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1.
Clin Pharmacol Ther ; 111(2): 477-484, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34674222

RESUMO

Palbociclib is an oral inhibitor of cyclin-dependent kinases 4 and 6 used in the treatment of locally advanced and metastatic breast cancer, and is extensively metabolized by cytochrome P450 enzyme 3A4 (CYP3A4). A pharmacokinetic/pharmacodynamic relationship between palbociclib exposure and neutropenia is well known. This study aimed to investigate the effects of the moderate CYP3A4 inhibitor erythromycin on the pharmacokinetics of palbociclib. We performed a randomized crossover trial comparing the pharmacokinetics of palbociclib monotherapy 125 mg once daily (q.d.) with palbociclib 125 mg q.d. plus oral erythromycin 500 mg three times daily for seven days. Pharmacokinetic sampling was performed at steady-state for both dosing schedules. Eleven evaluable patients have been enrolled. For palbociclib monotherapy, geometric mean area under the plasma concentration-time curve from zero to infinity (AUC0-24h ), maximum plasma concentration (Cmax ), and minimum plasma concentration (Cmin ) were 1.46 × 103  ng•h/mL (coefficient of variation (CV) 45.0%), 80.5 ng/mL (CV 48.5%), and 48.4 ng/mL (CV 38.8%), respectively, compared with 2.09 × 103  ng•h/mL (CV 49.3%, P = 0.000977), 115 ng/mL (CV 53.7%, P = 0.00562), and 70.7 ng/mL (CV 47.5%, P = 0.000488) when palbociclib was administered concomitantly with erythromycin. Geometric mean ratios (90% confidence intervals) of AUC0-24h , Cmax , and Cmin for palbociclib plus erythromycin vs. palbociclib monotherapy were 1.43 (1.24-1.66), 1.43 (1.20-1.69), and 1.46 (1.30-1.63). Minor differences in adverse events were observed, and only one grade ≥ 3 toxicity was observed in this short period of time. To conclude, concomitant intake of palbociclib with the moderate CYP3A4 inhibitor erythromycin resulted in an increase in palbociclib AUC0-24h and Cmax of both 43%. Therefore, a dose reduction of palbociclib to 75 mg q.d. is rational, when palbociclib and moderate CYP3A4 inhibitors are used concomitantly.


Assuntos
Antineoplásicos/farmacocinética , Neoplasias da Mama/tratamento farmacológico , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Eritromicina/administração & dosagem , Piperazinas/farmacocinética , Inibidores de Proteínas Quinases/farmacocinética , Piridinas/farmacocinética , Administração Oral , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Estudos Cross-Over , Inibidores do Citocromo P-450 CYP3A/efeitos adversos , Esquema de Medicação , Interações Medicamentosas , Monitoramento de Medicamentos , Eritromicina/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Países Baixos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Piperazinas/sangue , Estudos Prospectivos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/sangue , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Piridinas/sangue , Resultado do Tratamento
2.
Pharmacol Res Perspect ; 9(6): e00865, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34697899

RESUMO

QTc interval prolongation is an adverse effect associated with the use of fluoroquinolones and macrolides. Ciprofloxacin and erythromycin are both frequently prescribed QTc-prolonging drugs in critically ill patients. Critically ill patients may be more vulnerable to developing QTc prolongation, as several risk factors can be present at the same time. Therefore, it is important to know the QTc-prolonging potential of these drugs in the intensive care unit (ICU) population. The aim of this study was to assess the dynamics of the QTc interval over a 24-hour dose interval during intravenous ciprofloxacin and low-dose erythromycin treatment. Therefore, an observational study was performed in ICU patients (≥18 years) receiving ciprofloxacin 400 mg t.i.d. or erythromycin 100 mg b.i.d. intravenously. Continuous ECG data were collected from 2 h before to 24 h after the first administration. QT-analyses were performed using high-end holter software. The effect was determined with a two-sample t-test for clustered data on all QTc values. A linear mixed model by maximum likelihood was applied, for which QTc values were assessed for the available time intervals and therapy. No evident effect over time on therapy with ciprofloxacin and erythromycin was observed on QTc time. There was no significant difference (p = 0.22) in QTc values between the ciprofloxacin group (mean 393 ms) and ciprofloxacin control group (mean 386 ms). The erythromycin group (mean 405 ms) and erythromycin control group (mean 404 ms) neither showed a significant difference (p = 0.80). In 0.6% of the registrations (1.138 out of 198.270 samples) the duration of the QTc interval was longer than 500 ms. The index groups showed slightly more recorded QTc intervals over 500 ms. To conclude, this study could not identify differences in the QTc interval between the treatments analyzed.


