RESUMEN
Weight loss interventions are delivered through various mediums including, increasingly, mobile phones. This systematic review and meta-analysis assesses whether interventions delivered via mobile phones reduce body weight and which intervention characteristics are associated with efficacy. The study included randomised controlled trials assessing the efficacy of weight loss interventions delivered via mobile phones. A meta-analysis to test intervention efficacy was performed, and subgroup analyses were conducted to determine whether interventions' delivery mode(s), inclusion of personal contact, duration and interaction frequency improve efficacy. Pooled body weight reduction (d = -0.23; 95% confidence interval = -0.38, -0.08) was significant. Interventions delivered via other modes in addition to the mobile phone were associated with weight reduction. Personal contact and more frequent interactions in interventions were also associated with greater weight reduction. In conclusion, the current body of evidence shows that interventions delivered via mobile phones produce a modest reduction in body weight when combined with other delivery modes. Delivering interventions with frequent and personal interactions may in particular benefit weight loss results.
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Teléfono Celular/estadística & datos numéricos , Obesidad/prevención & control , Obesidad/terapia , Prevención Primaria , Conductas Relacionadas con la Salud , Humanos , Aplicaciones Móviles/estadística & datos numéricos , Obesidad/psicología , Prevención Primaria/instrumentación , Prevención Primaria/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto , Envío de Mensajes de Texto , Factores de Tiempo , Pérdida de Peso/fisiologíaRESUMEN
RATIONALE: High levels of impulsivity have been associated with psychiatric disorders such as attention-deficit/hyperactivity disorder (ADHD) and substance abuse. In addition, acute stress is known to exacerbate many psychiatric symptoms in impulse control disorders. OBJECTIVES: The purpose of the current study was to investigate the acute effects of the pharmacological stressor yohimbine on response inhibition and impulsive choice. METHODS: A group of male rats (n = 12) was trained in the delayed reward task (DRT) to assess impulsive choice. A separate group (n = 10) was trained in the stop-signal task (SST) to measure response inhibition. Upon stable responding, the effects of yohimbine (0, 1.25, 2.5, and 5 mg/kg i.p.) were tested in a Latin square design. RESULTS: Acute yohimbine significantly increased the preference for the large and delayed reinforcer in the DRT, indicating a decrease in impulsive choice. On the contrary, the effect size of 1.25 mg/kg yohimbine on stop-signal reaction times correlated negatively with baseline performance, suggesting a baseline-dependent effect on response inhibition as measured in the SST. CONCLUSIONS: The current data suggest that the effects of the pharmacological stressor yohimbine on impulse control strongly depend on the type of impulsive behavior. Pharmacological stress decreased impulsive decision making, an observation that is in line with previously published rodent studies. By contrast, the lowest dose of yohimbine revealed a baseline-dependent effect on response inhibition. As such, the effects of yohimbine are largely comparable to the effects of psychostimulants on impulsivity and may support the notion of cross sensitization of stress and psychostimulants.
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Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Toma de Decisiones/efectos de los fármacos , Conducta Impulsiva/efectos de los fármacos , Inhibición Psicológica , Yohimbina/farmacología , Animales , Trastorno por Déficit de Atención con Hiperactividad/psicología , Conducta de Elección/efectos de los fármacos , Modelos Animales de Enfermedad , Masculino , Ratas , Ratas Wistar , Tiempo de Reacción/efectos de los fármacos , RecompensaRESUMEN
Yersinia pestis, the causative agent of bubonic, septicemic, and pneumonic plague, is classified as a CDC category A bioterrorism pathogen. Streptomycin and doxycycline are the "gold standards" for the treatment of plague. However, streptomycin is not available in many countries, and Y. pestis isolates resistant to streptomycin and doxycycline occur naturally and have been generated in laboratories. Moxifloxacin is a fluoroquinolone antibiotic that demonstrates potent activity against Y. pestis in in vitro and animal infection models. However, the dose and frequency of administration of moxifloxacin that would be predicted to optimize treatment efficacy in humans while preventing the emergence of resistance are unknown. Therefore, dose range and dose fractionation studies for moxifloxacin were conducted for Y. pestis in an in vitro pharmacodynamic model in which the half-lives of moxifloxacin in human serum were simulated so as to identify the lowest drug exposure and the schedule of administration that are linked with killing of Y. pestis and with the suppression of resistance. In the dose range studies, simulated moxifloxacin regimens of ≥175 mg/day killed drug-susceptible bacteria without resistance amplification. Dose fractionation studies demonstrated that the AUC (area under the concentration-time curve)/MIC ratio predicted kill of drug-susceptible Y. pestis, while the C(max) (maximum concentration of the drug in serum)/MIC ratio was linked to resistance prevention. Monte Carlo simulations predicted that moxifloxacin at 400 mg/day would successfully treat human infection due to Y. pestis in 99.8% of subjects and would prevent resistance amplification. We conclude that in an in vitro pharmacodynamic model, the clinically prescribed moxifloxacin regimen of 400 mg/day is predicted to be highly effective for the treatment of Y. pestis infections in humans. Studies of moxifloxacin in animal models of plague are warranted.
