Clinical characteristics and factors associated with acute kidney injury among patients hospitalized with coronavirus disease: an observational retrospective study

ABSTRACT BACKGROUND: Coronavirus disease 19 (COVID-19) is a multisystemic disease with high incidence of acute kidney injury (AKI). OBJECTIVE: To describe the clinical characteristics and factors associated with AKI among patients hospitalized with COVID-19. DESIGN AND SETTING: Retrospective cohort conducted at Hospital Civil de Culiacan, Mexico. METHODS: We included 307 patients hospitalized due to COVID-19. AKI was defined and staged based on serum creatinine levels in accordance with the criteria of the Acute Kidney Injury Network (AKIN). Multivariate logistic regression analysis was used to determine factors associated with AKI. RESULTS: The patients' age was 56 ± 15 years (64.5% male). The incidence of AKI was 33.6% (n = 103). Overall, 53.4% of patients had community-acquired AKI, and 46.6% had hospital-acquired AKI. Additionally, 15.5% of them presented AKIN stage 1; 34% had AKIN stage 2; and 50.5% had AKIN stage 3. Hemodialysis was required for 10.7% of the patients. The factors associated with AKI were chronic kidney disease (odds ratio, OR: 10.8; P = 0.04), use of norepinephrine (OR: 7.3; P = 0.002), diabetes mellitus (OR: 2.9; P = 0.03), C-reactive protein level (OR: 1.005; P = 0.01) and COVID-19 severity index based on chest tomography (OR: 1.09; statistical trend, P = 0.07). Hospital stay (11 ± 7 days; P < 0.001) and mortality (83.5 versus 31.4%; P < 0.05) were greater among patients with AKI. CONCLUSION: AKI was a frequent and serious complication in our cohort of patients hospitalized with COVID-19, which was associated with high mortality and long hospital stay.

Clinical characteristics and factors associated with acute kidney injury among patients hospitalized with coronavirus disease: an observational retrospective study.

BACKGROUND: Coronavirus disease 19 (COVID-19) is a multisystemic disease with high incidence of acute kidney injury (AKI). OBJECTIVE: To describe the clinical characteristics and factors associated with AKI among patients hospitalized with COVID-19. DESIGN AND SETTING: Retrospective cohort conducted at Hospital Civil de Culiacan, Mexico. METHODS: We included 307 patients hospitalized due to COVID-19. AKI was defined and staged based on serum creatinine levels in accordance with the criteria of the Acute Kidney Injury Network (AKIN). Multivariate logistic regression analysis was used to determine factors associated with AKI. RESULTS: The patients' age was 56 ± 15 years (64.5% male). The incidence of AKI was 33.6% (n = 103). Overall, 53.4% of patients had community-acquired AKI, and 46.6% had hospital-acquired AKI. Additionally, 15.5% of them presented AKIN stage 1; 34% had AKIN stage 2; and 50.5% had AKIN stage 3. Hemodialysis was required for 10.7% of the patients. The factors associated with AKI were chronic kidney disease (odds ratio, OR: 10.8; P = 0.04), use of norepinephrine (OR: 7.3; P = 0.002), diabetes mellitus (OR: 2.9; P = 0.03), C-reactive protein level (OR: 1.005; P = 0.01) and COVID-19 severity index based on chest tomography (OR: 1.09; statistical trend, P = 0.07). Hospital stay (11 ± 7 days; P < 0.001) and mortality (83.5 versus 31.4%; P < 0.05) were greater among patients with AKI. CONCLUSION: AKI was a frequent and serious complication in our cohort of patients hospitalized with COVID-19, which was associated with high mortality and long hospital stay.

Phase III Trial of Adjuvant Capecitabine After Standard Neo-/Adjuvant Chemotherapy in Patients With Early Triple-Negative Breast Cancer (GEICAM/2003-11_CIBOMA/2004-01).

