Leishmaniasis are diseases caused by parasites belonging to
genus. The treatment with pentavalent antimonials present high toxicity. Secondary line drugs, such as amphotericin B and miltefosine also ...have a narrow therapeutic index. Therefore, there is an urgent need to develop new drugs to treat leishmaniasis. Here, we present the in vitro anti-leishmanial activity of unusual dimeric flavonoids purified from
. Three compounds were tested against
sp. Compound 2 was the most active against promastigotes. Quantifying the in vitro infected macrophages revealed that compound 2 was also the most active against intracellular amastigotes of
, without displaying host cell toxicity. Drug combinations presented an additive effect, suggesting the absence of interaction between amphotericin B and compound 2. Amastigotes treated with compound 2 demonstrated alterations in the Golgi and accumulation of vesicles inside the flagellar pocket. Compound 2-treated amastigotes presented a high accumulation of cytoplasmic vesicles and a myelin-like structure. When administered in
-infected mice, neither the oral nor the topical treatments were effective against the parasite. Based on the high in vitro activity, dimeric flavonoids can be used as a lead structure for the development of new molecules that could be useful for structure-active studies against
.
Abstract Perivascular medical devices and perivascular drug delivery systems are conceived for local application around a blood vessel during open vascular surgery. These systems provide mechanical ...support and/or pharmacological activity for the prevention of intimal hyperplasia following vessel injury. Despite abundant reports in the literature and numerous clinical trials, no efficient perivascular treatment is available. In this review, the existing perivascular medical devices and perivascular drug delivery systems, such as polymeric gels, meshes, sheaths, wraps, matrices, and metal meshes, are jointly evaluated. The key criteria for the design of an ideal perivascular system are identified. Perivascular treatments should have mechanical specifications that ensure system localization, prolonged retention and adequate vascular constriction. From the data gathered, it appears that a drug is necessary to increase the efficacy of these systems. As such, the release kinetics of pharmacological agents should match the development of the pathology. A successful perivascular system must combine these optimized pharmacological and mechanical properties to be efficient.
•Precision medicine is necessary to treat multiple facets of osteoarthritis.•Disease-modifying osteoarthritis drugs (DMOADs) and drug delivery systems (DDSs) are discussed.•DMOADs should be combined ...with adequate DDSs for long-term intra-articular (IA) therapy.•Clinical trials of small molecules delivered by IA injections are summarized.•Hydrogels, liposomes, nanoparticles and microparticles are reviewed.
Osteoarthritis (OA) is the most common degenerative disease of the joint. Despite many reports and numerous clinical trials, OA is not entirely understood, and there is no effective treatment available for this disease. To satisfy this unmet medical need, drug delivery systems (DDSs) containing disease-modifying OA drugs (DMOADs) for intra-articular (IA) administration are required to improve the health of OA patients. DDSs should provide controlled and/or sustained drug release, enabling long-term treatment with a reduced number of injections. This paper reviews the role and interaction among different tissues involved in OA and summarizes recent clinical trials and research on DDSs, focusing on small-molecule delivery. To achieve an ideal treatment, various key criteria have been identified to design and develop an IA DDS matching the clinical needs.
Optimized intra-articularly administered drug delivery systems associated with potent disease-modifying osteoarthritis drugs that can stop and/or reverse osteoarthritis evolution represent a promising approach for effective therapy.
•The leaves of Ocimum gratissimum L. was subjected to identification of its chemical constituents.•The in vitro cytotoxic activity of compounds against lung adenocarcinoma (A549), breast carcinoma ...(MCF-7), acute monocytic leukemia (THP-1), murine macrophages Raw 264.7 cancer cell lines and the normal fibroblast A7R5 cell line were studied.•THP-1 was the most sensitive to compounds 1-6.•Compound 4 and paclitaxel have similar IC50 value against THP-1 cells.
