Untargeted-based metabolomics analysis and in vitro/in silico antiviral activity of extracts from Phyllanthus brasiliensis (Aubl.) Poir.

INTRODUCTION: This study describes the molecular profile and the potential antiviral activity of extracts from Phyllanthus brasiliensis, a plant widely found in the Brazilian Amazon. The research aims to shed light on the potential use of this species as a natural antiviral agent. METHODS: The extracts were analysed using liquid chromatography-mass spectrometry (LC-MS) system, a potent analytical technique to discover drug candidates. In the meantime, in vitro antiviral assays were performed against Mayaro, Oropouche, Chikungunya, and Zika viruses. In addition, the antiviral activity of annotated compounds was predicted by in silico methods. RESULTS: Overall, 44 compounds were annotated in this study. The results revealed that P. brasiliensis has a high content of fatty acids, flavones, flavan-3-ols, and lignans. Furthermore, in vitro assays revealed potent antiviral activity against different arboviruses, especially lignan-rich extracts against Zika virus (ZIKV), as follows: methanolic extract from bark (MEB) [effective concentration for 50% of the cells (EC50 ) = 0.80 µg/mL, selectivity index (SI) = 377.59], methanolic extract from the leaf (MEL) (EC50 = 0.84 µg/mL, SI = 297.62), and hydroalcoholic extract from the leaf (HEL) (EC50 = 1.36 µg/mL, SI = 735.29). These results were supported by interesting in silico prediction, where tuberculatin (a lignan) showed a high antiviral activity score. CONCLUSIONS: Phyllanthus brasiliensis extracts contain metabolites that could be a new kick-off point for the discovery of candidates for antiviral drug development, with lignans becoming a promising trend for further virology research.

Putative Identification of New Phragmaline-Type Limonoids from the Leaves of Swietenia macrophylla King: A Case Study Using Mass Spectrometry-Based Molecular Networking.

Swietenia macrophylla King is a plant commonly known as Brazilian mahogany. The wood from its stem is highly prized for its exceptional quality, while its leaves are valued for their high content of phragmalin-type limonoids, a subclass of compounds known for their significant biological activities, including antimalarial, antitumor, antiviral, and anti-inflammatory properties. In this context, twelve isolated limonoids from S. macrophylla leaves were employed as standards in mass spectrometry-based molecular networking to unveil new potential mass spectrometry signatures for phragmalin-type limonoids. Consequently, ultra-performance liquid chromatography coupled with high-resolution mass spectrometry was utilized for data acquisition. Subsequently, the obtained data were analyzed using the Global Natural Products Social Molecular Networking platform based on spectral similarity. In summary, this study identified 24 new putative phragmalin-type limonoids for the first time in S. macrophylla. These compounds may prove valuable in guiding future drug development efforts, leveraging the already established biological activities associated with limonoids.

Echocardiographic characteristics of successful deployment of the Das AngelWings atrial septal defect closure device: initial multicenter experience in the United States.

The AngelWings device is a newer transcatheter device used for closure of secundum atrial septal defects (ASD) and patent foramen ovale (PFO), which consists of a self-centering, 2-disk system. Transesophageal echocardiography (TEE) plays a pivotal role in the deployment of the 2 disks of this device, on the appropriate sides of the atrial septum. The objective of this study is to describe the echocardiographic findings associated with successful deployment of the AngelWings device for closure of ASD and PFO. We evaluated the TEE studies of 70 patients enrolled in 4 United States centers, for closure of ASD and PFO with the AngelWings device. The TEE characteristics of successful and unsuccessful deployments were analyzed. Residual shunts across the atrial septum were assessed by TEE at the end of the procedure, 24 hours later by transthoracic echocardiography, and at 6 months by TEE. The deployment of the device was successful in 65 patients (93%). In the unsuccessful group, ASD size by TEE was larger (13.4 +/- 3.1 vs 8.9 +/- 4.7 mm, p <0.05). TEE was successful in identifying snagging of the device by intracardiac structures and prolapse of corners of the left or right atrial disk through the ASD, features that were difficult to identify by fluoroscopy. The echocardiographic characteristics outlined here are important guidelines for successful deployment of the AngelWings device.

Use of plasma glow for surface-engineering biomolecules to enhance bloodcompatibility of Dacron and PTFE vascular prosthesis.