PURPOSE: Operable triple-negative breast cancers (TNBCs) have a higher risk of relapse than non-TNBCs with standard therapy. The GEICAM/2003-11_CIBOMA/2004-01 trial explored extended adjuvant capecitabine after completion of standard chemotherapy in patients with early TNBC. PATIENTS AND METHODS: Eligible patients were those with operable, node-positive-or node negative with tumor 1 cm or greater-TNBC, with prior anthracycline- and/or taxane-containing chemotherapy. After central confirmation of TNBC status by immunohistochemistry, patients were randomly assigned to either capecitabine or observation. Stratification factors included institution, prior taxane-based therapy, involved axillary lymph nodes, and centrally determined phenotype (basal v nonbasal, according to cytokeratins 5/6 and/or epidermal growth factor receptor positivity by immunohistochemistry). The primary objective was to compare disease-free survival (DFS) between both arms. RESULTS: Eight hundred seventy-six patients were randomly assigned to capecitabine (n = 448) or observation (n = 428). Median age was 49 years, 55.9% were lymph node negative, 73.9% had a basal phenotype, and 67.5% received previous anthracyclines plus taxanes. Median length of follow-up was 7.3 years. DFS was not significantly prolonged with capecitabine versus observation [hazard ratio (HR), 0.82; 95% CI, 0.63 to 1.06; P = .136]. In a preplanned subgroup analysis, nonbasal patients seemed to derive benefit from the addition of capecitabine with a DFS HR of 0.53 versus 0.94 in those with basal phenotype (interaction test P = .0694) and an HR for overall survival of 0.42 versus 1.23 in basal phenotype (interaction test P = .0052). Tolerance of capecitabine was as expected, with 75.2% of patients completing the planned 8 cycles. CONCLUSION: This study failed to show a statistically significant increase in DFS by adding extended capecitabine to standard chemotherapy in patients with early TNBC. In a preplanned subset analysis, patients with nonbasal phenotype seemed to obtain benefit with capecitabine, although this will require additional validation.

Efficacy of the Antibody-Drug Conjugate W0101 in Preclinical Models of IGF-1 Receptor Overexpressing Solid Tumors.

The insulin-like growth factor type 1 receptor (IGF-1R) is important in tumorigenesis, and its overexpression occurs in numerous tumor tissues. To date, therapeutic approaches based on mAbs and tyrosine kinase inhibitors targeting IGF-1R have only shown clinical benefit in specific patient populations. We report a unique IGF-1R-targeted antibody-drug conjugate (ADC), W0101, designed to deliver a highly potent cytotoxic auristatin derivative selectively to IGF-1R overexpressing tumor cells. The mAb (hz208F2-4) used to prepare the ADC was selected for its specific binding properties to IGF-1R compared with the insulin receptor, and for its internalization properties. Conjugation of a novel auristatin derivative drug linker to hz208F2-4 did not alter its binding and internalization properties. W0101 induced receptor-dependent cell cytotoxicity in vitro when applied to various cell lines overexpressing IGF-1R, but it did not affect normal cells. Efficacy studies were conducted in several mouse models expressing different levels of IGF-1R to determine the sensitivity of the tumors to W0101. W0101 induced potent tumor regression in certain mouse models. Interestingly, the potency of W0101 correlated with the expression level of IGF-1R evaluated by IHC. In an MCF-7 breast cancer model with high-level IGF-1R expression, a single injection of W0101 3 mg/kg led to strong inhibition of tumor growth. W0101 provides a potential new therapeutic option for patients overexpressing IGF-1R. A first-in-human trial of W0101 is currently ongoing to address clinical safety.

Phase Field Modelling of Abnormal Grain Growth.

Heterogeneous grain structures may develop due to abnormal grain growth during processing of polycrystalline materials ranging from metals and alloys to ceramics. The phenomenon must be controlled in practical applications where typically homogeneous grain structures are desired. Recent advances in experimental and computational techniques have, thus, stimulated the need to revisit the underlying growth mechanisms. Here, phase field modelling is used to systematically evaluate conditions for initiation of abnormal grain growth. Grain boundaries are classified into two classes, i.e., high- and low-mobility boundaries. Three different approaches are considered for having high- and low-mobility boundaries: (i) critical threshold angle of grain boundary disorientation above which boundaries are highly mobile, (ii) two grain types A and B with the A-B boundaries being highly mobile, and (iii) three grain types, A, B and C with the A-B boundaries being fast. For these different scenarios, 2D simulations have been performed to quantify the effect of variations in the mobility ratio, threshold angle and fractions of grain types, respectively, on the potential onset of abnormal grain growth and the degree of heterogeneity in the resulting grain structures. The required mobility ratios to observe abnormal grain growth are quantified as a function of the fraction of high-mobility boundaries. The scenario with three grain types (A, B, C) has been identified as one that promotes strongly irregular abnormal grains including island grains, as observed experimentally.

