A Clinical, Pharmacological, and Formulation Evaluation of Melatonin in the Treatment of Ocular Disorders-A Systematic Review.

Melatonin's cytoprotective properties may have therapeutic implications in treating ocular diseases like glaucoma and age-related macular degeneration. Literature data suggest that melatonin could potentially protect ocular tissues by decreasing the production of free radicals and pro-inflammatory mediators. This study aims to summarize the screened articles on melatonin's clinical, pharmacological, and formulation evaluation in treating ocular disorders. The identification of relevant studies on the topic in focus was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020) guidelines. The studies were searched in the following databases and web search engines: Pubmed, Scopus, Science Direct, Web of Science, Reaxys, Google Scholar, Google Patents, Espacenet, and Patentscope. The search time interval was 2013-2023, with the following keywords: melatonin AND ocular OR ophthalmic AND formulation OR insert AND disease. Our key conclusion was that using melatonin-loaded nano-delivery systems enabled the improved permeation of the molecule into intraocular tissues and assured controlled release profiles. Although preclinical studies have demonstrated the efficacy of developed formulations, a considerable gap has been observed in the clinical translation of the results. To overcome this failure, revising the preclinical experimental phase might be useful by selecting endpoints close to clinical ones.

Coating Lacticaseibacillus rhamnosus GG in Alginate Systems: an Emerging Strategy Towards Improved Viability in Orange Juice.

Fruit juices are successfully proposed as suitable probiotic vehicles, but researchers' efforts should be developed to avoid effects of bacteria overgrowing on sensory and nutritional cues of final products and to preserve viability of probiotic bacteria during storage. In the present study, encapsulation of Lacticaseibacillus rhamnosus GG strain in alginate systems was performed through ionotropic gelation technology. The alginate systems were optimized by using Box-Behnken Design to investigate the influence of three independent variables at three different levels: particle mean size and polydispersity index. The optimized probiotic-loaded alginate particles were added to orange juice samples. The viability of the probiotic strain, both as free and microencapsulated, was evaluated in orange juice stored at 5°C for 35 days. Morphology and size of probiotic-loaded alginate particles were found suitable for incorporation into juice. TEM analysis revealed that unloaded systems were clustered as nanoparticles (CL_NP), while the loaded sample appeared as a coated system (Coated_LGG). Microbiological evaluation revealed that the encapsulation assured the survival of Coated_LGG, with a reduction of less than 1-unit log in cellular density after 35 days of refrigerated storage in orange juice. Results indicated that the encapsulated bacteria did not affect the macroscopic properties neither the microbiological characteristic of orange juice; thus, it can be proposed as functional food.

The outcome of intra-aortic balloon pump support in acute myocardial infarction complicated by cardiogenic shock according to the type of revascularization: a comprehensive meta-analysis.

AIMS: Despite the recommendations of the current guidelines, scientific evidence continue to challenge the effectiveness of intra-aortic balloon pump (IABP) in acute myocardial infarction (AMI) complicated by cardiogenic shock. Moreover, 2 recent meta-analyses showed contrasting results. The aim of this study is to test the effect of IABP according to the type of therapeutic treatment of AMI: percutaneous coronary intervention (PCI), thrombolytic therapy (TT), or medical therapy without reperfusion. Articles published from January 1, 1986, to December 31, 2012, were collected and analyzed by meta-analysis. METHODS AND RESULTS: We evaluated the IABP impact on inhospital mortality, on safety end points (stroke, severe bleeding) and long-term survival, using risk ratio (RR) and risk difference (RD) estimates. We found that the risk of death was (i) not significantly different between the IABP and control groups (RR 0.95, P = .52; RD -0.04, P = .28), (ii) significantly reduced in the TT subgroup (RR 0.77, P < .0001; RD -0.16, P < .0001), and (iii) significantly increased in the PCI subgroup (RR 1.18, P = .01; RD 0.07, P = .01). There were no significant differences in secondary end points (P, not significant). In addition, we compared the meta-analyses collected over the same search period. CONCLUSION: The results show that IABP support is significantly effective in TT reperfusion but is associated with a significant increase of the inhospital mortality with primary PCI. The comparison of the meta-analyses demonstrates the key role of analysing primary clinical treatments to avoid systematic errors.

Formulation and Characterization of Electrospun Nanofibers for Melatonin Ocular Delivery.