The search for a nonthrombogenic material having patency to be used for small diameter vascular graft applications continues to be a field of extensive investigation. The purpose of the present study was to examine whether surface modification of polytetra fluoroethylene (PTFE, Teflon) and polyethylene-terephthalate (Dacron) vascular grafts might extend graft biocompatibility without modifying the graft structure. A series of surface coatings were prepared by modifying the argon plasma-treated PTFE and Dacron grafts with collagen IV and laminin and subsequently immobilizing bioactive molecules like PGE1, heparin or phosphatidyl choline via the carbodiimide functionalities. Surface analysis by Fourier transform infrared spectroscopy-attenuated total reflectance revealed the presence of new functional groups on the modified graft surfaces. In vitro studies showed that fibrinogen adsorption and platelet adhesion on modified grafts were significantly reduced. This study proposes that surface grafting of matrix components (collagen-type IV and laminin) and subsequent immobilization of bioactive molecules (PGE1, heparin or phosphatidyl choline) changed the surface conditioning of vascular grafts and subsequently improved their biocompatibility. However, more detailed in vivo studies are needed to confirm these observations.

Transcatheter closure of patent foramen ovale for hypoxemia during left ventricular assist device support.

A patent foramen ovale with right-to-left shunting was responsible, in part, for profound hypoxemia in a patient who required mechanical support with a left ventricular assist device for cardiogenic shock. The patent foramen ovale was detected with contrast transesophageal echocardiography, and the defect was closed successfully with a transcatheter septal defect closure device.

Physiologic assessment of the coronary collateral circulation in transplanted human hearts.

Coronary arteries of transplanted hearts frequently develop a vasculopathy characterized by severe lumenal narrowing in the distal coronary arteries. It has been thought, on the basis of angiographic studies, that the coronary circulation of transplanted hearts with vasculopathy fails to develop collateral vessels normally. To determine the extent of the collateral circulation in transplanted hearts with a significant coronary stenosis, we measured an index of the collateral circulation, the coronary artery occlusion pressure, during single-vessel coronary angioplasty in seven patients with allograft vasculopathy and 18 patients with atherosclerotic disease who did not undergo transplantation. Aortic and coronary artery pressure distal to the stenosis in the epicardial artery were measured during balloon occlusion (> or = 45 seconds). Measurement variability for determination of coronary occlusion pressure was assessed by measuring occlusion pressure on two separate balloon inflations (n = 17). The severity of the dilated stenotic lesion was assessed with quantitative angiography (Reiber-PIE Data method). The indexes of stenosis severity were similar in coronary arteries of transplanted and native hearts. Coronary occlusion pressure measurements were highly reproducible (mean absolute difference between measurements, 1 +/- 1 mm Hg, r = 0.98). Coronary occlusion pressure in transplanted hearts (32 +/- 4 mm Hg) was nearly identical to that measured in coronary arteries of native hearts (29 +/- 2 mm Hg). When vessels with total occlusion were excluded and corrections were made for minor differences in hemodynamics (heart rate and blood pressure) were made, the coronary occlusion pressure in transplanted hearts remained nearly identical to native hearts.(ABSTRACT TRUNCATED AT 250 WORDS)

Cross-sectional and Doppler echocardiographic diagnosis of anomalous origin of the left coronary artery from the pulmonary artery and right coronary artery from posterior aortic sinus.

A six-year-old asymptomatic child on evaluation for a cardiac murmur, was found on cross-sectional and Doppler echocardiography to have an anomalous origin of the left coronary artery from the pulmonary artery and right coronary artery from posterior sinus of aorta. Doppler studies revealed a continuous signal in the pulmonary artery, indicating a left to right flow. The diagnosis was subsequently confirmed at cardiac catheterization and surgery.

Surface-immobilized biomolecules on albumin modified porcine pericardium for preventing thrombosis and calcification.

The search for a noncalcifying tissue material to be used for valve replacement application continues to be a field of extensive investigation. A series of porcine pericardial membranes was prepared by modifying the glutaraldehyde--treated tissues with albumin and subsequently immobilizing bioactive molecules like PGE1, PGI2 or heparin via the carbodiimide functionalities. The in vitro calcification and collagenase degradation of these modified tissues were studied as a function of exposure time. Furthermore, the biocompatibility aspects of such novel interfaces were established by platelet adhesion and fibrinogen adsorption. The results reported in this article propose that the treatment with antiplatelet agents such as albumin, heparin and prostaglandins (PGE1 or PGI2) change the surface conditioning of pericardial tissues, suggesting a possible role of deposited serum components in affecting mineralization process on bioprosthesis. Therefore, it is worthy to hypothesize that besides inhibiting the accumulation of calcium in the devitalized cells, the early formation of a conditioning layer on the bioprosthesis surface may affect salt precipitations, determining the propensity of the implant to calcify. More detailed studies are needed to understand the involvement of plasma proteins and cellular components of the recipient blood in tissue-associated calcification.

