly and orally at a total dose of greater than 3 g pre-incision, intraoperatively and postoperatively, ranked the highest, with an anticipated absolute effect of 147 fewer blood transfusions per 1000 people (150 fewer to 104 fewer) (53% chance of ranking 1st) within the NMA (risk ratio (RR) 0.02, 95% credible interval (CrI) 0 to 0.31; moderate-certainty evidence). This was followed by TXA given orally at a total dose of 3 g pre-incision and postoperatively (RR 0.06, 95% CrI 0.00 to 1.34; low-certainty evidence) and TXA given intravenously and orally at a total dose of greater than 3 g intraoperatively and postoperatively (RR 0.10, 95% CrI 0.02 to 0.55; low-certainty evidence). Aprotinin (RR 0.59, 95% CrI 0.36 to 0.96; low-certainty evidence), topical fibrin (RR 0.86, CrI 0.25 to 2.93; very low-certainty evidence) and EACA (RR 0.60, 95% CrI 0.29 to 1.27; very low-certainty evidence) were not shown to be as effective compared with TXA at reducing the risk of blood transfusion. We were unable to perform an NMA for our primary outcome all-cause mortality within 30 days of surgery due to the large number of studies with zero events, or because the outcome was not reported. In the NMA for deep vein thrombosis (DVT), we included 19 studies (2395 participants). Most studies examined TXA (27 arms, 64%). No studies assessed desmopressin, EACA or topical fibrin. We found that TXA given intravenously and orally at a total dose of greater than 3 g intraoperatively and postoperatively ranked the highest, with an anticipated absolute effect of 67 fewer DVTs per 1000 people (67 fewer to 34 more) (26% chance of ranking first) within the NMA (RR 0.16, 95% CrI 0.02 to 1.43; low-certainty evidence). This was followed by TXA given intravenously and intra-articularly at a total dose of 2 g pre-incision and intraoperatively (RR 0.21, 95% CrI 0.00 to 9.12; low-certainty evidence) and TXA given intravenously and intra-articularly, total dose greater than 3 g pre-incision, intraoperatively and postoperatively (RR 0.13, 95% CrI 0.01 to 3.11; low-certainty evidence). Aprotinin was not shown to be as effective compared with TXA (RR 0.67, 95% CrI 0.28 to 1.62; very low-certainty evidence). We were unable to perform an NMA for our secondary outcomes pulmonary embolism, myocardial infarction and CVA (stroke) within 30 days, mean number of transfusion episodes per person (up to 30 days), re-operation due to bleeding (within seven days), or length of hospital stay, due to the large number of studies with zero events, or because the outcome was not reported by enough studies to build a network. There are 30 ongoing trials planning to recruit 3776 participants, the majority examining TXA (26 trials). We found that of all the interventions studied, TXA is probably the most effective intervention for preventing bleeding in people undergoing hip or knee replacement surgery. Aprotinin and EACA may not be as effective as TXA at preventing the need for allogeneic blood transfusion. We were not able to draw strong conclusions on the optimal dose, route and timing of administration of TXA. We found that TXA given at higher doses tended to rank higher in the treatment hierarchy, and we also found that it may be more beneficial to use a mixed route of administration (oral and intra-articular, oral and intravenous, or intravenous and intra-articular). Oral administration may be as effective as intravenous administration of TXA. We found little to no evidence of harm associated with higher doses of tranexamic acid in the risk of DVT. However, we are not able to definitively draw these conclusions based on the trials included within this review.

Magnetic studies of ultrafine CoFe2O4 nanoparticles with different molecular surface coatings.

