RESUMO
Chronic venous disease (CVD) significantly impacts global health, presenting a complex challenge in medical management. Despite its prevalence and the burden it places on healthcare systems, CVD remains underdiagnosed and undertreated. This review aims to provide a comprehensive analysis of the bioactive compounds in the Citrus genus, exploring their therapeutic potential in CVD treatment and addressing the gap in current treatment modalities. A narrative review methodology was adopted, focusing on the pharmacological effects of Citrus-derived bioactive compounds, including flavonoids and terpenes. Additionally, the review introduced the DBsimilarity method for analyzing the chemical space and structural similarities among Citrus compounds. The review highlights the Citrus genus as a rich source of pharmacologically active compounds, notably flavonoids and terpenes, which exhibit significant anti-inflammatory, antioxidant, and veno-protective properties. Some of these compounds have been integrated into existing therapies, underscoring their potential for CVD management. The DBsimilarity analysis further identified many clusters of compounds with more than 85% structural similarity. Citrus-derived bioactive compounds offer promising therapeutic potential for managing CVD, showcasing significant anti-inflammatory, antioxidant, and veno-protective effects. The need for further comparative studies, as well as safety and efficacy investigations specific to CVD treatment, is evident. This review underlines the importance of advancing our understanding of these natural compounds and encouraging the development of novel treatments and formulations for effective CVD management. The DBsimilarity method's introduction provides a novel approach to exploring the chemical diversity within the Citrus genus, opening new pathways for pharmacological research.
Assuntos
Citrus , Citrus/química , Humanos , Doença Crônica , Flavonoides/farmacologia , Flavonoides/química , Flavonoides/isolamento & purificação , Flavonoides/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/química , Antioxidantes/uso terapêutico , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Anti-Inflamatórios/isolamento & purificação , Doenças Vasculares/tratamento farmacológicoRESUMO
We have developed a microemulsion (ME)-based hydrogel, containing propylene glycol, Azone®, Labrasol®, isobutanol and water (20:3:18:3:56), for the transdermal delivery of rivaroxaban (RVX). Formulation ME-1:RVX, which was loaded with 0.3 mg/g of RVX, presented as a clear, homogenous fluid with a droplet size of 82.01 ± 6.32 nm and a PdI of 0.207 ± 0.01. To provide gelation properties, 20 % (w/w) of Pluronic® F-127 was added to ME-1:RVX to generate formulation PME-1a. An added benefit was an increased capacity for RVX to 0.4 mg/g (formulation PME-1b). PME-1b displayed spherical droplets with a nanoscale diameter as observed by Transmission Electron Microscopy. The release of RVX from PME-1b was 20.71 ± 0.76 µg/cm2 with a permeation through pig epidermis of 18.32 ± 8.87 µg/cm2 as measured in a Franz Cell for 24 h. PME-1b presented a pseudoplastic behavior, pH value compatible with the skin and good stability over 60 days at room and elevated temperatures. The prothrombin time was assessed for each concentration of RVX obtained in the permeation assay and each demonstrated a relevant anticoagulant activity. PME-1b also presented no cytotoxicity against HaCaT cells. Utilizing GastroPlus® software, an in silico analysis was performed to simulate the delivery of PME-1b through a transdermal system that suggested a minimum dose of RVX for the treatment and prevention of venous thromboembolism could be achieved with an 8 h administration regimen. These results suggest that PME-1b is a promising transdermal formulation for the effective delivery of RVX that could be a viable alternative for the treatment and prevention of venous thromboembolism.