Colchicine encapsulation within poly(ethylene glycol)-coated poly(lactic acid)/poly(epsilon-caprolactone) microspheres-controlled release studies.

Smooth muscle cell proliferation plays a major role in the genesis of restenosis after angioplasty or vascular injury. Local delivery of agents capable of modulating vascular responses have the potential to prevent restenosis. However, the development of injectable microspheres for maintaining high tissue levels of drugs at the site of vascular injury is a major challenge. We demonstrated the possibility of entrapping an antiproliferative agent, colchicine, in polyethylene glycol (PEG)-coated biodegradable microspheres composed of poly(lactic acid)/poly(epsilon-caprolactone) blends, with a mean diameter of 3-6 microm. A solution of colchicine and blends of polylactic acid (PLA)/polycaprolactone (PCL) dissolved in acetone-dichloromethane mixture was poured into an aqueous solution of PEG (or polyvinyl alcohol) with stirring by a high-speed homogenizer to form microspheres. Colchicine recovery in microspheres ranged from 30-50% depending on the emulsification system and the ratio of polymer blends used for the preparations. Scanning electron microscopy revealed that the PLA/PCL microspheres were spherical in shape and had a smooth surface texture. Results of in vitro release studies showed that it is possible to control the colchicine release by choosing the appropriate particle size, loading, and PLA/PCL composition. Water permeability through the PLA membrane was greater, when compared with PCL blends. The amount of drug release also was much higher (58.3%) in PLA compared with PCL (39.3%) microspheres, for 30 days. Therefore, we concluded that the drug release from the microspheres followed a diffusion mechanism where bulk erosion and surface deposition were negligible. These PEG-coated PLA/PCL microspheres may have potential for targeting antiproliferative agents for prolonged periods to treat restenosis.

Development of poly(Lactic acid)/chitosan co-matrix microspheres: controlled release of taxol-heparin for preventing restenosis.

Smooth muscle cell proliferation plays a major role in the genesis of restenosis after angioplasty or vascular injury. Controlled release of appropriate drugs alone and in combinations is one approach for treating coronary obstructions, balloon angioplasty, restenosis associated with thrombosis, and calcification. We demonstrated the possibility of encapsulating taxol-loaded polylactic acid (PLA) microspheres within heparin-chitosan spheres to develop a prolonged release co-matrix form. The in vitro release profile of taxol and heparin from this co-matrix system was monitored in phosphate buffered saline pH 7.4, using an ultraviolet spectrophotometer. The amount of taxol/heparin release was initially much higher, followed by a constant slow release profile for a prolonged period. The initial burst release of taxol (15.8%) and heparin (32.7%) from the co-matrix was modified with polyethylene glycol coatings (13.5% and 25.4%, respectively, for 24 hr). From scanning electron microscopy studies, it appears that these drugs diffuse out slowly to the dissolution medium through the micropores of the co-matrix. However, the surface micropores were modified with polyethylene glycol (PEG) coatings for a constant slow release profile. This PEG-coated PLA/chitosan co-matrix may target drug combinations having synergestic effects for prolonged periods to treat restenosis.

Comparison of exercise and dipyridamole equilibrium blood pool scintigraphy (EBPS) in angina pectoris.

Twelve patients with exertional angina underwent exercise treadmill testing, exercise equilibrium blood pool scintigraphy (Ex EBPS). Dipyridamole equilibrium blood pool scintigraphy (Dip EBPS) and coronary angiography by the Judkin's technique. Dipyridamole was infused through a venous cannula placed in the antecubital vein, in a dose of 0.56 mg/kg over four minutes. Four patients had single vessel disease, three double vessel disease, four triple vessel disease, and one had normal coronary arteries. Exercise equilibrium blood pool scintigraphy was found to have a sensitivity of 81%, and a positive predictive value for significant coronary artery disease of 100%. Dipyridamole EBPS had a sensitivity of 72% with a positive predictive value of 100%. The occurrence of regional wall motion abnormalities, following dipyridamole infusion, occurs up to fifteen minutes after exercise, and, therefore, serial acquisition for up to 20 minutes after the infusion is recommended. In patients with angina, who are unable to exercise because of orthopaedic disabilities or peripheral vascular disease, dipyridamole stress blood pool scintigraphy is a feasible alternative.

Double wire technique for additional guiding catheter support in anomalous left circumflex coronary artery angioplasty.

