Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.444
Filtrar
1.
Microb Drug Resist ; 27(3): 281-290, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33729874

RESUMO

The coronavirus disease 2019 (COVID-19), caused by infection with severe acute respiratory syndrome coronavirus 2, has recently emerged worldwide. In this context, there is an urgent need to identify safe and effective therapeutic strategies for treatment of such highly contagious disease. We recently reported promising results of combining hydroxychloroquine and azithromycin as an early treatment option. Although ongoing clinical trials are challenging the efficacy of this combination, many clinicians claim the authorization to or have already begun to use it to treat COVID-19 patients worldwide. The aim of this article is to share pharmacology considerations contributing to the rationale of this combination, and to provide safety information to prevent toxicity and drug-drug interactions, based on available evidence.


Assuntos
Antibacterianos/uso terapêutico , Antivirais/uso terapêutico , Azitromicina/uso terapêutico , Hidroxicloroquina/uso terapêutico , Antibacterianos/administração & dosagem , Antibacterianos/efeitos adversos , Antibacterianos/farmacologia , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/farmacologia , Azitromicina/administração & dosagem , Azitromicina/efeitos adversos , Azitromicina/farmacologia , Relação Dose-Resposta a Droga , Interações Medicamentosas , Quimioterapia Combinada , Humanos , Hidroxicloroquina/administração & dosagem , Hidroxicloroquina/efeitos adversos , Hidroxicloroquina/farmacologia
2.
Int J Mol Sci ; 22(4)2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33669352

RESUMO

Cystic fibrosis (CF) is an inherited disorder caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an ATP-gated chloride channel expressed on the apical surface of airway epithelial cells. CFTR absence/dysfunction results in defective ion transport and subsequent airway surface liquid dehydration that severely compromise the airway microenvironment. Noxious agents and pathogens are entrapped inside the abnormally thick mucus layer and establish a highly inflammatory environment, ultimately leading to lung damage. Since chronic airway inflammation plays a crucial role in CF pathophysiology, several studies have investigated the mechanisms responsible for the altered inflammatory/immune response that, in turn, exacerbates the epithelial dysfunction and infection susceptibility in CF patients. In this review, we address the evidence for a critical role of dysfunctional inflammation in lung damage in CF and discuss current therapeutic approaches targeting this condition, as well as potential new treatments that have been developed recently. Traditional therapeutic strategies have shown several limitations and limited clinical benefits. Therefore, many efforts have been made to develop alternative treatments and novel therapeutic approaches, and recent findings have identified new molecules as potential anti-inflammatory agents that may exert beneficial effects in CF patients. Furthermore, the potential anti-inflammatory properties of CFTR modulators, a class of drugs that directly target the molecular defect of CF, also will be critically reviewed. Finally, we also will discuss the possible impact of SARS-CoV-2 infection on CF patients, with a major focus on the consequences that the viral infection could have on the persistent inflammation in these patients.


Assuntos
Anti-Inflamatórios/uso terapêutico , Fibrose Cística/tratamento farmacológico , Inflamação/tratamento farmacológico , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Anti-Inflamatórios/farmacologia , Azitromicina/farmacologia , Azitromicina/uso terapêutico , /tratamento farmacológico , Canabinoides/farmacologia , Canabinoides/uso terapêutico , Fibrose Cística/complicações , Fibrose Cística/metabolismo , Regulador de Condutância Transmembrana em Fibrose Cística/metabolismo , Eicosanoides/metabolismo , Humanos , Inflamação/complicações , Inflamação/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Roscovitina/farmacologia , Roscovitina/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Timalfasina/farmacologia , Timalfasina/uso terapêutico
3.
Lancet ; 397(10279): 1063-1074, 2021 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-33676597