Assuntos
Rivaroxabana , Tromboembolia Venosa , Administração Cutânea , Animais , Emulsões , Hidrogéis , Pele , SuínosRESUMO
Tuberculosis (TB) is one of the most fatal diseases and is responsible for the infection of millions of people around the world. Most recently, scientific frontiers have been engaged to develop new drugs that can overcome drug-resistant TB. Following this direction, using a designed scaffold based on the combination of two separate pharmacophoric groups, a series of menadione-derived selenoesters was developed with good yields. All products were evaluated for their in vitro activity against Mycobacterium tuberculosis H37Rv and attractive results were observed, especially for the compounds 8a, 8c and 8f (MICs 2.1, 8.0 and 8.1 µM, respectively). In addition, 8a, 8c and 8f demonstrated potent in vitro activity against multidrug-resistant clinical isolates (CDCT-16 and CDCT-27) with promising MIC values ranging from 0.8 to 3.1 µM. Importantly, compounds 8a and 8c were found to be non-toxic against the Vero cell line. The SI value of 8a (>23.8) was found to be comparable to that of isoniazid (>22.7), which suggests the possibility of carrying out advanced studies on this derivative. Therefore, these menadione-derived selenoesters obtained as hybrid compounds represent promising new anti-tubercular agents to overcome TB multidrug resistance.
Assuntos
Antituberculosos/farmacologia , Mycobacterium tuberculosis/efeitos dos fármacos , Selênio/farmacologia , Vitamina K 3/farmacologia , Animais , Antituberculosos/síntese química , Antituberculosos/química , Chlorocebus aethiops , Humanos , Modelos Moleculares , Selênio/química , Tuberculose/tratamento farmacológico , Células Vero , Vitamina K 3/análogos & derivados , Vitamina K 3/síntese químicaRESUMO
Rivaroxaban (RXB), an oral direct factor Xa inhibitor, presents innovative therapeutic profile. However, RXB has shown adverse effects, mainly due to pharmacokinetic limitations, highlighting the importance of developing more effective formulations. Therefore, this work aims at the preparation, physicochemical characterization and in vitro evaluation of time-dependent anticoagulant activity and toxicology profile of RXB-loaded poly(lactic-co-glycolic acid) (PLGA)/poloxamer nanoparticles (RXBNps). RXBNp were produced by nanoprecipitation method and physicochemical characteristics were evaluated. In vitro analysis of time-dependent anticoagulant activity was performed by prothrombin time test and toxicological profile was assessed by hemolysis and MTT reduction assays. The developed RXBNp present spherical morphology with average diameter of 205.5 ± 16.95 nm (PdI 0.096 ± 0.04), negative zeta potential (-26.28 ± 0.77 mV), entrapment efficiency of 91.35 ± 2.40%, yield of 41.81 ± 1.68% and 3.72 ± 0.07% of drug loading. Drug release was characterized by an initial fast release followed by a sustained release with 28.34 ± 2.82% of RXB available in 72 h. RXBNp showed an expressive time-dependent anticoagulant activity in human and rat blood plasma and non-toxic profile. Based on the results presented, it is possible to consider that RXBNp may be able to assist in the development of promising new therapies for treatment of thrombotic disorders.
Assuntos
Anticoagulantes/química , Inibidores do Fator Xa/química , Nanopartículas/química , Poloxâmero/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Rivaroxabana/química , Animais , Anticoagulantes/farmacocinética , Sobrevivência Celular , Chlorocebus aethiops , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Inibidores do Fator Xa/farmacocinética , Hemólise , Humanos , Nanopartículas/ultraestrutura , Tamanho da Partícula , Ratos , Rivaroxabana/farmacocinética , Células VeroRESUMO
BACKGROUND: Leishmaniasis is a neglected tropical disease caused by protozoa of the genus Leishmania. Current treatments are restricted to a small number of drugs that display both severe side effects and a potential for parasites to develop resistance. A new N-(3,4-methylenedioxyphenyl)-N'- (2-phenethyl) thiourea compound (thiourea 1) has shown promising in vitro activity against Leishmania amazonensis with an IC50 of 54.14 µM for promastigotes and an IC50 of 70 µM for amastigotes. OBJECTIVE: To develop a formulation of thiourea 1 as an oral treatment for leishmaniasis, it was incorporated into Nanoparticles (NPs), a proven approach to provide long-acting drug delivery systems. METHODS: Poly (D,L-Lactic-co-Glycolic Acid) (PLGA) polymeric NPs containing thiourea 1 were obtained through a nanoprecipitation methodology associated with solvent evaporation. The NPs containing thiourea 1 were characterized for Encapsulation Efficiency (EE%), reaction yield (% w/w), surface charge, particle size and morphology by Transmission Electron Microscopy (TEM). RESULTS: NPs with thiourea 1 showed an improved in vitro leishmanicidal activity with a reduction in its cytotoxicity against macrophages (CC50>100 µg/mL) while preserving its IC50 against intracellular amastigotes (1.46 ± 0.09 µg/mL). This represents a parasite Selectivity Index (SI) of 68.49, which is a marked advancement from the reference drug pentamidine (SI = 30.14). CONCLUSION: The results suggest that the incorporation into NPs potentiated the therapeutic effect of thiourea 1, most likely by improving the selective delivery of the drug to the phagocytic cells that are targeted for infection by L. amazonensis. This work reinforces the importance of nanotechnology in the acquisition of new therapeutic alternatives for oral treatments.