Assuntos
Antibacterianos/efeitos adversos , Ciprofloxacina/efeitos adversos , Eritromicina/efeitos adversos , Síndrome do QT Longo/induzido quimicamente , Administração Intravenosa , Adulto , Idoso , Antibacterianos/administração & dosagem , Ciprofloxacina/administração & dosagem , Estado Terminal , Eletrocardiografia , Eritromicina/administração & dosagem , Feminino , Humanos , Unidades de Terapia Intensiva , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo
4.
Pharm Res ; 38(1): 165-177, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33534130

RESUMO

AIM: The aim of this study was to fabricate polymeric microneedles, loaded with macrolides (erythromycin, azithromycin), using hyaluronic acid and polyvinyl pyrollidone. METHODS: These microneedles were fabricated using a vacuum micromolding technique. The integrity of the microneedle patches was studied by recording their morphologic features, folding endurance, swelling and micro-piercing. Physicochemical characteristics were studied by differential scanning calorimetry, thermogravimetric analysis and fourier transform infrared spectroscopy. In-vitro drug release, antibiofilm and effect of microneedle patch on wound healing were also studied to confirm the efficacy of the formulations. RESULTS: Formulated patches displayed acceptable folding endurance (>100) and uniform distribution of microneedles (10 × 10) that can penetrate parafilm. Differential scanning calorimetry results depict a decrease in the crystallinity of macrolides following their incorporation in to a polymer matrix. Percentage release of azithromycin and erythromycin from the polymeric patch formulations (over 30 min) was 90% and 63% respectively. Broadly, the zone of bacterial growth inhibition follows the same order for Staphylococcus aureus, Escherichia coli and Salmonella enterica. After 5 days of treatment with azithromycin patches, the wound healing was complete and skin structure (e.g. hair follicles and dermis) was regenerated. CONCLUSION: It was concluded that azithromycin loaded microneedle patches can be used to treat biofilms in the infected wounds.


Assuntos
Antibacterianos/administração & dosagem , Biofilmes/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Cicatrização/efeitos dos fármacos , Infecção dos Ferimentos/tratamento farmacológico , Administração Cutânea , Animais , Antibacterianos/farmacocinética , Azitromicina/administração & dosagem , Azitromicina/farmacocinética , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Eritromicina/administração & dosagem , Eritromicina/farmacocinética , Escherichia coli/efeitos dos fármacos , Humanos , Masculino , Testes de Sensibilidade Microbiana , Ratos , Salmonella enterica/efeitos dos fármacos , Pele/lesões , Pele/metabolismo , Pele/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Adesivo Transdérmico , Infecção dos Ferimentos/microbiologia
5.
Pak J Pharm Sci ; 34(6(Special)): 2447-2454, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35039258

RESUMO

This study aimed to investigate the effect of erythromycin sequential therapy plus azithromycin on lung function and inflammatory factors in children with severe mycoplasma pneumonia (MP). Ninety-three severe MP children were selected and randomized into azithromycin group, erythromycin group, and combination group, 31 cases in each. The disappearance time of cough, fever, lung rale and X-ray shadow in the combination group were shorter than those in the azithromycin group and erythromycin group. The clinical treatment efficiency of the combination group was higher than that of the azithromycin group. After treatment, FVC, FEV1/FVC and PEF in combination group were higher than before treatment; IL-8, IL-6, CRP in combination group were lower than erythromycin group and azithromycin group. IL-8, IL-6, CRP are negatively correlated with disappearance time of cough, fever, pulmonary rale, X-ray shadow and clinical treatment efficiency; FEV1/FVC is positively correlated with disappearance time of cough and fever, pulmonary rales and X-ray shadow, and clinical treatment efficiency. Sequential erythromycin therapy combined with azithromycin in the treatment of MP can effectively inhibit high inflammatory reactions, control the disease in a timely manner, improve lung function and produce fewer adverse reactions.


Assuntos
Antibacterianos/administração & dosagem , Azitromicina/administração & dosagem , Eritromicina/administração & dosagem , Mediadores da Inflamação/sangue , Pulmão/efeitos dos fármacos , Mycoplasma pneumoniae/patogenicidade , Pneumonia por Mycoplasma/tratamento farmacológico , Antibacterianos/efeitos adversos , Azitromicina/efeitos adversos , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Estudos de Casos e Controles , Criança , Pré-Escolar , China , Quimioterapia Combinada , Eritromicina/efeitos adversos , Feminino , Interações Hospedeiro-Patógeno , Humanos , Interleucina-6/sangue , Interleucina-8/sangue , Pulmão/metabolismo , Pulmão/microbiologia , Pulmão/fisiopatologia , Masculino , Pneumonia por Mycoplasma/sangue , Pneumonia por Mycoplasma/microbiologia , Pneumonia por Mycoplasma/fisiopatologia , Distribuição Aleatória , Recuperação de Função Fisiológica , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
6.
J Obstet Gynaecol ; 41(4): 569-572, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-32799726