The poor ocular bioavailability of melatonin (MEL) limits the therapeutic action the molecule could exert in the treatment of ocular diseases. To date, no study has explored the use of nanofiber-based inserts to prolong ocular surface contact time and improve MEL delivery. Here, the electrospinning technique was proposed to prepare poly (vinyl alcohol) (PVA) and poly (lactic acid) (PLA) nanofiber inserts. Both nanofibers were produced with different concentrations of MEL and with or without the addition of Tween® 80. Nanofibers morphology was evaluated by scanning electron microscopy. Thermal and spectroscopic analyses were performed to characterize the state of MEL in the scaffolds. MEL release profiles were observed under simulated physiological conditions (pH 7.4, 37 °C). The swelling behavior was evaluated by a gravimetric method. The results confirmed that submicron-sized nanofibrous structures were obtained with MEL in the amorphous state. Different MEL release rates were achieved depending on the nature of the polymer. Fast (20 min) and complete release was observed for the PVA-based samples, unlike the PLA polymer, which provided slow and controlled MEL release. The addition of Tween® 80 affected the swelling properties of the fibrous structures. Overall, the results suggest that membranes could be an attractive vehicle as a potential alternative to liquid formulations for ocular administration of MEL.

Fluorescent Nanosystems for Drug Tracking and Theranostics: Recent Applications in the Ocular Field.

The greatest challenge associated with topical drug delivery for the treatment of diseases affecting the posterior segment of the eye is to overcome the poor bioavailability of the carried molecules. Nanomedicine offers the possibility to overcome obstacles related to physiological mechanisms and ocular barriers by exploiting different ocular routes. Functionalization of nanosystems by fluorescent probes could be a useful strategy to understand the pathway taken by nanocarriers into the ocular globe and to improve the desired targeting accuracy. The application of fluorescence to decorate nanocarrier surfaces or the encapsulation of fluorophore molecules makes the nanosystems a light probe useful in the landscape of diagnostics and theranostics. In this review, a state of the art on ocular routes of administration is reported, with a focus on pathways undertaken after topical application. Numerous studies are reported in the first section, confirming that the use of fluorescent within nanoparticles is already spread for tracking and biodistribution studies. The first section presents fluorescent molecules used for tracking nanosystems' cellular internalization and permeation of ocular tissues; discussions on the classification of nanosystems according to their nature (lipid-based, polymer-based, metallic-based and protein-based) follows. The following sections are dedicated to diagnostic and theranostic uses, respectively, which represent an innovation in the ocular field obtained by combining dual goals in a single administration system. For its great potential, this application of fluorescent nanoparticles would experience a great development in the near future. Finally, a brief overview is dedicated to the use of fluorescent markers in clinical trials and the market in the ocular field.

Melatonin loaded hybrid nanomedicine: DoE approach, optimization and in vitro study on diabetic retinopathy model.

Melatonin (MEL) is a pleiotropic neurohormone of increasing interest as a neuroprotective agent in ocular diseases. Improving the mucoadhesiveness is a proposed strategy to increase the bioavailability of topical formulations. Herein, the design and optimization of MEL-loaded lipid-polymer hybrid nanoparticles (mel-LPHNs) using Design of Experiment (DoE) was performed. LPHNs consisted of PLGA-PEG polymer nanoparticles coated with a cationic lipid-shell. The optimized nanomedicine showed suitable size for ophthalmic administration (189.4 nm; PDI 0.260) with a positive surface charge (+39.8 mV), high encapsulation efficiency (79.8 %), suitable pH and osmolarity values, good mucoadhesive properties and a controlled release profile. Differential Scanning Calorimetry and Fourier-Transform Infrared Spectroscopy confirmed the encapsulation of melatonin in the systems and the interaction between lipids and polymer matrix. Biological evaluation in an in vitro model of diabetic retinopathy demonstrated enhanced neuroprotective and antioxidant activities of mel-LPHNs, compared to melatonin aqueous solution at the same concentration (0.1 and 1 µM). A modified Draize test was performed to assess the ocular tolerability of the formulation showing no signs of irritation. To the best our knowledge, this study reported for the first time the development of mel-LPHNs, a novel and safe hybrid platform suitable for the topical management of retinal diseases.

Transcatheter aortic valve implantation in patients with unruptured aortic root pseudoaneurysm: an observational study.

