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1.
Ecotoxicol Environ Saf ; 196: 110549, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32251953

RESUMO

Chemicals used to assure agricultural production and the feasibility of planting sites often end up in bodies of water used for crop irrigation. In a pot study, we investigated the consequences associated with the irrigation of maize with water contaminated by ciprofloxacin (Cipro; 0, 0.2, 0.8, 1.4 and 2.0 µg l-1) and/or glyphosate (0, 5, 25 and 50 mg l-1) on yields and food safety. Glyphosate in concentrations ≥25 mg l-1 prevented plant establishment, regardless of Cipro presence. Evaluations made at the V5 stage of plants reveal that Cipro concentrations ≥0.8 µg l-1 and glyphosate decreased photosynthesis and induced changes in leaf anatomy and stem biophysical properties that may contribute to decreased kernel yields. When those chemicals were applied together, kernel yield reductions were accentuated, evidencing their interactive effects. Irrigation with contaminated water resulted in accumulations of Cipro and glyphosate (as well as its metabolite, aminomethylphosphonic acid) in plant tissues. Accumulation of these chemicals in plant tissues such as leaves and kernels is a problem, since they are used to feed animals and humans. Moreover, these chemicals are of potential toxicological concern, principally due to residue accumulations in the food chain. Specially, the antibiotic residue accumulations in maize tissues can assist the induction of antibiotic resistance in dangerous bacteria. Therefore, we point out the urgency of monitoring the quality of water used for crop irrigation to avoid economic and food-quality losses.


Assuntos
Antibacterianos/toxicidade , Ciprofloxacino/toxicidade , Glicina/análogos & derivados , Poluentes Químicos da Água/toxicidade , Zea mays/efeitos dos fármacos , Irrigação Agrícola , Animais , Antibacterianos/farmacocinética , Ciprofloxacino/farmacocinética , Produtos Agrícolas/anatomia & histologia , Produtos Agrícolas/efeitos dos fármacos , Produtos Agrícolas/economia , Inocuidade dos Alimentos , Glicina/farmacocinética , Glicina/toxicidade , Humanos , Fotossíntese/efeitos dos fármacos , Folhas de Planta/anatomia & histologia , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/metabolismo , Poluentes Químicos da Água/farmacocinética , Zea mays/anatomia & histologia , Zea mays/metabolismo
2.
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
3.
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
4.
Int J Biol Macromol ; 147: 809-820, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31751709

RESUMO

Polyelectrolyte multilayer (PEC) films of sodium alginate (Na-Alg) and poly(4-vinylpyridine) (P4VP) were prepared and were loaded with an antibacterial agent, ciprofloxacin HCl (CIP.HCl) aiming to design new hydrophilic films with controlled physicochemical properties and drug release behaviour that may find application as components of transdermal drug delivery systems. The PEC films were characterized by SEM, XRD, TGA, AFM and FTIR spectroscopy. The hydrophilicity of the PEC films was examined by using contact angle measurement. The number of layers and the nature of the outer layer affect the physicochemical characteristics, CIP.HCl loading and release behaviour of the films. The three layer film PEC-3, which is composed of Na-Alg outer layer deposited on a P4VP/Na-Alg double layer, is characterized by the lowest roughness (Rq = 16.3 nm) and the most hydrophilic surface with a contact angle value of 38.1° among all other films. Its crystallinity index is 0.36, and starts to degrade at 195 °C. It exhibits 130-135% equilibrium swelling capacity in acid buffer and water respectively. PEC-3 is the film with the highest drug loading capacity and drug loading efficiency values of 3.51% and 87% respectively. A cumulative drug release of 65% is obtained from PEC-3 within 24 h in pH = 1.2 buffer solution.


Assuntos
Alginatos , Ciprofloxacino , Membranas Artificiais , Polivinil , Alginatos/química , Alginatos/farmacocinética , Alginatos/farmacologia , Ciprofloxacino/química , Ciprofloxacino/farmacocinética , Preparações de Ação Retardada/síntese química , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Polieletrólitos/síntese química , Polieletrólitos/química , Polieletrólitos/farmacocinética , Polieletrólitos/farmacologia , Polivinil/química , Polivinil/farmacocinética , Polivinil/farmacologia
5.
Biopharm Drug Dispos ; 41(1-2): 32-43, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31691979

