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1.
Arch Med Res ; 51(3): 268-277, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32143939

RESUMO

BACKGROUND: There is evidence that the pharmacokinetics of certain drugs in Mexicans may differ with respect to other ethnic groups. On the other hand, there is controversy about the existence of interethnic variability in the pharmacokinetics of ciprofloxacin. AIM OF THE STUDY: To study oral ciprofloxacin pharmacokinetics in Mexicans at various dose levels and make comparisons with other populations in order to gain insight on interethnic variability. METHODS: Healthy Mexican volunteers received oral ciprofloxacin as 250 mg and 500 mg immediate-release tablets or a 1,000 mg extended-release formulation. Plasma concentration against time curves were constructed, and pharmacokinetic parameters were compared with those reported for other populations. RESULTS: Ciprofloxacin pharmacokinetics in Mexicans was linear and no significant differences between males and females were detected. When several populations were compared, it appeared that bioavailability in Mexicans was similar to that of Caucasians, being lower than that of Asians. These variations were attenuated when data were normalized by body weight. CONCLUSIONS: Ciprofloxacin pharmacokinetics exhibit interethnic variability, Asians exhibiting an increased bioavailability with regard to Mexicans and Caucasians. Data suggest that these differences are due to body weight.


Assuntos
Ciprofloxacino/sangue , Ciprofloxacino/farmacocinética , Voluntários Saudáveis/estatística & dados numéricos , Administração Oral , Adulto , Grupo com Ancestrais do Continente Asiático , Disponibilidade Biológica , Peso Corporal/fisiologia , Grupos Étnicos , Grupo com Ancestrais do Continente Europeu , Feminino , Humanos , Masculino , México , Adulto Jovem
2.
Pharmacol Res Perspect ; 8(1): e00544, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31988753

RESUMO

Prediction of the intestinal absorption of new chemical entities (NCEs) is still difficult, in part because drug efflux transporters, including breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp), restrict their intestinal permeability. We have demonstrated that the absorptive quotient (AQ) obtained from the in vitro Caco-2 permeability study would be a valuable parameter for estimating the impact of BCRP on the intestinal absorption of drugs. In this study, in order to assess the correlation between the in vitro AQ for BCRP and in vivo contribution of BCRP on drug absorption, we evaluated the oral absorption of various compounds by portal-systemic blood concentration (P-S) difference method in wild-type (WT), Bcrp(-/-), and Mdr1a/1b(-/-) mice. In addition, we also calculated a rate of BCRP contribution (Rbcrp ). Ciprofloxacin and nitrofurantoin showed the low Rbcrp value (0.05 and 0.15), and their apparent fractions of intestinal absorption in WT mice were 46.5% and 63.7%, respectively. These results suggest that BCRP hardly affects their intestinal absorption in mice. On the other hand, the apparent fraction of intestinal absorption of topotecan and sulfasalazine was significantly lower in WT mice than in Bcrp(-/-) mice. Moreover, their Rbcrp values were 0.42 and 0.79, respectively, indicating the high contribution of BCRP to their oral absorption. Furthermore, in vivo Rbcrp calculated in this study was almost comparable to in vitro AQ obtained from Caco-2 permeability study. This study provides useful concepts in assessing the contribution of BCRP on intestinal absorption in drug discovery and development process.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Ciprofloxacino/farmacocinética , Proteínas de Neoplasias/metabolismo , Nitrofurantoína/farmacocinética , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Administração Intravenosa , Animais , Células CACO-2 , Ciprofloxacino/administração & dosagem , Ciprofloxacino/sangue , Humanos , Absorção Intestinal , Masculino , Camundongos , Modelos Animais , Nitrofurantoína/administração & dosagem , Nitrofurantoína/sangue
3.
J Pharm Biomed Anal ; 174: 256-262, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31181488

RESUMO

A rapid and highly sensitive ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) assay was developed for quantification of 7 antibiotics in low sample volumes (50 µL): amoxicillin, azithromycin, cefotaxime, ciprofloxacin, meropenem, metronidazole and piperacillin, for both routine monitoring and pharmacokinetic studies. After protein precipitation by acetonitrile, the antibiotics were separated on an Acquity UPLC HSS T3 column (run time, 4 min). The mobile phase consisted of a mixture of (A) ammonium acetate (pH 2.4; 5 mM) and (B) acetonitrile acidified with 0.1% formic acid, delivered at 500 µl/min in a gradient elution mode. Total time run was 2.75 min. Ions were detected in the turbo-ion-spray-positive and multiple-reaction-monitoring modes. The assay was accurate and reproductible for the quantification of the seven antibiotics in serum samples over large concentration ranges.