Surface functionalized ultrafine CoFe2O4 nanoparticles (NPs), with mean diameter ∼5 nm, were investigated by means of DC magnetization and AC susceptibility over the temperature range of 4-400 K. All NPs present the same CoFe2O4 core, with different molecular surface coatings, increasing gradually the number of carbon atoms in the coating layer: glycine (C2H5NO2), alanine (C3H7NO2), aminobutanoic acid (C4H9NO2), aminohexanoic acid (C6H13NO2), and aminododecanoic acid (C12H25NO2). Samples were intentionally fabricated in order to modulate the core-core magnetic dipolar interaction, as the thickness of the coating layer increases with the number of carbon atoms in the coating molecule. The magnetic data of the uncoated CoFe2O4 NPs were also collected for comparison. All investigated CoFe2O4 NPs (coated and uncoated) are in a magnetically blocked state at room temperature as evidenced by ZFC/FC measurements and the presence of hysteresis with ∼700 Oe coercivity. Low temperature magnetization scans show slightly constricted hysteresis loops with coercivity decreasing systematically with a decreasing number of carbon atoms in the coating molecule, possibly resulting from differences in magnetic dipole coupling between NPs. Large thermomagnetic irreversibility, slow monotonic increase in the FC magnetization and non-saturation of the magnetization give evidence for the cluster glass (CG) nature in the CoFe2O4 NPs. The out of phase part (χ'') of AC susceptibility for all samples shows a clear frequency dependent hump which was analyzed to distinguish superparamagnetic (SPM), cluster glass (CG) and spin glass (SG) behavior by using Néel-Arrhenius, Vogel-Fulcher, and power law fittings. These analyses rule out the SPM state and suggest the presence of significant inter-cluster dipolar interaction, giving rise to CG cooperative freezing in the high-temperature region. In the low-temperature range, however, the disordered spins on the nanoparticle's surface play an important role in the formation of the SG-like state, as evidenced by Arrott plots and temperature dependency of dM/dH in the initial magnetization curves. In summary, the magnetic measurements showed that undercooling the system evolves from a SPM state of weakly interacting spin clusters, through the CG state induced by strong dipolar interaction, to the SG state resulting from the frustration of the disordered surface spins.

Клініко-фармакоекономічні аспекти лікування хворих на COVID-19 нетяжкого перебігу та наявністю факторів ризику прогресування захворювання

Abstract. COVID-19 treatment issues are still a difficult problem worldwide because of huge economic losses of society as a result of the widespread disease, the peculiarity of its course and the development of complications. The aim of the work is to study the clinical efficiency, safety and economic feasibility of the use of aminocaproic acid (AСA) in the treatment of patients with mild COVID-19 and the presence of modifying risk factors compared to nirmatrelvir/ritonavir and symptomatic therapy. Materials and research methods. 96 patients with mild COVID-19 and the presence of factors of increased risk of progression of the disease to a severe form (old age; overweight; pregnancy; chronic kidney disease; diabetes; primary or secondary immunodeficiency; cardiovascular diseases; chronic lung diseases, etc.). Depending on the treatment regimen, all patients were divided into three groups. Patients of group 1 (n = 33) received ACA inhalation through a compressor inhaler (nebulizer), patients of the 2nd (n = 31) — antiviral therapy with combined drug nirmatrelvir /ritonavir, and patients of the 3rd (n = 32) — symptomatic inhalation Ektobris. The study analyzed the clinical condition, manifestations of certain symptoms of the disease, undesirable phenomena and quality of life of patients, as well as indicators of the cost of drug treatment. The effectiveness of treatment was evaluated by the clinical condition of the patient on the 1st, 3rd, 8th and 14th day of observation. The safety of therapy was evaluated by the frequency of unwanted phenomena, their severity and the emergence of clinically significant changes in laboratory testing. Results. Based on the analysis of the dynamics of individual symptoms, it was found that on the 8th day of treatment in the 1st and 2nd groups of patients was observed faster and reliably (p &lt; 0.05) reduction of the main clinical manifestations of the disease in comparison with patients of 3rd group. But at the end of treatment, the effectiveness of treatment in all groups was almost the same (p &gt; 0.05) recovery was reached in the 1st, 2nd and 3rd groups in 84.6 %, 83.8 % and 75.0 %. In the rest of the patients, a positive dynamic of symptoms was observed. When assessing the safety of the proposed treatment regimens in patients of the 1st and 3rd study groups no treatment side effects were observed in all cases. At the same time, 19.4 % of patients of group 2 for the 2nd day of treatment were registered with undesirable mild side effects from the gastrointestinal tract, but their intensity and duration did not require termination or correction of further therapy. Given the same clinical efficiency and safety of the proposed treatment schemes of patients with Covid-19, the method of "minimizing value" was applied to carry out pharmacoeconomic research. According to the results of this analysis, it was found that the most optimal in these indicators was the treatment of the 1st group of patients, which was significantly the smallest of all comparison groups (p &lt; 0.05). Conclusions. The results of the study of clinical efficacy, safety and pharmacoeconomic aspects of the treatment of patients with a mild course of Covid-19 and the presence of risk factors for the progression of the disease indicate the unconditional advantages of the use of ACA inhalation in the treatment of this category of patients in comparison with the use of nirmatrelvir. The use of this therapeutic tactics allows you to achieve significantly faster clinical improvement, prevent the development of unwanted phenomena and the progression of the disease, as well as reduce the cost of treatment of this category of patients.