Assuntos
Antiprotozoários/administração & dosagem , Portadores de Fármacos/química , Leishmania mexicana/efeitos dos fármacos , Leishmaniose Cutânea/tratamento farmacológico , Tioureia/administração & dosagem , Animais , Antiprotozoários/farmacocinética , Antiprotozoários/toxicidade , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Humanos , Leishmaniose Cutânea/parasitologia , Macrófagos/parasitologia , Camundongos , Nanopartículas/química , Testes de Sensibilidade Parasitária , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Cultura Primária de Células , Tioureia/análogos & derivados , Tioureia/farmacocinética , Tioureia/toxicidade , Testes de Toxicidade AgudaRESUMO
Bacterial infections represent one of the leading causes of mortality in the world. Among causative pathogens, S. aureus is prominently known as the underlying cause of many multidrug resistant infections that are often treated with the first-line choice antibiotic vancomycin (VCM). Loading antibiotics into polymeric nanoparticles (Np) displays promise as an alternative method to deliver therapy due to the greater access and accumulation of the antibiotic at the site of the infection as well as reducing toxicity, irritation and degradation. The aim of this work was to prepare, characterize and evaluate VCM-loaded nanoparticles (VNp) for use against S. aureus strains. Moreover, conjugation of Nps with holo-transferrin (h-Tf) was investigated as an approach for improving targeted drug delivery. VNp were prepared by double emulsion solvent evaporation method using PLGA and PVA or DMAB as surfactants. The particles were characterized for size distribution, Zeta Potential, morphology by transmission electron microscopy, encapsulation yield and protein conjugation efficiency. Process yield and drug loading were also investigated along with an in vitro evaluation of VNp antimicrobial effects against S. aureus strains. Results showed that Np were spontaneously formed with a mean diameter lower than 300 nm in a narrow size distribution that presented a spherical shape. The bioconjugation with h-Tf did not appear to increase the antimicrobial effect of VNp. However, non-bioconjugated Np presented a minimal inhibitory concentration lower than free VCM against a MRSA (Methicillin-resistant S. aureus) strain, and slightly higher against a VISA (VCM intermediate S. aureus) strain. VNp without h-Tf showed potential to assist in the development of new therapies against S. aureus infections.
Assuntos
Antibacterianos/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Nanopartículas/química , Vancomicina/farmacologia , Antibacterianos/química , Portadores de Fármacos/química , Testes de Sensibilidade Microbiana , Tamanho da Partícula , Staphylococcus aureus/efeitos dos fármacos , Transferrina/química , Vancomicina/químicaRESUMO
Leishmaniasis is a group of diseases caused by a protozoa parasite from one of over 20 Leishmania species. Depending on the tissues infected, these diseases are classified as cutaneous, mucocutaneous and visceral leishmaniasis. For the treatment of leishmaniasis refractory to antimony-based drugs, pentamidine (PTM) is a molecule of great interest. However, PTM displays poor bioavailability through oral routes due to its two strongly basic amidine moieties, which restricts its administration by a parenteral route and limits its clinical use. Among various approaches, nanotechnology-based drug delivery systems (nano-DDS) have potential to overcome the challenges associated with PTM oral administration. Here, we present the development of PTM-loaded PLGA nanoparticles (NPs) with a focus on the characterization of their physicochemical properties and potential application as an oral treatment of leishmaniasis. NPs were prepared by a double emulsion methodology. The physicochemical properties were characterized through the mean particle size, polydispersity index (PdI), zeta potential, entrapment efficiency, yield process, drug loading, morphology, in vitro drug release and in vivo pharmacological activity. The PTM-loaded PLGA NPs presented with a size of 263 ± 5 nm (PdI = 0.17 ± 0.02), an almost neutral charge (-3.2 ± 0.8 mV) and an efficiency for PTM entrapment of 91.5%. The release profile, based on PTM dissolution, could be best described by a zero-order model, followed by a drug diffusion profile that fit to the Higuchi model. In addition, in vivo assay showed the efficacy of orally given PTM-loaded PLGA NPs (0.4 mg kg-1) in infected BALB/c mice, with significant reduction of organ weight and parasite load in spleen (p-value < 0.05). This work successfully reported the oral use of PTM-loaded NPs, with a high potential for the treatment of visceral leishmaniasis, opening a new perspective to utilization of this drug in clinical practice.