Disentangling and Lamellar Thickening of Linear Polymers during Crystallization: Simulation of Bimodal and Unimodal Molecular Weight Distribution Systems.

We have performed coarse-grained molecular dynamics simulations to study the isothermal crystallization of bimodal and unimodal molecular weight distribution (MWD) polymers with equivalent average molecular weight (Mw). By using primitive path analysis, we can monitor the entanglement evolution during the process of crystallization. We have discovered a quantitative correlation between the degree of disentanglement and crystallinity, indicating that chain disentanglement permits the process of crystallization. In addition, the crystalline stem length also displays a linear relation with the degree of disentanglement at different temperatures. Based on the observation in our simulations, we can build a scenario of the whole process of chain disentangling and lamellar thickening on the basis of chain sliding diffusion. Furthermore, we have enough evidence to infer that the temperature dependence of crystalline stem length is basically a result of temperature dependence of chain sliding diffusion. Our observations are also in agreement with Hikosaka's sliding diffusion theory. Compared to the unimodal system, the disentanglement degree of the bimodal system is more delayed than its crystallinity due to the slower chain sliding of the long-chain component; the bimodal system reaches a larger crystalline stem length at all temperatures due to the promotion of higher chain sliding mobility of the short-chain component.

Role of the Intercrystalline Tie Chains Network in the Mechanical Response of Semicrystalline Polymers.

We examine the microscopic origin of the tensile response in semicrystalline polymers by performing large-scale molecular dynamics simulations of various chain lengths. We investigate the microscopic rearrangements of the polymers during tensile deformation and show that the intercrystalline chain connections known as tie chains contribute significantly to the elastic and plastic response. These results suggest that the mechanical behavior of semicrystalline polymers is controlled by two interpenetrated networks of entanglements and tie chains.

Abordaje operatorio de la bursopatía olecraneana asociada a espolón por tracción / Surgical intervention on olecranon bursopathy associated to heel spur by traction

Fundamento: la bursopatía olecraneana asociada a espolón por tracción, de etiología traumática mínima, roce continuado, actividades o recreaciones asociadas a vigorosa extensión del codo, ha tenido poca información investigativa. Objetivo: describir los resultados operatorios en esta afección, donde el tratamiento conservador no fue satisfactorio, en pacientes atendidos en el Hospital General Docente Dr. Ernesto Guevara de la Serna de Las Tunas, de diciembre de 2010 a julio de 2016. Métodos: se realizó un estudio observacional en pacientes con diagnóstico de bursitis olecraneana en sus diferentes variedades, atendidos en la institución y tiempo ya declarados. El universo estuvo conformado por la totalidad de los casos con dolor y deformidad en región posterior del codo y la muestra por 28 pacientes seleccionados al azar. El tratamiento quirúrgico estuvo condicionado a la clasificación de la lesión en grados, según características macroscópicas de la bursa, adherencias, tabiques, hipertrofia esclerótica, recidivas o fractura del espolón. Resultados: el promedio de edad fue de 33,6 años; más frecuente en el sexo masculino en relación de 8:1. Los procederes operatorios empleados fueron la resección de la bursa, resección del espolón y resección del espolón con hueso olecraneano indemne, la complicación encontrada fue el retardo de la cicatrización. Los resultados clasifican de excelentes, según Mayo Elbow Performance Index y Escala Visual Analógica, en 98 y 97 por ciento, respectivamente. Conclusiones: los resultados operatorios en pacientes con bursopatía olecraneana asociada a espolón por tracción fueron satisfactorios(AU)

Background: Olecranon bursopathy associated to heel spur by traction with a minimal traumatic etiology, continued friction and activities or leisure pursuits associated to a vigorous spreading of the elbow, has had slender research information. Objective: to describe the operating results for this condition, where the conservative treatment was not satisfactory, on patients attended to at the Dr. Ernesto Guevara de la Serna General Teaching Hospital of Las Tunas, from December 2010 to July 2016. Methods: an observational study was carried out with patients diagnosed with olecranon bursitis in its different types, attended to at the institution and during the period herein mentioned. The universe was made up of the whole of the cases with pain and deformity in the posterior region of the elbow and the sample consisted of 28 patients chosen at random. The surgical treatment was conditioned to the classification of the lesion in degrees, according to the macroscopic characteristics of the bursa, the adherences, septa, sclerotic hypertrophy, relapses or heel spur fractures. Results: the age average was 33,6 years; it was more frequent in the male sex with an 8:1 relation. The surgical procedures used were bursal resection, heel spur resection and unharmed-olecranon-bone heel spur resection. Cicatrization delay was the main complication. The results were excellent according Mayo Elbow Performance Index and Analogical Visual Scale on 98 percent and 97 percent respectively. Conclusions: the operating results on patients with olecranon bursitis associated to heel spur by traction were satisfactory(AU)

Crystallization of finite-extensible nonlinear elastic Lennard-Jones coarse-grained polymers.