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Antibacterianos/farmacología , Compuestos Aza/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Modelos Biológicos , Peste/tratamiento farmacológico , Quinolinas/farmacología , Yersinia pestis/efectos de los fármacos , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Área Bajo la Curva , Compuestos Aza/administración & dosificación , Compuestos Aza/uso terapéutico , Recuento de Colonia Microbiana , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Fluoroquinolonas/farmacología , Fluoroquinolonas/uso terapéutico , Humanos , Pruebas de Sensibilidad Microbiana , Método de Montecarlo , Moxifloxacino , Mutación , Peste/microbiología , Peste/prevención & control , Quinolinas/administración & dosificación , Quinolinas/uso terapéutico , Resultado del Tratamiento , Yersinia pestis/genética , Yersinia pestis/crecimiento & desarrolloRESUMEN
BACKGROUND: Zarzio, a new recombinant human granulocyte colony-stimulating factor (filgrastim), was evaluated in healthy volunteers and neutropenic patients in phase I and III studies. PATIENTS AND METHODS: Healthy volunteers in randomized, two-period crossover studies received single- and multiple-dose s.c. injections of 1 microg/kg (n = 24), 2.5 microg/kg (n = 28), 5 microg/kg (n = 28), or 10 microg/kg (n = 40), as well as single-dose i.v. infusions of 5 microg/kg (n = 26), of Zarzio or the reference product (Neupogen). Filgrastim serum levels were monitored; pharmacodynamic parameters were absolute neutrophil count (all studies) and CD34(+) cells (multiple-dose studies). Supportive efficacy and safety data were obtained from an open phase III study in 170 breast cancer patients undergoing four cycles of doxorubicin and docetaxel (Taxotere) chemotherapy, receiving Zarzio (300 or 480 microg) as primary prophylaxis of severe neutropenia. RESULTS: The results of the studies in healthy volunteers confirm the comparability of the test and reference products with respect to their pharmacodynamics and pharmacokinetics. Confidence intervals were within the predefined equivalence boundaries. In the phase III study in breast cancer patients, the administration of Zarzio was efficacious and safe, triggering no immunogenicity. CONCLUSION: The results of these studies demonstrate the biosimilarity of Zarzio with its reference product Neupogen.
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Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Neutropenia/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/patología , Estudios Cruzados , Docetaxel , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Doxorrubicina/administración & dosificación , Femenino , Filgrastim , Humanos , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Proteínas Recombinantes , Tasa de Supervivencia , Taxoides/administración & dosificación , Resultado del Tratamiento , Adulto JovenRESUMEN
Simulating the average non-protein-bound (free) human serum drug concentration-time profiles for linezolid in an in vitro pharmacodynamic model, we characterized the pharmacodynamic parameter(s) of linezolid predictive of kill and for prevention of resistance in Bacillus anthracis. In 10-day dose-ranging studies, the average exposure for > or =700 mg of linezolid given once daily (QD) resulted in >3-log CFU/ml declines in B. anthracis without resistance selection. Linezolid at < or =600 mg QD amplified for resistance. With twice-daily (q12h) dosing, linezolid at > or =500 mg q12 h was required for resistance prevention. In dose fractionation studies, killing of B. anthracis was predicted by the area under the time-concentration curve (AUC)/MIC ratio. However, resistance prevention was linked to the maximum serum drug concentration (C(max))/MIC ratio. Monte Carlo simulations predicted that linezolid at 1,100 mg QD would produce in 96.7% of human subjects a free 24-h AUC that would match or exceed the average 24-h AUC of 78.5 mg x h/liter generated by linezolid at 700 mg QD while reproducing the shape of the concentration-time profile for this pharmacodynamically optimized regimen. However, linezolid at 700 mg q12h (cumulative daily dose of 1,400 mg) would produce an exposure that would equal or exceed the average free 24-h AUC of 90 mg x h/liter generated by linezolid at 500 mg q12h in 93.8% of human subjects. In conclusion, in our in vitro studies, the QD-administered, pharmacodynamically optimized regimen for linezolid killed drug-susceptible B. anthracis and prevented resistance emergence at lower dosages than q12h regimens. The lower dosage for the pharmacodynamically optimized regimen may decrease drug toxicity. Also, the QD administration schedule may improve patient compliance.
