Novel Orthosteric/Allosteric Ligands of Cannabinoid Receptors: An Unexpected Pharmacological Profile.

The design of dualsteric/bitopic receptor ligands as compounds capable of simultaneously interacting with both the orthosteric and an allosteric binding site has gained importance to achieve enhanced receptor specificity and minimize off-target effects. In this work, we reported the synthesis and biological evaluation of a new series of compounds, namely, the series, obtained by chemically combining the CB1R ago-positive allosteric modulators (PAM) with the cannabinoid receptors (CBRs) orthosteric agonist . Therefore, compounds were designed as dualsteric/bitopic ligands for CB1R with the aim of obtaining stronger CB1R agonists or ago-PAMs, with improved receptor subtype selectivity and reduction of central side effects.

GFP Farnesylation as a Suitable Strategy for Selectively Tagging Exosomes.

Exosomes are small extracellular vesicles (EVs) constituting fully biological, cell-derived nanovesicles with great potential in cell-to-cell communication and drug delivery applications. The current gold standard for EV labeling and tracking is represented by fluorescent lipophilic dyes which, however, importantly lack selectivity, due to their unconditional affinity for lipids. Herein, an alternative EV fluorescent labeling approach is in-depth evaluated, by taking advantage of green fluorescent protein (GFP) farnesylation (GFP-f), a post-translational modification to directly anchor GFP to the EV membrane.

The activity of a Ga(III) catecholate complex against Aspergillus fumigatus in conditions mimicking cystic fibrosis lung and inhaled formulations for its pulmonary administration.

Azole-resistant Aspergillus fumigatus (A. fumigatus) is an emerging worldwide pathogen. Pulmonary aspergillosis primarily affects severely immunocompromised patients and is also a particularly critical condition for cystic fibrosis (CF) patients.

Evaluation of orphan maintained biological medicinal products in the European Union between 2018 to 2023: a regulatory perspective.

Objectives: Orphan medicinal products (OMPs) authorized by the European Union (EU) benefit from market exclusivity, fee waivers, and national incentives. Maintaining orphan status during a marketing authorization application requires meeting eligibility criteria, especially demonstrating significant benefit (SB), which is challenging. This study identifies key features linked to successful orphan status maintenance for biological OMPs approved in the EU between 2018 and 2023.

Aerosol of Enoximone/Hydroxypropyl-β-Cyclodextrin Inclusion Complex, Biopharmaceutical Evidence for ARDS Applicability.

Background: Phosphodiesterase (PDE) inhibitors are gaining interest in the context of pulmonary pathologies. In particular, the PDE3 inhibitor enoximone (ENXM) has shown potential relative to the cure of asthma, chronic obstructive pulmonary disease (COPD), and acute respiratory distress syndrome (ARDS). Despite its administration via inhalation being planned for use against COVID-19 related ARDS (C-ARDS), presently, no inhalable medicine containing ENXM is available.

Quantitative proteomic analysis reveals Ga(III) polypyridyl catecholate complexes disrupt Aspergillus fumigatus mitochondrial function.

Infections caused by the airborne fungal pathogen, Aspergillus fumigatus, are increasing in severity due to growing numbers of immunocompromised individuals and the increasing incidence of antifungal drug resistance, exacerbating treatment challenges. Gallium has proven to be a strong candidate in the fight against microbial pathogens due to its iron-mimicking capability and substitution of Ga(III) in place of Fe(III), disrupting iron-dependent pathways. Since the antimicrobial properties of 2,2'-bipyridine and derivatives have been previously reported, we assessed the in vitro activity and proteomic effects of a recently reported heteroleptic Ga(III) polypyridyl catecholate compound against A.

Ocular antibacterial chitosan-maleic acid hydrogels: In vitro and in vivo studies for a promising approach with enhanced mucoadhesion.

The aim was to design and evaluate a chitosan-based conjugate providing high mucoadhesiveness and antibacterial activity for ocular infections treatment. Chitosan was conjugated with maleic acid via amide bond formation and infrared spectroscopy. Furthermore, 2,4,6-Trinitrobenzene sulfonic acid (TNBS) allowed characterization and quantification of conjugated groups, respectively.

Polymeric Nanoformulation of Zoledronic Acid Rescues Osteoblasts from the Harmful Effect of its Native Form: An In Vitro Investigation of Cytotoxic Potential on Osteoblasts and Osteosarcoma Cells.

