RESUMO
Infectious diseases are among the leading causes of morbidity and mortality worldwide. Combating them becomes more complex when caused by the pathogens of the ESKAPE group, which are Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp. The purpose of this study was to investigate the repositioning potential of the benzodiazepines clonazepam and diazepam individually and in combination with the antibacterial ciprofloxacin against ESKAPE. The minimum inhibitory concentration and minimum bactericidal concentration against seven American Type Culture Collection (ATCC) reference standard strains and 64 ESKAPE clinical isolates were determined. In addition, the interaction with ciprofloxacin was determined by the checkerboard method and fractional inhibitory concentration index (FICI) of clonazepam against 11 ESKAPE and diazepam against five ESKAPE. We also list the results found and their clinical significance. Benzodiazepines showed similar antibacterial activity against Gram-positive and Gram-negative. The checkerboard and FICI results showed a synergistic effect of these drugs when associated with ciprofloxacin against almost all tested isolates. Viewing the clinical cases studied, benzodiazepines have potential as treatment alternatives. The results allow us to conclude that clonazepam and diazepam, when in combination with ciprofloxacin, have promising activity against ESKAPE, therefore, assuming the position of candidates for repositioning.
Assuntos
Benzodiazepinas , Ciprofloxacina , Ciprofloxacina/farmacologia , Benzodiazepinas/farmacologia , Clonazepam , Reposicionamento de Medicamentos , Antibacterianos/farmacologia , DiazepamRESUMO
Infectious diseases are among the main causes of morbidity and mortality today. In facing this crisis, the development of new drug options and combat strategies is necessary. In this sense, drug repositioning or drug redirection has emerged for the faster identification of effective drugs. In this "Commentary," the anti-infective properties of the class of proton pump inhibitors (PPIs) are emphasized. Studies report activities against bacterial, fungal, parasitic, and viral agents. In addition, we have provided in a table a summary of the specific characteristics of PPIs and some of their anti-infective activities.
Assuntos
Anti-Infecciosos , Inibidores da Bomba de Prótons , Anti-Infecciosos/farmacologiaRESUMO
PURPOSE: The absence of specific treatments for COVID-19 leads to an intense global effort in the search for new therapeutic interventions and better clinical outcomes for patients. This review aimed to present a selection of accepted studies that reported the activity of antidepressant drugs belonging to the selective serotonin receptor inhibitor (SSRI) class for treating the novel coronavirus. METHODS: A search was performed in PubMed and SciELO databases using the following search strategies: [(coronavirus) OR (COVID) OR (SARS-CoV-2) AND (antidepressant) OR (serotonin) OR (selective serotonin receptor inhibitors)]. In the end, eleven articles were included. We also covered information obtained from ClinicalTrials.gov in our research. RESULTS: Although several clinical trials are ongoing, only a few drugs have been officially approved to treat the infection. Remdesivir, an antiviral drug, despite favorable preliminary results, has restricted the use due to the risk of toxicity and methodological flaws. Antidepressant drugs were able to reduce the risk of intubation or death related to COVID-19, decrease the need for intensive medical care, and severely inhibit viral titers by up to 99%. Among the SSRIs studied so far, fluoxetine and fluvoxamine have shown to be the most promising against SARS-CoV-2. CONCLUSION: If successful, these drugs can substantially reduce hospitalization and mortality rates, as well as allow for fully outpatient treatment for mild-to-moderate infections. Thus, repositioning SSRIs can provide benefits when faced with a rapidly evolving pandemic such as COVID-19.
Assuntos
Tratamento Farmacológico da COVID-19 , Inibidores Seletivos de Recaptação de Serotonina , Antidepressivos/uso terapêutico , Antivirais/uso terapêutico , Fluoxetina , Fluvoxamina , Humanos , Receptores de Serotonina , SARS-CoV-2 , Serotonina , Inibidores Seletivos de Recaptação de Serotonina/uso terapêuticoRESUMO
Cancer and infectious diseases are among the leading causes of death in the world. Despite the diverse array of treatments available, challenges posed by resistance, side effects, high costs, and inaccessibility persist. In the Solanaceae plant family, few studies with Vassobia breviflora species relating to biological activity are known, but promising results have emerged. The phytochemicals present in the ethyl acetate fraction were obtained using ESI-MS-QTOF, and the antioxidants assays 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2'-azinobis (3-ethylbenzothiazoline-6-sulfonic acid) radical capture (ABTS), plasma ferric reduction capacity (FRAP), and total antioxidant capacity (TAC). Cytotoxic activity was evaluated by MTT, Neutral Red, and lactate dehydrogenase (LDH) released. The production of reactive oxygen species, nitric oxide, and purinergic enzymes was also investigated. Antibacterial activity was measured through minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), and antibiofilm activity, in addition to genotoxicity in plasmid DNA. Five major masses were identified D-glucopyranose II, allyl disulfide, γ-lactones, pharbilignoside, and one mass was not identified. V. breviflora exhibited relevant antioxidant and cytotoxic activity against the HeLa cell line and enhanced expression effect in modulation of purinergic signaling. Antibacterial activities in the assays in 7 ATCC strains and 8 multidrug-resistant clinical isolates were found. V. breviflora blocked biofilm formation in producing bacteria at the highest concentrations tested. However, there was no plasmid DNA cleavage at the concentrations tested. Data demonstrated that V. breviflora exhibited an antioxidant effect through several methods and proved to be a promising therapeutic alternative for use against tumor cells via purinergic signaling and multidrug-resistant microorganisms, presenting an anti-biofilm effect.