RESUMO

Antimicrobial prophylaxis is widely recommended for pregnant women who have preterm premature rupture of the membranes. Erythromycin prophylaxis was used during an initial period (control) and then changed to intravenous amoxicillin for 48 h, followed by 5 days of oral amoxicillin along with a single dose of azithromycin (case). Healthcare records were reviewed retrospectively. The primary outcome was latency (between membrane rupture and delivery) and the secondary outcomes were mode of delivery, maternal high dependency unit (HDU) admission, and several laboratory parameters. There were 78 women in the case group (amoxicillin and azithromycin) and controls were selected on a 1:1 ratio. There was no statistically significant difference between cases and controls with respect to group B Streptococcus or E.coli carriage, previous preterm birth, assissted fertility and parity. No babies had a positive blood culture with Group B Streptococcus. There was a longer latency to delivery for those prescribed amoxicillin and azithromycin (median = 5.5 days), compared with controls on erythromycin (median = 2 days, p < .001). There was no difference in the mode of delivery or maternal HDU admission. Given the potential sequelae of preterm birth, this warrants further prospective investigation in a randomised control trial.IMPACT STATEMENTWhat is already known on this subject? Antimicrobial prophylaxis is recommended for women who have preterm premature rupture of the membranes (PPROM). It has been shown to increase latency of delivery. However there are different regimens recommended in North America (amoxicillin and a macrolide) and the United Kingdom (macrolide monotherapy).What do the results of this study add? This study has shown that in our population, women who were prescribed the PPROM regimen of amoxicillin with azithromycin had a longer median latency from time of rupture of membranes to delivery, than women in a historical control group who were prescribed erythromycin monotherapy.What are the implications of these findings for clinical practice and/or further research? This retrospective study has shown that there may be a difference in latency between different antimicrobial prophylaxis regimens for PPROM. A randomised control trial, with sufficient patient numbers, is needed to determine the best regimen for prophylaxis, and would allow harmonisation of international guidelines.


Assuntos
Antibioticoprofilaxia/métodos , Ruptura Prematura de Membranas Fetais/microbiologia , Transmissão Vertical de Doenças Infecciosas/prevenção & controle , Complicações Infecciosas na Gravidez/tratamento farmacológico , Infecções Estreptocócicas/transmissão , Adulto , Amoxicilina/administração & dosagem , Azitromicina/administração & dosagem , Parto Obstétrico/estatística & dados numéricos , Eritromicina/administração & dosagem , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , Complicações Infecciosas na Gravidez/microbiologia , Estudos Retrospectivos , Streptococcus agalactiae , Fatores de Tempo , Resultado do Tratamento
7.
Life Sci ; 264: 118675, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33127513

RESUMO

Among the bacterial resistance mechanisms, efflux pumps are responsible for expelling xenobiotics, including bacterial cell antibiotics. Given this problem, studies are investigating new alternatives for inhibiting bacterial growth or enhancing the antibiotic activity of drugs already on the market. With this in mind, this study aimed to evaluate the antibacterial activity of Estragole against the RN4220 Staphylococcus aureus strain, which carries the MsrA efflux pump, as well as Estragole's toxicity in the Drosophila melanogaster arthropod model. The broth microdilution method was used to perform the Minimum Inhibitory Concentration (MIC) tests. Estragole was used at a Sub-Inhibitory Concentration (MIC/8) in association with erythromycin and ethidium bromide to assess its combined effect. As for Estragole's toxicity evaluation over D. melanogaster, the fumigation bioassay and negative geotaxis methods were used. The results were expressed as an average of sextuplicate replicates. A Two-way ANOVA followed by Bonferroni's post hoc test was used. The present study demonstrated that Estragole did not show a direct antibacterial activity over the RN4220 S. aureus strain, since it obtained a MIC ≥1024 µg/mL. The association of estragole with erythromycin demonstrated a potentiation of the antibiotic effect, reducing the MIC from 512 to 256 µg/mL. On the other hand, when estragole was associated with ethidium bromide (EtBr), an antagonism was observed, increasing the MIC of EtBr from 32 to 50.7968 µg/mL, demonstrating that estragole did not inhibited directly the MsrA efflux pump mechanism. We conclude that estragole has no relevant direct effect over bacterial growth, however, when associated with erythromycin, this reduced its MIC, potentiating the effect of the antibiotic.


