RESUMO
Escherichia coli and Staphylococcus aureus are important agents of urinary tract infections that can often evolve to severe infections. The rise of antibiotic-resistant strains has driven the search for novel therapies to replace the use or act as adjuvants of antibiotics. In this context, plant-derived compounds have been widely investigated. Cuminaldehyde is suggested as the major antimicrobial compound of the cumin seed essential oil. However, this effect is not fully understood. Herein, we investigated the in silico and in vitro activities of cuminaldehyde, as well as its ability to potentiate ciprofloxacin effects against S. aureus and E. coli. In silico analyses were performed by using different computational tools. The PASS online and SwissADME programmes were used for the prediction of biological activities and oral bioavailability of cuminaldehyde. For analysis of the possible toxic effects and the theoretical pharmacokinetic parameters of the compound, the Osiris, SwissADME and PROTOX programmes were used. Estimations of cuminaldehyde gastrointestinal absorption, blood brain barrier permeability and skin permeation by using SwissADME; and drug likeness and score by using Osiris, were also evaluated The in vitro antimicrobial effects of cuminaldehyde were determined by using microdilution, biofilm formation and time-kill assays. In silico analysis indicated that cuminaldehyde may act as an antimicrobial and as a membrane permeability enhancer. It was suggested to be highly absorbable by the gastrointestinal tract and likely to cross the blood brain barrier. Also, irritative and harmful effects were predicted for cuminaldehyde if swallowed at its LD50. Good oral bioavailability and drug score were also found for this compound. Cuminaldehyde presented antimicrobial and anti-biofilm effects against S. aureus and E. coli.. When co-incubated with ciprofloxacin, it enhanced the antibiotic antimicrobial and anti-biofilm actions. We suggest that cuminaldehyde may be useful as an adjuvant therapy to ciprofloxacin in S. aureus and E. coli-induced infections.
Assuntos
Antibacterianos/administração & dosagem , Benzaldeídos/administração & dosagem , Ciprofloxacina/administração & dosagem , Cimenos/administração & dosagem , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Adjuvantes Farmacêuticos/administração & dosagem , Adjuvantes Farmacêuticos/farmacocinética , Adjuvantes Farmacêuticos/toxicidade , Administração Oral , Benzaldeídos/farmacocinética , Benzaldeídos/toxicidade , Biofilmes/efeitos dos fármacos , Biofilmes/crescimento & desenvolvimento , Disponibilidade Biológica , Simulação por Computador , Cimenos/farmacocinética , Cimenos/toxicidade , Sinergismo Farmacológico , Escherichia coli/patogenicidade , Escherichia coli/fisiologia , Infecções por Escherichia coli/tratamento farmacológico , Humanos , Técnicas In Vitro , Testes de Sensibilidade Microbiana , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/patogenicidade , Staphylococcus aureus/fisiologia , Infecções Urinárias/tratamento farmacológicoRESUMO
Leishmaniasis are a group of neglected infectious diseases caused by protozoa of the genus Leishmania with distinct presentations. The available leishmaniasis treatment options are either expensive and/or; cause adverse effects and some are ineffective for resistant Leishmania strains. Therefore, molecules derived from natural products as the monoterpene carvacrol, have attracted interest as promising anti-leishmania agents. However, the therapeutic use of carvacrol is limited due to its low aqueous solubility, rapid oxidation and volatilization. Thus, the development of nanostructured lipid carriers (NLCs) was proposed in the present study as a promising nanotechnology strategy to overcome these limitations and enable the use of carvacrol in leishmaniasis therapy. Carvacrol NLCs were obtained using a warm microemulsion method, and evaluated regarding the influence of lipid matrix and components concentration on the NLCs formation. NLCs were characterized by DSC and XRD as well. In addition, to the in vitro carvacrol release from NLCs, the in vitro cytotoxicity and leishmanicidal activity assays, and the in vivo pharmacokinetics evaluation of free and encapsulated carvacrol were performed. NLCs containing carvacrol were obtained successfully using a warm microemulsion dilution method. The NLCs formulation with the lowest particle size (98.42 ± 0.80 nm), narrowest size distribution (suitable for intravenous administration), and the highest encapsulation efficiency was produced by using beeswax as solid lipid (HLB=9) and 5% of lipids and surfactant. The in vitro release of carvacrol from NLCs was fitted to the Korsmeyer and Peppas, and Weibull models, demonstrating that the release mechanism is probably the Fickian diffusion type. Moreover, carvacrol encapsulation in NLCs provided a lower cytotoxicity in comparison to free carvacrol (p<0.05), increasing its in vitro leishmanicidal efficacy in the amastigote form. Finally, the in vivo pharmacokinetics of carvacrol after IV bolus administration suggests that this phenolic monoterpene undergoes enterohepatic circulation and therefore presented a long half-life (t1/2) and low clearance (Cl). In addition, C0, mean residence time (MRT) and Vdss of encapsulated carvacrol were higher than free carvacrol (p < 0.05), favoring a higher distribution of carvacrol in the target tissues. Thus, it is possible to conclude that the developed NLCs are a promising delivery system for leishmaniasis treatment.
Assuntos
Antiprotozoários/administração & dosagem , Cimenos/administração & dosagem , Portadores de Fármacos/administração & dosagem , Leishmania/efeitos dos fármacos , Nanoestruturas/administração & dosagem , Animais , Antiprotozoários/sangue , Antiprotozoários/química , Antiprotozoários/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Cimenos/sangue , Cimenos/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Liberação Controlada de Fármacos , Humanos , Leishmaniose/tratamento farmacológico , Lipídeos/administração & dosagem , Lipídeos/química , Lipídeos/farmacocinética , Macrófagos Peritoneais/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB C , Nanoestruturas/química , Ratos Wistar , Células THP-1RESUMO
The search for new drugs with anti-inflammatory properties remains a challenge for modern medicine. Among the various strategies for drug discovery, deriving new chemical entities from known bioactive natural and/or synthetic compounds remains a promising approach. Here, we designed and synthesized CVIB, a codrug developed by association of carvacrol (a phenolic monoterpene) with ibuprofen (a non-steroidal anti-inflammatory drug). In silico pharmacokinetic and physicochemical properties evaluation indicated low aqueous solubility (LogP ≥5.0). Nevertheless, the hybrid presented excellent oral bioavailability, gastrointestinal tract absorption, and low toxicity. CVIB did not present cytotoxicity in peripheral blood mononuclear cells (PBMCs), and promoted a significant reduction in IL-2, IL-10, IL-17, and IFN-γ cytokine levels in vitro. The LD50 was estimated to be approximately 5000â¯mg/kg. CVIB was stable and detectable in human plasma after 24â¯h. In vivo anti-inflammatory evaluations revealed that CVIB at 10 and 50â¯mg/kgâ¯i.p. caused a significant decrease in total leukocyte count (pâ¯<â¯0.01) and provoked a significant reduction in IL-1ß (pâ¯<â¯0.01). CVIB at 10â¯mg/kgâ¯i.p. efficiently decreased inflammatory parameters better than the physical mixture (carvacrol + ibuprofen 10â¯mg/kgâ¯i.p.). The results suggest that the codrug approach is a good option for drug design and development, creating the possibility of combining NSAIDs with natural products in order to obtain new hybrid drugs may be useful for treatment of inflammatory diseases.