RESUMO

The kinetic clarification of lung disposition for inhaled drugs in humans via pharmacokinetic (PK) modeling aids in their development and regulation for systemic and local delivery, but remains challenging due to its multiplex nature. This study exercised our lung delivery and disposition kinetic model to derive the kinetic descriptors for the lung disposition of four drugs [calcitonin, tobramycin, ciprofloxacin and fluticasone propionate (FP)] inhaled via different inhalers from the published PK profile data. With the drug dose delivered to the lung (DTL) estimated from the corresponding γ-scintigraphy or in vivo predictive cascade impactor data, the model-based curve-fitting and statistical moment analyses derived the rate constants of lung absorption (ka ) and non-absorptive disposition (knad ). The ka values differed substantially between the drugs (0.05-1.00 h-1 ), but conformed to the lung partition-based membrane diffusion except for FP, and were inhaler/delivery/deposition-independent. The knad values also varied widely (0.03-2.32 h-1 ), yet appeared to be explained by the presence or absence of non-absorptive disposition in the lung via mucociliary clearance, local tissue degradation, binding/sequestration and/or phagocytosis, and to be sensitive to differences in lung deposition. For FP, its ka value of 0.2 h-1 was unusually low, suggesting solubility/dissolution-limited slow lung absorption, but was comparable between two inhaler products. Thus, the difference in the PK profile was attributed to differences in the DTL and the knad value, the latter likely originating from different aerosol sizes and regional deposition in the lung. Overall, this empirical, rather simpler model-based analysis provided a quantitative kinetic understanding of lung absorption and non-absorptive disposition for four inhaled drugs from PK profiles in humans.


Assuntos
Calcitonina/farmacocinética , Ciprofloxacino/farmacocinética , Fluticasona/farmacocinética , Pulmão/metabolismo , Modelos Biológicos , Tobramicina/farmacocinética , Administração por Inalação , Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacocinética , Disponibilidade Biológica , Calcitonina/administração & dosagem , Hormônios e Agentes Reguladores de Cálcio/administração & dosagem , Hormônios e Agentes Reguladores de Cálcio/farmacocinética , Ciprofloxacino/administração & dosagem , Fluticasona/administração & dosagem , Humanos , Distribuição Tecidual , Tobramicina/administração & dosagem
6.
J Vet Pharmacol Ther ; 43(1): 19-25, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31271466

RESUMO

To the best of the authors' knowledge, pharmacokinetic information to establish suitable therapeutic plans for freshwater crocodiles is limited. Therefore, the purpose of this study was to clarify the pharmacokinetic characteristics of enrofloxacin (ENR) in freshwater crocodiles, Crocodylus siamensis, following single intravenous and intramuscular administration at a dosage of 5 mg/kg body weight (b.w.). Blood samples were collected at assigned times up to 168 hr. The plasma concentrations of ENR and its metabolite ciprofloxacin (CIP) were measured by liquid chromatography tandem-mass spectrometry. The concentrations of ENR and CIP in the plasma were quantified up to 144 hr after both the administrations. The half-life was long (43-44 hr) and similar after both administrations. The absolute i.m. bioavailability was 82.65% and the binding percentage of ENR to plasma protein ranged from 9% to 18% with an average of 10.6%. Percentage of CIP (plasma concentrations) was 15.9% and 19.9% after i.v. and i.m. administration, respectively. Based on the pharmacokinetic data, susceptibility break point and PK-PD indexes, i.m. single administration of ENR at a dosage of 5 mg/kg b.w. might be appropriate for treatment of susceptible bacteria (MIC > 1 µg/mL) in freshwater crocodiles, C. siamensis.


Assuntos
Jacarés e Crocodilos , Antibacterianos/farmacocinética , Ciprofloxacino/metabolismo , Ciprofloxacino/farmacocinética , Enrofloxacina/farmacocinética , Animais , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Antibacterianos/metabolismo , Área Sob a Curva , Ciprofloxacino/administração & dosagem , Enrofloxacina/administração & dosagem , Meia-Vida , Injeções Intramusculares , Injeções Intravenosas , Masculino
7.
Molecules ; 24(24)2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31835489

RESUMO

Sepsis and septic shock exhibit a rapid course and a high fatality rate. Antibiotic treatment is time-critical and precise knowledge of the antibiotic concentration during the patients' treatment would allow individual dose adaption. Over- and underdosing will increase the antimicrobial efficacy and reduce toxicity. We demonstrated that fiber enhanced Raman spectroscopy (FERS) can be used to detect very low concentrations of ciprofloxacin in clinically relevant doses, down to 1.5 µM. Fiber enhancement was achieved in bandgap shifted photonic crystal fibers. The high linearity between the Raman signals and the drug concentrations allows a robust calibration for drug quantification. The needed sample volume was very low (0.58 µL) and an acquisition time of 30 s allowed the rapid monitoring of ciprofloxacin levels in a less invasive way than conventional techniques. These results demonstrate that FERS has a high potential for clinical in-situ monitoring of ciprofloxacin levels.