Malignancies constitute a global health concern and chemotherapy remains the main mode of treatment. The present study was designed to evaluate the cytotoxicity of metabolites isolated from Ocimum gratissimum L. The phytochemical investigation of the leaves of O. gratissimum L. (Lamiaceae) led to the isolation and characterization of eight compounds. Structures of isolated compounds were elucidated using 1D and 2D NMR, as well as MS. The purified compounds, were identified as five triterpenes (1-5), one flavonoid (6) and two steroidal compounds (7-8). The cytotoxicity effects of purified compounds were assessed in vitro by the WST-1 assay on three cancer cell lines including lung adenocarcinoma (A549), breast carcinoma (MCF-7), acute monocytic leukemia (THP-1), murine macrophages (Raw 264.7) and the normal fibroblast (A7R5) cells. Compound 4 had an IC50 value of 3.21±0.4 µM similar to that of the reference drug, paclitaxel against THP-1 cells. The THP-1 cell lines were the most sensitive to compounds 1-6. All the compounds showed low cytotoxicity against the normal cell line A7R5 as compared to cancer cell lines. The constituents of Ocimum gratissimum L. and especially pomolic acid (4) is a potent cytotoxic compound that deserves more investigations toward developing novel antiproliferative drugs against acute monocytic leukemia (THP-1).
Osteoarthritis (OA) is a complex multi-target disease with an unmet medical need for the development of therapies that slow and potentially revert disease progression. Intra-articular (IA) delivery ...has seen a surge in osteoarthritis research in recent years. As local administration of molecules, this represents a way to circumvent systemic drug delivery struggles. When developing intra-articular formulations, the main goals are a sustained and controlled release of therapeutic drug doses, taking into account carrier choice, drug molecule, and articular joint tissue target. Therefore, the selection of models is critical when developing local administration formulation in terms of accurate outcome assessment, target and off-target effects and relevant translation to in vivo. The current review highlights the applications of OA in vitro models in the development of IA formulation by means of exploring their advantages and disadvantages. In vitro models are essential in studies of OA molecular pathways, understanding drug and target interactions, assessing cytotoxicity of carriers and drug molecules, and predicting in vivo behaviors. However, further understanding of molecular and tissue-specific intricacies of cellular models for 2D and 3D needs improvement to accurately portray in vivo conditions.
The role of the gut microbiota in health and the pathogenesis of several diseases has been highlighted in recent years. Even though the precise mechanisms involving the microbiome in these ailments ...are still unclear, microbiota-modulating therapies have been developed. Fecal microbiota transplantation (FMT) has shown significant results against Clostridioides difficile infection (CDI), and its potential has been investigated for other diseases. Unfortunately, the technical aspects of the treatment make it difficult to implement. Pharmaceutical technology approaches to encapsulate microorganisms could play an important role in providing this treatment and render the treatment modalities easier to handle.
After an overview of CDI, this narrative review aims to discuss the current formulations for FMT and specifically addresses the technical aspects of the treatment. This review also distinguishes itself by focusing on the hurdles and emphasizing the possible improvements using pharmaceutical technologies.
FMT is an efficient treatment for recurrent CDI. However, its standardization is overlooked. The approach of industrial and hospital preparations of FMT are different, but both show promise in their respective methodologies. Novel FMT formulations could enable further research on dysbiotic diseases in the future.
This study aimed to formulate nanocrystal-polymer particles (NPPs) containing the potent p38α/β MAPK inhibitor PH-797804 (PH-NPPs) and to test their extended-release properties over months in ...comparison to those of conventional PH microparticles for the intra-articular treatment of inflammatory and mechanistic murine models mirroring aspects of human osteoarthritis (OA). The steps of the study were (i) to formulate PH nanocrystals (wet milling), (ii) to encapsulate a high payload of PH nanocrystals in fluorescent particles (spray drying), (iii) to assess in vitro drug release, (iv) to evaluate PH-NPP toxicity to human OA synoviocytes (MTT test), (v) to investigate the in vivo bioactivity of the particles in mice in an inflammatory antigen-induced arthritis (AIA) model (using histology and RT-qPCR) and (vi) to investigate the in vivo bioactivity of the particles in the OA model obtained by mechanistic surgical destabilization of the medial meniscus (DMM) (using histology, micro-CT, and multiplex ELISA). The PH nanocrystals stabilized with vitamin E TPGS had a monomodal size distribution. The PH-NPPs had a mean diameter of 14.2 μm and drug loading of ~31.5% (w/w), and ~20% of the PH was released over 3 months. The NPPs did not exhibit toxicity to cultured human OA synoviocytes at 100 × IC50. Finally, in vivo studies showed good retention of PH-NPPs in the joint and adjacent tissues for up to 2 months, and the PH-NPPs exhibited good functional relevance by significantly reducing inflammation and joint destruction and by inhibiting several biomarkers (e.g., IL-1β). In conclusion, local treatment with PH-NPPs, used as an extended-release drug delivery system, improved inflammation and joint degradation in two distinct mouse models, indicating treatment potential for human OA.