Supplementation of dietary areca nut extract modulates the growth performance, cecal microbiota composition, and immune function in Wenchang chickens.

The study was aimed at evaluating the effects of areca nut extract (ANE) on the growth performance, cecal microbiota, and immunity of Wenchang chickens. For this study, 42-day-old healthy Wenchang chickens (n = 450) with similar body weight were chosen. The animals were randomly divided into five groups, with six replicates per group and 15 chickens per replicate. One group was fed a basal diet (control; CCK). The remaining four groups were fed a basal diet supplemented with varying ANE concentrations: 0.038, 0.063, 0.100, and 0.151 g/kg, with the groups denoted as CNT1, CNT2, CNT3, and CNT4, respectively. The feeding experiment lasted 35 days. The ligated cecum segments of the control and experimental groups were collected for metabolomic and metagenomic analysis, while the bone marrow samples were extracted for tandem mass tag (TMT)-based proteomic analysis. All the experimental groups exhibited significantly higher average daily gain (ADG) and significantly lower feed-to-weight (F/G) ratios than CCK. Metabolomic screening of the cecum contents revealed the presence of 544 differential metabolites, including several gut health-related metabolites, such as xanthine, hydroxy hypoxanthine, 2,5-dimethylhydrazine, ganoderic acid, and 2-aminohexanoic acid. Metagenomic analysis of the cecum contents showed an upregulation in the abundance of Prevotella spp. in the experimental groups. However, we observed no significant differences in the abundances of other cecal microbes at phylum and genus levels. Furthermore, we observed significant associations between Prevotella spp. and the differentially abundant metabolites, such as cherubins, thiaburimamide, and 3,4-dihydroxy-L-phenylalanine, (r)-mevalonate, 5-O-methylalloptaeroxylin, nalidixic acid, and deoxyloganin (p < 0.05). Proteomic analysis revealed that the differentially expressed proteins (such as interferon-induced protein with tetratricopeptide repeats 5 (IFIT5), MHC-BF1, and death domain-associated protein (Daxx)) in the bone marrow of the chickens were primarily enriched in the immune network for IgA production and B cell receptor signaling pathway. In conclusion, dietary ANE supplementation was found to enhance metabolic activity and energy utilization, improve growth performance, modulate cecal microbiota, and strengthen the immunity of Wenchang chickens.

Controlled Oxidant-to-Fuel Ratios for Synthesis of Inorganic Hematite Pigment (α-Fe2O3) Using Solution Combustion Method with 6-Aminohexanoic Acid as Fuel

Controlled Oxidant-to-Fuel Ratios for Synthesis of Inorganic Hematite Pigment (α-Fe2O3) Using Solution Combustion Method with 6-Aminohexanoic Acid as Fuel

High red/far-red ratio promotes root colonization of Serratia plymuthica A21-4 in tomato by root exudates-stimulated chemotaxis and biofilm formation