Assuntos
Antioxidantes , Solanaceae , Acetatos , Antibacterianos/farmacologia , Antioxidantes/química , Antioxidantes/farmacologia , Bactérias , DNA/farmacologia , Células HeLa , Humanos , Lactato Desidrogenases , Lactonas/farmacologia , Testes de Sensibilidade Microbiana , Vermelho Neutro/farmacologia , Óxido Nítrico , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Espécies Reativas de Oxigênio , Ácidos SulfônicosRESUMO
The identification of molecules that exhibit potent antibacterial activity and are capable of circumventing resistance mechanisms is an unmet need. The repositioning of approved drugs is considered an advantageous alternative in this case, and has gained prominence. In addition, drug synergism can reduce morbidity and mortality in the treatment of nosocomial infections caused by multi-drug resistant microorganisms (MDR). Whole cell growth inhibition assays were used to define the in vitro antibacterial activity of disulfiram against two standard American Type Culture Collection (ATCC) strains and 35 clinical isolates of vancomycin-resistant enterococci (VRE). The ability of disulfiram to synergize with vancomycin was determined by fractional inhibitory concentration index, preceded by the checkerboard test. The cytotoxicity of drugs alone and in combination was tested against Raw 264.7 cells. Disulfiram exhibited potent antibacterial activity against VRE (MIC 16-64 µg mL-1). Results: Associated with vancomycin, disulfiram it had a reduction in MIC of up to 64 times, with values of 0.5-4 µg mL-1. Vancomycin had a MIC of 128-1024 µg mL-1; combined, reduced this value by up to 124 times (8 µg mL-1), with synergy occurring against all strains. Disulfiram and vancomycin alone and in combination did not show cytotoxicity against the eukaryotic cell line. Based on these results, we suggest that the redirection of disulfiram may be promising in the treatment of infections caused by VRE, since it was able to potentiate the activity of vancomycin against the strains, being able to act as an adjuvant in cases of serious infections caused by Enterococcus.
Assuntos
Enterococcus , Vancomicina , Dissulfiram/farmacologia , Reposicionamento de Medicamentos , Testes de Sensibilidade Microbiana , Vancomicina/farmacologiaRESUMO
BACKGROUND: The worldwide increase in the occurrence of cancer associated with the limitations of immunotherapy and the emergence of resistance have impaired the prognosis of cancer patients, which leads to the search for alternative treatment methods. Drug repositioning, a well-established process approved by regulatory agencies, is considered an alternative strategy for the fast identification of drugs, because it is relatively less costly and represents lower risks for patients. AREAS OF UNCERTAINTY: We report the most relevant studies about drug repositioning in oncology, emphasizing that its implementation faces financial and regulatory obstacles, making the creation of incentives necessary to stimulate the involvement of the pharmaceutical industry. DATA SOURCES: We present 63 studies in which 52 non-anticancer drugs with anticancer activity against a number of malignancies are described. THERAPEUTIC INNOVATIONS: Some have already been the target of phase III studies, such as the Add-Aspirin trial for nonmetastatic solid tumors, as well as 9 other drugs (aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, and sertraline) in the CUSP9* clinical trial for the treatment of recurrent glioblastoma. Others have already been successful in repositioning such as thalidomide, zoledronic acid, celecoxib, methotrexate, and gemcitabine. CONCLUSIONS: Therefore, drug repositioning represents a promising alternative for the treatment of oncological disorders; however, the support from funding agencies and from the government is still needed, the latter regarding regulatory issues.