RESUMO

BACKGROUND: Azithromycin, an antibiotic with potential antiviral and anti-inflammatory properties, has been used to treat COVID-19, but evidence from community randomised trials is lacking. We aimed to assess the effectiveness of azithromycin to treat suspected COVID-19 among people in the community who had an increased risk of complications. METHODS: In this UK-based, primary care, open-label, multi-arm, adaptive platform randomised trial of interventions against COVID-19 in people at increased risk of an adverse clinical course (PRINCIPLE), we randomly assigned people aged 65 years and older, or 50 years and older with at least one comorbidity, who had been unwell for 14 days or less with suspected COVID-19, to usual care plus azithromycin 500 mg daily for three days, usual care plus other interventions, or usual care alone. The trial had two coprimary endpoints measured within 28 days from randomisation: time to first self-reported recovery, analysed using a Bayesian piecewise exponential, and hospital admission or death related to COVID-19, analysed using a Bayesian logistic regression model. Eligible participants with outcome data were included in the primary analysis, and those who received the allocated treatment were included in the safety analysis. The trial is registered with ISRCTN, ISRCTN86534580. FINDINGS: The first participant was recruited to PRINCIPLE on April 2, 2020. The azithromycin group enrolled participants between May 22 and Nov 30, 2020, by which time 2265 participants had been randomly assigned, 540 to azithromycin plus usual care, 875 to usual care alone, and 850 to other interventions. 2120 (94%) of 2265 participants provided follow-up data and were included in the Bayesian primary analysis, 500 participants in the azithromycin plus usual care group, 823 in the usual care alone group, and 797 in other intervention groups. 402 (80%) of 500 participants in the azithromycin plus usual care group and 631 (77%) of 823 participants in the usual care alone group reported feeling recovered within 28 days. We found little evidence of a meaningful benefit in the azithromycin plus usual care group in time to first reported recovery versus usual care alone (hazard ratio 1·08, 95% Bayesian credibility interval [BCI] 0·95 to 1·23), equating to an estimated benefit in median time to first recovery of 0·94 days (95% BCI -0·56 to 2·43). The probability that there was a clinically meaningful benefit of at least 1·5 days in time to recovery was 0·23. 16 (3%) of 500 participants in the azithromycin plus usual care group and 28 (3%) of 823 participants in the usual care alone group were hospitalised (absolute benefit in percentage 0·3%, 95% BCI -1·7 to 2·2). There were no deaths in either study group. Safety outcomes were similar in both groups. Two (1%) of 455 participants in the azothromycin plus usual care group and four (1%) of 668 participants in the usual care alone group reported admission to hospital during the trial, not related to COVID-19. INTERPRETATION: Our findings do not justify the routine use of azithromycin for reducing time to recovery or risk of hospitalisation for people with suspected COVID-19 in the community. These findings have important antibiotic stewardship implications during this pandemic, as inappropriate use of antibiotics leads to increased antimicrobial resistance, and there is evidence that azithromycin use increased during the pandemic in the UK. FUNDING: UK Research and Innovation and UK Department of Health and Social Care.


Assuntos
Gestão de Antimicrobianos , Azitromicina/uso terapêutico , Síndrome da Liberação de Citocina/prevenção & controle , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Azitromicina/farmacologia , /diagnóstico , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Farmacorresistência Bacteriana , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Admissão do Paciente/estatística & dados numéricos , Fatores de Risco , /isolamento & purificação , Fatores de Tempo , Resultado do Tratamento , Reino Unido
5.
J Med Microbiol ; 70(3)2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33570485

RESUMO

Introduction. Mycobacterium abscessus complex (MABC) is an infectious agent associated with macrolide resistance and treatment failure.Hypothesis/Gap Statement. Despite drug-susceptibility testing for MABC isolates including clarithromycin (CAM), long-term treatment with azithromycin (AZM) for MABC disease is recommended.Aim. We compared phenotypic and genotypic resistance to AZM and CAM in clinical isolates and evaluated the accumulation of intrinsic macrolide resistance (AIM) and morphological changes by macrolides exposure.Methodology. Forty-nine isolates were characterized regarding erm(41) sequevars. Sequencing data were compared to the nucleotide sequence of rrl and whiB7. The AIM MIC was performed in three reference strains and 15 isolates were randomized [each set of five isolates with M. abscessus subsp. abscessus (MAA) T28, MAA C28 and subsp. massiliense (MAM)].Results. The 49 isolates were distributed as 24 MAA T28, 5 MAA C28 and 20 MAM. The MIC50 values to CAM at day 3 in MAA T28, C28 and MAM were 1, 0.12 and 0.12 µg ml-1, while those at day 14 were 32, 0.5 and 0.12 µg ml-1, respectively. The AZM-MIC50 values at day 3 of the above isolates were 4, 0.25 and 0.5 µg ml-1, while those at day 14 were >64, 0.5 and 0.5 µg ml-1, respectively. Neither mutations in rrl of MAA T28 with acquired resistance nor deletions in whiB7 of MAA T28 without inducible resistance were observed . For AIM MIC, MAA T28 showed that the time-to-detection of AZM resistance was significantly faster over that of CAM (P<0.05). Morphological changes were not determined in all isolates.Conclusion. Our findings did not support the suggestion for the preferential use of AZM for, at least, MAA T28 disease due to the high-level MIC value and the increased AIM. The long duration of AZM-based treatment eventually may favour the emergence of isolates with a high-level of intrinsic resistance.