Assuntos
Antibacterianos/sangue , Análise Química do Sangue/métodos , Cromatografia Líquida de Alta Pressão/métodos , Espectrometria de Massas em Tandem/métodos , Adolescente , Amoxicilina/sangue , Azitromicina/sangue , Calibragem , Cefotaxima/sangue , Criança , Pré-Escolar , Ciprofloxacino/sangue , Infecções por Escherichia coli/tratamento farmacológico , Humanos , Lactente , Recém-Nascido , Leucemia Mieloide Aguda/complicações , Leucemia Mieloide Aguda/microbiologia , Limite de Detecção , Masculino , Meropeném/sangue , Metronidazol/sangue , Pediatria , Piperacilina/sangue , Reprodutibilidade dos Testes
4.
J Control Release ; 307: 32-43, 2019 08 10.
Artigo em Inglês | MEDLINE | ID: mdl-31152749

RESUMO

The development of inhalable 'nanomedicines' based on biocompatible lipids and polymers is attracting increasing interest worldwide. Our understanding of how pulmonary inflammation impacts on lung distribution and clearance kinetics however, is limited. Similarly, there is limited information on how the inhaled delivery of biocompatible nanomaterials affects existing respiratory disease. We have addressed these knowledge gaps by describing and comparing the pulmonary pharmacokinetic behaviour of a 3H-labelled PEGylated liposome loaded with a model drug (ciprofloxacin) after intratracheal administration to healthy rats and rats with bleomycin-induced lung inflammation by following both 3H label and drug. Cell- and cytokine-based markers of lung inflammation were used to evaluate the response of healthy and inflamed lungs to the liposome. Liposomes were initially cleared more rapidly from inflamed lungs than from healthy lungs, but exhibited similar rates of lung clearance after 3 days. This was interesting given that mucociliary clearance was more efficient from healthy lungs, despite evidence of higher mucus retention in inflamed lungs and reduced association of the liposome with lung tissue. Although the plasma pharmacokinetics of ciprofloxacin did not differ between rats with healthy or inflamed lungs after pulmonary administration, the plasma pharmacokinetics of 3H-phosphatidylcholine suggested higher liposome bioavailability and more prolonged absorption from inflamed lungs. Concentrations of the pro-inflammatory cytokine IL-1ß were increased in bronchoalveolar lavage fluid after a single pulmonary dose of liposomes to rats with inflamed lungs, but no other significant changes in lung inflammatory markers were identified in healthy or bleomycin-challenged rats.


Assuntos
Antibacterianos/administração & dosagem , Ciprofloxacino/administração & dosagem , Inflamação/tratamento farmacológico , Pneumopatias/tratamento farmacológico , Pulmão/metabolismo , Polietilenoglicóis/administração & dosagem , Animais , Antibacterianos/sangue , Antibacterianos/farmacocinética , Bleomicina , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Ciprofloxacino/sangue , Ciprofloxacino/farmacocinética , Citocinas/imunologia , Inflamação/induzido quimicamente , Inflamação/imunologia , Inflamação/metabolismo , Lipossomos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pneumopatias/induzido quimicamente , Pneumopatias/imunologia , Pneumopatias/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Polietilenoglicóis/farmacocinética , Ratos Sprague-Dawley , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
5.
Eur J Clin Pharmacol ; 75(5): 647-654, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30649602

RESUMO

PURPOSE: To evaluate pharmacokinetic parameters of ciprofloxacin in patients undergoing Roux-en-Y gastric surgery (RYGS). METHODS: Controlled, single-dose, open-label study in patients undergoing RYGS. Healthy overweight/obese patients 18-60 years old were included. The assessment was performed once in control patients and three times in case patients (before surgery and 1 and 6 months after surgery). In each visit, the subjects received a single oral dose of ciprofloxacin 500 mg. Venous blood samples were obtained at baseline and 0.5, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 8 and 14 h after ciprofloxacin intake. Pre- and post-surgery variables were compared using paired ANOVA or the Wilcoxon tests and control vs cases using ANOVA or Mann Whitney. Given the post-surgery change in body weight, the parameters were corrected by dose (mg)/body weight (kg). The analysis was performed using SPSS. RESULTS: Ciprofloxacin Cmax was significantly reduced 1 month after surgery (1840.9 ± 485.2 vs 1589.6 ± 321.8 ng/ml; p = 0.032) but not 6 months after. Cmax on the sixth month was lower than Cmax in control group (2160.4 ± 408.6 vs 1589.6 ± 321.8 ng/ml; p < 0.001). After correcting by the dose (mg)/patient's body weight, both Cmax and AUClast showed significant decrease 1 and 6 months after surgery: Cmax, 289.1 ± 65.3 and 263.5 ± 52.1 (ng/ml)/(dose (mg)/weight (kg)) respectively vs 429.3 ± 127.6 (ng/ml)/(dose (mg)/weight (kg)) at baseline; AUC, 1340.6 ± 243.0 and 1299.2 ± 415.4 (h × ng/ml)/(dose (mg)/weight (kg)) respectively vs 1896.7 ± 396.8 (h × ng/ml)/(dose (mg)/weight (kg)) at baseline. Cmax 1 month post-surgery showed lower values than the control group (375.4 ± 77.4 vs 263.5 ± 52.1 ng/ml; p < 0.001). CONCLUSION: Ciprofloxacin absorption is impaired 1 month and 6 months after RYGS. The effect on Cmax and AUClast faded on the sixth month due to weight loss. It is no necessary to modify the doses of ciprofloxacin in these patients.