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Acetamidas/farmacología , Antibacterianos/farmacología , Bacillus anthracis/efectos de los fármacos , Modelos Biológicos , Oxazolidinonas/farmacología , Acetamidas/administración & dosificación , Acetamidas/farmacocinética , Carbunco/tratamiento farmacológico , Carbunco/microbiología , Carbunco/prevención & control , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Bacillus anthracis/genética , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Farmacorresistencia Bacteriana/genética , Humanos , Técnicas In Vitro , Linezolid , Método de Montecarlo , Mutación , Oxazolidinonas/administración & dosificación , Oxazolidinonas/farmacocinéticaRESUMEN
Respiratory tract infections cause 90% of premature mortality in patients with cystic fibrosis (CF). Treatment of Pseudomonas aeruginosa infection is often very problematic. Piperacillin-tazobactam has good activity against P. aeruginosa, but its pharmacokinetics (PK) in CF patients has not been compared to the PK in healthy volunteers in a controlled clinical study. Therefore, we compared the population PK and pharmacodynamics (PD) of piperacillin between CF patients and healthy volunteers. We studied 8 adult (median age, 20 years) CF patients (average total body weight [WT], 43.1 +/- 7.8 kg) and 26 healthy volunteers (WT, 71.1 +/- 11.8 kg) who each received 4 g piperacillin as a 5-min intravenous infusion. We determined piperacillin levels by high-performance liquid chromatography, and we used NONMEM for population PK and Monte Carlo simulation. We used a target time of nonprotein-bound concentration above the MIC of 50%, which represents near-maximal bacterial killing. Unscaled total clearance was 25% lower, and the volume of distribution was 31% lower in CF patients. Allometric scaling by lean body mass reduced the unexplained (random) between-subject variability in clearance by 26% compared to the variability of linear scaling by WT. A standard dosage regimen of 3 g/70 kg body WT every 4 h as a 30-min infusion (daily dose, 18 g) achieved a robust (> or =90%) probability-of-target attainment (PTA) for MICs of < or =12 mg/liter in CF patients and < or =16 mg/liter in healthy volunteers. Alternative modes of administration allowed a marked dose reduction to 9 g daily. Prolonged (4-h) infusions of 3 g/70 kg WT every 8 h and continuous infusion (daily dose, 9 g), achieved a robust PTA for MICs of < or =16 mg/liter in both groups. Piperacillin achieved PTA expectation values of 64% and 89% against P. aeruginosa infection in CF patients, based on susceptibility data from two German CF clinics.
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Antibacterianos/farmacología , Antibacterianos/farmacocinética , Fibrosis Quística/tratamiento farmacológico , Piperacilina/farmacología , Piperacilina/farmacocinética , Adulto , Antibacterianos/administración & dosificación , Antibacterianos/sangre , Estudios de Casos y Controles , Simulación por Computador , Fibrosis Quística/sangre , Femenino , Semivida , Humanos , Infusiones Intravenosas , Masculino , Tasa de Depuración Metabólica , Pruebas de Sensibilidad Microbiana , Método de Montecarlo , Piperacilina/administración & dosificación , Piperacilina/sangre , Población , Infecciones por Pseudomonas/complicaciones , Infecciones por Pseudomonas/tratamiento farmacológico , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/aislamiento & purificaciónRESUMEN
Honeybees, Apis mellifera, gradually increase their rate of forage uptake as they gain foraging experience. This increase in foraging performance has been proposed to occur as a result of learning; however, factors affecting flight ability such as changes in physiological components of flight metabolism could also contribute to this pattern. Thus, the purpose of this study was to assess the contribution of physiological changes to the increase in honeybee foraging performance. We investigated aspects of honeybee flight muscle biochemistry throughout the adult life, from non-foraging hive bees, through young and mature foragers, to old foragers near the end of their lifespan. Two-dimensional gel proteomic analysis on honeybee thorax muscle revealed an increase in several proteins from hive bees to mature foragers including troponin T 10a, aldolase and superoxide dismutase. By contrast, the activities (V(max)) of enzymes involved in aerobic performance, phosphofructokinase, hexokinase, pyruvate kinase and cytochrome c oxidase, did not increase in the flight muscles of hive bees, young foragers, mature foragers and old foragers. However, citrate synthase activity was found to increase with foraging experience. Hence, our results suggest plasticity in both structural and metabolic components of flight muscles with foraging experience.