Assuntos
Anisóis/toxicidade , Antibacterianos/toxicidade , Farmacorresistência Bacteriana Múltipla/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Derivados de Alilbenzenos , Animais , Anisóis/administração & dosagem , Antibacterianos/administração & dosagem , Relação Dose-Resposta a Droga , Drosophila melanogaster , Farmacorresistência Bacteriana Múltipla/fisiologia , Eritromicina/administração & dosagem , Aromatizantes/administração & dosagem , Aromatizantes/toxicidade , Testes de Sensibilidade Microbiana/métodos , Staphylococcus aureus/fisiologia
8.
Obstet Gynecol Clin North Am ; 47(4): 595-603, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33121647

RESUMO

"For many years, providers have been using antibiotics to prevent infection in women who present with preterm prelabor rupture of membranes (PPROM). Given the polymicrobial nature of intra-amniotic infection, the recommended regimen includes a 7-day course of ampicillin and erythromycin, although many substitute of azithromycin. This regimen is used from viability to 34 weeks, independent of the number of fetuses present. Meta-analyses have shown that antibiotics for this indication are associated with lower rates of maternal and fetal infection, as well as longer pregnancy latency. Thus, latency antibiotics are recommended for all women with PPROM through 34 weeks of gestation."


Assuntos
Ampicilina/administração & dosagem , Antibacterianos/administração & dosagem , Antibioticoprofilaxia/métodos , Eritromicina/administração & dosagem , Ruptura Prematura de Membranas Fetais/tratamento farmacológico , Azitromicina/administração & dosagem , Vias de Administração de Medicamentos , Quimioterapia Combinada , Feminino , Ruptura Prematura de Membranas Fetais/microbiologia , Idade Gestacional , Humanos , Recém-Nascido , Gravidez , Complicações Infecciosas na Gravidez/prevenção & controle
9.
Cochrane Database Syst Rev ; 9: CD001862, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32959365

RESUMO

BACKGROUND: Ophthalmia neonatorum is an infection of the eyes in newborns that can lead to blindness, particularly if the infection is caused by Neisseria gonorrhoeae. Antiseptic or antibiotic medication is dispensed into the eyes of newborns, or dispensed systemically, soon after delivery to prevent neonatal conjunctivitis and potential vision impairment. OBJECTIVES: 1. To determine if any type of systemic or topical eye medication is better than placebo or no prophylaxis in preventing ophthalmia neonatorum. 2. To determine if any one systemic or topical eye medication is better than any other medication in preventing ophthalmia neonatorum. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, LILACS, and three trials registers, date of last search 4 October 2019. We also searched references of included studies and contacted pharmaceutical companies.  SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials of any topical, systemic, or combination medical interventions used to prevent ophthalmia neonatorum in newborns compared with placebo, no prophylaxis, or with each other. DATA COLLECTION AND ANALYSIS: We used standard methods expected by Cochrane. Outcomes were: blindness or any adverse visual outcome at 12 months, conjunctivitis at 1 month (gonococcal (GC), chlamydial (CC), bacterial (BC), any aetiology (ACAE), or unknown aetiology (CUE)), and adverse effects.  MAIN RESULTS: We included 30 trials with a total of 79,198 neonates. Eighteen studies were conducted in high-income settings (the USA, Europe, Israel, Canada), and 12 were conducted in low- and middle-income settings (Africa, Iran, China, Indonesia, Mexico). Fifteen of the 30 studies were quasi-randomised. We judged every study to be at high risk of bias in at least one domain. Ten studies included a comparison arm with no prophylaxis. There were 14 different prophylactic regimens and 12 different medications in the 30 included studies. Any prophylaxis compared to no prophylaxis  Unless otherwise indicated, the following evidence comes from studies assessing one or more of the following interventions: tetracycline 1%, erythromycin 0.5%, povidone-iodine 2.5%, silver nitrate 1%. None of the studies reported data on the primary outcomes: blindness or any adverse visual outcome at any time point. There was only very low-certainty evidence on the risk of GC with prophylaxis (4/5340 newborns) compared to no prophylaxis (5/2889) at one month (risk ratio (RR) 0.79, 95% confidence interval (CI) 0.24 to 2.65, 3 studies). Low-certainty evidence suggested there may be little or no difference in effect on CC (RR 0.96, 95% CI 0.57 to 1.61, 4874 newborns, 2 studies) and BC (RR 0.84, 95% CI 0.37 to 1.93, 3685 newborns, 2 studies). Moderate-certainty evidence suggested a probable reduction in risk of ACAE at one month (RR 0.65, 95% 0.54 to 0.78, 9666 newborns, 8 studies assessing tetracycline 1%, erythromycin 0.5%, povidone-iodine 2.5%, silver nitrate 1%, colostrum, bacitracin-phenacaine ointment). There was only very low-certainty evidence on CUE  (RR 1.75, 95% CI 0.37 to 8.28, 330 newborns, 1 study). Very low-certainty evidence on adverse effects suggested no increased nasolacrimal duct obstruction (RR 0.93, 95% CI 0.68 to 1.28, 404 newborns, 1 study of erythromycin 0.5% and silver nitrate 1%) and no increased keratitis (single study of 40 newborns assessing silver nitrate 1% with no events).    Any prophylaxis compared to another prophylaxis Overall, evidence comparing different interventions did not suggest any consistently superior intervention. However, most of this evidence was of low-certainty and was extremely limited. AUTHORS' CONCLUSIONS: There are no data on whether prophylaxis for ophthalmia neonatorum prevents serious outcomes such as blindness or any adverse visual outcome. Moderate-certainty evidence suggests that the use of prophylaxis may lead to a reduction in the incidence of ACAE in newborns but the evidence for effect on GC, CC or BC was less certain. Comparison of individual interventions did not suggest any consistently superior intervention, but data were limited. A trial comparing tetracycline, povidone-iodine (single administration), and chloramphenicol for GC and CC could potentially provide the community with an effective, universally applicable prophylaxis against ophthalmia neonatorum.


