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1.
Drug Des Devel Ther ; 15: 3349-3378, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34376971

RESUMO

Dalbavancin is a novel, long-acting lipoglycopeptide characterized by a long elimination half-life coupled with excellent in vitro activity against multidrug-resistant Gram-positives. Although it is currently approved only for the treatment of acute bacterial skin and skin structure infections, an ever-growing amount of evidence supports the efficacy of dalbavancin as a long-term therapy in osteomyelitis, prosthetic joint infections, endocarditis, and bloodstream infections. This article provides a critical reappraisal of real-world use of dalbavancin for off-label indications. A search strategy using specific keywords (dalbavancin, osteomyelitis, endocarditis, long-term suppressive therapy, bloodstream infection, pharmacokinetic/pharmacodynamic profile) until April 2021 was performed on the PubMed-MEDLINE database. As for other novel antibiotics, a conundrum between approved indications and potential innovative therapeutic uses has emerged for dalbavancin as well. The promising efficacy in challenging scenarios (i.e., osteomyelitis, endocarditis, prosthetic joint infections), coupled with the unique pharmacokinetic/pharmacodynamic properties, makes dalbavancin a valuable alternative to daily in-hospital intravenous or outpatient antimicrobial regimens in the treatment of long-term Gram-positive infections. This makes dalbavancin valuable in the current COVID-19 scenario, in which hospitalization and territorial medicine empowerment are unavoidable.


Assuntos
Assistência Ambulatorial , Antibacterianos/uso terapêutico , COVID-19 , Infecções por Bactérias Gram-Positivas/tratamento farmacológico , Uso Off-Label , Participação do Paciente , Teicoplanina/análogos & derivados , Algoritmos , Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Tomada de Decisão Clínica , Técnicas de Apoio para a Decisão , Infecções por Bactérias Gram-Positivas/diagnóstico , Infecções por Bactérias Gram-Positivas/microbiologia , Humanos , Teicoplanina/efeitos adversos , Teicoplanina/farmacocinética , Teicoplanina/uso terapêutico , Resultado do Tratamento
2.
Medicine (Baltimore) ; 100(32): e26889, 2021 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-34397910

RESUMO

ABSTRACT: Our purpose was to assess pediatricians' knowledge of augmented renal clearance (ARC).We conducted cross-sectional analyses of 500 pediatricians from 16 tertiary hospitals in Anhui Province, China. Pediatricians provided demographic information and were asked questions about their knowledge of ARC, including risk factors, evaluation tools, and the impact on patient prognosis, with a focus on the attitude and practice of pediatricians related to adjusting vancomycin regimens when ARC occurs.A total of 491 valid questionnaires were finally included, only 276 pediatricians stated that they "know about ARC." Compared with the "do not know about ARC" group, the "know about ARC" group was younger (43.7 ±â€Š8.0 vs 48.0 ±â€Š7.9, P < .001), and their main source of ARC knowledge was from social networking platforms. A total of 193 (70%) chose at least 4 of the following factors as risk factors for children with ARC: severe trauma, sepsis, burns, major surgery, lower disease severity, and hematological malignancies. A total of 110 (40%) and 105 (38%) pediatricians chose the Schwartz formula and cystatin C, respectively, as the indicators to evaluate the renal function of ARC children. Concerning the estimated glomerular filtration rate threshold to identify ARC children, 201 (73%) pediatricians chose 130 mL/min/1.73 m2, while 55 (20%) chose "age-dependent ARC thresholds." Overall, 220 (80%) respondents indicated that ARC would impact the treatment effect of vancomycin, but 149/220 (68%) were willing to adjust the vancomycin regimen; only 22/149 (8%) considered that the dose should be increased, but no one knew how to increase. Regarding the prognosis of ARC children, all respondents chose "unclear."ARC is relatively common in critically ill children, but pediatricians do not know much about it, as most of the current knowledge is based on adult studies. Furthermore, ARC is often confused with acute kidney injury, which would lead to very serious treatment errors. Therefore, more pediatric studies about ARC are needed, and ARC should be written into official pediatric guidelines as soon as possible to provide reference for pediatricians.


Assuntos
Antibacterianos/farmacocinética , Taxa de Filtração Glomerular/efeitos dos fármacos , Conhecimentos, Atitudes e Prática em Saúde , Pediatras/normas , Insuficiência Renal/tratamento farmacológico , Adulto , Criança , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal/metabolismo , Fatores de Risco
3.
Molecules ; 26(16)2021 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-34443429

RESUMO

A series of 16 new derivatives of harmine N9-Cinnamic acid were synthesized and fully characterized using NMR and MS. The in vitro antibacterial evaluation revealed that most of the synthesized harmine derivatives displayed better antibacterial activities against Gram-positive strains (S. aureus, S. albus and MRSA) than Gram-negative strains (E. coli and PA). In particular, compound 3c showed the strongest bactericidal activity with a minimum inhibitory concentration of 13.67 µg/mL. MTT assay showed that compound 3c displayed weaker cytotoxicity than harmine with IC50 of 340.30, 94.86 and 161.67 µmol/L against WI-38, MCF-7 and HepG2 cell lines, respectively. The pharmacokinetic study revealed that the distribution and elimination of 3c in vivo were rapid in rats with an oral bioavailability of 6.9%.


Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacocinética , Cinamatos/síntese química , Cinamatos/farmacocinética , Animais , Antibacterianos/administração & dosagem , Antibacterianos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Cinamatos/administração & dosagem , Cinamatos/química , Feminino , Humanos , Injeções Intravenosas , Masculino , Testes de Sensibilidade Microbiana , Conformação Molecular , Ratos Sprague-Dawley , Fatores de Tempo
4.
Molecules ; 26(11)2021 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-34198944

RESUMO

Single crystal of furazolidone (FZL) has been successfully obtained, and its crystal structure has been determined. Common and distinctive features of furazolidone and nitrofurantoin (NFT) crystal packing have been discussed. Combined use of QTAIMC and Hirshfeld surface analysis allowed characterizing the non-covalent interactions in both crystals. Thermophysical characteristics and decomposition of NFT and FZL have been studied by differential scanning calorimetry (DSC), thermogravimetric analysis (TG) and mass-spectrometry. The saturated vapor pressures of the compounds have been measured using the transpiration method, and the standard thermodynamic functions of sublimation were calculated. It was revealed that the sublimation enthalpy and Gibbs energy of NFT are both higher than those for FZL, but a gain in the crystal lattice energy of NFT is leveled by an entropy increase. The solubility processes of the studied compounds in buffer solutions with pH 2.0, 7.4 and in 1-octanol was investigated at four temperatures from 298.15 to 313.15 K by the saturation shake-flask method. The thermodynamic functions of the dissolution and solvation processes of the studied compounds have been calculated based on the experimental data. Due to the fact that NFT is unstable in buffer solutions and undergoes a solution-mediated transformation from an anhydrate form to monohydrate in the solid state, the thermophysical characteristics and dissolution thermodynamics of the monohydrate were also investigated. It was demonstrated that a combination of experimental and theoretical methods allows performing an in-depth study of the relationships between the molecular and crystal structure and pharmaceutically relevant properties of nitrofuran antibiotics.


Assuntos
Antibacterianos/química , Furazolidona/química , Nitrofurantoína/química , Antibacterianos/farmacocinética , Varredura Diferencial de Calorimetria , Cristalografia por Raios X , Teoria da Densidade Funcional , Furazolidona/farmacocinética , Espectrometria de Massas , Estrutura Molecular , Nitrofurantoína/farmacocinética , Solubilidade , Termodinâmica , Termogravimetria
5.
Molecules ; 26(12)2021 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-34199316

RESUMO

Herbs and spices have been used since antiquity for their nutritional and health properties, as well as in traditional remedies for the prevention and treatment of many diseases. Therefore, this study aims to perform a chemical analysis of both essential oils (EOs) from the seeds of Carum carvi (C. carvi) and Coriandrum sativum (C. sativum) and evaluate their antioxidant, antimicrobial, anti-acetylcholinesterase, and antidiabetic activities alone and in combination. Results showed that the EOs mainly constitute monoterpenes with γ-terpinene (31.03%), ß-pinene (18.77%), p-cymene (17.16%), and carvone (12.20%) being the major components present in C. carvi EO and linalool (76.41%), γ-terpinene (5.35%), and α-pinene (4.44%) in C. sativum EO. In comparison to standards, statistical analysis revealed that C. carvi EO showed high and significantly different (p < 0.05) antioxidant activity than C. sativum EO, but lower than the mixture. Moreover, the mixture exhibited two-times greater ferric ion reducing antioxidant power (FRAP) (IC50 = 11.33 ± 1.53 mg/mL) and equipotent chelating power (IC50 = 31.33 ± 0.47 mg/mL) than the corresponding references, and also potent activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) (IC50 = 19.00 ± 1.00 mg/mL), ß-carotene (IC50 = 11.16 ± 0.84 mg/mL), and superoxide anion (IC50 = 10.33 ± 0.58 mg/mL) assays. Antimicrobial data revealed that single and mixture EOs were active against a panel of pathogenic microorganisms, and the mixture had the ability to kill more bacterial strains than each EO alone. Additionally, the anti-acetylcholinesterase and α-glucosidase inhibitory effect have been studied for the first time, highlighting the high inhibition effect of AChE by C. carvi (IC50 = 0.82 ± 0.05 mg/mL), and especially by C. sativum (IC50 = 0.68 ± 0.03 mg/mL), as well as the mixture (IC50 = 0.63 ± 0.02 mg/mL) compared to the reference drug, which are insignificantly different (p > 0.05). A high and equipotent antidiabetic activity was observed for the mixture (IC50 = 0.75 ± 0.15 mg/mL) when compared to the standard drug, acarbose, which is about nine times higher than each EO alone. Furthermore, pharmacokinetic analysis provides some useful insights into designing new drugs with favorable drug likeness and safety profiles based on a C. carvi and C. sativum EO mixture. In summary, the results of this study revealed that the combination of these EOs may be recommended for further food, therapeutic, and pharmaceutical applications, and can be utilized as medicine to inhibit several diseases.


