RESUMEN
A rare cause of megaloblastic anemia (MA) is thiamine-responsive megaloblastic anemia (TRMA), a genetic disorder caused by mutations in SLC19A2 (encoding THTR1), a thiamine transporter. The study objectives were to (1) functionally characterize selected TRMA-associated SLC19A2 variants and (2) determine whether current prescription drugs associated with drug-induced MA (DIMA) may act via inhibition of SLC19A2. Functional characterization of selected SLC19A2 variants was performed by confocal microscopy and isotopic uptake studies of [3H]-thiamine in HEK293 cells. Sixty-three drugs associated with DIMA were screened for SLC19A2 inhibition in isotopic uptake studies. Three previously uncharacterized SLC19A2 variants identified in TRMA patients exhibited disrupted localization to the plasma membrane along with near-complete loss-of-function. Ten of 63 drugs inhibited SLC19A2-mediated thiamine transport ≥ 50% at screening concentrations; however, with the exception of erythromycin, none was predicted to inhibit SLC19A2 at clinically relevant unbound plasma concentrations. Data from electronic health records revealed reduced levels of thiamine pyrophosphate (TPP) in patients prescribed erythromycin, consistent with inhibition of SLC19A2-mediated thiamine transport. Here, we confirmed the role of three SLC19A2 variants in TRMA pathology. Additionally, we report that inhibition of SLC19A2 is a potential, but uncommon mechanism for DIMA.
Asunto(s)
Anemia Megaloblástica/genética , Diabetes Mellitus/genética , Eritromicina/efectos adversos , Pérdida Auditiva Sensorineural/genética , Proteínas de Transporte de Membrana/genética , Deficiencia de Tiamina/congénito , Tiamina Pirofosfato/antagonistas & inhibidores , Adulto , Anemia Megaloblástica/sangre , Anemia Megaloblástica/inducido químicamente , Membrana Celular/metabolismo , Diabetes Mellitus/sangre , Diabetes Mellitus/inducido químicamente , Interacciones Farmacológicas , Eritromicina/farmacocinética , Femenino , Variación Genética , Células HEK293 , Pérdida Auditiva Sensorineural/sangre , Pérdida Auditiva Sensorineural/inducido químicamente , Humanos , Mutación con Pérdida de Función , Masculino , Proteínas de Transporte de Membrana/metabolismo , Deficiencia de Tiamina/sangre , Deficiencia de Tiamina/inducido químicamente , Deficiencia de Tiamina/genética , Tiamina Pirofosfato/sangre , Tiamina Pirofosfato/metabolismoRESUMEN
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.
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Antibacterianos/administración & dosificación , Biopelículas/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Cicatrización de Heridas/efectos de los fármacos , Infección de Heridas/tratamiento farmacológico , Administración Cutánea , Animales , Antibacterianos/farmacocinética , Azitromicina/administración & dosificación , Azitromicina/farmacocinética , Modelos Animales de Enfermedad , Liberación de Fármacos , Eritromicina/administración & dosificación , Eritromicina/farmacocinética , Escherichia coli/efectos de los fármacos , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Ratas , Salmonella enterica/efectos de los fármacos , Piel/lesiones , Piel/metabolismo , Piel/microbiología , Staphylococcus aureus/efectos de los fármacos , Parche Transdérmico , Infección de Heridas/microbiologíaRESUMEN
The aim of this study was to apply individualized, physiologically based pharmacokinetic modeling of 14 CO2 production rates (iPBPK-R) measured by the erythromycin breath test to characterize the effect of hemodialysis on the function of nonrenal clearance pathways in patients with end-stage renal disease. Twelve patients previously received 14 C-erythromycin intravenously pre- and post-hemodialysis. Serial breath samples were collected after each dose over 2 hours. Eight PBPK parameters were co-estimated across periods, whereas activity of cytochrome P450 (CYP) 3A4 clearance was independently estimated for each period. Inhibition coefficients for organic anion transporting polypeptide (OATP), P-glycoprotein, and multidrug resistance-associated protein 2 activities were also estimated. Nonrenal clearance parameter estimates were explored regarding sex differences and correlations with uremic toxins and were used in hierarchical cluster analysis (HCA). Relationships between the function of nonrenal clearance pathways and uremic toxin concentrations were explored. Mean CYP 3A4 clearance increased by 2.2% post-hemodialysis. Uptake transporter activity was highly intervariable across hemodialysis. Females had 22% and 30% higher median CYP3A4 activity than males pre- and post-hemodialysis, respectively. Exploratory HCA indicated that using both CYP3A4 and OATP activity parameters at pre- and post-hemodialysis best identifies heterogeneous patients. This is the first study to use the iPBPK-R approach to simultaneously estimate multiple in vivo nonrenal elimination pathways in individual patients with kidney disease and to assess the effect of hemodialysis.