Assuntos
Antibacterianos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Farmacorresistência Bacteriana/genética , Macrolídeos/farmacologia , Mycobacterium abscessus/isolamento & purificação , Azitromicina/farmacologia , Azitromicina/uso terapêutico , Proteínas de Bactérias/genética , Claritromicina/farmacologia , Claritromicina/uso terapêutico , Genótipo , Humanos , Testes de Sensibilidade Microbiana , Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Infecções por Mycobacterium não Tuberculosas/microbiologia , Mycobacterium abscessus/efeitos dos fármacos , Mycobacterium abscessus/genética , Fenótipo
6.
J Mol Graph Model ; 104: 107834, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33516966

RESUMO

Since 2020, the world is facing the first global pandemic of 21st century. Among all the solutions proposed to treat this new strain of coronavirus, named SARS-CoV-2, the vaccine seems a promising way but the delays are too long to be implemented quickly. In the emergency, a dual therapy has shown its effectiveness but has also provoked a set of debates around the dangerousness of a particular molecule, hydroxychloroquine. In particular, the doses to be delivered, according to the studies, were well beyond the acceptable doses to support the treatment without side effects. We propose here to use all the advantages of nanovectorization to address this question of concentration. Using quantum and classical simulations we will show in particular that drug transport on boron nitrogen oxide nanosheets increases the effectiveness of the action of these drugs. This will definitely allow to decrease the drug quantity needing to face the disease.


Assuntos
/química , Antivirais/química , Azitromicina/química , Hidroxicloroquina/química , Glicoproteína da Espícula de Coronavírus/química , /metabolismo , Antivirais/farmacologia , Azitromicina/farmacologia , Sítios de Ligação , Compostos de Boro/química , /virologia , Sistemas de Liberação de Medicamentos/métodos , Cálculos da Dosagem de Medicamento , Humanos , Hidroxicloroquina/farmacologia , Cinética , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Nanomedicina/métodos , Nanoestruturas/química , Óxidos de Nitrogênio/química , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Teoria Quântica , /efeitos dos fármacos , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/metabolismo , Termodinâmica
9.
Bratisl Lek Listy ; 122(2): 101-110, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33502877

RESUMO

BACKGROUND: SARS-CoV-2, which started in Wuhan and later affected the whole world, is the most important disease of the world today. Many ways to inhibit SARS-CoV-2 virus are sought to prevent the spread of this virus. Azithromycin and clarithromycin are considered for the treatment of the SARS-CoV-2 virus, which has a high similarity to previous colonic diseases. AIM: We aimed to determine whether azithromycin and clarithromycin, the RNA-dependent RNA polymerase protein inhibitor used in the treatment of COVID-19, is effective against SARS Cov-2 in silico. RESULTS AND CONCLUSION: The 503 analogues of azithromycin and clarithromycin were studied to target SARS-CoV-2 the RNA-dependent RNA polymerase protein inhibition. Maestro program was used to compare the inhibition activities of these analogues. A detailed comparison was made using the numerical value of many parameters obtained. ADME / T properties were then examined to determine the effects and reactions of analogues on human metabolism. In this study, the SARS-CoV2 virus is 6NUR and 6NUS, which is the RNA-dependent RNA polymerase protein. Among these proteins, the best inhibitor among the 503 analogues according to the docking score parameter was 9851445 with a great difference. This analogue was an analogue of azithromycin (Tab. 3, Fig. 6, Ref. 58).