The ability of a simple coarse-grained finite-extensible nonlinear elastic (FENE) Lennard-Jones (LJ) polymer model to be crystallized is investigated by molecular dynamics simulations. The optimal FENE Lennard-Jones parameter combinations (ratio between FENE and LJ equilibrium distances) and the optimal lattice parameters are calculated for five different perfect crystallite structures: simple tetragonal, body-centered tetragonal, body-centered orthorhombic, hexagonal primitive, and hexagonal close packed. It was found that the most energetically favorable structure is the body-centered orthorhombic. Starting with an equilibrated polymer liquid and with the optimal parameters found for the body-centered orthorhombic, an isothermal treatment led to the formation of large lamellar crystallites with a typical chain topology: folded, loop, and tie chains, and with a crystallinity of about 60%-70%, similar to real semicrystalline polymers. This simple coarse-grained Lennard-Jones model provides a qualitative tool to study semicrystalline microstructures for polymers.

Resultados del tratamiento a pacientes con tríada terrible del codo / Results of treatment of patients suffering from terrible triad of the elbow

La luxación del codo, asociada a la fractura del proceso coronoideo y a la fractura de la cabeza radial, es denominada tríada terrible del codo, debido a la complejidad al abordar el tratamiento correcto y lo desalentador de los resultados que se obtienen con el mismo. Se realizó un estudio prospectivo, donde se recogen los resultados postoperatorios, obtenidos en cuatro pacientes con inestabilidad traumática aguda del codo, tratados entre enero de 2012 y mayo de 2013, que acudieron inicialmente al cuerpo de guardia del Hospital General Docente Dr. Ernesto Guevara de La Serna y tuvieron un seguimiento medio de ocho meses. El proceder consistió en reparación de la coronoides, del ligamento lateral externo, reparación de la cúpula radial, cupulectomía y colocación de pin endomedular; la técnica operatoria a emplear se definió por los estudios radiográficos realizados y los hallazgos en el transcurso del proceder. Los pacientes, tres hombres y una mujer, tuvieron cinco codos lesionados y un promedio de edad de 34 años. Como resultado del tratamiento la flexión fue normal entre 130-135° en 4 codos y limitada en uno a 110°, la extensión se encontró limitada de 8 a 21° en todos los pacientes, la pronosupinación se mantuvo limitada en todos los casos entre 5 y 22°. La intervención quirúrgica mediante fijación y reparación de los estabilizadores del codo proporcionó a corto plazo una funcionabilidad del codo cercana a la normalidad, los pacientes evolucionaron positivamente. Las complicaciones fueron: reluxación, infección local y aflojamiento de la osteosíntesis (AU)

The dislocation of the elbow, associated to the coronoid process fracture and radial head fracture is known as terrible triad of the elbow because of the complexity of the correct treatment application and its discouraging results. A prospective study was carried out to collect the postoperative results obtained from four patients with acute traumatic instability of the elbow, who initially came to the emergency department of Dr. Ernesto Guevara de la Serna Teaching General Hospital, were treated there from January, 2012 to May, 2013, and had an average follow-up of eight months. The procedure consisted of repairing the coronoid, the external lateral ligament and the radial cupula, cupulectomy and placing the endo-medullar pin. The surgical technique was determined by the radiographic studies and findings during the procedure. The patients were three men and a woman who had five injured elbows and an average age of 34 years old. As a result of the treatment, flexion was normal between 130º - 135º in 4 elbows and limited in one at 110º; extension was limited at 8° to 21° in all the patients, and prone supination was limited between 5° y 22° in all them, too. The surgical interventions by means of fixation and repair of the stabilizers of the elbow provided the elbow with an almost normal functionality; the patients evolved positively. Complications were: re-dislocation, surgical wound infection, and loosening of the osteosynthesis (AU)

A sensitive multidimensional method for the detection, characterization, and quantification of trace free drug species in antibody-drug conjugate samples using mass spectral detection.