Assuntos
Antibacterianos/farmacocinética , Ciprofloxacino/farmacocinética , Derivação Gástrica , Obesidade/cirurgia , Adulto , Antibacterianos/sangue , Peso Corporal , Estudos de Casos e Controles , Ciprofloxacino/efeitos adversos , Ciprofloxacino/sangue , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Perda de Peso , Adulto Jovem
6.
J Vet Pharmacol Ther ; 42(3): 346-354, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30656701

RESUMO

South Africa currently loses over 1000 white rhinoceros (Ceratotherium simum) each year to poaching incidents, and numbers of severely injured victims found alive have increased dramatically. However, little is known about the antimicrobial treatment of wounds in rhinoceros. This study explores the applicability of enrofloxacin for rhinoceros through the use of pharmacokinetic-pharmacodynamic modelling. The pharmacokinetics of enrofloxacin and its metabolite ciprofloxacin were evaluated in five white rhinoceros after intravenous (i.v.) and after successive i.v. and oral administration of 12.5 mg/kg enrofloxacin. After i.v. administration, the half-life, area under the curve (AUCtot ), clearance and the volume of distribution were 12.41 ± 2.62 hr, 64.5 ± 14.44 µg ml-1  hr-1 , 0.19 ± 0.04 L h-1  kg-1 , and 2.09 ± 0.48 L/kg, respectively. Ciprofloxacin reached 26.42 ± 0.05% of the enrofloxacin plasma concentration. After combined i.v. and oral enrofloxacin administration oral bioavailability was 33.30 ± 38.33%. After i.v. enrofloxacin administration, the efficacy marker AUC24 : MIC exceeded the recommended ratio of 125 against bacteria with an MIC of 0.5 µg/mL. Subsequent intravenous and oral enrofloxacin administration resulted in a low Cmax: MIC ratio of 3.1. The results suggest that intravenous administration of injectable enrofloxacin could be a useful drug with bactericidal properties in rhinoceros. However, the maintenance of the drug plasma concentration at a bactericidal level through additional per os administration of 10% oral solution of enrofloxacin indicated for the use in chickens, turkeys and rabbits does not seem feasible.


Assuntos
Antibacterianos/farmacocinética , Enrofloxacina/farmacocinética , Perissodáctilos , Administração Oral , Animais , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Disponibilidade Biológica , Ciprofloxacino/sangue , Enrofloxacina/administração & dosagem , Enrofloxacina/sangue , Feminino , Meia-Vida , Injeções Intravenosas/veterinária , Masculino , Testes de Sensibilidade Microbiana/veterinária , Perissodáctilos/sangue , Perissodáctilos/metabolismo
7.
Biomed Chromatogr ; 33(3): e4450, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30513138

RESUMO

A simple and rapid ultra-high-performance liquid chromatographic (UHPLC) for the simultaneous determination of meropenem and ciprofloxacin in human plasma was developed and validated. All of the analytes were separated in <5 min. A solid-phase extraction method was applied from sample preparation. Analytical separation was performed on a Poroshell SB C18 column (50 × 2.1 mm, 2.7 µm particle size) with photodiode array (PDA) detection. Meropenem and ciprofloxacin were determined at wavelengths of 300 and 277 nm, respectively. The mobile phase was a mixture of acetonitrile-10 mm ammonium acetate-methanol in gradient elution. The method has been validated for both drugs in gastric surgery for cancer patients. The method showed good linearity with correlation coefficients, r2  = 0.994 for the two drugs, as well as high precision (RSD < 10.5% in each case); accuracy ranged from -5.8 to +6.0%. The limit of quantitation of the two drugs was established at 0.02 and 0.01 µg/mL, respectively. Meropenem, ciprofloxacin and the internal standard were extracted from human plasma with a mean recovery ranging from 92.5 to 98.6%. The method was applied to quantify the drugs dosage in complicated gastric surgery patients.


Assuntos
Antibacterianos/sangue , Cromatografia Líquida de Alta Pressão/métodos , Ciprofloxacino/sangue , Meropeném/sangue , Extração em Fase Sólida/métodos , Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Antibioticoprofilaxia , Ciprofloxacino/farmacocinética , Ciprofloxacino/uso terapêutico , Infecção Hospitalar/tratamento farmacológico , Infecção Hospitalar/prevenção & controle , Humanos , Limite de Detecção , Modelos Lineares , Meropeném/farmacocinética , Meropeném/uso terapêutico , Reprodutibilidade dos Testes , Neoplasias Gástricas/cirurgia
8.
Equine Vet J ; 51(4): 544-551, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30449030