Assuntos
Azitromicina/uso terapêutico , Claritromicina/uso terapêutico , Antivirais/farmacologia , Azitromicina/farmacologia , Claritromicina/farmacologia , Humanos , RNA Viral
10.
PLoS Comput Biol ; 16(12): e1008489, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33382685

RESUMO

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus poses serious threats to the global public health and leads to worldwide crisis. No effective drug or vaccine is readily available. The viral RNA-dependent RNA polymerase (RdRp) is a promising therapeutic target. A hybrid drug screening procedure was proposed and applied to identify potential drug candidates targeting RdRp from 1906 approved drugs. Among the four selected market available drug candidates, Pralatrexate and Azithromycin were confirmed to effectively inhibit SARS-CoV-2 replication in vitro with EC50 values of 0.008µM and 9.453 µM, respectively. For the first time, our study discovered that Pralatrexate is able to potently inhibit SARS-CoV-2 replication with a stronger inhibitory activity than Remdesivir within the same experimental conditions. The paper demonstrates the feasibility of fast and accurate anti-viral drug screening for inhibitors of SARS-CoV-2 and provides potential therapeutic agents against COVID-19.


Assuntos
Aminopterina/análogos & derivados , Antivirais/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Reposicionamento de Medicamentos , /fisiologia , Aminopterina/química , Aminopterina/farmacologia , Animais , Azitromicina/química , Azitromicina/farmacologia , Chlorocebus aethiops , Simulação por Computador , Aprendizado Profundo , Simulação de Dinâmica Molecular , Células Vero , Replicação Viral/efeitos dos fármacos
12.
Proc Natl Acad Sci U S A ; 117(52): 33519-33529, 2020 12 29.
Artigo em Inglês | MEDLINE | ID: mdl-33318204

RESUMO

Pseudomonas aeruginosa causes severe multidrug-resistant infections that often lead to bacteremia and sepsis. Physiologically relevant conditions can increase the susceptibility of pathogens to antibiotics, such as azithromycin (AZM). When compared to minimal-inhibitory concentrations (MICs) in laboratory media, AZM had a 16-fold lower MIC in tissue culture medium with 5% Mueller Hinton broth (MHB) and a 64-fold lower MIC in this tissue culture medium with 20% human serum. AZM also demonstrated increased synergy in combination with synthetic host-defense peptides DJK-5 and IDR-1018 under host-like conditions and in a murine abscess model. To mechanistically study the altered effects of AZM under physiologically relevant conditions, global transcriptional analysis was performed on P. aeruginosa with and without effective concentrations of AZM. This revealed that the arn operon, mediating arabinosaminylation of lipopolysaccharides and related regulatory systems, was down-regulated in host-like media when compared to MHB. Inactivation of genes within the arn operon led to increased susceptibility of P. aeruginosa to AZM and great increases in synergy between AZM and other antimicrobial agents, indicating that dysregulation of the arn operon might explain increased AZM uptake and synergy in host-like media. Furthermore, genes involved in central and energy metabolism and ribosome biogenesis were dysregulated more in physiologically relevant conditions treated with AZM, likely due to general changes in cell physiology as a result of the increased effectiveness of AZM in these conditions. These data suggest that, in addition to the arn operon, there are multiple factors in host-like environments that are responsible for observed changes in susceptibility.


Assuntos
Azitromicina/farmacologia , Meios de Cultura/farmacologia , Pseudomonas aeruginosa/crescimento & desenvolvimento , Antibacterianos/farmacologia , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Sinergismo Farmacológico , Regulação Bacteriana da Expressão Gênica/efeitos dos fármacos , Humanos , Macrolídeos/farmacologia , Testes de Sensibilidade Microbiana , Óperon/genética , Peptídeos/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/genética , Soro
13.
N Engl J Med ; 383(20): 1941-1950, 2020 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-33176084