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Conducta Apetitiva/fisiología , Abejas/fisiología , Conducta Alimentaria/fisiología , Vuelo Animal , Músculos/fisiología , Factores de Edad , Análisis de Varianza , Animales , Secuencia de Bases , Abejas/enzimología , Citrato (si)-Sintasa/metabolismo , Electroforesis en Gel Bidimensional , Fructosa-Bifosfato Aldolasa/genética , Fructosa-Bifosfato Aldolasa/metabolismo , Espectrometría de Masas , Datos de Secuencia Molecular , Músculos/enzimología , Ontario , Análisis de Secuencia de ADN , Superóxido Dismutasa/metabolismo , Troponina T/genética , Troponina T/metabolismoRESUMEN
The present study was conducted to assess a possible in vivo effect of propiverine, an anticholinergic drug to treat urinary incontinence and related disorders, on the activity of intestinal CYP3A4 and of hepatic CYP3A4, CYP2C9, CYP2C19, and CYP1A2. The activity of the respective cytochromes P450 was measured using the following metrics of selective substrates given as a tailored low-dose phenotyping cocktail: intestinal availability of midazolam (2 mg orally), clearance of midazolam (1 mg i.v.), apparent clearance of tolbutamide (125 mg orally), urinary excretion of 4'-hydroxymephenytoin 0 to 8 h postdose (50 mg of mephenytoin orally), and the paraxanthine/caffeine plasma ratio 6 h postdose (150 mg of caffeine orally). These metrics were determined in 16 healthy young men at the end of 7 days of treatment with 15 mg of propiverine (test) or placebo (reference) twice daily. All phenotyping drugs were quantified by liquid chromatography-tandem mass spectrometry. Chronic propiverine treatment reduced hepatic and intestinal CYP3A4 activity slightly to 0.89-fold and 0.80-fold, respectively [90% confidence interval (CI) for test/reference ratios 0.85-0.93 and 0.72-0.89], with the combined effect resulting in a 1.46-fold increase in area under the curve of oral midazolam (90% CI 1.36-1.57). Propiverine had no relevant effect on CYP2C9, CYP2C19, and CYP1A2 (90% CI for test/reference ratios 0.93-1.00, 0.84-0.96, and 0.97-1.07, respectively). All study drugs were well tolerated. In conclusion, propiverine has a minor potential to cause drug-drug interactions.