Conjugation processes and stability studies associated with the production and shelf life of antibody-drug conjugates (ADCs) can result in free (non-conjugated) drug species. These free drug species can increase the risk to patients and reduce the efficacy of the ADC. Despite stringent purification steps, trace levels of free drug species may be present in formulated ADCs, reducing the therapeutic window. The reduction of sample preparation steps through the incorporation of multidimensional techniques has afforded analysts more efficient methods to assess trace drug species. Multidimensional methods coupling size-exclusion and reversed phase liquid chromatography with ultra-violet detection (SEC-RPLC/UV) have been reported, but offer limited sensitivity and can limit method optimization. The current study addresses these challenges with a multidimensional method that is specific, sensitive, and enables method control in both dimensions via coupling of an on-line solid phase extraction column to RPLC with mass spectral detection (SPE-RPLC/MS). The proposed method was evaluated using an antibody-fluorophore conjugate (AFC) as an ADC surrogate to brentuximab vedotin and its associated parent maleimide-val-cit-DSEA payload and the derived N-acetylcysteine adduct formed during the conjugation process. Assay sensitivity was found to be 2 orders more sensitive using MS detection in comparison to UV-based detection with a nominal limit of quantitation of 0.30 ng/mL (1.5 pg on-column). Free-drug species were present in an unadulterated ADC surrogate sample at concentrations below 7 ng/mL, levels not detectable by UV alone. The proposed SPE-RPLC/MS method provides a high degree of specificity and sensitivity in the assessment of trace free drug species and offers improved control over each dimension, enabling straightforward integration into existing or novel workflows.

Correlation of structure and mechanical response in solid-like polymers.

Employing large scale molecular dynamics simulations, we measure the uniaxial tensile response of amorphous and semicrystalline states of a coarse-grained PVA bead-spring model. The response beyond the elastic limit encompasses strain-softening and strain-hardening regimes. To understand the underlying mechanisms of plastic deformation, we analyse conformational and structural changes of polymers. In particular, we characterise the volume distribution of crystalline domains along the stress-strain curve. The strain-softening regime in semicrystalline samples is dominated by deformation of crystalline parts, while strain-hardening involves unfolding and alignment of chains in both amorphous and crystalline parts. Comparing the tensile response of semicrystalline and amorphous polymers, we find similar conformations of polymers for both systems in the strain-hardening regime.

Plastic Deformation Mechanisms of Semicrystalline and Amorphous Polymers.

We use large-scale molecular dynamics simulations to investigate plastic deformation of semicrystalline polymers with randomly nucleated crystallites. The strain-softening regime is dominated by deformation of crystallites via reorientation of chain-folded lamellae toward the tensile axis, fragmentation of largest crystalline domains, and a partial loss of crystallinity. The strain-hardening regime coincides with unfolding of chains and recrystallization as a result of strain-induced chain alignment. These observed deformation mechanisms are consistent with experimental findings. We compare the tensile behavior of semicrystalline polymers with their amorphous counterparts at temperatures above and below the glass transition temperature.

A novel method for calculating the energy barriers for carbon diffusion in ferrite under heterogeneous stress.

A novel method for accurate and efficient evaluation of the change in energy barriers for carbon diffusion in ferrite under heterogeneous stress is introduced. This method, called Linear Combination of Stress States, is based on the knowledge of the effects of simple stresses (uniaxial or shear) on these diffusion barriers. Then, it is assumed that the change in energy barriers under a complex stress can be expressed as a linear combination of these already known simple stress effects. The modifications of energy barriers by either uniaxial traction/compression and shear stress are determined by means of atomistic simulations with the Climbing Image-Nudge Elastic Band method and are stored as a set of functions. The results of this method are compared to the predictions of anisotropic elasticity theory. It is shown that, linear anisotropic elasticity fails to predict the correct energy barrier variation with stress (especially with shear stress) whereas the proposed method provides correct energy barrier variation for stresses up to ∼3 GPa. This study provides a basis for the development of multiscale models of diffusion under non-uniform stress.

Antibody-drug conjugate model fast characterization by LC-MS following IdeS proteolytic digestion.