Assuntos
Antiprotozoários/administração & dosagem , Leishmaniose/tratamento farmacológico , Pentamidina/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Administração Oral , Animais , Antiprotozoários/química , Antiprotozoários/farmacocinética , Disponibilidade Biológica , Modelos Animais de Doenças , Leishmaniose/parasitologia , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/química , Tamanho do Órgão/efeitos dos fármacos , Carga Parasitária , Tamanho da Partícula , Pentamidina/química , Pentamidina/farmacocinéticaRESUMO
In this study, the formation of caffeine/dapsone (CAF/DAP) cocrystals by scalable production methods, such as liquid-assisted grinding (LAG) and spray drying, was investigated in the context of the potential use of processed cocrystal powder for pulmonary delivery. A CAF/DAP cocrystal (1:1 M ratio) was successfully prepared by slow evaporation from both acetone and ethyl acetate. Acetone, ethyl acetate, and ethanol were all successfully used to prepare cocrystals by LAG and spray drying. The powders obtained were characterized by X-ray diffractometry (XRD), differential scanning calorimetry (DSC), thermogravimetry (TGA), and Fourier transform infrared spectroscopy (FTIR). Laser diffraction analysis indicated a median particle size (D50) for spray-dried powders prepared from acetone, ethanol, and ethyl acetate of 5.4 ± 0.7, 5.2 ± 0.1, and 5.1 ± 0.0 µm respectively, which are appropriate sizes for pulmonary delivery by means of a dry powder inhaler. The solubility of the CAF/DAP cocrystal in phosphate buffer pH 7.4, prepared by spray drying using acetone, was 506.5 ± 31.5 µg/mL, while pure crystalline DAP had a measured solubility of 217.1 ± 7.8 µg/mL. In vitro cytotoxicity studies using Calu-3 cells indicated that the cocrystals were not toxic at concentrations of 0.1 and of 1 mM of DAP, while an in vitro permeability study suggested caffeine may contribute to the permeation of DAP by hindering the efflux effect. The results obtained indicate that the CAF/DAP cocrystal, particularly when prepared by the spray drying method, represents a possible suitable approach for inhalation formulations with applications in pulmonary pathologies.