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Citocromo P-450 CYP3A/metabolismo , Eritromicina/farmacocinética , Fallo Renal Crónico/metabolismo , Modelos Biológicos , Diálisis Renal , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/antagonistas & inhibidores , Pruebas Respiratorias , Femenino , Humanos , Masculino , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos/antagonistas & inhibidores , Transportadores de Anión Orgánico/antagonistas & inhibidores , Factores Sexuales , Tóxinas Urémicas/sangreRESUMEN
Objective: This study aims to explore the role of erythromycin-regulated histone deacetylase-2 in benign tracheal stenosis. Methods: The rabbit model of tracheal stenosis was established. The rabbits were randomly divided into 8 groups. Histone deacetylase-2 (HDAC2) expression was detected by immunofluorescence. The expression of type I collagen and type III collagen was detected by immunohistochemical method. The expression of TGF-ß1, VEGF and IL-8 in serum and alveolar lavage fluid was detected by ELISA. The expression of HDAC2, TGF-ß1, VEGF and IL-8 in serum and alveolar lavage fluid was detected by ELISA. The expression of HDAC2, TGF. Results: In Erythromycin (ERY) group, ERY + Budesonide group, ERY + Vorinostat group and ERY + Budesonide + Vorinostat group, the degree of bronchial stenosis was alleviated, and the mucosal epithelium was still slightly proliferated. The effect of ERY combined with other drugs was more obvious. The HDAC2 protein expression increased significantly in ERY group, ERY + Budesonide group and ERY + Budesonide + Vorinostat group and decreased significantly in Vorinostat group, the expression of collagen I and III decreased significantly in ERY group, ERY + Budesonide group and ERY + Budesonide + Vorinostat group (P < 0.05). The TGF-ß1, VEGF and IL-8 in serum and alveolar lavage fluid was detected by ELISA. The expression of HDAC2, TGF-P < 0.05). The TGF. Conclusions: Erythromycin inhibited inflammation and excessive proliferation of granulation tissue after tracheobronchial mucosal injury by up-regulating the expression of HDAC2, it promoted wound healing and alleviated tracheobronchial stenosis. When combined with budesonide, penicillin and other glucocorticoids and antibiotics, it had a good synergistic effect. However, vorinostat could attenuate erythromycin's effect by down-regulating the expression of HDAC2. It may have good clinical application prospects in the treatment of tracheal stenosis.
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Eritromicina/farmacocinética , Histona Desacetilasa 2 , Mucosa Respiratoria , Estenosis Traqueal , Regulación hacia Arriba/efectos de los fármacos , Animales , Líquido del Lavado Bronquioalveolar/inmunología , Budesonida/farmacocinética , Glucocorticoides/farmacocinética , Tejido de Granulación/efectos de los fármacos , Tejido de Granulación/metabolismo , Histona Desacetilasa 2/genética , Histona Desacetilasa 2/metabolismo , Inhibidores de Histona Desacetilasas/farmacocinética , Inmunohistoquímica , Inhibidores de la Síntesis de la Proteína/farmacocinética , Conejos , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/inmunología , Estenosis Traqueal/tratamiento farmacológico , Estenosis Traqueal/inmunología , Estenosis Traqueal/metabolismo , Factor de Crecimiento Transformador beta1/sangre , Factor de Crecimiento Transformador beta1/metabolismo , Resultado del Tratamiento , Vorinostat/farmacocinéticaRESUMEN
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.
Asunto(s)
Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Citocromo P-450 CYP3A/metabolismo , Indazoles/farmacocinética , Indoles/farmacocinética , Itraconazol/farmacocinética , Oxazoles/farmacocinética , Inhibidores de las Quinasa Fosfoinosítidos-3/farmacocinética , Piperazinas/farmacocinética , Administración por Inhalación , Adolescente , Adulto , Anciano , Área Bajo la Curva , Claritromicina/administración & dosificación , Claritromicina/farmacocinética , Simulación por Computador , Estudios Cruzados , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Interacciones Farmacológicas , Eritromicina/administración & dosificación , Eritromicina/farmacocinética , Voluntarios Sanos , Humanos , Indazoles/administración & dosificación , Indoles/administración & dosificación , Itraconazol/administración & dosificación , Masculino , Microsomas Hepáticos , Midazolam/administración & dosificación , Midazolam/farmacocinética , Persona de Mediana Edad , Modelos Biológicos , Oxazoles/administración & dosificación , Inhibidores de las Quinasa Fosfoinosítidos-3/administración & dosificación , Piperazinas/administración & dosificación , Estudios Prospectivos , Estudios Retrospectivos , Adulto JovenRESUMEN