Assuntos
Acetilcolinesterase/química , Antibacterianos/farmacologia , Antioxidantes/farmacologia , Carum/química , Coriandrum/química , Hipoglicemiantes/farmacologia , Óleos Voláteis/farmacologia , Antibacterianos/química , Antibacterianos/farmacocinética , Antioxidantes/química , Antioxidantes/farmacocinética , Hipoglicemiantes/química , Hipoglicemiantes/farmacocinética , Óleos Voláteis/química , Óleos Voláteis/farmacocinética , Sementes/química
6.
Expert Opin Drug Metab Toxicol ; 17(9): 1039-1048, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34225556

RESUMO

Introduction: Usage of ceftriaxone-based therapy to treat Methicillin-Susceptible Staphylococcus aureus (MSSA) infections is a controversial issue, from in vitro to clinical studies.Area covered: We conducted a literature review using PubMed of articles with ceftriaxone pharmacokinetics parameters and built a probability of target attainment (PTA) based on PK values from stable conditions (non-critically-ill patients) with goals of fT>55%, fT>75%, and fT>100%. Ceftriaxone's minimal inhibitory concentration from 31 MSSA strains (0.25-64 mg/L) was used to build the cumulative fraction response (CFR). The isolates were clinically relevant from blood, bronchoalveolar lavage, and soft tissue biopsy.Expert opinion: The results from controversies about using ceftriaxone for MSSA infections have been commonly addressed in the literature. However, variables such as (i) pharmacokinetic profile, (ii) pharmacodynamic target, (iii) site of infection, and (iv) MIC distributions may influence divergences. From this pharmacokinetics-pharmacodynamics perspective, ceftriaxone may be a reasonable option for MSSA infections when the MIC50 and MIC90 were 4 mg/L and 8 mg/L. CFR analysis demonstrated that ceftriaxone 1 g q24 h could be used if bacteriostasis is the aim (fT>55%), while 1 g q12h should be used for bactericidal effects (fT>75% or fT>100%). These dosing regimens should be considered in other clinical trials.


Assuntos
Antibacterianos/administração & dosagem , Ceftriaxona/administração & dosagem , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Ceftriaxona/farmacocinética , Ceftriaxona/farmacologia , Esquema de Medicação , Farmacorresistência Bacteriana , Humanos , Meticilina/farmacologia , Testes de Sensibilidade Microbiana , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/isolamento & purificação
7.
Int J Nanomedicine ; 16: 4031-4044, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34140770

RESUMO

Introduction: Topical agents typically remain in the wound site for time duration that are too short to effectively eradicate MRSA tradition formation of BZK that can be maintained within the wound site for longer time periods, should be more effective. Methods: The novel chitosan and poly (D,L-lactide-co-glycoside) nanoparticles loaded with benzalkonium bromide (BZK) were designed, for the promotion wound healing after MRSA infection. The physical characterization of these nanoparticles, as well as their antibacterial activity in vitro, release profile in simulated wound fluid, cell toxicity, anti-biofilm activity, and their ability to improve the skin wound healing in a mouse model were also studied. Results: These novel nanoparticles were found to have a significant antibacterial activity (p<0.01), both in vitro and in vivo test. The stronger anti-biofilm ability of the nanoparticles to inhibit the formation of bacterial biofilms, at a concentration of 3.33 µg/mL, and clear existing bacterial biofilms, at a concentration of 5 mg/mL, compared with its water solution. In addition, significant damage to bacterial cell walls also was found, providing insight into the mechanism of antibacterial activity. Conclusion: Taken together, these results demonstrated the ability of BZK-loaded nanoparticles in the promotion of skin wound healing with MRSA infection. The current findings open a new avenue for nanomedicine development and future clinical applications in the treatment of wounds.