Here we report the design and production of an antibody-fluorophore conjugate (AFC) as a non-toxic model of an antibody-drug conjugate (ADC). This AFC is based on the conjugation of dansyl sulfonamide ethyl amine (DSEA )-linker maleimide on interchain cysteines of trastuzumab used as a reference antibody. The resulting AFC was first characterized by routine analytical methods (SEC, SDS-PAGE, CE-SDS, HIC and native MS), resulting in similar chromatograms,electropherograms and mass spectra to those reported for hinge Cys-linked ADCs. IdeS digestion of the AFC was then performed, followed by reduction and analysis by liquid chromatography coupled to mass spectrometry analysis. Dye loading and distribution on light chain and Fd fragments were calculated, as well as the average dye to antibody ratio (DAR) for both monomeric and multimeric species. In addition, by analyzing the Fc fragment in the same run, full glycoprofiling and demonstration of the absence of additional conjugation was easily achieved. As for naked antibodies and Fc-fusion proteins, IdeS proteolytic digestion may rapidly become a reference analytical method at all stages of ADC discovery, preclinical and clinical development. The method can be routinely used for comparability assays, formulation, process scale-up and transfer, and to define critical quality attributes in a quality-by-design approach.

Caracterización de las cirugías palpebrales con láser de CO2 / Characterization of the eyelid surgery with CO2 laser

Objetivo: Determinar la caracterización de las cirugías palpebrales con láser de CO2. Métodos: Estudio observacional, descriptivo, longitudinal prospectivo, cuya muestra estuvo constituida por 93 pacientes (136 ojos) operados con láser de dióxido de carbono en el Servicio de Oculoplastia del Instituto Cubano de Oftalmología "Ramón Pando Ferrer" desde enero a octubre de 2009. Resultados: Según el sexo, 40 eran femeninos y 53 masculinos. Por edad, de 20 a 39 años, 9,7 %; de 40 a 59, 15 %; de 60 a 79, 48,4 %; y más de 80 años, 23,7 %. La piel tipo I se presentó en el 53,8 % de los pacientes, el tipo II en 33,3 %. El láser se utilizó como instrumento de corte y coagulación en la dermatochalasis (31,6 %) y en el ectropión (20,6 %). Como escáner en 11 queratosis seborreicas. El 94,6 % no mostró complicaciones, solo 5 pacientes. Conclusiones: Este equipo se utilizó en múltiples afecciones anexiales. La técnica quirúrgica transcutánea predominó en más de la mitad de los pacientes con dermatochalasis y la fijación cantal externa en las anomalías de posición. Las complicaciones fueron mínimas y la retracción cicatrizal fue la más frecuente.

Objective: To determine the behavior of eyelid surgery with CO2 laser. Methods: A prospective, longitudinal, observational and descriptive study whose sample consisted of 136 eyes from 93 patients, who underwent carbon dioxide laser surgery at the oculoplasty service of "Ramón Pando Ferrer" Cuban Institute of Ophthalmology from January to October, 2009. Results: Of the total number of patients, 40 were females and 53 males; 9.7% aged 20 to 39 years, 15% aged 40 to 59 years; 48.4 % were 60 to 79 years and 23.7% over 80 years. Skin type I was present in 50 patients (53,8 %), and type II in 33,3 % of cases. C02 laser was used for cutting and coagulation in dermatochalasis, accounting for 31.6% and in ectropion for 20,6 %. As a scanner it was used in 11 seborrheic keratoses. No complications were observed in 94.6% of cases; just 5 patients did for 5.4% of the total. Conclusion: The highest number of patients was older than 60 years males with skin type I. This equipment was used to treat multiple adnexal conditions, being dermatochalasis the most common followed by eyelid malpositions. The surgical transcutaneous technique dominated in more than half of patients with dermatochalasis and the external canthal fixation in positional abnormalities. This equipment was mostly used as cutting and coagulation tool. Complications were minimal and the most frequent one was scar retraction.

Nanoscale buckling deformation in layered copolymer materials.

In layered materials, a common mode of deformation involves buckling of the layers under tensile deformation in the direction perpendicular to the layers. The instability mechanism, which operates in elastic materials from geological to nanometer scales, involves the elastic contrast between different layers. In a regular stacking of "hard" and "soft" layers, the tensile stress is first accommodated by a large deformation of the soft layers. The inhibited Poisson contraction results in a compressive stress in the direction transverse to the tensile deformation axis. The hard layers sustain this transverse compression until buckling takes place and results in an undulated structure. Using molecular simulations, we demonstrate this scenario for a material made of triblock copolymers. The buckling deformation is observed to take place at the nanoscale, at a wavelength that depends on strain rate. In contrast to what is commonly assumed, the wavelength of the undulation is not determined by defects in the microstructure. Rather, it results from kinetic effects, with a competition between the rate of strain and the growth rate of the instability.