Assuntos
Anti-Infecciosos/administração & dosagem , Oftalmia Neonatal/prevenção & controle , Viés , Cegueira/prevenção & controle , Eritromicina/administração & dosagem , Humanos , Recém-Nascido , Povidona-Iodo/administração & dosagem , Ensaios Clínicos Controlados Aleatórios como Assunto , Nitrato de Prata/administração & dosagem , Tetraciclina/administração & dosagem , Tracoma/prevenção & controle , Transtornos da Visão/prevenção & controle
10.
Infect Dis Obstet Gynecol ; 2020: 2093530, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32694907

RESUMO

Objective: To determine if antibiotic regimens including azithromycin versus erythromycin has an impact on pregnancy latency and development of clinical chorioamnionitis in the context of preterm prelabor rupture of membranes. Study Design. We conducted a prospective observational cohort study and followed all women receiving antibiotic regimens including either azithromycin or erythromycin in the context of preterm prelabor rupture of membranes. Primary outcomes were the duration of pregnancy latency period and development of chorioamnionitis. Secondary outcomes included neonatal sepsis with positive blood culture, cesarean delivery, postpartum endometritis, and meconium-stained amniotic fluid. Results: This study included 310 patients, with 142 receiving the azithromycin regimen and 168 receiving the erythromycin regimen. Patients receiving the azithromycin regimen had a statistically significant advantage in overall rates of clinical chorioamnionitis (13.4% versus 25%, p = 0.010), neonatal sepsis (4.9% versus 14.9%, p = 0.004), and postpartum endometritis (14.8% versus 31%, p = 0.001). In crude and adjusted models, when comparing the azithromycin group with the erythromycin group, a decreased risk was noted for the development of clinical chorioamnionitis, neonatal sepsis, and postpartum endometritis. Pregnancy latency by regimen was not significantly different in crude and adjusted models. Conclusion: Our study suggests that latency antibiotic regimens substituting azithromycin for erythromycin have lower rates and decreased risk of clinical chorioamnionitis, neonatal sepsis, and postpartum endometritis with no difference in pregnancy latency.


Assuntos
Antibioticoprofilaxia , Azitromicina/uso terapêutico , Corioamnionite/prevenção & controle , Endometrite/prevenção & controle , Eritromicina/uso terapêutico , Ruptura Prematura de Membranas Fetais/tratamento farmacológico , Adolescente , Adulto , Antibacterianos/administração & dosagem , Antibacterianos/uso terapêutico , Azitromicina/administração & dosagem , Cesárea , Esquema de Medicação , Eritromicina/administração & dosagem , Feminino , Humanos , Pessoa de Meia-Idade , Sepse Neonatal , Período Pós-Parto , Gravidez , Estudos Prospectivos , Adulto Jovem
11.
BMJ Case Rep ; 13(6)2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32606124

RESUMO

We report an unusual case of an 11-day-old neonate presenting with haemolacria on a background of sticky conjunctival discharge. This was secondary to Chlamydia pseudomembranous conjunctivitis which responded well to systemic erythromycin. Early appropriate treatment is important to prevent progression of the ophthalmic infection, which could lead to blindness, and to prevent other manifestations of neonatal chlamydial infection, particularly pneumonia, which could be fatal. Management also includes treating the mother and educating about sexually transmitted infections.