Effective colonization on plant roots is a prerequisite for plant growth promoting rhizobacterias (PGPR) to exert beneficial activities. Light is essential for plant growth, development and stress response. However, how light modulates root colonization of PGPR remains unclear. Here, we found that high red/far red (R/FR) light promoted and low R/FR light inhibited the colonization and growth enhancement of Serratia plymuthica A21-4 (S. plymuthica A21-4) on tomato, respectively. Non-targeted metabolomic analysis of root exudates collected from different R/FR ratio treated tomato seedlings with or without S. plymuthica A21-4 inoculation by UPLC-MS/MS showed that 64 primary metabolites in high R/FR light-grown plants significantly increased compared with those determined for low R/FR light-grown plants. Among them, 7 amino acids, 1 organic acid and 1 sugar obviously induced the chemotaxis and biofilm formation of S. plymuthica A21-4 compared to the control. Furthermore, exogenous addition of five artificial root exudate compontents (leucine, methionine, glutamine, 6-aminocaproic acid and melezitose) regained and further increased the colonization ability and growth promoting ability of S. plymuthica A21-4 on tomato under low R/FR light and high R/FR light, respectively, indicating their involvement in high R/FR light-regulated the interaction of tomato root and S. plymuthica A21-4. Taken together, our results, for the first time, clearly demonstrate that high R/FR light-induced root exudates play a key role in chemotaxis, biofilm formation and root colonization of S. plymuthica A21-4. This study can help promote the combined application of light supplementation and PGPR to facilitate crop growth and health in green agricultural production.

Hijacking of the Fibrinolytic System By B-Cell Acute Lymphoblastic Leukaemia and Its Therapeutic Targeting

The fibrinolytic system plays a role in the mobilization of hematopoietic stem cells from their bone marrow microenvironment (BMM), but its function in leukemias is not well understood. The fibrinolytic system consists of the proenzyme plasminogen and its active form, plasmin, a serine protease. The activation of plasmin is tightly regulated by activators such as tissue plasminogen activator (tPA) and various inhibitors. A role of this plasminogen activation system in the microenvironment of solid tumors is being unravelled, but a function of this pathway in the BMM, where hematological cancers usually originate, has so far been elusive. Transcriptome analysis of mesenchymal cells in the BMM of mice with different leukemias had revealed annexin A2 ( Anxa2), an initiator of fibrinolysis, to be differentially expressed. Using an ANXA2-deficient BMM as a model for impaired fibrinolysis, we showed that ANXA2 promotes the activation of plasmin, leading to decreased levels of the extracellular matrix (ECM) protein fibronectin in the BMM and accelerating the progression of BCR-ABL1 + B-cell acute lymphoblastic (B-ALL), but not MLL-AF9 + acute myeloid leukemia. Consistently, induction of B-ALL in tPA-deficient mice led to fibronectin accumulation in the BMM and significant survival prolongation. The dense ECM in an ANXA2-deficient BMM is shown to entrap insulin-like growth factor (IGF) and to specifically reduce mTORC2-dependent signalling and proliferation in B-ALL cells. Conversely, B-ALL cell-derived interleukin (IL)-6 conditions hepatic generation of plasminogen, the precursor of plasmin, perpetuating this circuit. Treatment with -aminocaproic acid (EACA), an anti-hemorrhagic drug, which inhibits plasmin activation, reduces tumor burden and prolongs survival in syngeneic and xenogeneic murine models via increased fibronectin in the BMM. Human data confirm that IGF1 and fibronectin staining in trephine biopsies are correlated and that the mTORC2 pathway is distinctly activated in B-ALL. Higher expression of SERPINF2 (α2-antiplasmin), an inhibitor of plasmin, in human B-ALL cells leads to superior outcome. In summary, B-ALL-derived IL-6 impacts hepatic generation of fibrinolytic agents influencing B-ALL progression via ECM remodeling and regulation of the availability of B-ALL-supportive growth factors. Inhibition of plasmin-mediated degradation of the ECM by EACA may be beneficial as adjunct therapy in B-ALL.

