Glycoprotein Inhibitors Research Articles

Inclusion of a 3D-printed Hyperelastic Bone mesh improves mechanical and osteogenic performance of a mineralized collagen scaffold

Regenerative repair of craniomaxillofacial bone injuries is challenging due to both the large size and irregular shape of many defects. Mineralized collagen scaffolds have previously been shown to be a promising biomaterial implant to accelerate craniofacial bone regeneration in vivo. Here we describe inclusion of a 3D-printed polymer or ceramic-based mesh into a mineralized collagen scaffold to improve mechanical and biological activity. Mineralized collagen scaffolds were reinforced with 3D-printed Fluffy-PLG (ultraporous polylactide-co-glycolide co-polymer) or Hyperelastic Bone (90wt% calcium phosphate in PLG) meshes. We show degradation byproducts and acidic release from the printed structures have limited negative impact on the viability of mesenchymal stem cells. Further, inclusion of a mesh formed from Hyperelastic Bone generates a reinforced composite with significantly improved mechanical performance (elastic modulus, push-out strength). Composites formed from the mineralized collagen scaffold and either Hyperelastic Bone or Fluffy-PLG reinforcement both supported human bone-marrow derived mesenchymal stem cell osteogenesis and new bone formation. This was observed by increased mineral formation in Fluffy-PLG composites and increased cell viability and upregulation of RUNX2, Osterix, and COL1A2 genes in both composites. Strikingly, composites reinforced with Hyperelastic Bone mesh elicited significantly increased secretion of osteoprotegerin, a soluble glycoprotein and endogenous inhibitor of osteoclast activity. These results suggest that architectured meshes can be integrated into collagen scaffolds to boost mechanical performance and actively instruct cell processes that aid osteogenicity; specifically, secretion of a factor crucial to inhibiting osteoclast-mediated bone resorption. Future work will focus on further adapting the polymer mesh architecture to confer improved shape-fitting capacity as well as to investigate the role of polymer reinforcement on MSC-osteoclast interactions as a means to increase regenerative potential.

Acute coronary syndromes with high thrombotic burden: therapeutic innovations.

Antiplatelet agents represent one of the cornerstones of drug therapy for acute coronary syndromes (ACS). In the last decade, the arrival of prasugrel and ticagrelor, faster and more powerful oral platelet receptor P2Y12 inhibitors compared to clopidogrel, significantly improved platelet inhibition in patients with ACS. However, the reduction of thrombotic risk came at the cost of increased bleeding risk. Despite having similar indications, prasugrel and ticagrelor have different characteristics and methods of use, essentially due to a different design of the trials in which they have been studied. The optimal use of these antiplatelets in clinical practice should therefore be tailored in individual patients. In the acute phase of ACS with high thrombotic burden, all oral P2Y12 inhibitors have limitations, mainly due to the delay of onset of action related to oral administration. In this scenario, parenteral antiplatelet agents (glycoprotein inhibitors IIb/IIIa and cangrelor) may play a key role in case of percutaneous coronary interventions of high thrombotic coronary lesions and in the prevention of early thrombotic complications. Cangrelor, an intravenous inhibitor of the P2Y2 receptor, has peculiar pharmacokinetic and pharmacodynamic characteristics that make it particularly suitable to be used as an antiplatelet during coronary angioplasty as it achieves a rapid and powerful antiplatelet effect in patients not pretreated with oral medications, and has a favourable safety profile in relation to the bleeding risk.

Discovery of a potent dual inhibitor of wild-type and mutant respiratory syncytial virus fusion proteins through the modulation of atropisomer interconversion properties

The development of effective respiratory syncytial virus (RSV) fusion glycoprotein (F protein) inhibitors against both wild-type and the D486N-mutant F protein is urgently required. We recently reported a 15-membered macrocyclic pyrazolo[1,5-a]pyrimidine derivative 4 that exhibited potent anti-RSV activities against not only wild-type, but also D486N-mutant F protein. However, NMR studies revealed that the 15-membered derivative 4 existed as a mixture of atropisomers. An optimization study of the linker moiety between the 2-position of the benzoyl moiety and the 7-position of the pyrazolo[1,5-a]pyrimidine scaffold identified a 16-membered derivative 42c with an amide linker that showed a rapid interconversion of atropisomers. Subsequent optimization of the 5-position of the pyrazolo[1,5-a]pyrimidine scaffold and the 5-position of the benzoyl moiety resulted in the discovery of a potent clinical candidate 60b for the treatment of RSV infections.