Assuntos
Chlamydia trachomatis/isolamento & purificação , Conjuntivite de Inclusão , Eritromicina/administração & dosagem , Doenças do Recém-Nascido , Infecções Sexualmente Transmissíveis , Administração Oral , Administração Tópica , Adulto , Antibacterianos/administração & dosagem , Conjuntivite de Inclusão/tratamento farmacológico , Conjuntivite de Inclusão/etiologia , Conjuntivite de Inclusão/microbiologia , Conjuntivite de Inclusão/fisiopatologia , Diagnóstico Diferencial , Saúde da Família , Feminino , Humanos , Recém-Nascido , Doenças do Recém-Nascido/tratamento farmacológico , Doenças do Recém-Nascido/etiologia , Doenças do Recém-Nascido/microbiologia , Doenças do Recém-Nascido/fisiopatologia , Masculino , Pais , Infecções Sexualmente Transmissíveis/diagnóstico , Infecções Sexualmente Transmissíveis/tratamento farmacológico , Infecções Sexualmente Transmissíveis/fisiopatologia , Resultado do Tratamento
12.
Jpn J Infect Dis ; 73(5): 361-362, 2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-32350216

RESUMO

We report the first detection of a macrolide-resistant Bordetella pertussis strain in Japan. The isolate was highly resistant to the macrolides (minimum inhibitory concentrations for erythromycin and clarithromycin: > 256 µg/ml, for azithromycin: 32 µg/ml) and A2047G mutation was identified in the 23S rRNA. The Multilocus Sequence Typing and Multilocus Variable Number of Tandem Repeat Analysis genotypes of this isolate were MT195 and ptxP1/ptxA1/prn1/fim3A/fhaB3, respectively, suggesting a relationship with the macrolide-resistant B. pertussis lineage currently found in China. This raises the possibility that macrolide-resistant B. pertussis has already fully spread in Japan. For a better control of B. pertussis infections, the surveillance for macrolide-resistant B. pertussis is essential in not only Japan, but also other Asian countries.


Assuntos
Antibacterianos/administração & dosagem , Bordetella pertussis/efeitos dos fármacos , Bordetella pertussis/genética , Farmacorresistência Bacteriana/genética , Macrolídeos/administração & dosagem , Coqueluche/microbiologia , Azitromicina/administração & dosagem , Claritromicina/administração & dosagem , Eritromicina/administração & dosagem , Genótipo , Humanos , Lactente , Japão , Masculino , Testes de Sensibilidade Microbiana , Tipagem de Sequências Multilocus , Mutação , RNA Ribossômico 23S/genética , Coqueluche/tratamento farmacológico
13.
Physiol Rep ; 8(5): e14385, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32147975

RESUMO

The macrolide antibiotic erythromycin has been associated with QT interval prolongation and inhibition of the hERG-encoded channels responsible for the rapid delayed rectifier K+ current I(Kr ). It has been suggested that low concentrations of erythromycin may have a protective effect against hERG block and associated drug-induced arrhythmia by reducing the affinity of the pore-binding site for high potency hERG inhibitors. This study aimed to explore further the notion of a potentially protective effect of erythromycin. Whole-cell patch-clamp experiments were performed in which hERG-expressing mammalian (Human Embryonic Kidney; HEK) cells were preincubated with low to moderate concentrations of erythromycin (3 or 30 µM) prior to whole-cell patch clamp recordings of hERG current (IhERG ) at 37°C. In contrast to a previous report, exposure to low concentrations of erythromycin did not reduce pharmacological sensitivity of hERG to the antipsychotic thioridazine and antihistamine terfenadine. The IC50 value for IhERG tail inhibition by terfenadine was decreased by ~32-fold in the presence of 3 µM erythromycin (p < .05 vs. no preincubation). Sensitivity to thioridazine remained unchanged (p > .05 vs. no preincubation). The effects of low concentrations of erythromycin were investigated for a series of pore blocking drugs, and the results obtained were consistent with additive and/or synergistic effects. Experiments with the externally acting blocker BeKm-1 on WT hERG and a pore mutant (F656V) were used to explore the location of the binding site for erythromycin. Our data are inconsistent with the use of erythromycin for the management of drug-induced QT prolongation.


Assuntos
Antipsicóticos/administração & dosagem , Canal de Potássio ERG1/antagonistas & inibidores , Eritromicina/administração & dosagem , Antagonistas não Sedativos dos Receptores H1 da Histamina/administração & dosagem , Terfenadina/administração & dosagem , Tioridazina/administração & dosagem , Sítios de Ligação/efeitos dos fármacos , Canal de Potássio ERG1/fisiologia , Eritromicina/química , Células HEK293 , Humanos , Concentração Inibidora 50 , Macrolídeos/administração & dosagem , Macrolídeos/química , Técnicas de Patch-Clamp
14.
Drug Metab Dispos ; 48(4): 307-316, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32009006