Many antibiotics carry caution stickers that warn against alcohol consumption. Data regarding concurrent use are sparse. An awareness of data that address this common clinical scenario is important so health care professionals can make informed clinical decisions and address questions in an evidence-based manner. The purpose of this systematic review was to determine the evidence behind alcohol warnings issued for many common antimicrobials. The search was conducted from inception of each database to 2018 using PubMed, Medline via Ovid, and Embase. It included studies that involved interactions, effects on efficacy, and toxicity/adverse drug reactions (ADR) due to concomitant alcohol consumption and antimicrobials. All interactions were considered in terms of three components: (i) alteration in pharmacokinetics/pharmacodynamics (PK/PD) of antimicrobials and/or alcohol, (ii) change in antimicrobial efficacy, and (iii) development of toxicity/ADR. Available data support that oral penicillins, cefdinir, cefpodoxime, fluoroquinolones, azithromycin, tetracycline, nitrofurantoin, secnidazole, tinidazole, and fluconazole can be safely used with concomitant alcohol consumption. Data are equivocal for trimethoprim-sulfamethoxazole. Erythromycin may have reduced efficacy with alcohol consumption, and doxycycline may have reduced efficacy in chronic alcoholism. Alcohol low in tyramine may be consumed with oxazolidinones. The disulfiram-like reaction, though classically associated with metronidazole, occurs with uncertain frequency and with varied severity. Cephalosporins with a methylthiotetrazole (MTT) side chain or a methylthiodioxotriazine (MTDT) ring, ketoconazole, and griseofulvin have an increased risk of a disulfiram-like reaction. Alcohol and antimicrobial interactions are often lacking evidence. This review questions common beliefs due to poor, often conflicting data and identifies important knowledge gaps.
Asunto(s)
Alcoholes/efectos adversos , Alcoholes/farmacocinética , Antibacterianos/efectos adversos , Antibacterianos/farmacocinética , Antiinfecciosos/efectos adversos , Antiinfecciosos/farmacocinética , Azitromicina/efectos adversos , Azitromicina/farmacocinética , Cefalosporinas/efectos adversos , Cefalosporinas/farmacocinética , Doxiciclina/efectos adversos , Doxiciclina/farmacocinética , Interacciones Farmacológicas , Eritromicina/efectos adversos , Eritromicina/farmacocinética , Fluoroquinolonas/efectos adversos , Fluoroquinolonas/farmacocinética , Metronidazol/efectos adversos , Metronidazol/análogos & derivados , Metronidazol/farmacocinética , Penicilinas/efectos adversos , Penicilinas/farmacocinética , Tetraciclina/efectos adversos , Tetraciclina/farmacocinéticaRESUMEN
Potential drug-drug interactions of the antitumor drug abiraterone and the macrolide antibiotic erythromycin were studied at the stage of cytochrome P450 3A4 (CYP3A4) biotransformation. Using differential spectroscopy, we have shown that abiraterone is a type II ligand of CYP3A4. The dependence of CYP3A4 spectral changes on the concentration of abiraterone is sigmoidal, which indicates cooperative interactions of CYP3A4 with abiraterone; these interactions were confirmed by molecular docking. The dissociation constant (Kd ) and Hill coefficient (h) values for the CYP3A4-abiraterone complex were calculated as 3.8 ± 0.1 µM and 2.3 ± 0.2, respectively. An electrochemical enzymatic system based on CYP3A4 immobilized on a screen-printed electrode was used to show that abiraterone acts as a competitive inhibitor toward erythromycin N-demethylase activity of CYP3A4 (apparent Ki = 8.1 ± 1.2 µM), while erythromycin and its products of enzymatic metabolism do not affect abiraterone N-oxidation by CYP3A4. In conclusion, the inhibition properties of abiraterone toward CYP3A4-dependent N-demethylation of erythromycin and the biologically inert behavior of erythromycin toward abiraterone hydroxylation were demonstrated.