AIMS: Unruptured aortic root pseudoaneurysm (UARP) is a rare complication of aortic valve endocarditis. Infectious spread to the valvular annulus or myocardium can cause septic complications that manifest as wall thickening, and spontaneous abscess drainage leads to pseudoaneurysm formation. We report the first patient series in which transcatheter aortic valve implantation (TAVI) using a single valve-resolved aortic valvulopathy associated with UARP was performed. METHODS: At our center, from December 2017 to October 2019, 138 patients underwent TAVI for aortic valve stenosis and/or regurgitation, 20 of whom (12 female patients, 8 male patients) had associated incidental UARP and were considered as our study population. The average age of these patients was 76.9 ±â€Š5.2 years. All patients were assessed using preprocedural and postprocedural multimodality imaging, including transthoracic echocardiography, transesophageal echocardiography, and cardiac computed tomography angiography (CCTA). RESULTS: In all cases, the final angiographic examination showed correct valve positioning with complete coverage of the false aneurysm. Post-TAVI CCTA showed presence of total or subtotal UARP thrombosis. The mean follow-up period was 17.5 months (12-23 months). During follow-up, imaging showed normal prosthetic valve function, no significant leakage (trace or mild), and complete UARP exclusion in all patients, without any complications. CONCLUSION: In conclusion, percutaneous valve positioning can simultaneously solve pseudoaneurysm complications by excluding the sac and promoting thrombosis.

Ferulic Acid-Loaded Polymeric Nanoparticles for Potential Ocular Delivery.

Ferulic acid (FA) is an antioxidant compound that can prevent ROS-related diseases, but due to its poor solubility, therapeutic efficacy is limited. One strategy to improve the bioavailability is nanomedicine. In the following study, FA delivery through polymeric nanoparticles (NPs) consisting of polylactic acid (NPA) and poly(lactic-co-glycolic acid) (NPB) is proposed. To verify the absence of cytotoxicity of blank carriers, a preliminary in vitro assay was performed on retinal pericytes and endothelial cells. FA-loaded NPs were subjected to purification studies and the physico-hemical properties were analyzed by photon correlation spectroscopy. Encapsulation efficiency and in vitro release studies were assessed through high performance liquid chromatography. To maintain the integrity of the systems, nanoformulations were cryoprotected and freeze-dried. Morphology was evaluated by a scanning electron microscope. Physico-chemical stability of resuspended nanosystems was monitored during 28 days of storage at 5 °C. Thermal analysis and Fourier-transform infrared spectroscopy were performed to characterize drug state in the systems. Results showed homogeneous particle populations, a suitable mean size for ocular delivery, drug loading ranging from 64.86 to 75.16%, and a controlled release profile. The obtained systems could be promising carriers for ocular drug delivery, legitimating further studies on FA-loaded NPs to confirm efficacy and safety in vitro.

mPEG-PLGA Nanoparticles Labelled with Loaded or Conjugated Rhodamine-B for Potential Nose-to-Brain Delivery.

Nowdays, neurodegenerative diseases represent a great challenge from both the therapeutic and diagnostic points of view. Indeed, several physiological barriers of the body, including the blood brain barrier (BBB), nasal, dermal, and intestinal barriers, interpose between the development of new drugs and their effective administration to reach the target organ or target cells at therapeutic concentrations. Currently, the nose-to-brain delivery with nanoformulations specifically designed for intranasal administration is a strategy widely investigated with the goal to reach the brain while bypassing the BBB. To produce nanosystems suitable to study both in vitro and/or in vivo cells trafficking for potential nose-to-brain delivery route, we prepared and characterized two types of fluorescent poly(ethylene glycol)-methyl-ether-block-poly(lactide-co-glycolide) (PLGA-PEG) nanoparticles (PNPs), i.e., Rhodamine B (RhB) dye loaded- and grafted- PNPs, respectively. The latter were produced by blending into the PLGA-PEG matrix a RhB-labeled polyaspartamide/polylactide graft copolymer to ensure a stable fluorescence during the time of analysis. Photon correlation spectroscopy (PCS), UV-visible (UV-vis) spectroscopies, differential scanning calorimetry (DSC), atomic force microscopy (AFM) were used to characterize the RhB-loaded and RhB-grafted PNPs. To assess their potential use for brain targeting, cytotoxicity tests were carried out on olfactory ensheathing cells (OECs) and neuron-like differentiated PC12 cells. Both PNP types showed mean sizes suitable for nose-to-brain delivery (<200 nm, PDI < 0.3) and were not cytotoxic toward OECs in the concentration range tested, while a reduction in the viability on PC12 cells was found when higher concentrations of nanomedicines were used. Both the RhB-labelled NPs are suitable drug carrier models for exploring cellular trafficking in nose-to-brain delivery for short-time or long-term studies.