Protease-activated receptor-1 antagonist F 16618 reduces arterial restenosis by down-regulation of tumor necrosis factor α and matrix metalloproteinase 7 expression, migration, and proliferation of vascular smooth muscle cells.

Wound healing after angioplasty or stenting is associated with increased production of thrombin and the activation of protease-activated receptor 1 (PAR1). The aim of the present study was to examine the effects of a new selective PAR1 antagonist, 2-[5-oxo-5-(4-pyridin-2-ylpiperazin-1-yl)-penta-1,3-dienyl]-benzonitrile (F 16618), in restenosis and vascular smooth muscle cell (SMC) proliferation and migration using both in vivo and in vitro approaches. Daily oral administration of F 16618 inhibited the restenosis induced by balloon angioplasty on rat carotid artery in a dose-dependent manner. Furthermore, single intravenous administration of F 16618 during the angioplasty procedure was sufficient to protect the carotid artery against restenosis. In vitro, F 16618 inhibited the growth of human aortic SMCs in a concentration-dependent manner with maximal effects at 10 µM. At that concentration, F 16618 also prevented thrombin-mediated SMC migration. In vivo, oral and intravenous F 16618 treatments reduced by 30 and 50% the expression of the inflammatory cytokine tumor necrosis factor α (TNFα) 24 h after angioplasty. However, only acute intravenous administration prevented the induction of matrix metalloproteinase 7 expression. In contrast, F 16618 treatments had no effect on early SMC de-differentiation and transcription of monocyte chemoattractant protein-1 and interleukin-6 and late re-endothelialization of injured arteries. Furthermore, F 16618 compensated for the carotid endothelium loss by inhibiting PAR1-mediated contraction. Altogether, these data demonstrate that PAR1 antagonists such as F 16618 are a highly effective treatment of restenosis after vascular injury, by inhibition of TNFα, matrix metalloproteinase 7, and SMC migration and proliferation in addition to an antithrombotic effect.

Antithrombotic activity of F 16618, a new PAR1 antagonist evaluated in extracorporeal arterio-venous shunt in the rat.

The purpose of the present work was the evaluation of the antithrombotic activity of a new PAR1 antagonist, F 16618 in arterio-venous shunt in the rat. Arterial thrombosis was induced by insertion of a silk thread (thrombogenic substrate) into an extracorporeal shunt. F 16618 was administered either by intravenous route (0.63-2.5mg/kg) or by oral route (20-80mg/kg). Oral activity of F 16618 was compared to that of aspirin (20-80mg/kg) and clopidogrel (0.63-10mg/kg). Finally, F 16618 was associated to aspirin and/or clopidogrel to test for possible antithrombotic activity and its effects on bleeding time. SFLLR-induced human platelet aggregation was evaluated in the presence of F 16618, demonstrating the anti-aggregant activity of this compound. F 16618 (1.25mg/kg) significantly delayed the time leading to occlusion by 52+/-17%, without affecting bleeding time and in absence of hemodynamic effects. F 16618 given orally dose-dependently increased the time to occlusion. The maximal effect was observed at 40mg/kg (984+/-95s versus 644+/-17s in vehicle group). Aspirin and clopidogrel also dose-dependently lengthened time to occlusion, but this effect was associated with an increase of bleeding time. F 16618 (20mg/kg) orally associated with either aspirin (40mg/kg) or with clopidogrel (1.25mg/kg) potentiated the antithrombotic effects of both compounds without further increasing of bleeding time. In conclusion, F 16618 exerted a potent antithrombotic activity by intravenous and oral routes, without affecting bleeding time. Furthermore, the antithrombotic activity was potentiated when combined with aspirin or clopidogrel.

Exploration of a new series of PAR1 antagonists.

Two series of new PAR1 antagonists have been identified. The first incorporates a cinnamoylpiperidine motif and the second a cinnamoylpyridine pattern. The synthesis, biological activity and structure-activity relationship of these compounds are presented. In each series, one analog showed potent in vivo antithrombotic activity in a rat AV shunt model, with up to 53% inhibition at 1.25mpk iv for compound 30.