Assuntos
Antibacterianos/farmacocinética , Ciprofloxacino/farmacocinética , Análise Espectral Raman , Antibacterianos/administração & dosagem , Antibacterianos/química , Ciprofloxacino/administração & dosagem , Ciprofloxacino/química , Monitoramento de Medicamentos , Humanos , Sepse/sangue , Sepse/tratamento farmacológico , Sepse/etiologia , Análise Espectral Raman/métodos , Análise Espectral Raman/normas
8.
Artigo em Inglês | MEDLINE | ID: mdl-31636067

RESUMO

Fluoroquinolone treatments induce dysbiosis of the intestinal microbiota, resulting in loss of resistance to colonization by exogenous bacteria such as Clostridioides difficile that may cause severe diarrhea in humans and lethal infection in hamsters. We show here that DAV131A, a charcoal-based adsorbent, decreases the intestinal levels of the fluoroquinolone antibiotics levofloxacin and ciprofloxacin in hamsters, protects their intestinal microbiota, and prevents lethal infection by C. difficile.


Assuntos
Carvão Vegetal/administração & dosagem , Infecções por Clostridium/prevenção & controle , Administração Oral , Adsorção , Animais , Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Ciprofloxacino/efeitos adversos , Ciprofloxacino/farmacocinética , Modelos Animais de Doenças , Disbiose/induzido quimicamente , Disbiose/metabolismo , Disbiose/prevenção & controle , Fluoroquinolonas/efeitos adversos , Fluoroquinolonas/farmacocinética , Microbioma Gastrointestinal/efeitos dos fármacos , Levofloxacino/efeitos adversos , Levofloxacino/farmacocinética , Masculino , Mesocricetus
9.
Nat Commun ; 10(1): 4039, 2019 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-31492864

RESUMO

Antibiotic therapy is usually not recommended for salmonellosis, as it is associated with prolonged fecal carriage without reducing symptom duration or severity. Here we show that antibiotics encapsulated in hydrogen sulfide (H2S)-responsive glycovesicles may be potentially useful for the treatment of salmonellosis. The antibiotics are released in the presence of Salmonella, which is known to produce H2S. This approach prevents the quick absorption of antibiotics into the bloodstream, allows localized targeting of the pathogen in the gut, and alleviates disease symptoms in a mouse infection model. In addition, it reduces antibiotic-induced changes in the gut microbiota, and increases the abundance of potentially beneficial lactobacilli due to the release of prebiotic xylooligosaccharide analogs.


Assuntos
Antibacterianos/farmacologia , Glucuronatos/química , Sulfeto de Hidrogênio/farmacologia , Oligossacarídeos/química , Infecções por Salmonella/tratamento farmacológico , Salmonella/efeitos dos fármacos , Animais , Antibacterianos/química , Antibacterianos/farmacocinética , Ciprofloxacino/química , Ciprofloxacino/farmacocinética , Ciprofloxacino/farmacologia , Liberação Controlada de Fármacos , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Glucuronatos/metabolismo , Sulfeto de Hidrogênio/química , Sulfeto de Hidrogênio/farmacocinética , Camundongos , Oligossacarídeos/metabolismo , Salmonella/fisiologia , Infecções por Salmonella/microbiologia , Resultado do Tratamento
11.
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
12.
J Ocul Pharmacol Ther ; 35(6): 366-371, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31066613