Asunto(s)
Androstenos/farmacología , Antibacterianos/farmacocinética , Citocromo P-450 CYP3A/efectos de los fármacos , Eritromicina/farmacocinética , Antineoplásicos/farmacología , Citocromo P-450 CYP3A/metabolismo , Inhibidores del Citocromo P-450 CYP3A/farmacología , Interacciones Farmacológicas , Humanos , Hidroxilación , Simulación del Acoplamiento MolecularRESUMEN
Erythromycin is a substrate of cytochrome P4503A4 (CYP3A4) and multiple drug transporters. Although clinical evidence suggests that uptake transport is likely to play a dominant role in erythromycin's disposition, the relative contributions of individual pathways are unclear. Phenotypic evaluation of multiple pathways generally requires a probe drug cocktail. This approach can result in ambiguous conclusions due to imprecision stemming from overlapping specificity of multiple drugs. We hypothesized that an individualized physiologically based pharmacokinetic modeling approach incorporating 14CO2 production rates (iPBPK-R) of the erythromycin breath test (ERMBT) would enable us to differentiate the contribution of metabolic and transporter pathways to erythromycin disposition. A seven-compartmental physiologically based pharmacokinetic (PBPK) model was built for 14C-erythromycin administered intravenously. Transporter clearance and CYP3A4 clearance were embedded in hepatic compartments. 14CO2 production rates were simulated taking the first derivative of by-product 14CO2 concentrations. Parameters related to nonrenal elimination pathways were estimated by model fitting the ERMBT data of 12 healthy subjects individually. Optimized iPBPK-R models fit the individual rate data well. Using one probe, nine PBPK parameters were simultaneously estimated per individual. Maximum velocity of uptake transport, CYP3A4 clearance, total passive diffusion, and others were found to collectively control 14CO2 production rates. The median CYP3A4 clearance was 12.2% of the input clearance. Male subjects had lower CYP3A4 activity than female subjects by 11.3%. We applied iPBPK-R to ERMBT data to distinguish and simultaneously estimate the activity of multiple nonrenal elimination pathways in healthy subjects. The iPBPK-R framework is a novel tool for delineating rate-limiting and non-rate-limiting elimination pathways using a single probe. SIGNIFICANCE STATEMENT: Our developed individualized physiologically based pharmacokinetic modeling approach incorporating rate data (iPBPK-R) enabled us to distinguish and simultaneously estimate the activity of multiple nonrenal elimination pathways of erythromycin in healthy subjects. A new interpretation of erythromycin breath test (ERMBT) data was also obtained via iPBPK-R. We found that rate data have rich information allowing estimation of per-person PBPK parameters. This study serves as proof of principle that the iPBPK-R framework is a novel tool for delineating rate-limiting and non-rate-limiting elimination pathways using a single probe. iPBPK-R can be applied to other rate-derived data beyond ERMBT. Potential areas of application include drug-drug interaction, pathophysiological effects on drug disposition, and the role of biomarkers on hemodialysis efficiency utilizing estimated adjustment factors with correlation analysis.
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Dióxido de Carbono/metabolismo , Eritromicina/farmacocinética , Eliminación Hepatobiliar , Hígado/metabolismo , Modelación Específica para el Paciente , Pruebas Respiratorias/métodos , Citocromo P-450 CYP3A/metabolismo , HumanosRESUMEN
Ruxolitinib is mainly metabolized by cytochrome P450 (CYP) enzymes CYP3A4 and CYP2C9 followed by minor contributions of other hepatic CYP enzymes in vitro. A physiologically based pharmacokinetic (PBPK) model was established to evaluate the changes in the ruxolitinib systemic exposures with co-administration of CYP3A4 and CYP2C9 perpetrators. The fractions metabolized in the liver via oxidation by CYP enzymes (fm,CYP3A4 = 0.75, fm,CYP2C9 = 0.19, and fm,CYPothers = 0.06) for an initial ruxolitinib model based on in vitro data were optimized (0.43, 0.56, and 0.01, respectively) using the observed exposure changes of ruxolitinib (10 mg) with co-administered ketoconazole (200 mg). The reduced amount of fm,CYP3A4 was distributed to fm,CYP2C9. For the initial ruxolitinib model with co-administration of ketoconazole, the area under the curve (AUC) increase of 2.60-fold was over-estimated compared with the respective observation (1.91-fold). With the optimized fm values, the predicted AUC ratio was 1.82. The estimated AUC ratios of ruxolitinib by co-administration of the moderate CYP3A4 inhibitor erythromycin (500 mg) and the strong CYP3A4 inducer rifampicin (600 mg) were within a 20% error compared with the clinically observed values. The PBPK modeling results may provide information on the labeling, i.e. supporting a dose reduction by half for co-administration of strong CYP3A4 inhibitors. Furthermore, an AUC increase of ruxolitinib in the absence or presence of the dual CYP3A4 and CYP2C9 inhibitor fluconazole (100-400 mg) was prospectively estimated to be 1.94- to 4.31-fold. Fluconazole simulation results were used as a basis for ruxolitinib dose adjustment when co-administering perpetrator drugs. A ruxolitinib PBPK model with optimized fm,CYP3A4 and fm,CYP2C9 was established to evaluate victim DDI risks. The previous minimal PBPK model was supported by the FDA for the dose reduction strategy, halving the dose with the concomitant use of strong CYP3A4 inhibitors and dual inhibitors on CYP2C9 and CYP3A4, such as fluconazole at ≤200 mg. Fluconazole simulation results were used as supportive evidence in discussions with the FDA and EMA about ruxolitinib dose adjustment when co-administering perpetrator drugs. Thus, this study demonstrated that PBPK modeling can support characterizing DDI liabilities to inform the drug label and might help reduce the number of clinical DDI studies by simulations of untested scenarios, when a robust PBPK model is established.