Discovery of BT-114143, a Novel and Potent Small-Molecule Plasminogen Inhibitor for Hyperfibrinolysis

Blood coagulation and fibrinolysis are essential physiological functions, whose dysregulation is a life-threatening emergent situation requiring immediate medical intervention. In particular, hyperfibrinolysis-triggered bleeding occurs in certain medical conditions such as postpartum hemorrhage (PPH) or during perioperative procedures, natural disasters, traumatic accidents as well as battlefield situations, and is one of the major causes of mortalities worldwide during peacetime and war. Tranexamic acid (TXA) has been widely used as an antifibrinolytic drug since 1960s, however, the low potency of TXA has limited its clinical applications. Here, we have developed BT-114143, a novel and potent small-molecule plasminogen inhibitor. BT-114143 exhibited over four-fold higher affinity for recombinant human plasminogen than TXA in surface plasmon resonance (SPR) analysis. Similarly, affinity of BT-114143 was at least one magnitude higher than that of either epsilon-aminocaproic acid (EACA) or p-aminomethylbenzoic acid (PAMBA) (Table 1). In vivo efficacy studies were conducted in recombinant tissue plasminogen activator (rt-PA)-triggered rat tail bleeding model and rabbit liver bleeding model by hepatectomy. BT-114143 reduced bleeding time dose-dependently in both animal models, but also exhibited similar potency as compared to TXA. Similar potency between BT-114143 and TXA was further confirmed by rt-PA triggered fibrinolysis in either rat or rabbit whole blood in thromboelastography (TEG) assay, suggesting interspecies difference in response to bleeding. However, ex vivo studies on human plasma clot lysis assay and human whole blood TEG assay (Figure 1) demonstrated nearly ten-fold antifibrinolytic potency as compared to TXA, suggesting superior efficacy for treatment of hyperfibrinolysis-related bleedings. In addition, a panel of GLP toxicology studies has confirmed the preclinical safety of BT-114143. Moreover, electrophysiological analysis has demonstrated comparable inhibitory effect of BT-114143 and TXA on GABA A receptor and Glycine receptor. At present, BT-114143 is undergoing phase I clinical study in China (CTR20222910) and is expected to apply for FDA approval for clinical trial in 2024. Furthermore, BT-114143 is being developed for intramuscular (i.m.) injection, making it more suitable for emergency situations including PPH, traumatic injuries, natural disasters, and combat injuries.

2065. Efficacy of D-peptide-conjugated Antisense Compounds Against Pseudomonas aeruginosa

Abstract Background Pseudomonas aeruginosa (PA) causes significant morbidity and mortality in immunocompromised hosts and those with cystic fibrosis. Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) are antisense compounds designed to target specific genes and prevent translation. PPMOs with L-isomer peptides (L-PPMOs) were previously shown to have in vitro and in vivo activity. However, L-PPMOs are vulnerable to degradation by host proteases. We hypothesize that PPMOs with a D-isomer peptide (D-PPMOs) may be a more stable and potent alternative. We aimed to characterize the activity of L- and D-isomers in PA strains using planktonic and biofilm assays as well as an infected mouse model. Methods All L- and D-PPMOs were synthesized by Sarepta Therapeutics, Inc. We tested L- and D-isomers of the (RXR)4XB (X for 6-aminohexanoic acid and B for β-Ala) and R6G peptide [(Arg)6-Gly]. PMOs for rpsJ (ribosomal protein) and acpP (fatty acid synthesis protein) were conjugated to the 3’ end of each peptide. Minimum inhibitory concentration (MIC) assays were performed in unique lab and clinical (including MDR) isolates using MOPS medium. Strain PAO1 biofilms were grown in MBEC plates for 24 hours, with PPMOs then dosed every 8 hours for 24 hours, followed by colony enumeration. For in vivo studies, mice were infected with strain PA103 intratracheally and given intranasal PPMO at 6 hours post-infection. Lung burden was determined at 24 hours post-infection. Results MIC values of D-R6G-RpsJ and D-R6G-AcpP were comparable to their L-isomers, but D-RXR-RpsJ showed an improved MIC90 of 0.5 μM compared to the L-RXR-RpsJ MIC90 of 16 μM (Table 1). Both isomers demonstrated reduction of 48-hour biofilm to various degrees. D-PPMO biofilm reduction ranged from 1.5 logs to &amp;gt; 3 logs (D-R6G-AcpP and D-RXR-RpsJ, respectively). L-PPMO biofilm reduction ranged from 2 logs to &amp;gt; 4 logs. D-PPMOs were superior to their L-PPMO counterparts in our delayed in vivo acute pneumonia model, with most D-PPMOs resulting in an additional 50% decrease in lung burden. Conclusion D-PPMOs show similar or improved activity in vitro and in vivo when compared to L-PPMOs at the same dosage. Future studies will investigate the pharmacology of D-PPMOs, as they may represent a more biologically robust alternative to L-PPMOs for PA infections. Disclosures David E. Greenberg, MD, University of Texas Southwestern Medical Center: Dr. Greenberg has numerous patents on PPMOs