RESUMO

Purpose: Patients with open globe injuries routinely receive fluoroquinolone (FQ) prophylaxis to prevent bacterial infectious endophthalmitis. Owing to the rarity of this infection, there is an absence of clinical trials evaluating optimal prophylactic FQ dosing. To address this knowledge gap, we conducted a Monte Carlo simulation (MCS)-based study to identify the FQ dosing option(s) that optimize pharmacokinetic-pharmacodynamic FQ target attainment against common bacterial pathogens implicated in post-traumatic bacterial infectious endophthalmitis (PTBIE). Methods: Weighted mean pharmacokinetic parameters and standard deviations for ciprofloxacin, levofloxacin, and moxifloxacin were calculated from published studies in healthy volunteers. The incidence and FQ susceptibility profiles for the most common bacteria causing PTBIE were extracted from the literature. MCS was used to determine the cumulative fraction of response (CFR) for 5 FQ dosing options to determine the probability of attaining pathogen-specific target 24-hour area under the curve to minimum inhibitory concentration ratios in the vitreous humor of the eye against the 4 most common causative bacteria seen in PTBIE. Results: Moxifloxacin 400 mg po daily (M400) achieved the highest CFR (72%). Levofloxacin dosing options achieved CFRs between 54% and 63%. Ciprofloxacin dosing options achieved CFRs between 28% and 35%. Conclusion: M400 optimized the likelihood of prophylactic success in the prevention of PTBIE, and based on the study findings, M400 is predicted to optimize the probability of success compared with ciprofloxacin and levofloxacin dosing options currently endorsed by expert opinion.


Assuntos
Antibacterianos/administração & dosagem , Antibioticoprofilaxia/métodos , Endoftalmite/prevenção & controle , Infecções Oculares Bacterianas/prevenção & controle , Antibacterianos/farmacocinética , Antibacterianos/farmacologia , Ciprofloxacino/administração & dosagem , Ciprofloxacino/farmacocinética , Ciprofloxacino/farmacologia , Bases de Dados Factuais , Relação Dose-Resposta a Droga , Endoftalmite/microbiologia , Infecções Oculares Bacterianas/microbiologia , Ferimentos Oculares Penetrantes/complicações , Ferimentos Oculares Penetrantes/tratamento farmacológico , Humanos , Levofloxacino/administração & dosagem , Levofloxacino/farmacocinética , Levofloxacino/farmacologia , Testes de Sensibilidade Microbiana , Modelos Biológicos , Método de Monte Carlo , Moxifloxacina/administração & dosagem , Moxifloxacina/farmacocinética , Moxifloxacina/farmacologia , Probabilidade
13.
Artigo em Inglês | MEDLINE | ID: mdl-31061152

RESUMO

Fluoroquinolones are group A drugs in tuberculosis guidelines. We aim to compare the culture conversion between new-generation (levofloxacin and moxifloxacin) and old-generation (ciprofloxacin and ofloxacin) fluoroquinolones, develop pharmacokinetic models, and calculate target attainment for levofloxacin and moxifloxacin. We included three U.S. tuberculosis centers. Patients admitted between 1984 and 2015, infected with drug-resistant tuberculosis, and who had received fluoroquinolones for ≥28 days were included. Demographics, sputum cultures and susceptibility, treatment regimens, and serum concentrations were collected. A time-to-event analysis was conducted, and Cox proportional hazards model was used to compare the time to culture conversion. Using additional data from ongoing studies, pharmacokinetic modelling and Monte Carlo simulations were performed to assess target attainment for different doses. Overall, 124 patients received fluoroquinolones. The median age was 40 years, and the median weight was 60 kg. Fifty-six patients (45%) received old-generation fluoroquinolones. New-generation fluoroquinolones showed a faster time to culture conversion (median 16 versus 40 weeks, P = 0.012). After adjusting for isoniazid and clofazimine treatment, patients treated with new-generation fluoroquinolones were more likely to have culture conversion (adjusted hazards ratio, 2.16 [95% confidence interval, 1.28 to 3.64]). We included 178 patients in the pharmacokinetic models. Levofloxacin and moxifloxacin were best described by a one-compartment model with first-order absorption and elimination. At least 1,500 to 1,750 mg levofloxacin and 800 mg moxifloxacin may be needed for maximum kill at the current epidemiologic cutoff values. In summary, new-generation fluoroquinolones showed faster time to culture conversion compared to the old generation. For optimal target attainment at the current MIC values, higher doses of levofloxacin and moxifloxacin may be needed.