RESUMO

BACKGROUND: In selective cases, enrofloxacin may be an alternative antibacterial agent to treat unresponsive infections in pregnant mares. Supratherapeutic doses of enrofloxacin are toxic to adult horses and also to newborn foals, however, it is unknown if enrofloxacin crosses the equine placenta or if it is toxic to the fetus. OBJECTIVES: To assess the diffusion of enrofloxacin and its metabolite to fetal fluids and its effects on fetal cartilage when administered to pregnant mares. STUDY DESIGN: In vivo and terminal controlled experiment. METHODS: Healthy mares at 260 days of gestation were allocated into three groups: untreated (n = 3), therapeutic treatment (5 mg/kg enrofloxacin, i.v., n = 7) or supratherapeutic treatment (10 mg/kg, i.v., n = 6) for 11 days. Fetal fluids were collected on days 1, 5 and 11 of treatment. Premature delivery was induced on day 11 with oxytocin and fetal fluids and plasma were collected during delivery. Plasma and fetal fluid enrofloxacin and ciprofloxacin concentrations were measured by liquid chromatography-mass spectrometry. Fetal articular cartilage was examined macroscopically and histologically for lesions. RESULTS: Enrofloxacin and ciprofloxacin reached the minimum inhibitory concentrations for common pathogens in all fluids. Ciprofloxacin did not increase with the double enrofloxacin dose in maternal plasma, but allantoic fluid showed a 10-fold increase relative to fetal trough plasma concentrations. Administration of enrofloxacin at recommended doses did not result in cartilaginous lesions in fetuses. MAIN LIMITATIONS: Only one time point in gestation was evaluated and mares treated in the study were healthy at the time of treatment. It remains to be determined if enrofloxacin shows toxicity at other stages of pregnancy, after a longer duration of treatment, or once the foals are delivered and articular surfaces are weightbearing. CONCLUSIONS: Short-term administration of enrofloxacin to late gestation mares resulted in detectable enrofloxacin and ciprofloxacin concentrations in fetal fluids and did not result in macroscopic or microscopic lesions in the fetus. While further research is needed to address long-term foal outcomes, enrofloxacin may be useful for select bacterial infections in pregnant mares.


Assuntos
Líquidos Corporais/química , Cartilagem/efeitos dos fármacos , Enrofloxacina/farmacocinética , Cavalos , Aborto Animal/etiologia , Animais , Antibacterianos , Cartilagem/embriologia , Ciprofloxacino/sangue , Ciprofloxacino/metabolismo , Enrofloxacina/sangue , Enrofloxacina/química , Enrofloxacina/metabolismo , Feminino , Gravidez
9.
Eur J Pharm Sci ; 128: 171-179, 2019 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-30503378

RESUMO

In a recent multicenter population pharmacokinetic study of ciprofloxacin administered to children suffering from complicated urinary tract infection (cUTI), the apparent volume of distribution (V) and total plasma clearance (CL) were decreased by 83.6% and 41.5% respectively, compared to healthy children. To understand these differences, a physiologically-based pharmacokinetic model (PBPK) for ciprofloxacin was developed for cUTI children. First, a PBPK model in adults was developed, modified incorporating age-dependent functions and evaluated with paediatric data generated from a published model in healthy children. Then, the model was then adapted to a cUTI paediatric population according to the degree of renal impairment (KF) affecting renal clearance (CLRenal,) and CYP1A2 clearance (CLCYP1A2). Serum and urine samples obtained from 22 cUTI children were used for model evaluation. Lastly, a parameter sensitivity analysis identified the most influential parameters on V and CL. The PBPK model predicted the ciprofloxacin exposure in adults and children, capturing age-related pharmacokinetic changes. Plasma concentrations and fraction excreted unchanged in urine (fe) predictions improved in paediatric cUTI patients once CLrenal and CLCYP1A2 were corrected by KF. The presented PBPK model for ciprofloxacin demonstrates its adequacy to simulate different dosing scenarios to obtain PK predictions in a healthy population from 3 months old onwards. Model adaptation of CLRenal and CLCYP1A2 according to KF explained partially the differences seen in the plasma drug concentrations and fe vs time profiles between healthy and cUTI children. Nevertheless, it is necessary to further investigate the disease-related changes in cUTI to improve model predictions.


Assuntos
Antibacterianos/farmacocinética , Antibacterianos/uso terapêutico , Ciprofloxacino/farmacocinética , Ciprofloxacino/uso terapêutico , Modelos Biológicos , Infecções Urinárias/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Criança , Pré-Escolar , Ciprofloxacino/sangue , Humanos , Injeções Intravenosas
10.
J Chromatogr B Analyt Technol Biomed Life Sci ; 1097-1098: 94-100, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30218919

RESUMO

This study represents simple inexpensive chromatographic determination of ciprofloxacin (CIP) and tinidazole (TIN) simultaneously in human plasma using HPLC-DAD followed by a pharmacokinetic application. C18 column was used as stationary phase with isocratic elution of a mobile phase composed of acetic acid solution (2%) and acetonitrile (85: 15, v/v) and ornidazole as internal standard (IS) with UV detection at 318 nm. The two drugs and the IS were separated at 6.55, 7.91 and 11.07 min for CIP, TIN and IS, respectively, with good selectivity and sensitivity for their analysis in presence of plasma matrix components and the drugs' metabolites. Sample preparation involved only protein precipitation without any complicated extraction procedures decreasing analysis time. For method validation, FDA regulations for analysis in biological fluids were followed. Pharmacokinetic (PK) study on six healthy volunteers was conducted after single oral dose administration of 500 and 600 mg of CIP and TIN, respectively. Dugs' plasma levels were followed for 12 or 72 h post dosing for CIP and TIN, respectively, and different PK data for the two drugs were calculated and they were comparable to the reported values demonstrating successful future application of the presented method in PK, bioequivalence and bioavailability studies.