Assuntos
Antibacterianos/farmacologia , Compostos de Benzalcônio/administração & dosagem , Nanopartículas/administração & dosagem , Infecções Cutâneas Estafilocócicas/tratamento farmacológico , Cicatrização/efeitos dos fármacos , Animais , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Compostos de Benzalcônio/farmacocinética , Compostos de Benzalcônio/farmacologia , Biofilmes/efeitos dos fármacos , Quitosana/química , Sistemas de Liberação de Medicamentos , Feminino , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/patogenicidade , Camundongos Endogâmicos BALB C , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Álcool de Polivinil/administração & dosagem , Álcool de Polivinil/farmacologia , Infecções Cutâneas Estafilocócicas/microbiologia
8.
AAPS PharmSciTech ; 22(5): 195, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34184117

RESUMO

Microbial keratitis (MK) is a vision-threatening disease and the fourth leading cause of blindness worldwide. In this work, we aim to develop moxifloxacin (MXN)-loaded chitosan-based cationic mucoadhesive polyelectrolyte nanocapsules (PENs) for the effective treatment of MK. PENs were formulated by polyelectrolyte complex coacervation method and characterized for their particle size, surface charge, morphology, mucoadhesive property, in-vitro and ex-vivo release, ocular tolerance, and antimicrobial efficacy studies. The pharmacodynamic study was conducted on rabbit eye model of induced keratitis and it is compared with marketed formulation (MF). Developed PENs showed the size range from 230.7 ± 0.64 to 249.0 ± 0.49 nm and positive surface charge, spherical shape along with appropriate physico-chemical parameters. Both in-vitro and ex-vivo examination concludes that PENs having more efficiency in sustained release of MXN compared to MF. Ocular irritation studies demonstrated that no corneal damage or ocular irritation. The in-vivo study proved that the anti-bacterial efficacy of PENs was improved when compared with MF. These results suggested that PENs are a feasible choice for MK therapy because of their ability to enhance ocular retention of loaded MXN through interaction with the corneal surface of the mucous membrane.


Assuntos
Desenvolvimento de Medicamentos/métodos , Ceratite/tratamento farmacológico , Moxifloxacina/síntese química , Nanocápsulas/química , Polieletrólitos/síntese química , Animais , Antibacterianos/administração & dosagem , Antibacterianos/síntese química , Antibacterianos/farmacocinética , Embrião de Galinha , Córnea/efeitos dos fármacos , Córnea/metabolismo , Córnea/microbiologia , Cabras , Ceratite/metabolismo , Ceratite/microbiologia , Moxifloxacina/administração & dosagem , Moxifloxacina/farmacocinética , Nanocápsulas/administração & dosagem , Polieletrólitos/administração & dosagem , Polieletrólitos/farmacocinética , Coelhos
9.
J Med Chem ; 64(12): 8644-8665, 2021 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-34080858

RESUMO

Due to the poor permeability across Gram-negative bacterial membranes and the troublesome bacterial efflux mechanism, only a few GyrB/ParE inhibitors with potent activity against Gram-negative pathogens have been reported. Among them, pyrimido[4,5-b]indole derivatives represented by GP-1 demonstrated excellent broad-spectrum antibacterial activity against both Gram-positive and Gram-negative bacteria but were limited by hERG inhibition and poor pharmacokinetics profile. To improve their drug-like properties, we designed a series of novel pyrimido[4,5-b]indole derivatives based on the tricyclic scaffold of GP-1 and the C-7 moiety of acorafloxacin. These efforts have culminated in the discovery of a promising compound 18r with reduced hERG liability and an improved PK profile. Compound 18r exhibited superior broad-spectrum in vitro antibacterial activity compared to GP-1, including a variety of clinical multidrug G- pathogens, especially Acinetobacter baumannii, and the in vivo efficacy was also demonstrated in a neutropenic mouse thigh model of infection with multidrug-resistant A. baumannii.


Assuntos
Infecções por Acinetobacter/tratamento farmacológico , Antibacterianos/uso terapêutico , Bactérias/efeitos dos fármacos , Indóis/uso terapêutico , Pirimidinas/uso terapêutico , Animais , Antibacterianos/síntese química , Antibacterianos/metabolismo , Antibacterianos/farmacocinética , DNA Girase/metabolismo , Desenho de Fármacos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Estabilidade de Medicamentos , Células HEK293 , Humanos , Indóis/síntese química , Indóis/metabolismo , Indóis/farmacocinética , Testes de Sensibilidade Microbiana , Microssomos Hepáticos/metabolismo , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/metabolismo , Pirimidinas/farmacocinética , Ratos , Relação Estrutura-Atividade
10.
Biomed Pharmacother ; 140: 111768, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34058442