Comparison of efficacy between tranexamic acid and epsilon-aminocaproic acid for total knee arthroplasty: A meta-analysis of randomized controlled trials.

Tranexamic acid (TXA) and epsilon-aminocaproic acid (EACA) have been demonstrated to reduce blood loss following total knee arthroplasty (TKA). This meta-analysis aimed to compare the efficacy and safety of TXA and EACA in reducing blood loss in primary TKA patients. A search of the PubMed, Embase, and Cochrane Library databases identified all relevant studies published until December 2022. Randomized controlled trials (RCTs) reporting a comparison of TXA and EACA for TKA patients were selected. The main outcomes were total blood loss (TBL), hemoglobin (Hb) drop on postoperative day 3, intraoperative blood loss, operation time and the transfusion rate were evaluated. The weighted mean differences (WMD) and risk ratio (RR) with 95% confidence intervals (CI) were calculated using a fixed-effects or random-effects model. Stata 12.0 software was used for meta-analysis. Six studies involving 739 (TXA:372; EACA:367) patients were included in this meta-analysis. There was no significant difference in terms of intraoperative blood loss, Hb drop on postoperative day 3, operation time, tourniquet time (TT), transfusion rate and the occurrence of deep venous thrombosis (DVT) between the 2 treatments groups. However, compared with EACA, TXA significant reduced TBL (WMD, 174.60; 95% CI, -244.09 to -105.11). Our research did not demonstrate TXA to be superior to EACA in reducing need for transfusion and Hb drop. TXA was superior than EACA in reducing TBL in TKA patients. More RCTs with identical inclusion criteria and dose and duration of treatment, are required to confirm these findings.

Retracted: Tranexamic Acid versus Epsilon-Aminocaproic Acid in Total Knee Arthroplasty: A Meta-Analysis

Retracted: Tranexamic Acid versus Epsilon-Aminocaproic Acid in Total Knee Arthroplasty: A Meta-Analysis

Застосування антифібринолітичної терапії у періопераційному періоді у дітей та дорослих

перебіг оперативних втручань у дітей можуть ускладнюватися розвиткомперіопераційної кровотечі. Застосування препаратів із антифібринолітичною дією зменшуєта превентує розвиток інтраопераційної крововтрати у дорослих та пацієнтів дитячого віку.Антифібринолітичні препарати такі, як транексамова кислота (ТКК) проявила свою ефективністьу якості зменшення обсягу періопераційної крововтрати, трансфузії у дорослих пацієнтів тадітей при травмі, кардіохірургічних та великих ортопедичних втручань. Проте використанняданого препарату у категорії пацієнтів високого ризику та у навантажувальних дозах &gt; 100 мг/кг може асоціюватися із розвитком тромбоемболічних та судомних ускладнень. Однією із перевагзастосування амінокапронової кислоти (АКК) є її широка доступність, вартість і водночасефективність. Порівнюючи ефективність лізинових похідних у пацієнтів із краніостенозомА. Borst, C. Bonfield зазначають, що при використанні АКК в порівнянні із ТКК підвищуєтьсярівень інтраопераційної крововтрати (21 ± 13 vs. 17 ± 10), проте статистично вона не є значима.Апротинін, у якості препарату для зменшення крововтрати у кардіохірургічних пацієнтів впорівнянні із лізиновими похідними, являється більш ефективним для зниження періопераційної&#x0D; крововтрати. Проте після дослідження The Blood Conservation Using Antifibrinolytics in a Random-ized Trial (BART) (Fergusson D. et al. 2008) є обмежено доступний у багатьох країнах через високу&#x0D; кількість тромбоемболічних ускладнень та підвищену смертність. На даний момент активнодосліджуються протизапальні властивості не лише апротиніну, а й ТКК та АКК.