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Bencilatos/farmacología , Sistema Enzimático del Citocromo P-450/metabolismo , Adulto , Hidrocarburo de Aril Hidroxilasas/metabolismo , Estudios Cruzados , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2C19 , Citocromo P-450 CYP2C9 , Citocromo P-450 CYP3A , Interacciones Farmacológicas , Humanos , Masculino , Oxigenasas de Función Mixta/metabolismoRESUMEN
OBJECTIVE: This paper describes four studies investigating the dissolution, plasma pharmacokinetics and safety of a novel, fast-acting ibuprofen formulation, ibuprofen sodium dihydrate. MATERIAL AND METHOD: Four separate studies investigated: the in vitro dissolution rates of ibuprofen sodium dihydrate (at pH 1.2, 3.5 and 7.2); the bioavailability of ibuprofen sodium dihydrate (in two pharmacokinetic studies; combined n = 38) compared with conventional ibuprofen, ibuprofen lysinate, ibuprofen arginate and ibuprofen liquagels (all 2 x 200 mg ibuprofen); and the gastroduodenal tolerance of ibuprofen sodium dihydrate and ibuprofen arginate (both 2 x 200 mg ibuprofen t.i.d.) in an endoscopy safety study, where endoscopy was performed at baseline and at the end of each treatment period using a five-point scale to assess the integrity of the gastric and duodenal mucosa. RESULTS: Ibuprofen sodium dihydrate dissolved significantly more rapidly at pH 1.2, 3.5 and 7.2 than conventional ibuprofen, ibuprofen lysinate and ibuprofen liquagels. Ibuprofen sodium dihydrate had similar C(max) to ibuprofen lysinate and ibuprofen liquagels and significantly higher Cmax than conventional ibuprofen (p = 0.002). The mean plasma concentration for ibuprofen sodium dihydrate was significantly higher than for conventional ibuprofen (p = 0.028) 10 minutes post-dose and the t(max) for ibuprofen sodium dihydrate was reached significantly earlier than for conventional ibuprofen (p = 0.018). All three formulations were bioequivalent according to the acceptable boundaries (90% confidence intervals). No statistically significant difference was observed between the ibuprofen formulations in terms of adverse events and specifically with respect to hemorrhagic scores; 41 (46.0%) adverse events (AEs) occurred after administration of ibuprofen sodium dihydrate, and 46 (52.9%) after ibuprofen arginate. One occurrence of an invasive ulcer was observed after administration of ibuprofen arginate. CONCLUSIONS: The new formulation of ibuprofen sodium dihydrate dissolves quickly in vitro, has the same extent of absorption as other fast-acting ibuprofen formulations, and is absorbed into plasma more rapidly than conventional ibuprofen. In addition, the present studies suggest that the tolerability and safety profile of ibuprofen sodium dihydrate is comparable to existing ibuprofen formulations.
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Antiinflamatorios no Esteroideos/farmacocinética , Tracto Gastrointestinal/metabolismo , Ibuprofeno/farmacocinética , Adulto , Antiinflamatorios no Esteroideos/efectos adversos , Antiinflamatorios no Esteroideos/uso terapéutico , Área Bajo la Curva , Química Farmacéutica , Femenino , Semivida , Humanos , Ibuprofeno/efectos adversos , Ibuprofeno/uso terapéutico , Absorción Intestinal , Masculino , Persona de Mediana EdadRESUMEN
PURPOSE: Drug absorption within urinary diversions has been reported to cause prolonged and higher grade toxicity. Therefore, continuous urine drainage has been recommended during chemotherapy in patients with continent urinary diversion. We developed an animal model in which to examine the significance of drug absorption in normal rabbit bladders compared with ileal augmented bladders. MATERIALS AND METHODS: Ten rabbits with ileal bladder augmentation and 5 control animals were used for absorption studies with methotrexate and ofloxacin. One, 4 and 12 months after surgery the rabbits received an intravesical instillation of either drug. During 2 hours blood samples were drawn. To avoid overfilling the bladder by urine it was emptied after 30, 60, 90 and 120 minutes, and refilled with fresh solution to yield a relatively constant drug amount. After 12 months the animals were sacrificed. Area of the native bladder wall and of the intestinal segment was measured to allow the correction of absorbed drug amounts per surface area. Moreover, the median villous heights of native and augmented ileum were compared histologically. Serum levels of methotrexate and ofloxacin were determined by high performance liquid chromatography. RESULTS: The maximum serum concentration of the 2 drugs was typically seen after 60 to 120 minutes. During the 1-year period peak serum concentrations of ofloxacin remained consistently higher in ileal augmented than in control rabbits, although this did not achieve statistical significance at all instillation time points. For methotrexate a statistically significant difference was not shown for either time point. When absorption was corrected for total bladder surface area, the enhancement of ofloxacin absorption by ileal augmentation weakened and attained statistical significance only at the 1-month time point. Histological examinations after 12 months showed that augmented intestinal mucosa had a significantly smaller villous height than native ileum. CONCLUSIONS: Our data demonstrate that bladder surface is the most important factor for increased absorption but time dependent histological changes of the integrated intestinal mucosa also influence absorption. There is a broad interindividual discrepancy. Therefore, general rules in patients with urinary diversion may not be justified.