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Osteoarthritis (OA) is a chronic and inflammatory disease with no effective regenerative treatments to date. The therapeutic potential of mesenchymal stem cells (MSCs) remains to be ...fully explored. Intra-articular injection of these cells promotes cartilage protection and regeneration by paracrine signaling and differentiation into chondrocytes. However, joints display a harsh avascular environment for these cells upon injection. This phenomenon prompted researchers to develop suitable injectable materials or systems for MSCs to enhance their function and survival. Among them, hydrogels can absorb a large amount of water and maintain their 3D structure but also allow incorporation of bioactive agents or small molecules in their matrix that maximize the action of MSCs. These materials possess advantageous cartilage-like features such as collagen or hyaluronic acid moieties that interact with MSC receptors, thereby promoting cell adhesion. This review provides an up-to-date overview of the progress and opportunities of MSCs entrapped into hydrogels, combined with bioactive/small molecules to improve the therapeutic effects in OA treatment.
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Mesenchymal stem cell (MSC) therapy shows promise in regenerative medicine. For osteoarthritis (OA), MSCs delivered to the joint have a temporal window in which they can secrete ...growth factors and extracellular matrix molecules, contributing to cartilage regeneration and cell proliferation. However, upon injection in the non-vascularized joint, MSCs lacking energy supply, starve and die too quickly to efficiently deliver enough of these factors. To feed injected MSCs, we developed a hyaluronic acid (HA) derivative, where glucose is covalently bound to hyaluronic acid. To achieve this, the glucose moiety in 4-aminophenyl-β-D-glucopyranoside was linked to the HA backbone through amidation. The hydrogel was able to deliver glucose in a controlled manner using a trigger system based on hydrolysis catalyzed by endogenous ß-glucosidase. This led to glucose release from the hyaluronic acid backbone inside the cell. Indeed, our hydrogel proved to rescue starvation and cell mortality in a glucose-free medium. Our approach of adding a nutrient to the polymer backbone in hydrogels opens new avenues to deliver stem cells in poorly vascularized, nutrient-deficient environments, such as osteoarthritic joints, and for other regenerative therapies.
An efficient treatment for osteoarthritis (OA) can benefit from the local release of a high therapeutic dose over an extended period of time. Such a treatment will minimize systemic side effects and ...avoid the inconvenience of frequent injections. To this aim, nanocrystal–polymer particles (NPPs) are developed by combining the advantages of nanotechnology and microparticles. Nanocrystals are produced by wet milling kartogenin (KGN), which is known to promote chondrogenesis and to foster chondroprotection. A fluorescent biodegradable polymer is synthesized for intravital particle tracking. Polymer microparticles with 320 nm embedded KGN nanocrystals (KGN‐NPPs) show a high drug loading of 31.5% (w/w) and an extended drug release of 62% over 3 months. In vitro, these particles do not alter mitochondrial activity in cultured human OA synoviocytes. In vivo, KGN‐NPPs demonstrate higher bioactivity than a KGN solution in a murine mechanistic OA model based on histological assessment (Osteoarthritis Research Society International score), epiphyseal thickness (microcomputed tomography), OA biomarkers (e.g., vascular endothelial growth factor, Adamts5), and prolonged intra‐articular persistence (fluorescence analysis). This work provides proof‐of‐concept of a novel and innovative extended drug delivery system with the potential to treat human OA.
Nanocrystal‐Polymer Particles (NPPs) are an innovative drug delivery system. Nanocrystals of drug are embedded in biodegradable microparticles to provide a long‐term intra‐articular osteoarthritis therapy. The high drug loading and the sustained drug release (62% over 3 months) of NPPs allowed a therapeutic effect to be achieved on cartilage, bone, and biomarkers in diseased mice at 2 months.
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