Effect of intermolecular interactions on the glass transition temperature of chemically modified alternating polyketones

Thermal properties of polymers depend on the chemical structure of the polymer chain and intermolecular forces arising from hydrogen bonding and π-π stacking. Here we analyzed the effect of increasing the amount of supramolecular interactions on the glass transition temperature of polyketones by chemically modifying the same polymer backbone with five amine derivatives, namely (1-(3-aminopropyl)-imidazole, 4-(aminomethyl) benzoic acid, 6-aminohexanoic acid, benzylamine or hexylamine, at various molar concentrations. The grafting was performed via the Paal-Knorr reaction and the interactions between the pyrrole backbone and different grafted functional groups were elucidated by proton nuclear magnetic resonance, Fourier transform infrared and X-ray photoelectron spectroscopy as well as differential scanning calorimetry and computational modeling. The modification of polyketone with 4-(aminomethyl) benzoic acid and 6-aminohexanoic acid, allowed for new possibilities of hydrogen bonding and led to a significant increase in the glass transition temperature as compared to the neat polymer and pyrrole-containing polymers that did not bear reactive side groups. In contrast, modification with the imidazole derivative was found to introduce new and more robust CH⋯π interactions between imidazole groups and the π-system of the pyrrole backbone chain, based on electrostatic effects. Both types of supramolecular interactions affect the mobility of the backbone chains and this systematic study demonstrates how the combined effect of π-π stacking and hydrogen bonding to carboxylate moieties can be used to tune the molecular mobility and phase transition temperature of these chemically modified polyketones.

Evaluating the In Vitro Activity and Safety of Modified LfcinB Peptides as Potential Colon Anticancer Agents: Cell Line Studies and Insect-Based Toxicity Assessments.

Anticancer peptides are increasingly being considered as alternative treatments for cancer due to their potency, selectivity, and low toxicity. Previously, the peptide LfcinB (21-25)Pal showed in vitro anticancer effects against the Caco-2 colon cancer cell line (half-maximal inhibitory concentration (IC50): 86 μM). In this study, we developed modifications to the peptide sequence to increase its anticancer activity. Sequence modifications were made such as the inclusion of amino hexanoic acid (Ahx), N-terminal biotinylation, acetylation, and substitutions of Orn for Arg and/or d-Arg by l-Arg. The molecules were synthesized using manual solid-phase peptide synthesis (SPPS), and their synthetic feasibility (SAScore) ranged from 6.2 to 7.6. The chromatographic purities of the synthesized peptides were greater than 89%. We found that Ahx-RWQWRWQWR and RWQWRWQW-Orn showed activity against both Caco-2 and HT-29 cell lines and decreased IC50 values by approx. 50% in Caco-2 cells (IC50: 40 μM) when compared to the parent peptide RWQWRWQWR. Moreover, the modified peptides demonstrated lower hemolytic effects, with values <10% at 200 μg/mL. Toxicity was assessed using the Galleria mellonella model and the half-maximal lethal dose (LD50) for the best peptides was >100 mg/kg, indicating that their toxicity is classified as moderately toxic or lower. In contrast, cisplatin showed an LD50 of 13 mg/Kg. The designed anticancer peptides presented good in vitro activity and low toxicity, making them promising molecules for future drug development studies.