Osteosarcoma (OS) is a malignant tumor, fatal for pediatric patients who do not respond to chemotherapy, alternative therapies and drugs can provide better outcomes. Zoledronic acid (Zol) belonging to the class of bisphosphonates (BPs) has a direct antitumor ability to prevent Ras GTPases modification and stimulate apoptosis. Despite advances in maintaining balance in skeletal events and direct anticancer properties, Zol causes cytotoxicity to normal healthy pre-osteoblast cells, hampering mineralization and differentiation.

Biopharmaceutical Assessment of Mesh Aerosolised Plasminogen, a Step towards ARDS Treatment.

Acute respiratory distress syndrome (ARDS) is a severe complication of lung injuries, commonly associated with bacterial, fungal and viral infections, including SARS-CoV-2 viral infections. ARDS is strongly correlated with patient mortality and its clinical management is very complex, with no effective treatment presently available. ARDS involves severe respiratory failure, fibrin deposition in both airways and lung parenchyma, with the development of an obstructing hyaline membrane drastically limiting gas exchange.

Betaine- and L-Carnitine-Based Ionic Liquids as Solubilising and Stabilising Agents for the Formulation of Antimicrobial Eye Drops Containing Diacerein.

The therapeutic efficacy of topically administered drugs, however powerful, is largely affected by their bioavailability and, thus, ultimately, on their aqueous solubility and stability. The aim of this study was to evaluate the use of ionic liquids (ILs) as functional excipients to solubilise, stabilise, and prolong the ocular residence time of diacerein (DIA) in eye drop formulations. DIA is a poorly soluble and unstable anthraquinone prodrug, rapidly hydrolysed to rhein (Rhe), for the treatment of osteoarthritis.

Bergamot Essential Oil: A Method for Introducing It in Solid Dosage Forms.

Bergamot essential oil (BEO) possess antimicrobial, antiproliferative, anti-inflammatory, analgesic, neuroprotective, and cardiovascular effects. However, it is rich in volatile compounds, e.g.

Comparing Metabolomic and Essential Oil Fingerprints of F. Muell (Finger Lime) Varieties and Their In Vitro Antioxidant Activity.

Comparative chemical analyses among peel and pulp essential oils (EOs) and methanolic extracts of four varieties (Red, Collette, Pink Ice, and Yellow Sunshine), and the hybrid , were performed using GC-MS and UHPLC-DAD-HR-Orbitrap/ESI-MS. Peel and pulp extracts were also analysed for their in vitro antioxidant activity on a Balb/3T3 clone A31 mouse embryo fibroblast cell line. The results of peel and pulp EOs were mainly characterised by monoterpenes and sesquiterpenes, respectively.

Jellyfish Polysaccharides for Wound Healing Applications.

Jellyfishes are considered a new potential resource in food, pharmaceutical and biomedical industries. In these latter cases, they are studied as source of active principles but are also exploited to produce marine collagen. In the present work, jellyfish skin polysaccharides (JSP) with glycosaminoglycan (GAG) features were extracted from , a main blooming species of Mediterranean Sea, massively augmented by climate leaded "jellyfishication" of the sea.

Thiolated 2-Methyl-β-Cyclodextrin as a Mucoadhesive Excipient for Poorly Soluble Drugs: Synthesis and Characterization.

Thiolated cyclodextrins are structurally simple mucoadhesive macromolecules, which are able to host drugs and increase their apparent water solubility, as well as interact with the mucus layer prolonging drug residence time on the site of absorption. The aim of this study was to synthesize through green microwave-assisted process a freely soluble thiolated 2-methyl-β-cyclodextrin (MβCD-SH). Its inclusion complex properties with dexamethasone (Dex), a poor water soluble drug, and mucoadhesive characteristics were also determined.

Thiolated Hydroxypropyl-β-cyclodextrin: A Potential Multifunctional Excipient for Ocular Drug Delivery.

The goal of this study was the design and evaluation of a thiolated cyclodextrin providing high drug solubilizing and mucoadhesive properties for ocular drug delivery. Hydroxypropyl-β-cyclodextrin (HP-β-CD) was thiolated via a microwave-assisted method, resulting in a degree of thiolation of 33%. Mucoadhesive properties of thiolated HP-β-CD (HP-β-CD-SH) were determined via rheological measurements and ex vivo studies on isolated porcine cornea.