Inclusion of a 3d-Printed Hyperelastic Bone Mesh Improves Mechanical and Osteogenic Performance of a Mineralized Collagen Scaffold

Regenerative repair of craniomaxillofacial bone injuries is challenging due to both the large size and irregular shape of many defects. Mineralized collagen scaffolds have previously been shown to be a promising biomaterial implant to accelerate craniofacial bone regeneration in vivo . Here we describe inclusion of a 3D-printed polymer or ceramic-based mesh into a mineralized collagen scaffold to improve mechanical and biological activity. Mineralized collagen scaffolds were reinforced with 3D-printed Fluffy-PLG (ultraporous polylactide-co-glycolide co-polymer) or Hyperelastic Bone (90wt% calcium phosphate in PLG) meshes. We show degradation byproducts and acidic release from the printed structures have limited negative impact on the viability of mesenchymal stem cells. Further, inclusion of a mesh formed from Hyperelastic Bone generates a reinforced composite with significantly improved mechanical performance (elastic modulus, push-out strength). Composites formed from the mineralized collagen scaffold and either Hyperelastic Bone or Fluffy-PLG reinforcement both supported human bone-marrow derived mesenchymal stem cell osteogenesis and new bone formation. Strikingly, composites reinforced with Hyperelastic Bone mesh elicited significantly increased secretion of osteoprotegerin, a soluble glycoprotein and endogenous inhibitor of osteoclast activity. These results suggest that architectured meshes can be integrated into collagen scaffolds to boost mechanical performance and actively instruct cell processes that aid osteogenicity; specifically, secretion of a factor crucial to inhibiting osteoclast-mediated bone resorption. Future work will focus on further adapting the polymer mesh architecture to confer improved shape-fitting capacity as well as to investigate the role of polymer reinforcement on MSC-osteoclast interactions as a means to increase regenerative potential.

Design of novel viral attachment inhibitors of the spike glycoprotein (S) of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) through virtual screening and dynamics

To date, the global COVID-19 pandemic has been associated with 11.8 million cases and over 545481 deaths. In this study, we have employed virtual screening approaches and selected 415 lead-like compounds from 103 million chemical substances, based on the existing drugs, from PubChem databases as potential candidates for the S protein-mediated viral attachment inhibition. Thereafter, based on drug-likeness and Lipinski's rules, 44 lead-like compounds were docked within the active side pocket of the viral-host attachment site of the S protein. Corresponding ligand properties and absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile were measured. Furthermore, four novel inhibitors were designed and assessed computationally for efficacy. Comparative analysis showed the screened compounds in this study maintain better results than the proposed mother compounds, VE607 and SSAA09E2. The four designed novel lead compounds possessed more fascinating output without deviating from any of Lipinski's rules. They also showed higher bioavailability and the drug-likeness score was 0.56 and 1.81 compared with VE607 and SSAA09E2, respectively. All the screened compounds and novel compounds showed promising ADMET properties. Among them, the compound AMTM-02 was the best candidate, with a docking score of -7.5 kcal/mol. Furthermore, the binding study was verified by molecular dynamics simulation over 100 ns by assessing the stability of the complex. The proposed screened compounds and the novel compounds may give some breakthroughs for the development of a therapeutic drug to treat SARS-CoV-2 proficiently in vitro and in vivo.

Excimer laser coronary atherectomy during complex PCI: An analysis of 1,471 laser cases from the British Cardiovascular Intervention Society database.