RESUMO

A large number of infections are caused by multi-resistant bacteria worldwide, adding up to a figure of around 700,000 deaths per year. Because of that many strategies are being developed in order to combat the resistance of microorganisms to drugs, in recent times, chalcones have been studied for this purpose. Chalcones are known as α, ß-unsaturated ketones, characterized by having the presence of two aromatic rings that are joined by a three-carbon chain, they are a class of compounds considered an exceptional model due to chemical simplicity and a wide variety of biological activities, which include anticancer, anti-inflammatory, antioxidants, antimicrobials, anti-tuberculosis, anti-HIV, antimalarial, anti-allergic, antifungal, antibacterial, and antileishmanial. The objective of this work was evaluate the antibacterial and antibiotic modifying activity of chalcone (E)-1-(2-hydroxyphenyl)-3-(2,4-dimethoxy-3-methylphenyl)prop-2-en-1-one against the bacteria Staphylococcus aureus carrying a NorA and MepA efflux pump. The results showed that chalcone was able to synergistically modulate the action of Norfloxacin and Ethidium Bromide against the bacteria Staphylococcus aureus 1199B and K2068, respectively. The theoretical physicochemical and pharmacokinetic properties of chalcone showed that the chalcone did not present a severe risk of toxicity such as genetic mutation or cardiotoxicity, constituting a good pharmacological active ingredient.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/metabolismo , Chalconas/farmacologia , Proteínas de Membrana Transportadoras/metabolismo , Staphylococcus aureus/efeitos dos fármacos , Antibacterianos/farmacocinética , Proteínas de Bactérias/antagonistas & inibidores , Chalconas/farmacocinética , Etídio/farmacologia , Humanos , Absorção Intestinal , Testes de Sensibilidade Microbiana , Modelos Biológicos , Simulação de Acoplamento Molecular , Norfloxacino/farmacologia , Staphylococcus aureus/metabolismo
11.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33946793

RESUMO

For decades, local bone drug delivery systems have been investigated in terms of their application in regenerative medicine. Among them, inorganic polymers based on amorphous silica have been widely explored. In this work, we combined two types of amorphous silica: bioglass and doxycycline-loaded mesoporous silica MCM-41 into the form of spherical granules (pellets) as a bifunctional bone drug delivery system. Both types of silica were obtained in a sol-gel method. The drug adsorption onto the MCM-41 was performed via adsorption from concentrated doxycycline hydrochloride solution. Pellets were obtained on a laboratory scale using the wet granulation-extrusion-spheronization method and investigated in terms of physical properties, drug release, antimicrobial activity against Staphylococcus aureus, mineralization properties in simulated body fluid, and cytotoxicity towards human osteoblasts. The obtained pellets were characterized by satisfactory mechanical properties which eliminated the risk of pellets cracking during further investigations. The biphasic drug release from pellets was observed: burst stage (44% of adsorbed drug released within the first day) followed by prolonged release with zero-order kinetics (estimated time of complete drug release was 19 days) with maintained antimicrobial activity. The progressive biomimetic apatite formation on the surface of the pellets was observed. No cytotoxic effect of pellets towards human osteoblasts was noticed.


Assuntos
Substitutos Ósseos/administração & dosagem , Substitutos Ósseos/química , Cerâmica/química , Sistemas de Liberação de Medicamentos , Dióxido de Silício/administração & dosagem , Dióxido de Silício/química , Adsorção , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Regeneração Óssea , Substitutos Ósseos/farmacocinética , Calcificação Fisiológica , Varredura Diferencial de Calorimetria , Doxiciclina/administração & dosagem , Doxiciclina/farmacocinética , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Humanos , Técnicas In Vitro , Teste de Materiais , Microscopia Eletrônica de Varredura , Tamanho da Partícula , Medicina Regenerativa , Espectrometria por Raios X , Espectroscopia de Infravermelho com Transformada de Fourier , Staphylococcus aureus/efeitos dos fármacos
12.
AAPS PharmSciTech ; 22(3): 131, 2021 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-33839973

RESUMO

The high-drug-loaded sustained-release gastric-floating clarithromycin (CAM) tablets were proposed and manufactured via semisolid extrusion (SSE)-based 3D printing. The physical and mechanical properties, such as dimensions, weight variation, friability, and hardness, were accessed according to the quality standards of Chinese Pharmacopoeia (Ch.P). The interactions among the drug-excipients were evaluated via differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD) techniques. Next, the rheological properties of the paste and the effect of the excipients and solvents were evaluated. Finally, a very high drug-loading of up to 81.7% (w/w) with the sustain release time of 8 h (125 mg) and 12 h (250 mg) was achieved. The results revealed the potential of SSE for achieving a high drug loading and identified the suitable properties of the paste for SSE-based 3D printing.