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Citocromo P-450 CYP2C9/metabolismo , Citocromo P-450 CYP3A/metabolismo , Modelos Biológicos , Pirazoles/metabolismo , Pirazoles/farmacocinética , Administración Oral , Células CACO-2 , Interacciones Farmacológicas , Eritromicina/administración & dosificación , Eritromicina/metabolismo , Eritromicina/farmacocinética , Humanos , Cetoconazol/administración & dosificación , Cetoconazol/metabolismo , Cetoconazol/farmacocinética , Nitrilos , Pirazoles/administración & dosificación , Pirimidinas , Rifampin/administración & dosificación , Rifampin/metabolismo , Rifampin/farmacocinéticaRESUMEN
The effect of heat on the follicular absorption of drugs into the skin has not previously been investigated. In comparison to drug delivery across the continuous stratum corneum (SC), follicular absorption is known to be relatively rapid and therefore the use of short durations of heat may be particularly useful for enhancing drug delivery to the hair follicles, as well as being practical for patients to use. In this study erythromycin has been used as a model drug and the combined use of heat and chemical penetration enhancers was found to be able to synergistically increase the penetration of erythromycin into human skin via the follicular route. Moreover durations of heat application as short as 10â¯min in combination with particular enhancer systems were found to be sufficient to significantly increase erythromycin delivery to the skin. Overall the data indicate that the use of heat with chemical penetration enhancers offers a potentially valuable strategy for delivering drugs via the follicular route.
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Eritromicina/farmacocinética , Folículo Piloso/metabolismo , Calor , Absorción Cutánea/efectos de los fármacos , Piel/metabolismo , Solventes/farmacología , Administración Cutánea , Sistemas de Liberación de Medicamentos , Estabilidad de Medicamentos , Eritromicina/administración & dosificación , Humanos , Técnicas In Vitro , Solubilidad , Solventes/químicaRESUMEN
Erythromycin-loaded solid lipid microparticles (SLM) based on solidified reverse micellar solution (SRMS) as an oral delivery formulation was studied. Hot homogenization technique was employed to prepare erythromycin stearate-loaded SLMs using blends of Softisan® 154 and Phospholipon® 90H or beeswax in the ratio of 1:2, and characterized in vitro. Antibacterial evaluation of the formulations was carried out by agar diffusion technique against some selected clinical isolates of bacterial. Preliminary pharmacokinetic study was performed after oral administration in male Albino rats. The results of matrix contain Softisan® 154 and phospholipon® 90H (1:2) showed that erythromycin-loaded SLM was smooth; particle size ranged from 10.3⯱â¯11.24⯵m to 18.1⯱â¯10.11⯵m and maximum encapsulation efficiency and loading capacity were 95.11⯱â¯0.3% and 43.22⯱â¯0.1â¯mg, respectively. While that of beeswax- containing matrix showed maximum particle size of 18.9⯱â¯21.10⯵m, maximum encapsulation efficiency of 89.01⯱â¯0.11% and loading capacity of 39.02⯱â¯0.12â¯mg. All the formulations had prolonged release and antibacterial activity. Significantly (pâ¯>â¯0.05), prolonged plasma erythromycin concentration was obtained in the optimized formulation (>14â¯h) compared with commercial sample of erythromycin tablet (10h). Erythromycin stearate-loaded SLMs formulation could serve as an alternative to conventional oral formulation of erythromycin.
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Antibacterianos/administración & dosificación , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos , Eritromicina/análogos & derivados , Lípidos/química , Administración Oral , Animales , Antibacterianos/farmacocinética , Rastreo Diferencial de Calorimetría , Preparaciones de Acción Retardada/administración & dosificación , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacocinética , Portadores de Fármacos/administración & dosificación , Liberación de Fármacos , Eritromicina/administración & dosificación , Eritromicina/farmacocinética , Eritromicina/farmacología , Concentración de Iones de Hidrógeno , Masculino , Micelas , Pruebas de Sensibilidad Microbiana , Tamaño de la Partícula , Ratas , Ceras/químicaRESUMEN
Background: Studies of Pitted keratolysis (PK) treatment are limited. Objectives: To study cost-effectiveness and to compare the safety of 4% chlorhexidine scrub with 4% erythromycin gel, for PK infections. Materials and methods: This cohort study was conducted on naval rating cadets with a clinical diagnosis of PK at Chumpol Naval Rating School, Thailand in 2016. Participants were randomly treated with either 4% erythromycin gel or 4% chlorhexidine scrub for 4 weeks. The clinical examinations were evaluated at the baseline and at 1 and 2 months after treatment. A decision-tree model was used to evaluate the costs, resource utilization and outcomes as quality-adjusted life-years (QALYs). Results: Of 344 naval rating cadets, 125 (36.3%) were diagnosed with PK. Sixty-four were treated with erythromycin. Approximately 80% of participants had complete resolution Foot odor were significantly improved at 2 months (p < .001) for both groups. No adverse effects were reported. Total cost for 4 weeks' treatment with the erythromycin gel and chlorhexidine scrub was US$77.34, US$51.9, respectively. Chlorhexidine treatment and erythromycin gel had 0.1526 and 0.1425 QALYs, respectively. Conclusions: treatment of PK with either 4% chlorhexidine scrub or 4% erythromycin gel had similar outcomes. However, using chlorhexidine scrub was more cost-effective.