Assuntos
Reposicionamento de Medicamentos , Glioblastoma , Humanos , Itraconazol , Recidiva Local de Neoplasia , RitonavirRESUMO
Bacterial resistance has become one of the most serious public health problems, globally, and drug repurposing is being investigated to speed up the identification of effective drugs. The aim of this study was to investigate the repurposing of escitalopram oxalate and clonazepam drugs individually, and in combination with the antibiotics ciprofloxacin and sulfamethoxazole-trimethoprim, to treat multidrug-resistant (MDR) microorganisms and to evaluate the potential chemical nuclease activity. The minimum inhibitory concentration, minimum bactericidal concentration, fractional inhibitory concentration index, and tolerance level were determined for each microorganism tested. In vitro antibacterial activity was evaluated against 47 multidrug-resistant clinical isolates and 11 standard bacterial strains from the American Type Culture Collection. Escitalopram oxalate was mainly active against Gram-positive bacteria, and clonazepam was active against both Gram-positive and Gram-negative bacteria. When associated with the two antibiotics mentioned, they had a significant synergistic effect. Clonazepam cleaved plasmid DNA, and the mechanisms involved were oxidative and hydrolytic. These results indicate the potential for repurposing these non-antibiotic drugs to treat bacterial infections. However, further studies on the mechanism of action of these drugs should be performed to ensure their safe use.
Assuntos
Ciprofloxacina , Bactérias Gram-Negativas , Antibacterianos/farmacologia , Ciprofloxacina/farmacologia , Citalopram/farmacologia , Clonazepam/farmacologia , DNA , Reposicionamento de Medicamentos , Farmacorresistência Bacteriana Múltipla , Bactérias Gram-Positivas , Humanos , Testes de Sensibilidade Microbiana , Plasmídeos/genética , Sulfametoxazol/farmacologia , Trimetoprima/farmacologiaRESUMO
The repositioning of drugs has been shown to be an advantageous alternative for treating diseases caused by multidrug-resistant (MDR) microorganisms. The study aimed to investigate the in vitro antibacterial activity of the antidepressants fluoxetine and paroxetine alone and in combination with the antibacterial ciprofloxacin against standard strains and clinical isolates to explore the repositioning of these drugs in severe bacterial infections. Minimum inhibitory concentration (MIC), minimum bactericidal concentration (MBC), tolerance level, fractional inhibitory concentration index (FICI) and interaction of antidepressants with the ciprofloxacin antibiotic were determined using the Checkerboard method against six American Type Culture Collection (ATCC) standard strains and seventy MDR clinical isolates. Both antidepressants showed better antibacterial activity than ciprofloxacin, in addition to being separately bactericidal against all tested Gram-negative and Gram-positive strains. When associated with ciprofloxacin, fluoxetine and paroxetine exhibited significant synergism compared to seventy ciprofloxacin-resistant clinical isolates, demonstrating that these antidepressants were able to increase the antibacterial activity of the antibiotic by eight times. The combination of antidepressants with ciprofloxacin showed relatively better activity against Acinetobacter baumannii, Enterococcus faecium and Klebsiella pneumoniae, strains in which the FICI value obtained was 0.008. The MDR isolates tested in this study ratify the antibacterial properties of the non-antibiotic fluoxetine and paroxetine. In addition, synergism when associated with ciprofloxacin is an alternative for treating serious infections in hospitalized patients. However, additional in vivo studies must be conducted to elucidate the mechanisms of action of these drugs.
Assuntos
Antibacterianos/farmacologia , Antidepressivos/farmacologia , Ciprofloxacina/farmacologia , Reposicionamento de Medicamentos/métodos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Infecções por Acinetobacter , Acinetobacter baumannii/efeitos dos fármacos , Antidepressivos/uso terapêutico , Infecções Bacterianas , Humanos , Testes de Sensibilidade MicrobianaRESUMO
WHAT IS KNOWN AND OBJECTIVE: The widespread use of antibiotics as therapeutic agents caused an increase of multidrug resistant bacteria (MDR) appearance. Regarding MDRs, we highlight the Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter spp.., which are the ESKAPE group. COMMENT: New treatment alternatives for infections caused by ESKAPE are under current scientific research. The main suggestions are the use of actinomycetes that produce promising substances with antibiotic activity, the synergistic effect between antimicrobials and peptides, photoinactivation, peptide rich in cationic histidine, association of new antimicrobials; besides the repositioning of drugs already approved for the treatment of other diseases. WHAT IS NEW AND CONCLUSION: These selected studies showed that researchers from many countries are focused on the development of effective alternative strategies for the treatment of infections caused by these microorganisms.