Assuntos
Anti-Infecciosos/sangue , Ciprofloxacino/sangue , Tinidazol/sangue , Adulto , Anti-Infecciosos/química , Anti-Infecciosos/farmacocinética , Cromatografia Líquida de Alta Pressão/economia , Cromatografia Líquida de Alta Pressão/métodos , Ciprofloxacino/química , Ciprofloxacino/farmacocinética , Combinação de Medicamentos , Estabilidade de Medicamentos , Humanos , Limite de Detecção , Modelos Lineares , Masculino , Reprodutibilidade dos Testes , Tinidazol/química , Tinidazol/farmacocinética
11.
Spectrochim Acta A Mol Biomol Spectrosc ; 201: 382-391, 2018 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-29775931

RESUMO

A nanocomposite optosensor consisting of carboxylic acid functionalized multiwall carbon nanotubes and CdTe quantum dots embedded inside a molecularly imprinted polymer (COOH@MWCNT-MIP-QDs) was developed for trace ciprofloxacin detection. The COOH@MWCNT-MIP-QDs were synthesized through a facile sol-gel process using ciprofloxacin as a template molecule, 3-aminopropylethoxysilane as a functional monomer and tetraethoxysilane as a cross-linker at a molar ratio of 1:8:20. The synthesized nanocomposite optosensor had high sensitivity, excellent specificity and high binding affinity to ciprofloxacin. Under optimal conditions, the fluorescence intensity of the optosensor decreased in a linear fashion with the concentration of ciprofloxacin and two linear dynamic ranges were obtained, 0.10-1.0 µg L-1 and 1.0-100.0 µg L-1 with a very low limit of detection of 0.066 µg L-1. The imprinting factors of the two linear range were 17.67 and 4.28, respectively. The developed nanocomposite fluorescence probe was applied towards the determination of ciprofloxacin levels in chicken muscle and milk samples with satisfactory recoveries being obtained in the range of 82.6 to 98.4%. The results were also in good agreement with a HPLC method which indicates that the optosensor can be used as a sensitive, selective and rapid method to detect ciprofloxacin in chicken and milk samples.


Assuntos
Ciprofloxacino/sangue , Impressão Molecular/métodos , Nanocompostos/química , Nanotubos de Carbono/química , Pontos Quânticos , Humanos , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes
12.
J Pharm Biomed Anal ; 157: 92-99, 2018 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-29777985

RESUMO

A simple and precise ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method was developed for the simultaneous analysis of five anti-infective agents used to treat severe infections [three antibiotics (daptomycin, moxifloxacin, ciprofloxacin) and two antifungals (isavuconazole, caspofungin)] in human plasma. Sample preparation was based on protein precipitation with ice cold methanol. All five agents were analyzed with the corresponding isotopically labeled internal standards. All analytes were detected in multiple reactions monitoring (MRM) using API 4000 triple-quadrupole mass spectrometer with electrospray (ESI) source operating in positive mode. The calibration curves were linear over the selected ranges (r > 0.99). The method is precise and accurate with a total run time of 5.5 min. Accuracy of all target analytes ranged between 95.9-116.6%, measured with an imprecision of less than 10.8%. The lower limit of quantification was 1.25 mg/L for caspofungin, 0.3125 mg/L for isavuconazole, 3.125 mg/L for daptomycin, 0.075 mg/L for ciprofloxacin, and 0.1875 mg/L for moxifloxacin. The successful application of the method in patient samples proved its suitability for the medical surveillance of antimicrobial therapy in intensive care units as well as to other pharmacokinetic studies.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Ciprofloxacino/sangue , Daptomicina/sangue , Equinocandinas/sangue , Fluoroquinolonas/sangue , Lipopeptídeos/sangue , Nitrilos/química , Piridinas/química , Espectrometria de Massas em Tandem/métodos , Triazóis/química , Antibacterianos/sangue , Antifúngicos/sangue , Caspofungina , Humanos , Limite de Detecção , Moxifloxacina , Plasma/química , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/métodos
13.
Toxicol Lett ; 291: 184-193, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29679711