RESUMO

BACKGROUND: Mass distribution of azithromycin to preschool children twice yearly for 2 years has been shown to reduce childhood mortality in sub-Saharan Africa but at the cost of amplifying macrolide resistance. The effects on the gut resistome, a reservoir of antimicrobial resistance genes in the body, of twice-yearly administration of azithromycin for a longer period are unclear. METHODS: We investigated the gut resistome of children after they received twice-yearly distributions of azithromycin for 4 years. In the Niger site of the MORDOR trial, we enrolled 30 villages in a concurrent trial in which they were randomly assigned to receive mass distribution of either azithromycin or placebo, offered to all children 1 to 59 months of age every 6 months for 4 years. Rectal swabs were collected at baseline, 36 months, and 48 months for analysis of the participants' gut resistome. The primary outcome was the ratio of macrolide-resistance determinants in the azithromycin group to those in the placebo group at 48 months. RESULTS: Over the entire 48-month period, the mean (±SD) coverage was 86.6±12% in the villages that received placebo and 83.2±16.4% in the villages that received azithromycin. A total of 3232 samples were collected during the entire trial period; of the samples obtained at the 48-month monitoring visit, 546 samples from 15 villages that received placebo and 504 from 14 villages that received azithromycin were analyzed. Determinants of macrolide resistance were higher in the azithromycin group than in the placebo group: 7.4 times as high (95% confidence interval [CI], 4.0 to 16.7) at 36 months and 7.5 times as high (95% CI, 3.8 to 23.1) at 48 months. Continued mass azithromycin distributions also selected for determinants of nonmacrolide resistance, including resistance to beta-lactam antibiotics, an antibiotic class prescribed frequently in this region of Africa. CONCLUSIONS: Among villages assigned to receive mass distributions of azithromycin or placebo twice yearly for 4 years, antibiotic resistance was more common in the villages that received azithromycin than in those that received placebo. This trial showed that mass azithromycin distributions may propagate antibiotic resistance. (Funded by the Bill and Melinda Gates Foundation and others; ClinicalTrials.gov number, NCT02047981.).


Assuntos
Antibacterianos/administração & dosagem , Azitromicina/administração & dosagem , Farmacorresistência Bacteriana/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Macrolídeos/farmacologia , Administração Massiva de Medicamentos , Antibacterianos/farmacologia , Azitromicina/farmacologia , Mortalidade da Criança , Pré-Escolar , Farmacorresistência Bacteriana/genética , Feminino , Humanos , Lactente , Macrolídeos/uso terapêutico , Masculino , Metagenoma , Níger , Análise de Sequência de DNA
14.
Nat Commun ; 11(1): 5374, 2020 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-33097713

RESUMO

The emergence of resistance to azithromycin complicates treatment of Neisseria gonorrhoeae, the etiologic agent of gonorrhea. Substantial azithromycin resistance remains unexplained after accounting for known resistance mutations. Bacterial genome-wide association studies (GWAS) can identify novel resistance genes but must control for genetic confounders while maintaining power. Here, we show that compared to single-locus GWAS, conducting GWAS conditioned on known resistance mutations reduces the number of false positives and identifies a G70D mutation in the RplD 50S ribosomal protein L4 as significantly associated with increased azithromycin resistance (p-value = 1.08 × 10-11). We experimentally confirm our GWAS results and demonstrate that RplD G70D and other macrolide binding site mutations are prevalent (present in 5.42% of 4850 isolates) and widespread (identified in 21/65 countries across two decades). Overall, our findings demonstrate the utility of conditional associations for improving the performance of microbial GWAS and advance our understanding of the genetic basis of macrolide resistance.


Assuntos
Farmacorresistência Bacteriana/genética , Genoma Bacteriano , Estudo de Associação Genômica Ampla , Neisseria gonorrhoeae/efeitos dos fármacos , Neisseria gonorrhoeae/genética , Antibacterianos/farmacologia , Azitromicina/farmacologia , Sítios de Ligação/genética , Gonorreia/tratamento farmacológico , Gonorreia/microbiologia , Humanos , Macrolídeos/farmacologia , Testes de Sensibilidade Microbiana , Mutação/efeitos dos fármacos , RNA Ribossômico 23S/genética
15.
Int J Antimicrob Agents ; 56(2): 106020, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32862840