Combination of Two Kinds of Medicated Microparticles Based on Hyaluronic Acid or Chitosan for a Wound Healing Spray Patch.

Olive leaves extract (OLE) has been extensively studied as antioxidant and antibiotic and these characteristics make it particularly interesting for use on wounds. For this reason, the aim of this study was to introduce OLE in microparticles (MP) of hyaluronic acid (MPHA-OLE) or chitosan (MPCs-OLE) to obtain a spray patch for the treatment of wounds in anatomical areas that are difficult to protect with traditional patches. The MP were characterized for particle size and ability to protect OLE from degradation, to absorb water from wound exudate, to control OLE release from MP.

The Potential Role of Aerosolized Phosphodiesterase 3 Inhibitor Enoximone in the Management of Coronavirus Disease 2019 Hypoxemia: A Case Report.

Despite the various parenchymal presentation of coronavirus disease 2019 (COVID-19) pneumonia, the involvement of the vascular component, the reduction of perfusion in noninjured part of the lung and secondary right to left shunt play an important role in the genesis of the respiratory insufficiency. We present the case of a 72-year-old woman admitted to Livorno Hospital for severe respiratory insufficiency due to SARS-CoV-2 infection unresponsive to noninvasive in whom administration of nebulized phosphodiesterase 3 (PDE3) inhibitor enoximone was able to improve oxygenation avoiding tracheal intubation. Intravenous infusions of phosphodiesterase inhibitors are commonly used as pulmonary vasodilators in the management of pulmonary hypertension.

Antivirulence Properties of a Low-Molecular-Weight Quaternized Chitosan Derivative against .

The co-occurrence of increasing rates of resistance to current antibiotics and the paucity of novel antibiotics pose major challenges for the treatment of bacterial infections. In this scenario, treatments targeting bacterial virulence have gained considerable interest as they are expected to exert a weaker selection for resistance than conventional antibiotics. In a previous study, we demonstrated that a low-molecular-weight quaternized chitosan derivative, named QAL, displays antibiofilm activity against the major pathogen at subinhibitory concentrations.

Correction: Piras, A.M., et al. Antibacterial, Antibiofilm, and Antiadhesive Properties of Different Quaternized Chitosan Derivatives. 2019, , 6297.

The authors wish to make the following corrections to this paper [...

Nanoparticles Based on Quaternary Ammonium Chitosan-methyl-β-cyclodextrin Conjugate for the Neuropeptide Dalargin Delivery to the Central Nervous System: An In Vitro Study.

Peptide oral administration is a hard goal to reach, especially if the brain is the target site. The purpose of the present study was to set up a vehicle apt to promote oral absorption of the neuropeptide dalargin (DAL), allowing it to cross the intestinal mucosal barrier, resist enzymatic degradation, and transport drugs to the brain after crossing the blood-brain barrier. Therefore, a chitosan quaternary ammonium derivative was synthesized and conjugated with methyl-β-cyclodextrin to prepare DAL-medicated nanoparticles (DAL-NP).

Repurposing of Plasminogen: An Orphan Medicinal Product Suitable for SARS-CoV-2 Inhalable Therapeutics.

The SARS-CoV-2 infection is associated with pulmonary coagulopathy, which determines the deposition of fibrin in the air spaces and lung parenchyma. The resulting lung lesions compromise patient pulmonary function and increase mortality, or end in permanent lung damage for those who have recovered from the COVID-19 disease. Therefore, local pulmonary fibrinolysis can be efficacious in degrading pre-existing fibrin clots and reducing the conversion of lung lesions into lasting scars.

Quaternary Ammonium Chitosans: The Importance of the Positive Fixed Charge of the Drug Delivery Systems.

As a natural polysaccharide, chitosan has good biocompatibility, biodegradability and biosecurity. The hydroxyl and amino groups present in its structure make it an extremely versatile and chemically modifiable material. In recent years, various synthetic strategies have been used to modify chitosan, mainly to solve the problem of its insolubility in neutral physiological fluids.

Cell membrane coated nanocarriers - an efficient biomimetic platform for targeted therapy.

Targeted therapy approaches have become the core of modern translational science and as an intriguing field, it is the solution of the conventional drug delivery problems that were once unanswered. Traditional methods of delivering drugs and therapeutics faced issues of solubility, sustained release, not enough amount getting through the diseased site, for e.g a tumor.