RESUMO

In vitro data for low-dose inhaled phosphoinositide 3-kinase delta inhibitor nemiralisib revealed that it was a substrate and a potent metabolism-dependent inhibitor of cytochrome P450 (P450) 3A4 and a P-glycoprotein (P-gp) substrate. An integrated in silico, in vitro, and clinical approach including a clinical drug interaction study as well as a bespoke physiologically based pharmacokinetic (PBPK) model was used to assess the drug-drug interaction (DDI) risk. Inhaled nemiralisib (100 µg, single dose) was coadministered with itraconazole, a potent P4503A4/P-gp inhibitor, following 200 mg daily administrations for 10 days in 20 male healthy subjects. Systemic exposure to nemiralisib (AUC0-inf) increased by 2.01-fold versus nemiralisib alone. To extrapolate the clinical data to other P4503A4 inhibitors, an inhaled PBPK model was developed using Simcyp software. Retrospective simulation of the victim risk showed good agreement between simulated and observed data (AUC0-inf ratio 2.3 vs. 2.01, respectively). Prospective DDI simulations predicted a weak but manageable drug interaction when nemiralisib was coadministered with other P4503A4 inhibitors, such as the macrolides clarithromycin and erythromycin (simulated AUC0-inf ratio of 1.7), both common comedications in the intended patient populations. PBPK and static mechanistic models were also used to predict a negligible perpetrator DDI effect for nemiralisib on other P4503A4 substrates, including midazolam (a sensitive probe substrate of P4503A4) and theophylline (a narrow therapeutic index drug and another common comedication). In summary, an integrated in silico, in vitro, and clinical approach including an inhalation PBPK model has successfully discharged any potential patient DDI risks in future nemiralisib clinical trials. SIGNIFICANCE STATEMENT: This paper describes the integration of in silico, in vitro, and clinical data to successfully discharge potential drug-drug interaction risks for a low-dose inhaled drug. This work featured assessment of victim and perpetrator risks of drug transporters and cytochrome P450 enzymes, utilizing empirical and mechanistic approaches combined with clinical data (drug interaction and human absorption, metabolism, and pharmacokinetics) and physiologically based pharmacokinetic modeling approaches to facilitate bespoke risk assessment in target patient populations.


Assuntos
Inibidores do Citocromo P-450 CYP3A/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Indazóis/farmacocinética , Indóis/farmacocinética , Itraconazol/farmacocinética , Oxazóis/farmacocinética , Inibidores de Fosfoinositídeo-3 Quinase/farmacocinética , Piperazinas/farmacocinética , Administração por Inalação , Adolescente , Adulto , Idoso , Área Sob a Curva , Claritromicina/administração & dosagem , Claritromicina/farmacocinética , Simulação por Computador , Estudos Cross-Over , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Interações Medicamentosas , Eritromicina/administração & dosagem , Eritromicina/farmacocinética , Voluntários Saudáveis , Humanos , Indazóis/administração & dosagem , Indóis/administração & dosagem , Itraconazol/administração & dosagem , Masculino , Microssomos Hepáticos , Midazolam/administração & dosagem , Midazolam/farmacocinética , Pessoa de Meia-Idade , Modelos Biológicos , Oxazóis/administração & dosagem , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Piperazinas/administração & dosagem , Estudos Prospectivos , Estudos Retrospectivos , Adulto Jovem
15.
Int J Cancer ; 146(4): 1064-1074, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31283021

RESUMO

As a large number of cancers are caused by nonsense mutations in key genes, read-through of these mutations to restore full-length protein expression is a potential therapeutic strategy. Mutations in the adenomatous polyposis coli (APC) gene initiate the majority of both sporadic and hereditary colorectal cancers (CRC) and around 30% of these mutations are nonsense mutations. Our goal was to test the feasibility and effectiveness of APC nonsense mutation read-through as a potential chemo-preventive therapy in Familial Adenomatous Polyposis (FAP), an inherited CRC syndrome patients. Ten FAP patients harboring APC nonsense mutations were treated with the read-through inducing antibiotic erythromycin for 4 months. Endoscopic assessment of the adenomas was performed at baseline, after 4 and after 12 months. Adenoma burden was documented in terms of adenoma number, maximal polyp size and cumulative polyp size per procedure. Tissue samples were collected and subjected to molecular and genetic analyses. Our results show that in the majority of patients the treatment led to a decrease in cumulative adenoma burden, median reduction in cumulative adenoma size and median reduction in adenoma number. Molecular and genetic analyses of the adenomas revealed that the treatment led to a reduced number of somatic APC mutations, reduced cellular proliferation and restoration of APC tumor-suppressing activity. Together, our findings show that induced read-through of APC nonsense mutations leads to promising clinical results and should be further investigated to establish its therapeutic potential in FAP and sporadic CRCs harboring nonsense APC mutations.