Assuntos
Cafeína/análise , Cafeína/síntese química , Química Farmacêutica/métodos , Cristalização/métodos , Dapsona/síntese química , Administração por Inalação , Varredura Diferencial de Calorimetria/métodos , Linhagem Celular , Dapsona/análise , Dessecação/métodos , Composição de Medicamentos/métodos , Inaladores de Pó Seco , Humanos , Microscopia Eletrônica de Varredura/métodos , Tamanho da Partícula , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Termogravimetria/métodos , Difração de Raios X/métodosRESUMO
Fucoidan-loaded nanoparticles emerge as great candidates to oral anticoagulant therapy, due to increasing of bioavailability and circulation time of this natural anticoagulant. Crosslink between chitosan chains are performed using glutaraldehyde to confer higher gastric pH resistance to nanoparticle matrices. In this work, chitosan-fucoidan nanoparticles, without (NpCF) and with glutaraldehyde crosslink (NpCF 1% and NpCF 2%), were prepared to evaluate their anticoagulant, antithrombotic and hemorrhagic profile. Nanoparticles were characterized by average diameter, polydispersity index, zeta potential, Fourier transform infrared spectroscopy and fucoidan in vitro release. Anticoagulant and antithrombotic activities were determined by in vitro and in vivo models, respectively. Hemorrhagic profile was in vivo evaluated by tail bleeding assay. Preparations showed nanometric and homogeneous average diameters. Zeta potentials of NpCF and NpCF 1% were stable over gastrointestinal pH range, which was confirmed by low fucoidan release in gastric and enteric media. In pH 7.4, NpCF and NpCF 1% demonstrated fucoidan release of 65.5% and 60.6%, respectively, within the first 24 hours. In comparison to fucoidan, NpCF and NpCF 1% showed increased in vitro anticoagulant activity. A significant difference on oral antithrombotic profile of NpCF 1% was found in comparison to fucoidan. Bleeding profile of NpCF and NpCF 1% showed no differences to control group, indicating the safety of these systems. Surprisingly, oral antithrombotic profile of commercially available fucoidan, from Fucus vesiculosus, has not been previously determined, which reveals new possibilities. In this work, significant advances were observed in anticoagulant and antithrombotic profiles of fucoidan through the preparation of NpCF 1%.
RESUMO
BACKGROUND: Diarrhea in piglets is one of the main causes of animal death after weaning; zinc oxide (ZnO) has been used in high doses for the control of this sickness. The aim of this study was to determine the physicochemical properties of ZnO nanoparticles synthesized and immobilized on a chitosan/alginate (CH/SA) complex and investigate the antimicrobial activity and in vitro release profile of zinc (Zn2+) from these new compounds. The ZnO nanoparticles composites were prepared and combined with CH/SA or CH/SA and sodium tripolyphosphate (TPP). The structure and morphology of the composites were analyzed by characterization methods such as X-ray diffraction, FTIR spectroscopy, thermogravimetric analysis, atomic absorption spectrophotometry and scanning electron microscopy. RESULTS: The crystallite size of ZnO nano was 17 nm and the novel ZnO composites were effective in protecting ZnO in simulated gastric fluid, where Zn2+ reached a concentration six-fold higher than the levels obtained with the unprotected commercial-zinc oxide. In addition, the novel composites suggest effective antimicrobial activity against Escherichia coli and Staphylococcus aureus. CONCLUSIONS: The results described herein suggest that the novel nano composites may work as an alternative product for pig feeding as verified by the in vitro assays, and may also contribute to lower the zinc released in the environment by fecal excretion in animals waste.
Assuntos
Antibacterianos/farmacologia , Suco Gástrico/efeitos dos fármacos , Nanopartículas , Óxido de Zinco/farmacologia , Alginatos/química , Animais , Antibacterianos/administração & dosagem , Líquidos Corporais/efeitos dos fármacos , Quitosana/química , Escherichia coli/efeitos dos fármacos , Ácido Glucurônico/química , Ácidos Hexurônicos/química , Secreções Intestinais/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Nanopartículas/química , Espectroscopia de Infravermelho com Transformada de Fourier , Staphylococcus aureus/efeitos dos fármacos , Suínos , Difração de Raios X , Óxido de Zinco/administração & dosagemRESUMO
Prostate cancer remains an increasingly common malignancy worldwide. Many advances in drug development have been achieved for the conventional treatments; however, chemotherapeutic agents are distributed nonspecifically in the body where they affect both prostate cancer and healthy cells. Limited dose achievable within the prostate tumor and suboptimal treatment due to excessive toxicities reveal the importance of the development of more specific mechanisms and ways of drug targeting to prostate tumor. In this context, nanotechnology, molecular biology and biochemistry have been applied in the pharmaceutical area for development of new targeted drug delivery nanosystems in order to improve its pharmacokinetic profile, raise the effectiveness of treatment; reduce side effects due to the preferential accumulation in prostate cancer cells, causing low concentrations in healthy tissues; and/or increase the drug chemical stability for improving the prostate cancer therapeutic. Thus, in this review, we will discuss the molecular and biochemical basis of prostate cancer as well as the advantages and disadvantages of conventional clinical treatments, different types and basic characteristics of nanosystems; how these systems can be targeted to prostate cancer, show successful patent examples of prostate cancer targeted nanosystems and present perspectives for the next 10-20 years in this area.