Assuntos
Antibacterianos/administração & dosagem , Claritromicina/administração & dosagem , Impressão Tridimensional , Antibacterianos/farmacocinética , Claritromicina/farmacocinética , Simulação por Computador , Preparações de Ação Retardada , Liberação Controlada de Fármacos , Excipientes , Testes de Dureza , Reologia , Estômago , Comprimidos
13.
Ther Drug Monit ; 43(4): 451-454, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-33883521

RESUMO

OBJECTIVE: The authors report on a case of a 59-year-old man hospitalized in the intensive care unit because of severe SARS-COV-2 infection (COVID-19). BACKGROUND: The patient had several comorbidities, including liver cirrhosis. He developed ventilation-associated bacterial pneumonia for which he was administered cefepime at an initial dose of 2 g/8 hours. Therapeutic drug monitoring was performed, showing overexposure with an initial trough concentration of >60 mg/L. METHODS: Analysis of pharmacokinetic data and model-based dose adjustment was performed using BestDose software. RESULTS: The patient had unexpected pharmacokinetic parameter values. Serum creatinine was only moderately increased, whereas measured creatinine clearance based on urine collection showed impaired renal function. Bacterial minimum inhibitory concentration was also considered in the dosing decisions. After dose reduction to 0.5 g/8 hours, the cefepime trough concentration progressively declined and reached the target values by the end of the therapy. A post-hoc analysis provided a different interpretation of drug overexposure. CONCLUSION: This case report illustrates how physiological, microbiological, and drug concentration data can be used for model-based dosage individualization of cefepime in intensive care unit patients.


Assuntos
Antibacterianos/farmacocinética , Cefepima/farmacocinética , Estado Terminal/terapia , Cálculos da Dosagem de Medicamento , Medicina de Precisão/métodos , Injúria Renal Aguda/sangue , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/prevenção & controle , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Cefepima/administração & dosagem , Cefepima/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade
14.
Expert Rev Clin Pharmacol ; 14(7): 777-791, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33849355

RESUMO

Introduction: Increasing resistance of gram-negative bacteria poses a serious threat to global health. Thus, efficacious and safe antibiotics against resistant pathogens are urgently needed. Cefiderocol, a siderophore cephalosporin, addresses this unmet need.Areas covered: For this article, we screened all preclinical and clinical studies on cefiderocol published by January 2021 on PubMed. Also, regulatory documents, recent conference contributions, and selected data of antibiotic competitors are reviewed. We provide a comprehensive overview of the mode of action, in vitro and in vivo activity, pharmacokinetics/pharmacodynamics, and human pharmacokinetics. Last, we discuss the efficacy and safety data from the pivotal trials.Expert opinion: Cefiderocol was in vitro potent against virtually all gram-negative pathogens and resistance was rare. The target site pharmacokinetics (i.e. urinary and lung penetration) have been well described in humans and important PK/PD targets were reached. In the clinical trials, cefiderocol was non-inferior to carbapenems in the treatment of complicated urinary tract infections and nosocomial pneumonia. Against carbapenem-resistant gram-negative pathogens, cefiderocol was similar to the best available therapy, which was mainly based on the backbone agent colistin. Overall, a substantial body of evidence supports the clinical use of cefiderocol in patients with gram-negative infections and limited treatment options.


Assuntos
Antibacterianos/farmacologia , Cefalosporinas/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Animais , Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Cefalosporinas/efeitos adversos , Cefalosporinas/farmacocinética , Farmacorresistência Bacteriana , Bactérias Gram-Negativas/isolamento & purificação , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Infecções por Bactérias Gram-Negativas/microbiologia , Humanos
15.
Antimicrob Agents Chemother ; 65(7): e0214920, 2021 06 17.
Artigo em Inglês | MEDLINE | ID: mdl-33903114

RESUMO

The antibiotic combination trimethoprim (TMP)-sulfamethoxazole (SMX) has a broad spectrum of activity and is used for the treatment of numerous infections, but pediatric pharmacokinetic (PK) data are limited. We previously published population PK (popPK) models of oral TMP-SMX in pediatric patients based on sparse opportunistically collected data (POPS study) (J. Autmizguine, C. Melloni, C. P. Hornik, S. Dallefeld, et al., Antimicrob Agents Chemother 62:e01813-17, 2017, https://doi.org/10.1128/AAC.01813-17). We performed a separate PK study of oral TMP-SMX in infants and children with more-traditional PK sample collection and independently developed new popPK models of TMP-SMX using this external data set. The POPS data set and the external data set were each used to evaluate both popPK models. The external TMP model had a model and error structure identical to those of the POPS TMP model, with typical values for PK parameters within 20%. The external SMX model did not identify the covariates in the POPS SMX model as significant. The external popPK models predicted higher exposures to TMP (median overprediction of 0.13 mg/liter for the POPS data set and 0.061 mg/liter for the external data set) and SMX (median overprediction of 1.7 mg/liter and 0.90 mg/liter) than the POPS TMP (median underprediction of 0.016 mg/liter and 0.39 mg/liter) and SMX (median underprediction of 1.2 mg/liter and 14 mg/liter) models. Nonetheless, both models supported TMP-SMX dose increases in infants and young children for resistant pathogens with a MIC of 1 mg/liter, although the required dose increase based on the external model was lower. (The POPS and external studies have been registered at ClinicalTrials.gov under registration no. NCT01431326 and NCT02475876, respectively.).