RESUMO

Rhabdomyolysis is one of the serious side effects of ciprofloxacin (CPFX), a widely used antibacterial drug; and occasionally, acute kidney injury (AKI) occurs. Often, rhabdomyolysis has occurred in patients taking CPFX co-administered with statins. The purpose of this study is to establish a mouse model of drug-induced rhabdomyolysis by co-administration of CPFX and atorvastatin (ATV) and to clarify the mechanisms of its pathogenesis. C57BL/6J mice treated with L-buthionine-(S,R)-sulfoximine (BSO), a glutathione synthesis inhibitor, were orally administered with CPFX and ATV for 4 days. Plasma levels of creatinine phosphokinase (CPK) and aspartate aminotransferase (AST) were significantly increased in the CPFX and ATV-co-administered group. Histopathological examination of skeletal muscle observed degeneration in gastrocnemius muscle and an increased number of the satellite cells. Expressions of skeletal muscle-specific microRNA and mRNA in plasma and skeletal muscle, respectively, were significantly increased. The area under the curve (AUC) of plasma CPFX was significantly increased in the CPFX and ATV-co-administered group. Furthermore, cytoplasmic vacuolization and a positively myoglobin-stained region in kidney tissue and high content of myoglobin in urine were observed. These results indicated that AKI was induced by myoglobin that leaked from skeletal muscle. The established mouse model in the present study would be useful for predicting potential rhabdomyolysis risks in preclinical drug development.


Assuntos
Antibacterianos/toxicidade , Atorvastatina/toxicidade , Ciprofloxacino/toxicidade , Inibidores de Hidroximetilglutaril-CoA Redutases/toxicidade , Rabdomiólise/induzido quimicamente , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/patologia , Animais , Antibacterianos/sangue , Aspartato Aminotransferases/metabolismo , Atorvastatina/sangue , Butionina Sulfoximina/farmacologia , Ciprofloxacino/sangue , Creatina Quinase/metabolismo , Modelos Animais de Doenças , Interações Medicamentosas , Feminino , Glutationa Sintase/antagonistas & inibidores , Inibidores de Hidroximetilglutaril-CoA Redutases/sangue , Camundongos , Camundongos Endogâmicos C57BL , Músculo Esquelético/patologia , Rabdomiólise/patologia
14.
Anal Chem ; 90(9): 5696-5702, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29562126

RESUMO

With improved performances, miniature mass spectrometers are becoming suitable for more practical applications. At the same time, the coupling of an approximate ionization source is essential in terms of minimizing sample preparation and broadening the range of samples that could be analyzed. In this study, an atmospheric pressure laserspray ionization (AP-LSI) source was coupled with our home developed miniature ion trap mass spectrometer. The whole system is compact in size, and biological samples could be directly analyzed with minimum sample preparation. Direct detections of peptides, proteins, drugs in whole blood, and urine could be achieved with high sensitivity. The analyses of tissue sections were demonstrated, and different regions in a tissue section could be differentiated based on their lipid profiles. Results suggest that the coupling of AP-LSI with miniature mass spectrometer is a powerful technique, which could potentially benefit target molecule analysis in biological and medical applications.


Assuntos
Ciprofloxacino/sangue , Ciprofloxacino/urina , Oligopeptídeos/sangue , Oligopeptídeos/urina , Proteínas/análise , Animais , Pressão Atmosférica , Voluntários Saudáveis , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/instrumentação
15.
J Vet Pharmacol Ther ; 41(4): 599-604, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29465160

RESUMO

The pharmacokinetics of orbifloxacin was studied after a single dose (7.5 mg/kg) of intravenous or intramuscular administration to crucian carp (Carassius auratus) reared in freshwater at 25°C. Plasma samples were collected from six fish per sampling point. Orbifloxacin concentrations were determined by high-performance liquid chromatography with a 0.02 µg/ml limit of detection, then were subjected to noncompartmental analysis. After intravenous injection, initial concentration of 5.83 µg/ml, apparent elimination rate constant (λz ) of 0.039 hr-1 , apparent elimination half-life (T1/2λz ) of 17.90 hr, systemic total body clearance (Cl) of 75.47 ml hr-1  kg-1 , volume of distribution (Vz) of 1,948.76 ml/kg, and volume of distribution at steady-state (Vss) of 1,863.97 ml/kg were determined, respectively. While after intramuscular administration, the λz , T1/2λz , mean absorption time (MAT), absorption half-life (T1/2ka ), and bioavailability were determined as 0.027 hr-1 , 25.69, 10.26, 7.11 hr, and 96.46%, respectively, while the peak concentration was observed as 3.11 ± 0.06 µg/ml at 2.0 hr. It was shown that orbifloxacin was completely but relatively slowly absorbed, extensively distributed, and slowly eliminated in crucian carp, and an orbifloxacin dosage of 10 mg/kg administered intravenously or intramuscularly would be expected to successfully treat crucian carp infected by strains with MIC values ≤0.5 µg/ml.