A rare case of a giant circumflex coronary artery aneurysm 10 years after bentall surgery.

In this paper, we describe a rare case of coronary artery aneurysms occasionally found on a pre interventional Coronary Computed Tomography Angiography performed on a 67-year-old man with a history of aneurysm of the ascending aorta previously treated with Bentall surgery, who arrived at our hospital to have a percutaneous valve-in-valve implantation procedure. Even though the patient was considered not eligible for the procedure, due to his many comorbidities, and conservatively managed, at 1-year followup his angiographic condition remained stable.

Role of beta-adrenergic receptor gene polymorphisms in the long-term effects of beta-blockade with carvedilol in patients with chronic heart failure.

BACKGROUND: Beta-blockers are mainstay of current treatment of heart failure (HF). Beta-adrenergic receptors (AR) single nucleotide gene polymorphisms (SNPs) may influence the sensitivity and density of beta-AR. We assessed the relation between three common beta-AR SNPs and the response to carvedilol administration. METHODS AND RESULTS: We studied 183 consecutive patients with chronic HF due to ischemic or nonischemic cardiomyopathy, a LV ejection fraction (LVEF) < or = 0.35, not previously treated with beta-blockers. Each patient underwent gated-SPECT radionuclide ventriculography, cardiopulmonary exercise testing and invasive hemodynamic monitoring at baseline and after 12 months of carvedilol administration at maintenance dosages. The beta1-AR gene Arg389Gly and the beta2-AR gene Arg16Gly SNPs were not related to the response to carvedilol administration. Homozygotes for the Glu27Glu allele showed a greater increase in the LVEF, compared to the other patients (+13.0 +/- 12.2% versus +7.1 +/- 8.1% in the Gln27Gln homozygotes, and 8.3 +/- 11.4% units in the Gln27Glu heterozygotes; p = 0.022 by ANOVA). Glu27Glu homozygotes also showed a greater decline in the pulmonary wedge pressure both at rest and at peak exercise. Gln27Glu SNP was selected amongst the determinants of the LVEF response to carvedilol at multivariable analysis, in addition to the cause of cardiomyopathy, baseline systolic blood pressure and the dose of carvedilol administered. CONCLUSION: Beta1-AR Arg389Gly and beta2-AR Arg16Gly SNPs are not related to the response to carvedilol therapy. In contrast, the Gln27Glu SNP is a determinant of the LVEF response to this agent in patients with chronic HF.

Percutaneous assist devices in acute myocardial infarction with cardiogenic shock: Review, meta-analysis.

AIM: To assess the impact of percutaneous cardiac support in cardiogenic shock (CS) complicating acute myocardial infarction (AMI), treated with percutaneous coronary intervention. METHODS: We selected all of the studies published from January 1(st), 1997 to May 15(st), 2015 that compared the following percutaneous mechanical support in patients with CS due to AMI undergoing myocardial revascularization: (1) intra-aortic balloon pump (IABP) vs Medical therapy; (2) percutaneous left ventricular assist devices (PLVADs) vs IABP; (3) complete extracorporeal life support with extracorporeal membrane oxygenation (ECMO) plus IABP vs IABP alone; and (4) ECMO plus IABP vs ECMO alone, in patients with AMI and CS undergoing myocardial revascularization. We evaluated the impact of the support devices on primary and secondary endpoints. Primary endpoint was the inhospital mortality due to any cause during the same hospital stay and secondary endpoint late mortality at 6-12 mo of follow-up. RESULTS: One thousand two hundred and seventy-two studies met the initial screening criteria. After detailed review, only 30 were selected. There were 6 eligible randomized controlled trials and 24 eligible observational studies totaling 15799 patients. We found that the inhospital mortality was: (1) significantly higher with IABP support vs medical therapy (RR = +15%, P = 0.0002); (2) was higher, although not significantly, with PLVADs compared to IABP (RR = +14%, P = 0.21); and (3) significantly lower in patients treated with ECMO plus IABP vs IABP (RR = -44%, P = 0.0008) or ECMO (RR = -20%, P = 0.006) alone. In addition, Trial Sequential Analysis showed that in the comparison of IABP vs medical therapy, the sample size was adequate to demonstrate a significant increase in risk due to IABP. CONCLUSION: Inhospital mortality was significantly higher with IABP vs medical therapy. PLVADs did not reduce early mortality. ECMO plus IABP significantly reduced inhospital mortality compared to IABP.