Assuntos
Antibacterianos/farmacocinética , Combinação Trimetoprima e Sulfametoxazol/farmacocinética , Criança , Pré-Escolar , Humanos , Lactente
16.
J Zoo Wildl Med ; 52(1): 81-89, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33827164

RESUMO

Ceftiofur crystalline free acid (CCFA) is a third-generation, oil-based, cephalosporin antimicrobial marketed as a once weekly treatment in cattle and swine, and as a two-time dose with 10-day duration in horses. Because handling and restraint times can be reduced, long-acting antibiotic preparations are particularly useful for treatment of nondomestic species. This study evaluated the pharmacokinetics of CCFA in ringneck doves (Streptopelia risoria). A single intramuscular (IM) injection of CCFA at 50 mg/kg was administered to each of 30 doves, and blood was collected from subsamples of 6 birds at predetermined sampling times (i.e., with a postinjection range of 0.5 to 192 hr). All ringneck doves were scheduled for euthanasia because of reasons unrelated to the study; this was performed at the conclusion of the study; and complete postmortem and histopathologic examinations were performed. Plasma concentrations of CCFA remained above the minimum inhibitory concentration (1.0 µg/ml; observed for most avian pathogenic bacteria) for 108 hr. No abnormalities were identified on individual birds before and after clinical pathology results (i.e., hematocrits and plasma biochemistry profiles), and only minimal gross and histopathologic changes such as mild tissue inflammation at the injection site were observed. Based on these results, one IM injection of CCFA at 50 mg/kg seems to be a potential option for treatment of ringneck doves.


Assuntos
Antibacterianos/farmacocinética , Cefalosporinas/farmacocinética , Columbidae/metabolismo , Animais , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Área Sob a Curva , Cefalosporinas/administração & dosagem , Cefalosporinas/sangue , Columbidae/sangue , Preparações de Ação Retardada , Meia-Vida , Injeções Intramusculares
17.
J Zoo Wildl Med ; 52(1): 90-96, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33827165

RESUMO

Population pharmacokinetics utilizing sparse sampling were used to determine pharmacokinetics of ceftazidime in eastern hellbenders (Cryptobranchus alleganiensis alleganiensis) due to their slow growth rate and the limited number of appropriately sized individuals in the zoo-housed population. Twenty-five eastern hellbenders received a single subcutaneous injection of ceftazidime at 20 mg/kg. Each animal had blood samples collected up to four times between 0 and 192 hr postinjection. Plasma samples were analyzed by high-pressure liquid chromatography. A nonlinear mixed-effects model was fitted to the data to determine typical values for population parameters, an ideal method due to the sampling limitation of each hellbender. Results indicate an elimination half-life of 36.63 hr and volume of distribution of 0.31 L/kg. Antibiotic concentrations were above a minimum inhibitory concentration (MIC) value of 8 µg/ml for 120 hr. Prior to antibiotic administration, six hellbenders had oral and six other individuals had cloacal swabs taken for aerobic culture. Fifty-five bacterial isolates were obtained (24 cloacal, 31 oral) with 10/12 (83%) individuals growing three or more different isolates and 11/12 (92%) growing Shewanella putrefaciens. Twelve isolates had susceptibility testing performed and all were susceptible to ceftazidime. These results indicate that ceftazidime is an appropriate choice of antibiotic in hellbenders and when given at a dosage of 20 mg/kg subcutaneously, maintains concentrations above the MIC of susceptible bacteria for up to 5 days.


Assuntos
Anfíbios/metabolismo , Antibacterianos/farmacocinética , Ceftazidima/farmacocinética , Anfíbios/sangue , Animais , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Área Sob a Curva , Ceftazidima/administração & dosagem , Ceftazidima/sangue , Cloaca/microbiologia , Meia-Vida , Injeções Subcutâneas , Boca/microbiologia , Projetos Piloto
18.
J Med Chem ; 64(9): 6241-6261, 2021 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-33852302

RESUMO

In this study, we report the design and synthesis of a series of novel thiophene-arylamide compounds derived from the noncovalent decaprenylphosphoryl-ß-d-ribose 2'-epimerase (DprE1) inhibitor TCA1 through a structure-based scaffold hopping strategy. Systematic optimization of the two side chains flanking the thiophene core led to new lead compounds bearing a thiophene-arylamide scaffold with potent antimycobacterial activity and low cytotoxicity. Compounds 23j, 24f, 25a, and 25b exhibited potent in vitro activity against both drug-susceptible (minimum inhibitory concentration (MIC) = 0.02-0.12 µg/mL) and drug-resistant (MIC = 0.031-0.24 µg/mL) tuberculosis strains while retaining potent DprE1 inhibition (half maximal inhibitory concentration (IC50) = 0.2-0.9 µg/mL) and good intracellular antimycobacterial activity. In addition, these compounds showed good hepatocyte stability and low inhibition of the human ether-à-go-go related gene (hERG) channel. The representative compound 25a with acceptable pharmacokinetic property demonstrated significant bactericidal activity in an acute mouse model of tuberculosis. Moreover, the molecular docking study of template compound 23j provides new insight into the discovery of novel antitubercular agents targeting DprE1.