Excimer laser coronary atherectomy (ELCA) is a recognized adjunctive therapy utilized in the percutaneous management of complex coronary lesions. Studies examining its safety and utility have been limited by small sample sizes. Our study examines the determinants and outcomes of ELCA. Using the British Cardiac Intervention Society database, data were analyzed on all PCI procedures in the UK between 2006-2016. Descriptive statistics and multivariate logistic regressions were used to examine baseline, procedural and outcome associations with ELCA. We identified 1,471 (0.21%) ELCA cases out of 686,358 PCI procedures. Baseline covariates associated with ELCA use were age, BMI, number of lesions, CTO or restenosis attempted and history of prior MI, CABG or PCI. Procedural co-variates associated with ELCA were the use of glycoprotein inhibitors, intravascular imaging, rotational atherectomy, cutting balloons, microcatheters and intra-aortic balloon pumps. Adjusted rates of in-hospital major adverse cardiac/cerebrovascular events (MACCE) or its individual components (death, peri-procedural MI, stroke and major bleed) were not significantly altered by the use of ELCA. However, there were higher odds of dissection (OR 1.52, 95% CI 1.17-1.98), perforation (OR 2.18, 95% CI 1.44-3.30), slow flow (OR: 1.67, 95% CI 1.18-2.36), reintervention (OR: 2.12, 95% CI 1.14-3.93) and arterial complications (OR: 1.63, 95% CI 1.21-2.21). ELCA use during complex PCI is associated with higher risk baseline and procedural characteristics. Although increased rates of acute procedural complications were observed, ELCA does not increase likelihood of in-hospital MACCE or its individual components.

In silico Identification of Characteristics Spike Glycoprotein of SARS-CoV-2 in the Development Novel Candidates for COVID-19 Infectious Diseases

Background: The emergence of infectious diseases caused by SARS-CoV-2 has resulted in more than 90,000 infections and 3,000 deaths. The coronavirus spike glycoprotein encourages the entry of SARS-CoV-2 into cells and is the main target of antivirals. SARS-CoV-2 uses ACE2 to enter cells with an affinity similar to SARS-CoV, correlated with the efficient spread of SARS-CoV-2 among humans.Objective: In the research, identification, evaluation, and exploration of the structure of SARS-CoV and SARS-CoV-2 spike glycoprotein macromolecules and their effects on Angiotensin-Converting Enzyme 2 (ACE-2) using in silico studies.Methods: The spike glycoproteins of the two coronaviruses were prepared using the BIOVIA Discovery Studio 2020. Further identification of the three-dimensional structure and sequencing of the macromolecular spike glycoprotein structure using Chimera 1.14 and Notepad++. To ensure the affinity and molecular interactions between the SARS-CoV and SARS-CoV-2 spike glycoproteins against ACE-2 protein-protein docking simulations using PatchDock was accomplished. The results of the simulations were verified using the BIOVIA Discovery Studio 2020.Results: Based on the results of the identification of the macromolecular structure of the spike glycoprotein, it was found that there are some similarities in characteristics between SARS-CoV and SARS-CoV-2. Protein-protein docking simulations resulted that SARS-COV-2 spike glycoprotein has the strongest bond with ACE-2, with an ACE score of −1509.13 kJ/mol.Conclusion: Therefore, some information obtained from the results of this research can be used as a reference in the development of SARS-CoV-2 spike glycoprotein inhibitor candidates for the treatment of infectious diseases of COVID-19.

Abstract 3068: The glycoprotein inhibitors overcome the resistance of the topoisomerase inhibitors in small cell lung cancer

Abstract Small cell lung cancer (SCLC) is a highly aggressive disease with median survival of <2 years. Most patients respond initially to the topoisomerase inhibitors, resistance rapidly emerges. The purpose is overcoming the resistance of the topoisomerase inhibitors in SCLCs. To identify the key factors for the resistance of the topoisomerase I (SN38) or II (VP-16) inhibitors in SCLCs, we analyzed MTS cell proliferation assay. We identified 8 sensitive cell lines and 2 resistant cell lines. We established 4 resistant cell lines by continuous exposure to increasing concentrations of SN-38 or VP-16 stepwise. RNA sequencing was performed using the established cell lines to discover novel therapeutic targets associated with the resistance to topoisomerase inhibitors. We found that whenever the drug efflux protein ATP-binding cassette transporter B1 (ABCB1) was associated the with resistance of VP-16, ATP-binding cassette super-family G member 2 (ABCG2) was associated with the resistance of SN-38. The silencing of ABCG2 or ABCB1 in every resistant cell line, could induce synergistic apoptosis of every cell line. Elacridar and tariquidar which are glycoprotein inhibitors, recovered the sensitivity of SN38 or VP-16 in every resistant line, increased expression of signaling proteins associated with DNA damage and cell-cycle checkpoints, and promoted G2/M arrest and apoptosis. Furthermore, we are going to analyze the expressions of ABCG2 and ABCB1 in serum before and after the treatment of VP-16 or CPT-11. These results suggested the glycoprotein inhibitors, which phase I study is ongoing, could be a promising therapeutic strategy for the purpose of preventing the resistance of topoisomerase inhibitors in SCLCs. Citation Format: Rintaro Noro, Miwako Omori, Aya Fukuizumi, kuniko Matsuda, Mariko Hirao, Satoshi Takahashi, Natsuki Takano, Shinji Nakamichi, Teppei Sugano, Akihiko Miyanaga, Yuji Minegishi, Masahiro Seike, Kaoru Kubota, Akihiko Gemma. The glycoprotein inhibitors overcome the resistance of the topoisomerase inhibitors in small cell lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3068.