Stretchable metal oxide thin film transistors on engineered substrate for electronic skin applications.

Electronic skins aim at providing distributed sensing and computation in a large-area and elastic membrane. Control and addressing of high-density soft sensors will be achieved when thin film transistor matrices are also integrated in the soft carrier substrate. Here, we report on the design, manufacturing and characterization of metal oxide thin film transistors on these stretchable substrates. The TFTs are integrated onto an engineered silicone substrate with embedded strain relief to protect the devices from catastrophic cracking. The TFT stack is composed of an amorphous In-Ga-Zn-O active layer, a hybrid AlxOy/Parylene dielectric film, gold electrodes and interconnects. All layers are prepared and patterned with planar, low temperature and dry processing. We demonstrate the interconnected IGZO TFTs sustain applied tensile strain up to 20% without electrical degradation and mechanical fracture. Active devices are critical for distributed sensing. The compatibility of IGZO TFTs with soft and biocompatible substrates is an encouraging step towards wearable electronic skins.

Lack of intra-aortic balloon pump effectiveness in high-risk percutaneous coronary interventions without cardiogenic shock: a comprehensive meta-analysis of randomised trials and observational studies.

BACKGROUND: Although controversial, using prophylactic intra-aortic balloon pump (IABP) in patients undergoing high-risk percutaneous coronary intervention (PCI) has been reported to be effective by numerous registry studies. However, conflicting findings were observed in observational studies (Obs.) and randomised controlled trials (RCTs). OBJECTIVE: The purpose of this meta-analysis was to assess the impact of IABP on in-hospital deaths, major adverse cardiovascular events (MACCE), access-site complications and stroke in high-risk PCI cases from Obs. and RCTs published from 1st January, 1990 to 31st March, 2012 and indexed in PubMed. METHODS AND RESULTS: We retrieved 1125 studies from the database; 11 studies compared the effects of IABP support, i.e., prophylactic administration (P-IABP) vs. no support (No-IABP), in high-risk patients undergoing PCI. These studies were included in the meta-analysis. We then calculated risk ratios (RRs) and risk differences (RDs) between the two groups of patients (P-IABP vs. No-IABP). We did not observe significant in-hospital mortality, MACCE, access-site complications or stroke differences in the RRs and RDs of the two groups. CONCLUSIONS: The results suggest that PCI plus P-IABP support does not result in reduced in-hospital mortality or MACCE nor in significant higher access-site complications or stroke incidence compared with PCI alone in patients at high risk for peri-procedural PCI complications.

Effect of spironolactone on left ventricular ejection fraction and volumes in patients with class I or II heart failure.

The beneficial effects of spironolactone in chronic heart failure (HF) have been demonstrated in patients with New York Heart Association (NYHA) class III to IV HF. This study examined the effect of spironolactone on left ventricular (LV) function and functional capacity of patients with mild to moderate HF (NYHA class I to II). One hundred sixty-eight patients with NYHA class I to II HF and LV ejection fraction ≤40% were randomized to spironolactone or placebo and assessed by echocardiography, gated single-photon emission computed tomography, technetium-99m sestamibi single-photon emission computed tomographic radionuclide ventriculography, and cardiopulmonary exercise testing at baseline and after 6 months of treatment. In the spironolactone group LV ejection fraction increased from 35.2 ± 0.7% to 39.1 ± 3.5% (p <0.001), with a decrease in LV end-diastolic and end-systolic volumes and myocardial mass and an improvement in LV diastolic filling pattern. Cardiopulmonary exercise testing parameters did not change. In conclusion, administration of spironolactone to patients with NYHA class I to II HF has beneficial effects on LV remodeling and diastolic function.