Assuntos
Proteína da Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/tratamento farmacológico , Eritromicina/administração & dosagem , Transcrição Gênica/efeitos dos fármacos , Polipose Adenomatosa do Colo/diagnóstico por imagem , Polipose Adenomatosa do Colo/genética , Administração Oral , Adolescente , Adulto , Idoso , Criança , Códon sem Sentido , Códon de Terminação/genética , Colonoscopia , Eritromicina/efeitos adversos , Estudos de Viabilidade , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
16.
J Dermatolog Treat ; 31(7): 730-733, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30998422

RESUMO

Purpose: Erythromycin is an effective topical antibiotic for treating mild-to-moderate inflammatory acne vulgaris, especially papules acne during puberty as well as papules - pustular acne in adult women. Erythromycin is a macrolide antibiotic that has long been used as a topical dosage form to treat acne. It has favorable effects in resolving inflammatory acne lesions not only by reducing Propioni bacterium acnes density, but also by directly inhibiting neutrophil chemotactic factors and reactive oxygen species (ROS) production. Zinc, a metallic element has bacteriostatic activity against Propioni bacterium acnes. Combining zinc with antibiotic (erythromycin) can reduce antibiotic resistance and increase antibiotic absorption in-to the skin.Material and methods: In the present study, erythromycin (2% w/v) with zinc acetate (1.2% w/v) as 'topical gel' and erythromycin (2% w/v) gel alone were evaluated for treating mild to moderate inflammatory acne vulgaris. This double-blind study was carried out on 102 patients 13-25 years of age, divided into two groups. The group A received erythromycin and group B received erythromycin with zinc acetate topical gels during 3 weeks. Acne grading and lesion counts for comedones, papules and pustules were performed during each visit zero, first, second and third weeks.Results: Erythromycin treatment (with zinc acetate) gel showed to be more effective than erythromycin (alone) gel with respect to reducing the number of acne lesions and severity grade of acne.Number of lesions and severity of acne were significantly reduced at the end of 3rd week in both groups (p < .001). Conclusions: In conclusion, it can be stated that erythromycin with and without zinc acetate was clinically effective, and both formulations produced a significant reductions in acne grading as well as inflamed and noninflamed lesion counts (p < .000). Statistically, there was no significant difference between formulation A and B.


Assuntos
Acne Vulgar/tratamento farmacológico , Antibacterianos/administração & dosagem , Eritromicina/administração & dosagem , Acetato de Zinco/administração & dosagem , Administração Tópica , Adolescente , Adulto , Análise de Variância , Método Duplo-Cego , Combinação de Medicamentos , Resistência Microbiana a Medicamentos , Géis , Humanos , Masculino , Gravidade do Paciente , Resultado do Tratamento , Adulto Jovem
18.
PLoS One ; 14(10): e0223859, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31603921

RESUMO

The ocular surface microbiome of veterinary species has not been thoroughly characterized using next generation sequencing. Furthermore, alterations in the feline ocular surface microbiome over time or following topical antibiotic treatment are unknown. Aims of this study were to further characterize the ocular surface microbiome of healthy cats and to identify whether there are microbial community changes over time and following topical antibiotic use. Twenty-four eyes from twelve adult, research-bred, female spayed domestic shorthaired cats were evaluated. Erythromycin ophthalmic ointment (0.5%) was applied to the ocular surface of one randomly assigned eye per cat three times daily for 7 days, while the fellow eye served as an untreated control. The ocular surface was sampled by swabbing the inferior conjunctival fornix of both eyes prior to initiating treatment (day 0), after 1 week of treatment (day 7), and 4 weeks after concluding treatment (day 35). Genomic DNA was extracted from the swabs and sequenced using primers that target the V4 region of bacterial 16S rRNA genes. At baseline, the most common bacterial phyla identified were Proteobacteria (42.4%), Firmicutes (30.0%), Actinobacteria (15.6%), and Bacteroidetes (8.1%). The most abundant bacterial families sequenced were Corynebacteriaceae (7.8%), Helicobacteraceae (7.5%), Moraxellaceae (6.1%), and Comamonadaceae (5.6%). Alpha and beta diversity measurements were largely unchanged in both treatment and control eyes over time. However, univariate and linear discriminant analyses revealed significant and similar changes in the abundance of some bacterial taxa over time in both treatment and control eyes. Overall, the feline ocular surface microbiome remained stable over time and following topical antibiotic therapy.


Assuntos
Antibacterianos/administração & dosagem , Bactérias/classificação , Eritromicina/administração & dosagem , Olho/microbiologia , Administração Tópica , Animais , Antibacterianos/farmacologia , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Gatos , Análise Discriminante , Eritromicina/farmacologia , Olho/efeitos dos fármacos , Feminino , Pomadas/administração & dosagem , Pomadas/farmacologia , Filogenia , RNA Ribossômico 16S/genética , Distribuição Aleatória , Análise de Sequência de DNA/veterinária
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