In Silico Screening of Potential Spike Glycoprotein Inhibitors of SARS-CoV-2 with Drug Repurposing Strategy.

ObjectiveTo select potential molecules that can target viral spike proteins, which may potentially interrupt the interaction between the human angiotension-converting enzyme 2 (ACE2) receptor and viral spike protein by virtual screening.MethodsThe three-dimensional (3D)-coordinate file of the receptor-binding domain (RBD)-ACE2 complex for searching a suitable docking pocket was firstly downloaded and prepared. Secondly, approximately 15,000 molecular candidates were prepared, including US Food and Drug Administration (FDA)-approved drugs from DrugBank and natural compounds from Traditional Chinese Medicine Systems Pharmacology (TCMSP), for the docking process. Then, virtual screening was performed and the binding energy in Autodock Vina was calculated. Finally, the top 20 molecules with high binding energy and their Chinese medicine (CM) herb sources were listed in this paper.ResultsIt was found that digitoxin, a cardiac glycoside in DrugBank and bisindigotin in TCMSP had the highest docking scores. Interestingly, two of the CM herbs containing the natural compounds that had relatively high binding scores, Forsythiae fructus and Isatidis radix, are components of Lianhua Qingwen (莲花清瘟), a CM formula reportedly exerting activity against severe acute respiratory syndrome (SARS)-Cov-2. Moreover, raltegravir, an HIV integrase inhibitor, was found to have a relatively high binding score.ConclusionsA class of compounds, which are from FDA-approved drugs and CM natural compounds, that had high binding energy with RBD of the viral spike protein. Our work provides potential candidates for other researchers to identify inhibitors to prevent SARS-CoV-2 infection, and highlights the importance of CM and integrative application of CM and Western medicine on treating COVID-19.

Toward the Target: Tilorone, Quinacrine, and Pyronaridine Bind to Ebola Virus Glycoprotein.

Pyronaridine, tilorone, and quinacrine were recently identified by a machine learning model and demonstrated in vitro and in vivo activity against Ebola virus (EBOV) and represent viable candidates for drug repurposing. The target for these molecules was previously unknown. These drugs have now been docked into the crystal structure of the ebola glycoprotein and then experimentally validated in vitro using microscale thermophoresis to generate K d values for tilorone (0.73 μM), pyronaridine (7.34 μM), and quinacrine (7.55 μM). These molecules were shown to bind with a higher affinity than the previously reported toremifene (16 μM). These three structures provide more insight into the structural diversity of ebola glycoprotein inhibitors which can be utilized in the discovery and design of additional inhibitors.