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Clorhexidina/uso terapéutico , Análisis Costo-Beneficio , Eritromicina/uso terapéutico , Queratosis/tratamiento farmacológico , Clorhexidina/efectos adversos , Clorhexidina/farmacocinética , Estudios de Cohortes , Esquema de Medicación , Eritromicina/efectos adversos , Eritromicina/farmacocinética , Geles/química , Semivida , Humanos , Queratosis/economíaRESUMEN
The pharmacokinetic of deflazacort after intravenous and oral administration and the effect of erythromycin on the disposition of deflazacort in rabbits were investigated. A parallel study was carried out in twelve rabbits. The plasma concentration-time profiles of deflazacort were determined after intravenous and oral administration of single dosages of 5 mg/kg in the presence and absence (baseline) of multiple dose erythromycin regimens. Plasma concentrations of 21-desacetyldeflazacort were determined by HPLC. Plasma concentration-time curves were analysed by compartmental pharmacokinetic and noncompartmental methods. The t½λz values following intravenous and oral administration were 3.67 and 4.96 hr, respectively. The apparent volume of distribution at steady-state (Vss ) was 4.08 ± 0.31 L/kg, this value indicates that deflazacort is widely distributed into the extravascular tissues. Moreover, bioavailability after oral administration of deflazacort (F = 87.48%) was high. Pharmacokinetic analysis after both routes of administration revealed a significant reduction in total body clearance, a significant increase in mean residence time, half-life and plasma concentrations of the steroid in the presence of multiple dose erythromycin. The results indicated the influence of the erythromycin on deflazacort disposition, which is consistent with a pharmacokinetic-type interaction in the elimination of the drug from the body. Moreover, this interaction should be considered to avoid adverse effects when using both drugs concomitantly.
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Eritromicina/farmacocinética , Pregnenodionas/farmacocinética , Administración Oral , Animales , Relación Dosis-Respuesta a Droga , Semivida , Inyecciones Intravenosas , Pregnenodionas/administración & dosificación , Pregnenodionas/antagonistas & inhibidores , Pregnenodionas/sangre , ConejosRESUMEN
BACKGROUND: Guanfacine extended-release (GXR) is an orally administered, non-stimulant treatment for children and adolescents with attention-deficit/hyperactivity disorder (ADHD) and is primarily metabolized by the 3A4 isozyme of cytochrome P450 (CYP3A4). The results of clinical pharmacokinetic (PK) studies indicate that guanfacine is sensitive to drug-drug interactions (DDIs) perpetrated by strong inhibitors and inducers of CYP3A4. OBJECTIVE: The aim was to provide guidance on the possible requirement for GXR dose adjustment in children and adolescents with ADHD by predicting DDIs following co-administration with moderate CYP3A4 inhibitors and inducers. METHODS: A physiologically based PK model for GXR orally administered to healthy adults was developed based on physicochemical, in vitro and clinical PK data. The model was validated using clinical PK data for co-administration of GXR with ketoconazole (strong CYP3A4 inhibitor) or rifampicin (strong CYP3A4 inducer). RESULTS: Model predictions indicated that co-administration of GXR with the moderate CYP3A4 inhibitors erythromycin 500 mg three times a day or fluconazole 200 mg daily (q.d.) increased the guanfacine area under the plasma concentration-time curve (AUC) by 2.31-fold or 1.98-fold, respectively, compared with GXR monotherapy. The moderate CYP3A4 inducer efavirenz 400 mg or 600 mg q.d. was predicted to reduce guanfacine AUC to 58 or 33% of its value for GXR monotherapy, respectively. CONCLUSION: Without the requirement for additional clinical studies, the following GXR dose recommendations were developed and approved for US labeling for use in children and adolescents with ADHD: (1) decrease GXR to 50% of the usual target dose when it is co-administered with strong or moderate CYP3A4 inhibitors; (2) consider titrating GXR up to double the usual target dose over 1-2 weeks when it is co-administered with strong or moderate CYP3A4 inducers.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Inductores del Citocromo P-450 CYP3A/administración & dosificación , Inhibidores del Citocromo P-450 CYP3A/administración & dosificación , Citocromo P-450 CYP3A/metabolismo , Guanfacina/administración & dosificación , Adolescente , Agonistas de Receptores Adrenérgicos alfa 2/uso terapéutico , Alquinos , Antirretrovirales/farmacocinética , Antifúngicos/farmacocinética , Benzoxazinas/farmacocinética , Niño , Ciclopropanos , Inductores del Citocromo P-450 CYP3A/farmacocinética , Inhibidores del Citocromo P-450 CYP3A/farmacocinética , Preparaciones de Acción Retardada , Interacciones Farmacológicas , Eritromicina/farmacocinética , Fluconazol/farmacocinética , Guanfacina/farmacocinética , Humanos , Modelos BiológicosRESUMEN
A novel series of 6-O-substituted 8a-aza-8a-homoerythromycin A 3-O-acylides has been discovered with potent activity against key respiratory pathogens, including those inducibly and constitutively resistant to erythromycin. The best compounds in this series 15na and 15nd showed activity comparable to telithromycin, especially against Haemophilus influenzae and constitutively MLSB-resistant strains of Streptococcus pneumoniae and Streptococcus pyogenes. Furthermore, 15na exhibited a number of drug-like attributes including favorable pharmacokinetic properties and in vivo efficacy. For instance, 15na exhibited good oral bioavailability (average F = 42%) and demonstrated in vivo efficacy superior to telithromycin (1) against erythromycin-susceptible S. pneumoniae. As such, 15na has a significant potential for further development of this novel macrolide antibiotics class.