RESUMO

The emergence of SARS-coronavirus-2 (SARS-CoV-2) has led to a global pandemic disease referred to as coronavirus disease 19 (COVID-19). Hydroxychloroquine (CLQ-OH)/azithromycin (ATM) combination therapy is currently being tested for the treatment of COVID-19, with promising results. However, the molecular mechanism of action of this combination is not yet established. Using molecular dynamics (MD) simulations, this study shows that the drugs act in synergy to prevent any close contact between the virus and the plasma membrane of host cells. Unexpected molecular similarity is shown between ATM and the sugar moiety of GM1, a lipid raft ganglioside acting as a host attachment cofactor for respiratory viruses. Due to this mimicry, ATM interacts with the ganglioside-binding domain of SARS-CoV-2 spike protein. This binding site shared by ATM and GM1 displays a conserved amino acid triad Q-134/F-135/N-137 located at the tip of the spike protein. CLQ-OH molecules are shown to saturate virus attachment sites on gangliosides in the vicinity of the primary coronavirus receptor, angiotensin-converting enzyme-2 (ACE-2). Taken together, these data show that ATM is directed against the virus, whereas CLQ-OH is directed against cellular attachment cofactors. We conclude that both drugs act as competitive inhibitors of SARS-CoV-2 attachment to the host-cell membrane. This is consistent with a synergistic antiviral mechanism at the plasma membrane level, where therapeutic intervention is likely to be most efficient. This molecular mechanism may explain the beneficial effects of CLQ-OH/ATM combination therapy in patients with COVID-19. Incidentally, the data also indicate that the conserved Q-134/F-135/N-137 triad could be considered as a target for vaccine strategies.


Assuntos
Azitromicina/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Gangliosídeo G(M1)/metabolismo , Hidroxicloroquina/farmacologia , Pneumonia Viral/tratamento farmacológico , Glicoproteína da Espícula de Coronavírus/metabolismo , Ligação Viral/efeitos dos fármacos , Sequência de Aminoácidos , Antivirais/farmacologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/metabolismo , Sítios de Ligação/efeitos dos fármacos , Sinergismo Farmacológico , Quimioterapia Combinada/métodos , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Simulação de Dinâmica Molecular , Pandemias , Peptidil Dipeptidase A/metabolismo , Ligação Proteica/efeitos dos fármacos , Domínios Proteicos/efeitos dos fármacos , Alinhamento de Sequência
16.
Int J Antimicrob Agents ; 56(3): 106119, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32738306

RESUMO

Coronavirus disease 2019 (COVID-19) is a highly transmissible viral infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Clinical trials have reported improved outcomes resulting from an effective reduction or absence of viral load when patients were treated with chloroquine (CQ) or hydroxychloroquine (HCQ). In addition, the effects of these drugs were improved by simultaneous administration of azithromycin (AZM). The receptor-binding domain (RBD) of the SARS-CoV-2 spike (S) protein binds to the cell surface angiotensin-converting enzyme 2 (ACE2) receptor, allowing virus entry and replication in host cells. The viral main protease (Mpro) and host cathepsin L (CTSL) are among the proteolytic systems involved in SARS-CoV-2 S protein activation. Hence, molecular docking studies were performed to test the binding performance of these three drugs against four targets. The findings showed AZM affinity scores (ΔG) with strong interactions with ACE2, CTSL, Mpro and RBD. CQ affinity scores showed three low-energy results (less negative) with ACE2, CTSL and RBD, and a firm bond score with Mpro. For HCQ, two results (ACE2 and Mpro) were firmly bound to the receptors, however CTSL and RBD showed low interaction energies. The differences in better interactions and affinity between HCQ and CQ with ACE2 and Mpro were probably due to structural differences between the drugs. On other hand, AZM not only showed more negative (better) values in affinity, but also in the number of interactions in all targets. Nevertheless, further studies are needed to investigate the antiviral properties of these drugs against SARS-CoV-2.


Assuntos
Antivirais/farmacologia , Azitromicina/química , Betacoronavirus/química , Catepsina L/química , Cloroquina/química , Cisteína Endopeptidases/química , Hidroxicloroquina/química , Peptidil Dipeptidase A/química , Glicoproteína da Espícula de Coronavírus/química , Proteínas não Estruturais Virais/química , Motivos de Aminoácidos , Antivirais/química , Azitromicina/farmacologia , Betacoronavirus/metabolismo , Sítios de Ligação , Catepsina L/antagonistas & inibidores , Catepsina L/metabolismo , Cloroquina/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Cisteína Endopeptidases/metabolismo , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Humanos , Hidroxicloroquina/farmacologia , Simulação de Acoplamento Molecular , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Glicoproteína da Espícula de Coronavírus/antagonistas & inibidores , Glicoproteína da Espícula de Coronavírus/genética , Glicoproteína da Espícula de Coronavírus/metabolismo , Termodinâmica , Proteínas não Estruturais Virais/antagonistas & inibidores , Proteínas não Estruturais Virais/metabolismo , Ligação Viral/efeitos dos fármacos
17.
Am J Respir Cell Mol Biol ; 63(5): 707-709, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32857620
18.
PLoS One ; 15(7): e0236758, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32730301