SAT-032 Follistatin-Like 3 (FSTL3) and Early Postnatal Testicular Development

Activin, a TGFβ family ligand, induces Sertoli cell (SC) proliferation during the early postnatal stage in mice. Overexpression of activin, however, leads to the disruption of spermatogenesis. FSTL3, a glycoprotein inhibitor of activin, is highly expressed in the testis and its expression is induced by activin creating an inhbitory feedback loop. FSTL3 deletion in mice is therefore expected to produce a mouse model of increased activin action. Contrary to overexpression of activin, however, as we have shown before, global deletion of FSTL3 in mice results in increased numbers of SC and increased sperm production in older males. Stereological analyses show that although the overall number of SC increases with age in both genotypes during pre-pubertal stages, increase in SC numbers is significantly higher in FSTL3 KO males. Here we show our transcriptomic analyses of WT and FSTL3 KO mice at 3d and 8wk. mRNA sequencing data showed that more than 1000 genes are diffferentially regulated between WT and FSTL3 KO at 3d. There is a much lower number of genes differentially expressed at 8wk. Among several canonical pathways that are altered at 3d in FSTL3 KO mice compared to WT we investigated the “Sertoli-to-Sertoli cell Communication” pathway. We found increased expression of junction proteins, including those that are involved in the blood testis barrier (BTB) as well as earlier establishment of BTB in FSTL3 KO testis. Without the BTB, preleptotene spermatocytes cannot progress through the spermatogenic programme. Importantly, we found accelerated SYCP3 organisation, indicative of early entry into meiosis, concomitant with early establishment of BTB. To directly address whether FSTL3 deletion can induce SC proliferation we knocked down FSTL3 expression in the TM4 SC line. We found increased PCNA expression with FSTL3 siRNA compared to control siRNA transfection demonstrating FSTL3 impairment does induce SC proliferation. We are currently investigating the mechanisms for early establishment of BTB in FSTL3 KO testes and additional canonical pathways. The results of the study presented suggests that loss of FSTL3 promotes SC proliferation which likely allows establishment of SC-SC interactions including BTB formation earlier than in WT. Given that the difference in size between WT and FSTL3 KO testis persists at older ages, it is possible that the timing of increase in SC number and establishment of BTB has a sustained effect on testicular function later in life.

Discovery of Adamantane Carboxamides as Ebola Virus Cell Entry and Glycoprotein Inhibitors.

We identified and explored the structure-activity-relationship (SAR) of an adamantane carboxamide chemical series of Ebola virus (EBOV) inhibitors. Selected analogs exhibited half-maximal inhibitory concentrations (EC50 values) of ∼10-15 nM in vesicular stomatitis virus (VSV) pseudotyped EBOV (pEBOV) infectivity assays, low hundred nanomolar EC50 activity against wild type EBOV, aqueous solubility >20 mg/mL, and attractive metabolic stability in human and nonhuman liver microsomes. X-ray cocrystallographic characterizations of a lead compound with the EBOV glycoprotein (GP) established the EBOV GP as a target for direct compound inhibitory activity and further provided relevant structural models that may assist in identifying optimized therapeutic candidates.

Discovery of a Potent Dual Inhibitor of Wild-Type and Mutant Respiratory Syncytial Virus Fusion Proteins.

A novel series of macrocyclic pyrazolo[1,5-a]pyrimidine derivatives as respiratory syncytial virus (RSV) fusion glycoprotein (F protein) inhibitors were designed and synthesized based on docking studies of acyclic inhibitors. This effort resulted in the discovery of several macrocyclic compounds, such as 12b, 12f, and 12h, with low nanomolar to subnanomolar activities against the wild-type RSV F protein A2. In addition, 12h showed a single-digit nanomolar potency against the previously reported drug-resistant mutant D486N. Molecular modeling and computational analyses suggested that 12h binds to the D486N mutant while maintaining a rigid bioactive conformation via macrocyclization and that it interacts with a hydrophobic cavity of the mutant using a new interaction surface of 12h. This report describes the rational design of macrocyclic compounds with dual inhibitory activities against wild-type and mutant RSV F proteins.

Safety of Glycoprotein IIb-IIIa Inhibitors Used in Stroke-Related Treatment: A Systematic Review and Meta-Analysis.