Asunto(s)
Antibacterianos/química , Farmacorresistencia Bacteriana/efectos de los fármacos , Eritromicina/análogos & derivados , Animales , Antibacterianos/farmacocinética , Antibacterianos/farmacología , Disponibilidad Biológica , Eritromicina/síntesis química , Eritromicina/química , Eritromicina/farmacocinética , Eritromicina/farmacología , Humanos , Macrólidos/farmacología , Macrólidos/uso terapéutico , Relación Estructura-ActividadRESUMEN
Previous studies have identified a phenomenon in which the concentration-response curves (CRCs) for mixtures cross the curves for concentration addition model when predicting or judging joint toxic actions. However, mechanistic investigations of this phenomenon are extremely limited. In this study, a similar phenomenon was observed when we determined the joint toxic actions of sulfonamides (SAs) and erythromycin (ERY) on Escherichia coli (E. coli), which we named the "cross-phenomenon", and it was characterized by antagonism in the low-concentration range, addition in the medium-concentration range, and synergism in the high-concentration range. The mechanistic investigation of the cross-phenomenon was as follows: SAs and ERY could form a double block to inhibit the bacterial growth by exhibiting a synergistic effect; however, the hormetic effect of SAs on E. coli led to antagonism in the low-concentration range, resulting from the stimulation of sdiA mRNA expression by SAs, which increased the expression of the efflux pump (AcrAB-TolC) to discharge ERY. Furthermore, this cross-phenomenon was observed to be a time-dependent process induced by the increase of both the concentration and extent of stimulation of sdiA mRNA with exposure time. This work explains the dose-dependent and time-dependent cross-phenomenon and provides evidence regarding the interaction between hormesis and cross-phenomenon.
Asunto(s)
Eritromicina/farmacología , Escherichia coli/crecimiento & desarrollo , Modelos Biológicos , Sulfonamidas/farmacología , Proteínas de la Membrana Bacteriana Externa/metabolismo , Relación Dosis-Respuesta a Droga , Eritromicina/farmacocinética , Proteínas de Escherichia coli/metabolismo , Lipoproteínas/metabolismo , Proteínas de Transporte de Membrana/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismoRESUMEN
AIMS: Edoxaban, a novel factor Xa inhibitor, is a substrate of cytochrome P450 3 A4 (CYP3A4) and the efflux transporter P-glycoprotein (P-gp). Three edoxaban drug-drug interaction studies examined the effects of P-gp inhibitors with varying degrees of CYP3A4 inhibition. METHODS: In each study, healthy subjects received a single oral dose of 60 mg edoxaban with or without an oral dual P-gp/CYP3A4 inhibitor as follows: ketoconazole 400 mg once daily for 7 days, edoxaban on day 4; erythromycin 500 mg four times daily for 8 days, edoxaban on day 7; or single dose of cyclosporine 500 mg with edoxaban. Serial plasma samples were obtained for pharmacokinetics and pharmacodynamics. Safety was assessed throughout the study. RESULTS: Coadministration of ketoconazole, erythromycin, or cyclosporine increased edoxaban total exposure by 87%, 85%, and 73%, respectively, and the peak concentration by 89%, 68%, and 74%, respectively, compared with edoxaban alone. The half-life did not change appreciably. Exposure of M4, the major active edoxaban metabolite, was consistent when edoxaban was administered alone or with ketoconazole and erythromycin. With cyclosporine, M4 total exposure increased by 6.9-fold and peak exposure by 8.7-fold, suggesting an additional interaction. Pharmacodynamic effects were reflective of increased edoxaban exposure. No clinically significant adverse events were observed. CONCLUSIONS: Administration of dual inhibitors of P-gp and CYP3A4 increased edoxaban exposure by less than two-fold. This effect appears to be primarily due to inhibition of P-gp. The impact of CYP3A4 inhibition appears to be less pronounced, and its contribution to total clearance appears limited in healthy subjects.