Assuntos
Oxirredutases do Álcool/antagonistas & inibidores , Amidas/química , Antibacterianos/química , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Desenho de Fármacos , Tiofenos/química , Tiofenos/farmacologia , Oxirredutases do Álcool/química , Oxirredutases do Álcool/metabolismo , Animais , Antibacterianos/metabolismo , Antibacterianos/farmacocinética , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Farmacorresistência Bacteriana/efeitos dos fármacos , Humanos , Camundongos , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/enzimologia , Conformação Proteica , Relação Estrutura-Atividade , Tiofenos/metabolismo , Tiofenos/farmacocinética , Distribuição Tecidual
19.
Biomolecules ; 11(2)2021 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-33673069

RESUMO

Nitroaromatic antibiotics show activity against anaerobic bacteria and parasites, finding use in the treatment of Heliobacter pylori infections, tuberculosis, trichomoniasis, human African trypanosomiasis, Chagas disease and leishmaniasis. Despite this activity and a clear need for the development of new treatments for these conditions, the associated toxicity and lack of clear mechanisms of action have limited their therapeutic development. Nitroaromatic antibiotics require reductive bioactivation for activity and this reductive metabolism can convert the nitro group to nitric oxide (NO) or a related reactive nitrogen species (RNS). As nitric oxide plays important roles in the defensive immune response to bacterial infection through both signaling and redox-mediated pathways, defining controlled NO generation pathways from these antibiotics would allow the design of new therapeutics. This review focuses on the release of nitrogen oxide species from various nitroaromatic antibiotics to portend the increased ability for these compounds to positively impact infectious disease treatment.


Assuntos
Antibacterianos/farmacologia , Óxidos de Nitrogênio/metabolismo , Ativação Metabólica , Antibacterianos/química , Antibacterianos/farmacocinética , Doadores de Óxido Nítrico/farmacologia , Oxirredução , Espécies Reativas de Nitrogênio/metabolismo
20.
Int J Biol Macromol ; 180: 771-781, 2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33705836

RESUMO

A nanohybrid formulation of silver­titanium dioxide nanoparticles/poly(lactic acid) (Ag-TiO2/PLA) was designed for Norfloxacin/Tenoxicam (NOR/TENO) targeted delivery to maximize the bioavailability and minimize the side effects of the drugs. Ag-TiO2 nanoparticles were prepared via Stober method. NOR, TENO and a mixture of NOR/TENO (NT) were loaded onto Ag-TiO2 nanoparticles and coated by PLA via solution casting. The physical interaction between the drugs and carrier was confirmed by Fourier-transform infrared (FTIR) analysis. X-ray diffraction (XRD) demonstrated that Ag-TiO2 consists of a cubic phase of Ag with two phases of TiO2 (anatase and brookite). Ag nanoparticle fine spots coated with TiO2 were collected to form spheres averaging at 100 nm in size. In-vitro release behavior of drugs was studied at different pH (5.4, 7.4) and the release of drug from NT/Ag-TiO2/PLA was faster at pH 7.4. Gram-positive and Gram-negative bacteria were used to investigate antibacterial properties of the nanohybrid. Cytotoxicity of the nanohybrid using an MTT assay was studied against different tumor and normal cell lines. It was found that NT/Ag-TiO2/PLA has an excellent cytotoxic effect against various bacterial cells and tumor cell lines. In addition, antioxidant properties of the nanohybrids were tested using ABTS method and the nanohybrid showed moderate antioxidant activity.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Nanopartículas Metálicas/química , Norfloxacino/administração & dosagem , Piroxicam/análogos & derivados , Poliésteres/química , Prata/química , Titânio/química , Antibacterianos/administração & dosagem , Antibacterianos/química , Antibacterianos/farmacocinética , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/farmacocinética , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Células Hep G2 , Humanos , Nanopartículas Metálicas/ultraestrutura , Testes de Sensibilidade Microbiana/métodos , Microscopia Eletrônica de Varredura , Microscopia Eletrônica de Transmissão , Norfloxacino/química , Norfloxacino/farmacocinética , Piroxicam/administração & dosagem , Piroxicam/química , Piroxicam/farmacocinética , Espectrofotometria
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