Background:Endovascular therapy and intravenous thrombolysis with recombinant tissue plasminogen activator are the 2 most recommended treatments for acute ischemic stroke (AIS). Glycoprotein (GP) IIb-IIIa inhibitors are short-acting selective reversible antiplatelet agents that emerged as promising therapeutic agents for AIS about 10 years ago. Given the unclear safety profile and application coverage of GP inhibitors, we conducted this meta-analysis to explore the same.Methods:We used GP IIb-IIIa inhibitors, intracranial hemorrhage, and mortality as the key words on Medline, Web of Science, and the Embase databases. Randomized controlled trials, prospective literatures, and retrospective studies in English published between 1990 and 2020 were screened. The outcomes were relative risk (RR) of death and 90-day intracerebral hemorrhage (ICH). We pooled the results in 2 categories and conducted a subgroup analysis stratified by different drugs. The choice of the effects model depended on the value of I 2.Results:In all, 3700 patients from 20 studies were included. No GP IIb-IIIa inhibitors were found to have a remarkable influence on the ICH rate. The RR values of symptomatic ICH for abciximab and eptifibatide were 4.26 (1.89, 9.59) and 0.17 (0.04, 0.69), respectively. Both tirofiban and abciximab could decrease the mortality rate within 90 days. Age > 70 years, National Institutes of Health Stroke Scale > 15, and overall dose > 10 mg are risk factors for ICH events with tirofiban usage. Thrombectomy combined with tirofiban was safe for arterial reocclusion prevention.Conclusions:In stroke-related treatment, administration of GP IIb-IIIa inhibitors could be safe, but care should be taken regarding drug species and doses. Abciximab can increase the risk of symptomatic intracranial hemorrhage. Tirofiban and eptifibatide can be considered safe in low doses. Suitable patients should be selected using strict criteria.

From the Literature

From the Literature

Novel compounds of hybrid structure pyridazinone-coumarin as potent inhibitors of platelet aggregation.

Aim: The current limitations of antiplatelet therapy promote the search for new antithrombotic agents. Here we describe novel platelet aggregation inhibitors that combine pyridazinone and coumarin scaffolds in their structure. Results: The target compounds were synthesized in good yield from maleic anhydride, following a multistep strategy. The in vitro studies demonstrated significant antiplatelet activity in many of these compounds, with IC50 values in the low micromolar range, revealing that the activity was affected by the substitution pattern of the two selected cores. Additional studies point out their effect as inhibitors of glycoprotein (Gp) IIb/IIIa activation.Conclusion: This novel hybrid structure can be considered a good prototype for the development of potent platelet aggregation inhibitors.

Comparison between The Efficacy of Intracoronary Nitroglycerin versus Nitroglycerin Plus Glycoprotein Inhibitors for Treatment of Patients with Thrombolysis in Myocardial Infarction Flow Less Than Three during Primary Percutaneous Coronary Intervention

Background: Primary percutaneous coronary intervention (PPCI) is currently the cornerstone of management in patients with ST-segment elevation myocardial infarction (STEMI). Aim of the work: comparison between the efficacies of intracoronary nitroglycerin (NTG) versus nitroglycerin plus glycoprotein inhibitors (GP) IIb/IIIa for treatment of patients with thrombolysis in myocardial infarction flow less than three during primary percutaneous coronary intervention. Patients and methods: we prospectively enrolled 30 patients with STEMI undergoing PPCI randomized to receive IC NTG only (n = 15) versus NTG plus GP IIb/IIIa inhibitors (n = 15) during PPCI. The primary outcome was the incidence of angiographic MVO as defined by thrombolysis in myocardial infarction flow less than 3 or thrombolysis in myocardial infarction flow 3 with myocardial blush grade less than 2. Results: NTG plus GP IIb/IIIa inhibitors were associated with better primary outcome compared to NTG only TIMI 3 & MBG > = 2 (40%vs 73.3%, respectively; P = 0.036). There was a trend towards improved left ventricular ejection fraction with NTG plus GP IIb/IIIa inhibitors (44.33 ± 9.76 vs 52.87 ± 11.23, respectively; P = 0.035). In addition, NTG plus GP IIb/IIIa inhibitors was associated with lower incidence of 30-day major adverse cardiovascular events (26.7 vs. 66.7% respectively; P = 0.028). Conclusion: In PPCI, NTG plus GP IIb/IIIa inhibitors resulted in significant improvements in no-reflow and MVO with a better safety profile compared to NTG only. Larger trials should be conducted to confirm these results.