Asunto(s)
Ciclosporina/farmacocinética , Eritromicina/farmacocinética , Inhibidores del Factor Xa/farmacocinética , Cetoconazol/farmacocinética , Piridinas/farmacocinética , Tiazoles/farmacocinética , Miembro 1 de la Subfamilia B de Casetes de Unión a ATP/metabolismo , Administración Oral , Adolescente , Adulto , Estudios Cruzados , Ciclosporina/administración & dosificación , Ciclosporina/sangre , Citocromo P-450 CYP3A/metabolismo , Esquema de Medicación , Interacciones Farmacológicas , Eritromicina/administración & dosificación , Eritromicina/sangre , Inhibidores del Factor Xa/administración & dosificación , Inhibidores del Factor Xa/sangre , Voluntarios Sanos , Humanos , Cetoconazol/administración & dosificación , Cetoconazol/sangre , Tasa de Depuración Metabólica , Persona de Mediana Edad , Piridinas/administración & dosificación , Piridinas/sangre , Especificidad por Sustrato , Tiazoles/administración & dosificación , Tiazoles/sangre , Adulto JovenRESUMEN
The hydrophilic ion paring strategy (HIP) is a method explored to improve the cell/tissue uptake of poorly adsorbed drugs and to optimize their physico-chemical characteristics. In this context, we here describe the synthesis of some ion pairs of two model cationic antibiotics, erythromycin (ERY) and kanamycin A (KAN), with liposaccharides having different levels of lipophilicity and charge. The formation of drug-liposaccharide complexes was confirmed by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC) and powder X-ray diffraction (PXRD) analysis. The effect of the amphiphilic liposaccharide moieties on the antimicrobial activity of ERY and KAN was assessed by measuring the minimal inhibitory concentration (MIC) of the compounds against a panel of bacterial strains that were susceptible or resistant to the parent antibiotics. The ion pairing did not depress the in vitro antibiotic activity, although no lowering of MIC values was registered. The experimental findings would motivate the future investigation of this ion pairing strategy in drug design, for instance allowing improvement of the encapsulation efficiency of hydrophilic antibiotics in lipid-based nanocarriers, or changing their in vivo biodistribution and pharmacokinetic profile.
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Antibacterianos/farmacocinética , Eritromicina/farmacocinética , Kanamicina/farmacocinética , Antibacterianos/química , Eritromicina/química , Interacciones Hidrofóbicas e Hidrofílicas , Kanamicina/química , Lipopolisacáridos/química , Pruebas de Sensibilidad Microbiana , Distribución TisularRESUMEN
Hydraphiles are synthetic amphiphiles that form ion-conducting pores in liposomal membranes. These pores exhibit open-close behavior when studied by planar bilayer conductance techniques. In previous work, we showed that when co-administered with various antibiotics to the DH5α strain of Escherichia coli, they enhanced the drug's potency. We report here potency enhancements at low concentrations of hydraphiles for the structurally and mechanistically unrelated antibiotics erythromycin, kanamycin, rifampicin, and tetracycline against Gram negative E. coli (DH5α and K-12) and Pseudomonas aeruginosa, as well as Gram positive Bacillus subtilis. Earlier work suggested that potency increases correlated to ion transport function. The data presented here comport with the function of hydraphiles to enhance membrane permeability in addition to, or instead of, their known function as ion conductors.
Asunto(s)
Antibacterianos/farmacología , Bacillus subtilis/efectos de los fármacos , Escherichia coli/efectos de los fármacos , Permeabilidad/efectos de los fármacos , Pseudomonas aeruginosa/efectos de los fármacos , Tensoactivos/química , Tensoactivos/farmacología , Antibacterianos/farmacocinética , Bacillus subtilis/metabolismo , Eritromicina/farmacocinética , Eritromicina/farmacología , Escherichia coli/metabolismo , Infecciones por Escherichia coli/tratamiento farmacológico , Humanos , Kanamicina/farmacocinética , Kanamicina/farmacología , Pruebas de Sensibilidad Microbiana , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa/metabolismo , Rifampin/farmacocinética , Rifampin/farmacología , Tetraciclina/farmacocinética , Tetraciclina/farmacologíaRESUMEN
In this preliminary prospective noninterventional study, we assessed the prokinetic effect of 3 mgâ¢kg erythromycin in nonfasted emergency trauma patients. Ultrasonographic measurements of the antral area were performed 30 minutes and immediately before the erythromycin infusion and serially at 30, 60, and 90 minutes after the start of the infusion. Gastric emptying rates before and after erythromycin infusion, and at each 30-minute period after erythromycin infusion, were then calculated. We found that gastric emptying rates were increased after erythromycin infusion although gastric content and volume remained similar.