Assuntos
Antibacterianos/farmacocinética , Ciprofloxacino/análogos & derivados , Carpa Dourada/metabolismo , Animais , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Cromatografia Líquida de Alta Pressão/veterinária , Ciprofloxacino/administração & dosagem , Ciprofloxacino/sangue , Ciprofloxacino/farmacocinética , Carpa Dourada/sangue , Meia-Vida , Injeções Intramusculares/veterinária , Injeções Intravenosas/veterinária
16.
J Pharm Biomed Anal ; 152: 102-110, 2018 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-29414000

RESUMO

The aim of the current study was to develop and validate a robust multi-analyte high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) method for simultaneous quantification of cefepime, meropenem, ciprofloxacin, moxifloxacin, linezolid and piperacillin, which are the most commonly used antibiotics in intensive care units. Sample clean-up included a protein precipitation protocol, followed by chromatographic separation on a C8 reverse phase HPLC column within 4 min, using a formic acid-ammonium formiate methanol step-elution gradient. All compounds were detected with electrospray ionization (ESI+) mass spectrometry in multiple reaction time monitoring. The method was validated according to the protocol from the European Medicines Agency and was thoroughly evaluated for interferences and quantification linearity. Linear relationships between peak area responses and drug concentrations were obtained in the range of 0.25-200 mg/l for cefepime, 0.25-120 mg/l for meropenem, 0.05-10 mg/l for ciprofloxacin, 0.125-10 mg/l for moxifloxacin, 0.125-50 mg/l for linezolid and 0.5-400 mg/l for piperacillin with an R2 > 0.997. Imprecision and inaccuracy values (both intra- and inter-assay) were ≤ 6.8% and ≤10.9% for all analytes in quality control samples, respectively. The assay proved to be selective for the study antibiotics, and the internal standards consistently compensated for matrix effects. The described simple and reliable HPLC-MS/MS assay is a powerful tool for routine TDM of cefepime, meropenem, ciprofloxacin, moxifloxacin, linezolid and piperacillin in human serum in clinical laboratories. With a total process time of approximately 30 min, it allows for accurate and selective quantification up to the expected pharmacokinetic peak concentrations.


Assuntos
Antibacterianos/sangue , Isótopos/química , Soro/química , Cefepima , Cefalosporinas/sangue , Cromatografia Líquida de Alta Pressão/métodos , Ciprofloxacino/sangue , Monitoramento de Medicamentos/métodos , Fluoroquinolonas/sangue , Humanos , Limite de Detecção , Linezolida/sangue , Meropeném , Moxifloxacina , Piperacilina/sangue , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos , Tienamicinas/sangue
17.
J Vet Pharmacol Ther ; 41(4): 622-631, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29457247

RESUMO

To predict the orbifloxacin concentrations in rabbits after multiple routes of administration, a flow-limited multiroute physiologically based pharmacokinetic (PBPK) model was developed. Three routes of administration (IV, IM, and PO) were incorporated into this model. Physiological parameters including tissue weights and blood flows through different tissues were obtained from the literature. The tissue/plasma partition coefficients (PX s) for noneliminating tissues were calculated according to the area method, while the PX s for kidney and the rest of the body compartment, together with other parameters for absorption and elimination, were optimized based on the published concentrations. The comparisons between predicted and observed orbifloxacin concentrations proved its validity, and the present model predicted available concentration data well, including those in liver, kidney, muscle, lung, heart, and plasma after oral, intravenous, or intramuscular administration. A local sensitivity analysis was also performed, which showed that the parameters for oral absorption were most influential on the orbifloxacin concentrations. This model was used to predict plasma and tissue concentrations after multiple oral or intramuscular administration. This study demonstrated the feasibility of predicting drug residues in minor species after multiple routes of administration in the extra-label manner using the PBPK modeling.


Assuntos
Antibacterianos/farmacocinética , Ciprofloxacino/análogos & derivados , Administração Oral , Animais , Antibacterianos/administração & dosagem , Antibacterianos/análise , Antibacterianos/sangue , Ciprofloxacino/administração & dosagem , Ciprofloxacino/análise , Ciprofloxacino/sangue , Ciprofloxacino/farmacocinética , Feminino , Injeções Intramusculares/veterinária , Injeções Intravenosas/veterinária , Rim/química , Fígado/química , Masculino , Modelos Biológicos , Músculo Esquelético/química , Miocárdio/química , Coelhos/metabolismo , Coelhos/fisiologia
18.
Acta Otorrinolaringol Esp ; 69(1): 35-41, 2018.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-28859993