Assuntos
Antituberculosos/administração & dosagem , Antituberculosos/farmacocinética , Fluoroquinolonas/farmacocinética , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Ciprofloxacino/farmacocinética , Relação Dose-Resposta a Droga , Feminino , Fluoroquinolonas/administração & dosagem , Humanos , Levofloxacino/administração & dosagem , Levofloxacino/farmacocinética , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Modelos Biológicos , Moxifloxacina/administração & dosagem , Moxifloxacina/farmacocinética , Ofloxacino/farmacocinética , Estudos Retrospectivos , Tuberculose Resistente a Múltiplos Medicamentos/microbiologia , Tuberculose Pulmonar/tratamento farmacológico , Tuberculose Pulmonar/microbiologia , Adulto Jovem
14.
Chin Med J (Engl) ; 132(6): 638-646, 2019 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-30855292

RESUMO

BACKGROUND: Ciprofloxacin is usually used in the treatment of lower respiratory tract infections (LRTIs). Recent studies abroad have shown ciprofloxacin is inadequately dosed and might lead to worse outcomes. The aim of this study was to perform pharmacokinetic and pharmacodynamic analyses of ciprofloxacin in elderly Chinese patients with severe LRTIs caused by Gram-negative bacteria. METHODS: From September 2012 to June 2014, as many as 33 patients were empirically administered beta-lactam and ciprofloxacin combination therapy. Patients were infused with 200 or 400 mg of ciprofloxacin every 12 h, which was determined empirically by the attending physician based on the severity of the LRTI and the patient's renal condition. Ciprofloxacin serum concentrations were determined by high-performance liquid chromatography. Bacterial culture was performed from sputum samples and/or endotracheal aspirates, and the minimum inhibitory concentrations (MICs) of ciprofloxacin were determined. The ratios of the area under the serum concentration-time curve to the MIC (AUC/MIC) and of the maximum serum concentration of the drug to the MIC (Cmax/MIC) were calculated. The baseline data and pharmacokinetic parameters were compared between clinical success group and clinical failure group, bacteriologic success group and bacteriologic failure group. RESULTS: Among the 33 patients enrolled in the study, 17 were infected with Pseudomonas aeruginosa, 14 were infected with Acinetobacter baumannii, and two were infected with Klebsiella pneumoniae. The mean age of the patients was 76.9 ± 6.7 years. Thirty-one patients (93.4%) did not reach the target AUC/MIC value of >125, and 29 patients (87.9%) did not reach the target Cmax/MIC value of >8. The AUC/MIC and Cmax/MIC ratios in the clinical success group were significantly higher than those in the clinical failure group (61.1 [31.7-214.9] vs. 10.4 [3.8-66.1], Z = -4.157; 9.6 [4.2-17.8] vs. 1.3 [0.4-4.7], Z = -4.018; both P < 0.001). The AUC/MIC and Cmax/MIC ratios in the patients for whom the pathogens were eradicated were significantly higher than those in the patients without the pathogens eradicated (75.3 [31.7-214.9] vs. 10.5 [3.8-66.1], Z = -3.938; 11.4 [4.2-17.8] vs. 1.4 [0.4-5.4], Z = -3.793; P < 0.001 for both). Receiver operating characteristic curve analysis showed that the AUC/MIC and Cmax/MIC values were closely associated with clinical and bacteriologic efficacies (P < 0.001 in both). CONCLUSIONS: Ciprofloxacin is inadequately dosed against Gram-negative bacteria, especially for those with relatively high MIC values. Consequently, the target values, AUC/MIC > 125 and Cmax/MIC > 8, cannot be reached.


Assuntos
Ciprofloxacino/farmacologia , Ciprofloxacino/farmacocinética , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Negativas/patogenicidade , Infecções Respiratórias/tratamento farmacológico , Infecções Respiratórias/metabolismo , Acinetobacter baumannii/efeitos dos fármacos , Acinetobacter baumannii/patogenicidade , Idoso , Idoso de 80 Anos ou mais , Cromatografia Líquida de Alta Pressão , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/patogenicidade , Infecções Respiratórias/microbiologia
15.
J Antimicrob Chemother ; 74(6): 1662-1669, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30809648