Assuntos
Infecções Bacterianas/tratamento farmacológico , Acinetobacter baumannii/efeitos dos fármacos , Enterobacter/efeitos dos fármacos , Enterococcus faecium/efeitos dos fármacos , Humanos , Klebsiella pneumoniae/efeitos dos fármacos , Pseudomonas aeruginosa/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacosAssuntos
Antidepressivos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Reposicionamento de Medicamentos , Micoses/tratamento farmacológico , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Antidepressivos/farmacologia , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Biofilmes/efeitos dos fármacos , Ensaios Clínicos como Assunto , Farmacorresistência Bacteriana/efeitos dos fármacos , Farmacorresistência Fúngica/efeitos dos fármacos , Sinergismo Farmacológico , Quimioterapia Combinada/métodos , Humanos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Resultado do TratamentoRESUMO
INTRODUCTION: For years, platelet transfusion therapy has been playing an important role in controlling patients with hematological and oncological diseases. However, platelet transfusion represents a serious risk for bacterial sepsis. This study aimed to verify the bacterial contamination index in platelet concentrates (PCs) obtained from the Blood Center of the State of Rio Grande do Sul (HEMORGS). METHODS: All 612 samples of PCs from HEMORGS were analyzed in August 2009 and January 2010. We used a qualitative methodology which was modified manually in order to detect bacterial contamination. The patients who received the platelet units with confirmed positive cultures had their medical records analyzed. After the prospective study, a retrospective analysis of the samples of PCs checked by the bacteriological control from HEMORGS since its foundation (2008) until 2010 was made. RESULTS: Four hundred and eighty samples (10 monthly samples of plateletpheresis and 10 of whole blood-derived platelets) were analyzed in order to compare the contamination index for both studies. Of 1092 samples, 15 were found to be contaminated (6 of retrospective analysis and 9 of prospective). In prospective study, isolated microorganisms were nine Staphylococcus epidermidis, but in retrospective two Staphylococcus sp., two glucose non-fermenting gram negative bacilli, one Streptococcus sp. and one Proteus mirabilis. We report 3 feasible cases of bacterial sepsis associated with the transfusion of CPs analyzed by prospective study. CONCLUSION: Bacterial sepsis associated with platelet transfusion is today the most frequent infectious complication of transfusion medicine. Although complex, it is important to recognize transfusion sepsis in patients to reduce morbidity and mortality.
Assuntos
Bacteriemia/etiologia , Plaquetas/microbiologia , Transfusão de Plaquetas/efeitos adversos , Reação Transfusional , Adolescente , Bacteriemia/sangue , Bacteriemia/microbiologia , Técnicas Bacteriológicas/métodos , Feminino , Humanos , Recém-Nascido , Masculino , Infecções Estafilocócicas/sangue , Infecções Estafilocócicas/microbiologia , Staphylococcus epidermidis/isolamento & purificação , Adulto JovemRESUMO
The global spread of microbial resistance coupled with high costs and slow pace in the discovery of a new antibiotic have made drug repositioning an attractive and promising alternative in the treatment of infections caused by multidrug resistant (MDR) microorganisms. The reuse involves the production of compounds with lower costs and development time, using diversified production technologies. The present systematic review aimed to present a selection of studies published in the last 20 years, which report the antimicrobial activity of non-antibiotic drugs that are candidates for repositioning, which could be used against the current microbial multidrug resistance. A search was performed in the PubMed, SciELO and Google Scholar databases using the following search strategies: [(drug repurposing) OR (drug repositioning) OR (repositioning) AND (non-antibiotic) AND (antibacterial activity) AND (antimicrobial activity)]. Overall, 112 articles were included, which explored the antimicrobial activity in antidepressants, antihypertensives, anti-inflammatories, antineoplastics, hypoglycemic agents, among other drugs. It was concluded that they have significant antimicrobial activity in vitro and in vivo, against standard strain and clinical isolates (Gram-negative and Gram-positive) and fungi. When associated with antibacterials, most of these drugs had their antibacterial activity enhanced. It was also a consensus of the studies included in this review that the presence of aromatic rings in the molecular structure contributes to antimicrobial activity. This review highlights the potential repositioning of several classes of non-antibiotic drugs as promising candidates for repositioning in the treatment of severe bacterial infections of MDR bacteria, extensively resistant (XDR) and pan-resistant (PDR) to drugs.