This case report presents an example of the use of the double wire technique for additional guiding catheter bracing support in percutaneous transluminal coronary angioplasty (PTCA) of a stenosis in an anomalous circumflex (CX) artery arising within the ostium of the right coronary artery (RCA). It illustrates the ease of this technique in comparison to conventional guiding catheter cannulation, which may be more difficult and yield poor backup support in this unusual anatomic situation.

5-Fluorouracil-loaded chitosan coated polylactic acid microspheres as biodegradable drug carriers for cerebral tumours.

The development of injectable microspheres for anticancer drug delivery into the brain is a major challenge. The possibility of entrapping 5-fluorouracil (5-FU) in chitosan coated monodisperse biodegradable microspheres with a mean diameter of 10-25 um was demonstrated. An emulsion of 5-FU (in water) and polylactic acid (PLA) dissolved in acetone-dichloromethane mixture was poured into an aqueous solution of chitosan (or poly-vinyl alcohol) with stirring using a high-speed homogenizer, for the formation of microspheres. 5-FU recovery in microspheres ranged from 44-66% depending on the polymer and emulsification systems used for the preparation. Scanning electron microscopy revealed that the chitosan coated microspheres had less surface micropores compared to PVA based preparations. The drug release behaviour from microspheres suspended in phosphate buffered saline exhibited a biphasic pattern. The amount of drug release was much higher initially (approximately 25%), followed by a constant slow release profile for a 30 days period of study. This chitosan coated PLA/PLGA microsphere formulation may have potential for the targeted delivery of 5-FU to treat cerebral tumours.

Controlled delivery of taxol from poly(ethylene glycol)-coated poly(lactic acid) microspheres.

The development of injectable microspheres for sustained drug delivery to the arterial wall is a major challenge. We demonstrated the possibility of entrapping an antiproliferative agent, taxol, in poly(ethylene glycol) (PEG)-coated biodegradable poly(lactic acid) (PLA) microspheres with a mean diameter of 2-6 microm. A solution of taxol and PLA dissolved in an acetone/dichloromethane mixture was poured into an aqueous solution of PEG [or poly(vinyl alcohol) (PVA] with stirring with a high-speed homogenizer for the formation of microspheres. Taxol recovery in PLA-PEG microspheres was higher (61.2 +/- 2.3%) than with PVA-based (41.6 +/- 1.8%) preparations. An analysis by diffuse reflectance infrared Fourier transform spectroscopy revealed that PEG was incorporated well on the PLA microsphere surface. Scanning electron microscopy revealed that the PEG-coated PLA microspheres were spherical in shape and had a smooth surface texture like those of PVA-based preparations. The amount of drug release was much higher initially (25-30%); this was followed by a constant slow-release profile for a 30-day period of study. This PEG-coated PLA microsphere formulation may have potential for the targeted delivery of antiproliferative agents to treat restenosis.

Experimental atrial septal defect closure with a new, transcatheter, self-centering device.

BACKGROUND: Despite two decades of research, a transcatheter atrial septal defect closure device is not available for clinical use. We have designed a new superelastic Nitinol-Dacron, double-disk, self-centering, atrial septal defect closure device and studied its efficacy in a canine model of atrial septal defects. METHODS AND RESULTS: Atrial septal defects were created surgically in 20 adult dogs using either a 7.5-mm or 10-mm punch. Percutaneous transcatheter closures were attempted using a new device. The device sizes used were 20 mm in 6 dogs, 22 mm in 9, and 25 mm in 5 (22.1 +/- 1.9 mm, mean +/- SD). The stretched atrial septal defect diameter was 10.5 +/- 1.3 mm, and the device to stretched atrial septal defect diameter ratio was 2.1 +/- 0.3. Closures were successful in 19 studies and unsuccessful in 1. Angiography showed a left-to-right shunt in all 20 dogs before closure. Immediately after closure (n = 19), there were no shunts in 17 and trivial shunts in 2. Six dogs were followed for a period of 4.7 +/- 3.0 months (range, 2 to 8 months). The trivial shunt present in 1 animal immediately after closure had closed by the time of the repeat study. Spontaneous embolization of the device was not seen during follow-up. A solitary wire fracture was found 8 months after closure in 1 device. Light microscopy at 8 weeks in 3 dogs showed the devices to be covered by smooth endocardium, enmeshed in mature collagen tissue, with a minimal mononuclear cell infiltration. Retrievability was assessed by deliberately embolizing 4 devices in 2 dogs into the right atrium (n = 1) and pulmonary artery (n = 3). All devices were successfully retrieved with a snare. CONCLUSIONS: This feasibility study demonstrates that this new self-centering atrial septal defect closure device has a number of design features that permit effective and safe closures in a canine model. These results support the investigation of this device in human clinical trials.