RESUMO

BACKGROUND: Patients with septic shock may undergo extensive physiological alterations that can alter antibiotic pharmacokinetics. OBJECTIVES: To describe the population pharmacokinetics of ciprofloxacin in septic shock and to define recommendations for effective ciprofloxacin dosing in these patients. METHODS: Adult patients with septic shock treated with ciprofloxacin were eligible for inclusion. Concentrations were measured by HPLC-MS/MS. Population pharmacokinetic modelling was performed with Monte Carlo simulations then used to define dosing regimens that optimize the PTA of an AUC/MIC ratio >125 for different MICs and fractional target attainment (FTA) of empirical and targeted therapy against Pseudomonas aeruginosa. RESULTS: We included 48 patients with median Simplified Acute Physiology Score (SAPS) II of 49 and 90 day mortality of 33%. Ciprofloxacin pharmacokinetics was best described by a two-compartment linear model including CLCR and body weight as covariates on CL and central volume respectively. With a dose of 400 mg q8h and CLCR of 80 mL/min, >95% PTA was achieved for bacteria with MICs ≤0.25 mg/L. For empirical treatment of P. aeruginosa, 600 mg q8h only reached a maximum of 68% FTA. For directed therapy against P. aeruginosa, a dose of 600 mg q8h was needed to achieve sufficient AUC/MIC ratios. CONCLUSIONS: In patients with septic shock, standard ciprofloxacin dosing achieved concentrations to successfully treat bacteria with MICs ≤0.25 mg/L and then only in patients with normal or reduced CLCR. To cover pathogens with higher MICs or in patients with augmented renal CL, doses may have to be increased.


Assuntos
Antibacterianos/administração & dosagem , Ciprofloxacino/administração & dosagem , Choque Séptico/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibacterianos/farmacocinética , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Ciprofloxacino/farmacocinética , Monitoramento de Medicamentos , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Método de Monte Carlo , Índice de Gravidade de Doença , Choque Séptico/diagnóstico , Choque Séptico/microbiologia , Adulto Jovem
16.
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
17.
Q J Nucl Med Mol Imaging ; 63(1): 37-47, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28849632

RESUMO

BACKGROUND: Diagnosis of implant-associated infection is challenging. Several radiopharmaceuticals have been described but direct comparisons are limited. Here we compared in vitro and in an animal model 99mTc-UBI, 99mTc-ciprofloxacin, 99mTcN-CiproCS2 and 111In-DTPA-biotin for targeting E. coli (ATCC 25922) and S. aureus (ATCC 43335). METHODS: Stability controls were performed with the labelled radiopharmaceuticals during 6 hours in saline and serum. The in vitro binding to viable or killed bacteria was evaluated at 37 °C and 4 °C. For in vivo studies, Teflon cages were subcutaneously implanted in mice, followed by percutaneous infection. Biodistribution of i.v. injected radiolabelled radiopharmaceuticals were evaluated during 24 h in cages and dissected tissues. RESULTS: Labelling efficiency of all radiopharmaceuticals ranged between 94% and 98%, with high stability both in saline and in human serum. In vitro binding assays displayed a rapid but poor bacterial binding for all tested agents. Similar binding kinetic occurred also with heat-killed and ethanol-killed bacteria. In the tissue cage model, infection was detected at different time points: 99mTc-UBI and 99mTcN-CiproCS2 showed higher infected cage/sterile cage ratio at 24 hours for both E. coli and S. aureus; 99mTc-Ciprofloxacin at 24 hours for both E. coli and at 4 hours for S. aureus; 111In-DTPA-biotin accumulates faster in both E. coli and S. aureus infected cages. CONCLUSIONS: 99mTc-UBI, 99mTcN-CiproCS2 showed poor in vitro binding but good in vivo binding to E. coli only. 111In-DTPA-biotin showed poor in vitro binding but good in vivo binding to S. aureus and poor to E. coli. 99mTc-Ciprofloxacin showed poor in vitro binding but good in vivo binding to all tested bacteria. The mechanism of accumulation in infected sites remains to be elucidated.


Assuntos
Escherichia coli/fisiologia , Radioisótopos de Índio , Infecções Relacionadas à Prótese/diagnóstico por imagem , Compostos Radiofarmacêuticos/metabolismo , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único/métodos , Staphylococcus aureus/fisiologia , Animais , Biotina/metabolismo , Biotina/farmacocinética , Ciprofloxacino/análogos & derivados , Ciprofloxacino/metabolismo , Ciprofloxacino/farmacocinética , Escherichia coli/metabolismo , Marcação por Isótopo , Camundongos , Camundongos Endogâmicos C57BL , Compostos de Organotecnécio/metabolismo , Compostos de Organotecnécio/farmacocinética , Fragmentos de Peptídeos/metabolismo , Fragmentos de Peptídeos/farmacocinética , Infecções Relacionadas à Prótese/microbiologia , Controle de Qualidade , Compostos Radiofarmacêuticos/farmacocinética , Staphylococcus aureus/metabolismo , Tiocarbamatos/metabolismo , Tiocarbamatos/farmacocinética , Distribuição Tecidual
18.
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
19.
J Antimicrob Chemother ; 74(3): 682-690, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30500905