RESUMO

OBJECTIVE: Considering that all the evidence indicates that chronic rhinosinusitis without nasal polyps (CRSsNP) and chronic rhinosinusitis with nasal polyps (CRSwNP) are distinct entities, the aim of this study was to compare the concentrations obtained in plasma and in sinonasal mucosa with oral and nasal topical ciprofloxacin, in patients with and without nasal polyps, without evaluating the effectiveness of the use of an antibiotic. METHODS: Prospective clinical study with single-blind randomization. The population consisted of patients with chronic rhinosinusitis with eligible for endonasal surgery, over 18 years old. It took place between January 2010 and December 2014. A single preoperative dose of ciprofloxacin (oral or nasal topic- spray, gel or drops) was given and samples of plasma and nasal mucosa (inferior turbinate, middle turbinate, ethmoid and maxillary sinus) were collected prior to surgery. The plasma and mucosal ciprofloxacin concentrations were assayed with high performance liquid chromatography (HPLC) with fluorescence detection (FD). RESULTS: The oral ciprofloxacin achieved better mucosal concentrations but had a significant plasmatic expression in all patients. None of the topical formulations achieved measurable ciprofloxacin plasmatic levels. Among the topical formulations, the gel had the best mucosal results, despite the existence of polyposis.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/análise , Ciprofloxacino/administração & dosagem , Ciprofloxacino/análise , Mucosa Nasal/química , Rinite/metabolismo , Sinusite/metabolismo , Adulto , Idoso , Antibacterianos/sangue , Doença Crônica , Ciprofloxacino/sangue , Formas de Dosagem , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Rinite/sangue , Rinite/complicações , Método Simples-Cego , Sinusite/sangue , Sinusite/complicações , Adulto Jovem
19.
J Vet Intern Med ; 31(5): 1508-1513, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28771831

RESUMO

BACKGROUND: Ciprofloxacin generic tablets approved for human use frequently are administered to dogs for treatment of bacterial infections because they are inexpensive and readily available. However, previous work indicated low and variable oral absorption in healthy research dogs. OBJECTIVE: To examine orally administered ciprofloxacin in a group of clinical canine patients using population pharmacokinetics in order to identify minimum inhibitory concentrations (MIC) that potentially could be achieved with orally administered ciprofloxacin in dogs. ANIMALS: Thirty-four clinical canine patients; mean weight, 22.95 kg (range, 4.6-57 kg). METHODS: Ciprofloxacin generic tablets intended for human use were administered to dogs in a prospective study (mean dose, 23.5 mg/kg). Sparse blood sampling was used to obtain population pharmacokinetic results with nonlinear mixed-effects modeling. These data were used to estimate a breakpoint for susceptible bacteria. Monte Carlo simulations were used to determine the probability of target attainment (PTA) for an area under the curve (AUC)/MIC ratio of ≥100, the pharmacokinetic-pharmacodynamic target for fluoroquinolones. RESULTS: The values for volume of distribution, peak concentration, and half-life were 10.7 L/kg (11.7%), 1.9 µg/mL (11.66%), and 4.35 hours (7.62%), respectively (mean, % coefficient of variation [CV]). The size of the dog was an important covariate with larger dogs achieving lower plasma drug concentrations than smaller dogs, despite a similar mg/kg dose. Ninety percent PTA was obtained for a MIC ≤ 0.06 µg/mL. CONCLUSIONS AND CLINICAL IMPORTANCE: A breakpoint (susceptible) of ≤0.06 µg/mL should be considered when ciprofloxacin tablets are administered to dogs at a dose of 25 mg/kg once daily, which is much lower than the breakpoint of ≤1 µg/mL in humans.


Assuntos
Antibacterianos/farmacocinética , Infecções Bacterianas/veterinária , Ciprofloxacino/farmacocinética , Doenças do Cão/tratamento farmacológico , Animais , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Infecções Bacterianas/tratamento farmacológico , Ciprofloxacino/administração & dosagem , Ciprofloxacino/sangue , Doenças do Cão/microbiologia , Cães , Feminino , Meia-Vida , Masculino , Testes de Sensibilidade Microbiana/veterinária , Método de Monte Carlo , Estudos Prospectivos
20.
Talanta ; 174: 610-618, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-28738630

RESUMO

A simple and highly selective electrochemical method using a glassy carbon electrode (GCE) modified with graphene oxide (GO) and nickel oxide nanoparticles (NiONPs) was developed for the simultaneous determination of paracetamol (PAR) and ciprofloxacin (CIP). The electrochemical characterisation of the modified GCE was performed by cyclic voltammetry and electrochemical impedance spectroscopy. The morphological characterisation of the GO and NiONPs was performed by scanning electron microscopy and transmission electron microscopy. Under optimised conditions, using square wave voltammetry, the simultaneous determination of PAR and CIP using the NiONPs-GO-CTS: EPH/GCE sensor shows a linear concentration range from 0.10 to 2.9µmolL-1 and 0.040-0.97µmolL-1, with detection limits of 6.7 and 6.0 nmol L-1, respectively. The NiONPs-GO-CTS: EPH/GCE sensor showed good reproducibility, repeatability and stability. Furthermore, the proposed method was successfully applied for the simultaneous determination of PAR and CIP in synthetic biological fluid samples.


Assuntos
Acetaminofen/análise , Carbono/química , Ciprofloxacino/análise , Testes de Química Clínica/métodos , Grafite/química , Níquel/química , Óxidos/química , Acetaminofen/sangue , Acetaminofen/urina , Ciprofloxacino/sangue , Ciprofloxacino/urina , Testes de Química Clínica/instrumentação , Eletroquímica , Eletrodos , Vidro/química , Humanos , Concentração de Íons de Hidrogênio , Limite de Detecção , Fatores de Tempo
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