Assuntos
Antibacterianos/uso terapêutico , Anti-Infecciosos/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Reposicionamento de Medicamentos , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Humanos , Testes de Sensibilidade MicrobianaRESUMO
Given the extreme importance of the current pandemic caused by COVID-19, and as scientists agree there is no identified pharmacological treatment, where possible, therapeutic alternatives are raised through drug repositioning. This paper presents a selection of studies involving drugs from different pharmaceutical classes with activity against SARS-CoV-2 and SARS-CoV, with the potential for use in the treatment of COVID-19 disease.
Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Reposicionamento de Medicamentos/métodos , Pneumonia Viral/tratamento farmacológico , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , COVID-19 , Cloroquina/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Pandemias , SARS-CoV-2 , Teicoplanina/uso terapêutico , Tratamento Farmacológico da COVID-19RESUMO
Inga semialata (Vell.) C. Mart. belongs to the family Fabaceae. It is known for its therapeutic properties, highlighting its antimicrobial and antioxidant potential. The objective of the present work was to obtain crude extract leaves of Inga semialata, to identify and quantify active compounds, to evaluate the antioxidant potential of the crude extract in vitro, as well as to determine its antimicrobial activity. The crude extract was obtained by the maceration process. The identified and quantified of compounds present in the crude extract of Inga semialata was performed by high performance liquid chromatography. The evaluation of the antioxidant potential of the extract was realized by in vitro tests (DPPH, diacetate dichlorofluorescein test and nitric oxide test) and the evaluation of the antimicrobial activity was carried out using the minimum inhibitory concentration methodology.
Assuntos
Anti-Infecciosos/isolamento & purificação , Antioxidantes/isolamento & purificação , Fabaceae/química , Compostos Fitoquímicos/análise , Extratos Vegetais/farmacologia , Folhas de Planta/química , Anti-Infecciosos/química , Anti-Infecciosos/farmacologia , Antioxidantes/química , Cromatografia Líquida de Alta Pressão , Testes de Sensibilidade Microbiana , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/análise , Extratos Vegetais/químicaRESUMO
INTRODUCTION: The spread of multidrug-resistant Gram-negative bacilli is a health threat, limiting therapeutic options and increasing morbimortality rates. METHODS: This study aimed to evaluate the antimicrobial susceptibility profile of 1805 Klebsiella pneumoniae isolates collected from Hospital Universitário de Santa Maria between January 2015 and December 2016. RESULTS: Resistance to colistin (239.3%), meropenem (74.2%), ciprofloxacin (68%), gentamicin (35.1%), tigecycline (33.9%), imipenem (29.7%), ertapenem (26.8%), and amikacin (21.4%) was found increased. CONCLUSIONS: Infection control measures in the hospitals are necessary for reducing the spread of multidrug-resistant microorganisms and preventing efficacy loss of these drugs.
Assuntos
Antibacterianos/farmacologia , Hospitais Universitários/estatística & dados numéricos , Klebsiella pneumoniae/efeitos dos fármacos , Adolescente , Adulto , Brasil , Criança , Pré-Escolar , Farmacorresistência Bacteriana , Feminino , Humanos , Lactente , Recém-Nascido , Klebsiella pneumoniae/isolamento & purificação , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto JovemRESUMO
INTRODUCTION: Coagulase-negative staphylococci (CoNS) are a frequent cause of bacteremia, especially in neonates. The major virulence determinant in CoNS is the ability to produce biofilms, which is conferred by the icaADBC genes. This study aimed to assess different methods for the detection of biofilm formation in 176 CoNS isolates from blood cultures of newborns. METHODS: The presence of the icaACD genes was assessed by polymerase chain reaction (PCR), and biofilm formation was assessed on congo red agar (CRA), by the tube method (TM), and on tissue culture plates (TCP). RESULTS: Of the 176 CoNS isolates, 30.1% expressed icaACD and 11.4% expressed icaAD. The CRA assay and TM showed that 42% and 38.6% of the isolates were biofilm producing, respectively. On TCP, 40.9% of the isolates produced biofilms; 21% were weakly adherent and 19.9% were strongly adherent. When compared to the gold standard technique (PCR), the CRAassay showed 79% sensitivity and 84% specificity (kappa = 0.64), TM showed 78% sensitivity and 89% specificity (kappa = 0.68), and TCP showed 99% sensitivity and 100% specificity (kappa = 0.99). CONCLUSIONS: In this study, ~42% of CoNS isolates produced biofilms, and the presence of icaACD was associated with a greater capacity to form biofilms. Compared to the other phenotypic methodologies, TCP is an ideal procedure for routine laboratory use.