RESUMO

Chlamydiosis is the most significant infectious disease of koalas (Phascolarctos cinereus). It is primarily a systemic sexually transmitted disease caused by Chlamydia pecorum and was responsible for 46% of the 2348 koala admissions to Australia Zoo Wildlife Hospital between 2013 and 2017. Treatment of chlamydiosis in koalas is complicated by three major factors. Firstly, koalas rely on bacterial fermentation of their high fibre diet making antibiotic therapy a risk. Secondly, they possess efficient metabolic pathways for the excretion of plant toxins and potentially of therapeutic agents. Thirdly, wild koalas, often present to rehabilitation facilities with chronic and severe disease. Traditional anti-chlamydial antibiotics used in other species may cause fatal dysbiosis in koalas or be excreted before they can be effective. We compared five anti-chlamydial antibiotics, azithromycin, chloramphenicol, doxycycline, enrofloxacin and florfenicol, which were used to treat 86 wild koalas with chlamydiosis presented to Australia Zoo Wildlife Hospital under consistent conditions of nutrition, housing, husbandry and climate. Response to treatment was assessed by recovery from clinical signs, and clearance of detectable Chlamydia via quantitative PCR. Doxycycline was the most effective anti-chlamydial antibiotic of the five, producing a 97% cure rate, followed by chloramphenicol (81%), enrofloxacin (75%), florfenicol (66%) and azithromycin (25%). The long-acting injectable preparation of doxycycline was well tolerated by koalas when administered via the subcutaneous route, and the weekly dosing requirement is a major advantage when treating wild animals. These findings indicate that doxycycline is the current drug of choice for the treatment of chlamydiosis in koalas, with chloramphenicol being the best alternative.


Assuntos
Antibacterianos/farmacologia , Infecções por Chlamydia/tratamento farmacológico , Chlamydia/efeitos dos fármacos , Phascolarctidae/microbiologia , Animais , Austrália , Azitromicina/farmacologia , Infecções por Chlamydia/microbiologia , Infecções por Chlamydia/patologia , Cloranfenicol/farmacologia , Doxiciclina/farmacologia , Enrofloxacina/farmacologia , Feminino , Masculino , Tianfenicol/análogos & derivados , Tianfenicol/farmacologia
20.
Medicine (Baltimore) ; 99(28): e21128, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664140

RESUMO

RATIONALE: Fulminant macrolide-resistant Mycoplasma pneumoniae pneumonia (MPP) has seldom been reported, and cases of MPP usually show rapid improvement after fluoroquinolones or tetracyclines addition. The purpose of this case report is to highlight the importance of proper selection of antibiotics for treatment of severe MPP and increase awareness concerning the emergence of fluoroquinolone-resistant MPP. PATIENT CONCERNS: A case of severe life-threatening pneumonia in a 26-year-old man with high fever and cough was non-responsive to azithromycin and fluoroquinolones. DIAGNOSES: The patient was diagnosed with MPP based on the test results of bronchoalveolar lavage using real-time quantitative PCR method. INTERVENTIONS: Tigecycline was given to the patient after azithromycin and fluoroquinolones failed. OUTCOMES: The patients fever subsided within the first day of tigecycline therapy. He showed rapid symptom resolution and improvement in lung infiltration after 4 days of tigecycline therapy. LESSONS: The case suggests that fulminant MPP should be timely treated with proper antibiotics, and the possible emergence of fluoroquinolone-resistant MPP should be of concern.


Assuntos
Azitromicina/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Fluoroquinolonas/farmacologia , Mycoplasma pneumoniae/efeitos dos fármacos , Pneumonia por Mycoplasma/tratamento farmacológico , Tigeciclina/uso terapêutico , Doença Aguda , Adulto , Antibacterianos/uso terapêutico , Brochothrix , Humanos , Masculino , Mycoplasma pneumoniae/isolamento & purificação , Pneumonia por Mycoplasma/diagnóstico , Pneumonia por Mycoplasma/microbiologia , Tomografia Computadorizada por Raios X
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...