Comparison between The Efficacy of Intracoronary Nitroglycerin versus Nitroglycerin Plus Glycoprotein Inhibitors for Treatment of Patients with Thrombolysis in Myocardial Infarction Flow Less Than Three during Primary Percutaneous Coronary Intervention

Background: Primary percutaneous coronary intervention (PPCI) is currently the cornerstone of management in patients with ST-segment elevation myocardial infarction (STEMI). Aim of the work: comparison between the efficacies of intracoronary nitroglycerin (NTG) versus nitroglycerin plus glycoprotein inhibitors (GP) IIb/IIIa for treatment of patients with thrombolysis in myocardial infarction flow less than three during primary percutaneous coronary intervention. Patients and methods: we prospectively enrolled 30 patients with STEMI undergoing PPCI randomized to receive IC NTG only (n = 15) versus NTG plus GP IIb/IIIa inhibitors (n = 15) during PPCI. The primary outcome was the incidence of angiographic MVO as defined by thrombolysis in myocardial infarction flow less than 3 or thrombolysis in myocardial infarction flow 3 with myocardial blush grade less than 2. Results: NTG plus GP IIb/IIIa inhibitors were associated with better primary outcome compared to NTG only TIMI 3 & MBG > = 2 (40%vs 73.3%, respectively; P = 0.036). There was a trend towards improved left ventricular ejection fraction with NTG plus GP IIb/IIIa inhibitors (44.33 ± 9.76 vs 52.87 ± 11.23, respectively; P = 0.035). In addition, NTG plus GP IIb/IIIa inhibitors was associated with lower incidence of 30-day major adverse cardiovascular events (26.7 vs. 66.7% respectively; P = 0.028). Conclusion: In PPCI, NTG plus GP IIb/IIIa inhibitors resulted in significant improvements in no-reflow and MVO with a better safety profile compared to NTG only. Larger trials should be conducted to confirm these results.

Multi-organ system for the evaluation of efficacy and off-target toxicity of anticancer therapeutics.

A pumpless, reconfigurable, multi-organ-on-a-chip system containing recirculating serum-free medium can be used to predict preclinical on-target efficacy, metabolic conversion, and measurement of off-target toxicity of drugs using functional biological microelectromechanical systems. In the first configuration of the system, primary human hepatocytes were cultured with two cancer-derived human bone marrow cell lines for antileukemia drug analysis in which diclofenac and imatinib demonstrated a cytostatic effect on bone marrow cancer proliferation. Liver viability was not affected by imatinib; however, diclofenac reduced liver viability by 30%. The second configuration housed a multidrug-resistant vulva cancer line, a non-multidrug-resistant breast cancer line, primary hepatocytes, and induced pluripotent stem cell-derived cardiomyocytes. Tamoxifen reduced viability of the breast cancer cells only after metabolite generation but did not affect the vulva cancer cells except when coadministered with verapamil, a permeability glycoprotein inhibitor. Both tamoxifen alone and coadministration with verapamil produced off-target cardiac effects as indicated by a reduction of contractile force, beat frequency, and conduction velocity but did not affect viability. These systems demonstrate the utility of a human cell-based in vitro culture system to evaluate both on-target efficacy and off-target toxicity for parent drugs and their metabolites; these systems can augment and reduce the use of animals and increase the efficiency of drug evaluations in preclinical studies.

Coronary perforation complicating percutaneous coronary intervention in patients presenting with an acute coronary syndrome: An analysis of 1013 perforation cases from the British Cardiovascular Intervention Society database

BackgroundThe evidence base for coronary perforation occurring during percutaneous coronary intervention in patients presenting with an acute coronary syndrome (ACS-PCI) is limited and the specific role of acute pharmacology in its clinical presentation unclear. Methods and resultsUsing the BCIS PCI database, data were analysed on all ACS-PCI procedures performed in England and Wales between 2007 and 2014. Multiple regressions were used to identify predictors of coronary perforation and its association with outcomes. Propensity score matching was used to evaluate the association between differing P2Y12 inhibitors or glycoprotein inhibitors (GPI) and CP. During 270,329 ACS-PCI procedures, 1013 coronary perforations were recorded (0.37%) with a stable annual incidence. In multiple regression analysis, covariates associated with increased frequency of coronary perforation included age, female gender, CTO intervention, number and length of stents used, and rotational atherectomy use, whilst differing P2Y12 inhibitors were not predictive. Using propensity score matching, use of a GPI was independently associated with tamponade (OR 1.50, [1.08–2.06], p = 0.014). The adjusted odds ratios for all clinical outcomes were adversely affected by coronary perforation. ConclusionsCoronary perforation is an infrequent event during ACS-PCI but is closely associated with adverse clinical outcomes. GPI use was associated with higher rates of tamponade.