Assuntos
Antineoplásicos/farmacologia , Nanoestruturas/química , Nanotecnologia , Neoplasias da Próstata/tratamento farmacológico , Animais , Antineoplásicos/química , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Humanos , Masculino , Neoplasias da Próstata/patologiaRESUMO
The aim of this work was the development and characterization of nisin-loaded nanoparticles and the evaluation of its potential antifungal activity. Candidiasis is a fungal infection caused by Candida sp. considered as one of the major public health problem currently. The discovery of antifungal agents that present a reduced or null resistance of Candida sp. and the development of more efficient drug release mechanisms are necessary for the improvement of candidiasis treatment. Nisin, a bacteriocin commercially available for more than 50 years, exhibits antibacterial action in food products with potential antifungal activity. Among several alternatives used to modulate antifungal activity of bacteriocins, polymeric nanoparticles have received great attention due to an effective drug release control and reduction of therapeutic dose, besides the minimization of adverse effects by the preferential accumulation in specific tissues. The nisin nanoparticles were prepared by double emulsification and solvent evaporation methods. Nanoparticles were characterized by dynamic light scattering, zeta potential, Fourier transform infrared, X-ray diffraction, differential scanning calorimetry, and scanning electron microscopy. Antifungal activity was accessed by pour plate method and cell counting using Candida albicans strains. The in vitro release profile and in vitro permeation studies were performed using dialysis bag method and pig vaginal mucosa in Franz diffusion cell, respectively. The results revealed nisin nanoparticles (300 nm) with spherical shape and high loading efficiency (93.88 ± 3.26%). In vitro test results suggest a promising application of these nanosystems as a prophylactic agent in recurrent vulvovaginal candidiasis and other gynecological diseases.
Assuntos
Antifúngicos/administração & dosagem , Antifúngicos/química , Candidíase/tratamento farmacológico , Nanopartículas/administração & dosagem , Nanopartículas/química , Nisina/administração & dosagem , Nisina/química , Animais , Varredura Diferencial de Calorimetria/métodos , Candida albicans/efeitos dos fármacos , Candidíase/microbiologia , Feminino , Tamanho da Partícula , Polímeros/química , Suínos , Vagina/microbiologia , Difração de Raios X/métodosRESUMO
In the present study, we evaluated 457 patent applications filed for crystalline forms of nonprotein drugs during the period 1995-2005 in Brazil. Online searches were conducted using the Instituto Nacional da Propriedade Industrial patent database and the Derwent Innovations Index(®). It was found that no patent applications in this area were filed by Brazilian applicants. It was also noted that only 61% of patent applications included the characterization of three or more crystalline phase techniques. In most applications, no determination of purity was provided for chemical and/or crystalline phases. In a subset of patent applications, those for blockbuster drugs, we found that approximately 90% did not meet Instituto Nacional da Propriedade Industrial acceptance criteria nor the criteria developed in this study. These results reveal that appropriate and thorough characterization of the crystalline forms of drugs is, indeed, lacking in patent applications.
Assuntos
Patentes como Assunto , Brasil , Cristalização , Indústria Farmacêutica , Preparações Farmacêuticas/química , Difração de Raios XRESUMO
The aim of this study was to produce and characterize nanoparticles (NPs), combining chondroitin sulfate (CS) and fucoidan (FC) with chitosan for therapeutic purposes. These NPs were characterized by dynamic light scattering, zeta potential determination, and transmission electronic microscopy. The anticoagulant activity was determined for FC NPs and compared with FC solution at the same concentration. FC NPs showed regular shapes and better anticoagulant activity than free polysaccharide solution. FC solution did not affect coagulation compared to FC NPs, which increased up to two-fold, even at a lower concentration. Cytotoxicity and permeability tests were conducted using Caco-2 cell monolayer, exhibiting no toxic effect in this cell line and higher permeability for NP2 samples than FC solution at the same concentration.