RESUMO

BACKGROUND: Pathophysiological changes often result in altered pharmacokinetics of ciprofloxacin in critically ill patients. Although ciprofloxacin clearance (CLCIP) substantially depends on kidney function in healthy volunteers, its relationship to measured creatinine clearance (CLCRM) is weak in critically ill patients. OBJECTIVES: To assess the need for dose reductions in isolated or combined kidney and liver dysfunction in critically ill patients and to re-evaluate relationships between kidney parameters, demographics and ciprofloxacin pharmacokinetics. METHODS: A population pharmacokinetic model was developed based on 444 ciprofloxacin serum concentrations from 15 critically ill patients with severe infections. CLCIP relationships to parameters reflecting hepatic function, CLCRM, Cockcroft-Gault creatinine clearance (CLCRCG), serum creatinine, sex, weight and age were explored. A simulation study was conducted to integrate knowledge from the new and previously published models. RESULTS: Total bilirubin was identified as a hepatic parameter with a clear relationship to CLCIP. A significant relationship between CLCIP and CLCRCG could be attributed to age and sex only. CLCIP was not associated with CLCRM. The predicted risk of potential overexposure (AUC > 250 mg·h/L) was low even with 1200 mg/day ciprofloxacin daily for patients with reduced CLCRCG (<30 mL/min: risk of 0.7%), while the risk was remarkably higher in elderly female patients with elevated bilirubin (risk of about 20% for 65-year-old women with total bilirubin of 4 mg/dL). CONCLUSIONS: Bilirubin, age and sex should be considered to assess the need for dose reductions. For MICs ≤0.25 mg/L, it might be appropriate to reduce the dose to 400 mg/day for elderly female subjects with high bilirubin.


Assuntos
Antibacterianos/administração & dosagem , Antibacterianos/farmacocinética , Ciprofloxacino/administração & dosagem , Ciprofloxacino/farmacocinética , Estado Terminal , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Creatinina/sangue , Feminino , Humanos , Rim/efeitos dos fármacos , Rim/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Pessoa de Meia-Idade , Fatores Sexuais , Adulto Jovem
20.
Drug Dev Ind Pharm ; 45(2): 292-303, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30348012

RESUMO

OBJECTIVE: To study the potential influence of selected metal ions on absorption (and hence oral bioavailability of ciprofloxacin (Cipro) in presence and absence of a competing ligand. SIGNIFICANCE: The presence of metal ions together with Cipro results in complexes exhibiting a decreased bioavailability. Attempts were made to better understand the mechanism of decreased Cipro bioavailability in the presence of metals such as calcium and ferrous ions, and a small-sized ligand citric acid (CitA). METHODS: Effect of complex size or other potential factors was studied using diffusion through synthetic membrane, permeation studies across Caco-2 cells and capillary electrophoresis. A molecular dynamics (MD) simulation study was conducted to find the arrangement and the nature of the interactions between Cipro molecules and ferrous ions. RESULTS: Cipro was shown to form complexes with metals and CitA. The presence of CitA improved permeation of Cipro through the synthetic membrane but this was not as obvious in case of Caco-2 cells. Capillary electrophoresis suggested the existence of large molecular aggregates of Cipro: metal complexes. MD simulations offered clear evidence of large size aggregates in line with the experimental findings. CitA alone significantly improved permeation of Cipro through Caco-2 cells. CONCLUSIONS: The size of the formed complexes, rather than the decrease in the solubility of formed complexes, plays a significant role in permeation (absorption) of Cipro. CitA might ameliorate the effect of co-administered metal ions on the bioavailability of Cipro.


Assuntos
Anti-Infecciosos/farmacocinética , Cálcio/farmacologia , Ciprofloxacino/farmacocinética , Ácido Cítrico/farmacologia , Compostos Ferrosos/farmacologia , Absorção Intestinal/efeitos dos fármacos , Anti-Infecciosos/administração & dosagem , Disponibilidade Biológica , Células CACO-2 , Permeabilidade da Membrana Celular , Ciprofloxacino/administração & dosagem , Difusão , Eletroforese Capilar , Humanos , Íons , Solubilidade , Espectrofotometria Ultravioleta
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