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Íleon/metabolismo , Íleon/trasplante , Metotrexato/farmacocinética , Ofloxacino/farmacocinética , Vejiga Urinaria/metabolismo , Vejiga Urinaria/cirugía , Derivación Urinaria , Absorción , Administración Intravesical , Animales , Masculino , ConejosRESUMEN
OBJECTIVE: The aim of this in vitro study was to investigate the antibacterial depth effect of continuous wave laser irradiation with a wavelength of 980 nm in the root canal wall dentin of bovine teeth. BACKGROUND DATA: The long-term success of an endodontic therapy often fails due to remaining bacteria in the root canal or dentin tubules, which cannot be sufficiently eliminated through the classical root canal preparation technique nor through rinsing solutions. MATERIALS AND METHODS: A total of 102 slices of bovine root dentin of different thicknesses (100, 300 and 500 micro m) were prepared. The samples were inoculated from one side with 5 micro L of an enterococcus faecalis suspension of defined concentration. Four slices per slice thickness served as a control group; the rest of the 30 slices per thickness were subjected to laser irradiation - 10 each of these slices were irradiated with distal outputs of 1.75, 2.3, and 2.8 Watts (W). After drying them for 30 sec, the back of the inoculated dentin slice was irradiated for 32 seconds with a 200- micro m fiber optical waveguide under constant movement of the fibers. The remaining bacteria were then detached in NaCl under vibration. The eluate produced by this was - taking account of the degree of dilution - plated out on sheep blood agar plates. After 24 h of incubation, the grown bacterial colonies were able to be counted out and evaluated. By doing so, they were compared with the non-irradiated, but otherwise identically treated control group. RESULTS: With a slice thickness of 100 micro m, the 980-nm diode laser achieved a maximum bacterial reduction of 95% at 1.75 W, 96% at 2.3 W, and 97% at 2.8 W. With a slice thickness of 300 micro m, a maximum of 77% of the bacteria was destroyed at 1.75 W, 87% at 2.3 W, and 89% at 2.8 W. The maximum bacterial reduction with a slice thickness of 500 micro m was 57% at 1.75 W, 66% at 2.3 W, and 86% at 2.8 W. CONCLUSION: The results of this research show that the 980-nm diode laser can eliminate bacteria that have immigrated deep into the dentin, thus being able to increase the success rate in endodontic therapy.
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Bacterias/efectos de la radiación , Cavidad Pulpar/microbiología , Dentina/microbiología , Rayos Láser , Animales , Bovinos , Cavidad Pulpar/efectos de la radiación , Dentina/efectos de la radiación , Enterococcus faecalis/efectos de la radiación , Técnicas In VitroRESUMEN
The objective of this study was to determine serum bactericidal titers (SBT, the highest dilution of serum showing no growth) and the serum bactericidal activity (SBA, i.e. duration of SBT greater than 1:2) as well as the serum bactericidal rate of gemifloxacin and clarithromycin after single doses in healthy male volunteers against Streptococcus pneumoniae. Strains tested had various degrees of susceptibility to penicillin as well as different susceptibility to quinolones due to a different QRDR mutation pattern (parC, gyrA). Serum samples from volunteers (n = 12) who had received a single oral dose of either 320 mg gemifloxacin or 500 mg clarithromycin in an open-label crossover study were obtained over a 24-hour period. SBA was determined, using the microdilution method. SBA of wildtype strains for gemifloxacin ranged from 8.9 to 15.4 h (mean 12.6 h). For gemifloxacin, 2 strains with solitary gyrA mutation had an SBA from 4.5 to 4.7 h (median 4.5 h). One of the 2 strains with a single QRDR mutation in parC displayed an SBA of 4.5 h, comparable to the gyrA mutation strains, whereas the second strain had a nearly twice as long SBA of 8.9 h. Two strains with two mutations (parC and gyrA) did not display any SBA. For clarithromycin, the duration of SBA ranged from 11.3 to 15.5 h (mean 13.6 h) for 6 of the 12 strains with an MIC < or = 0.06 mg/L (no SBA was found for the remaining strains, with an MIC of 0.25 mg/L or higher). In conclusion, a correlation between individual serum concentrations and SBA was found for both antibiotics.
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Antibacterianos/farmacología , Claritromicina/farmacología , Fluoroquinolonas/farmacología , Naftiridinas/farmacología , Infecciones Neumocócicas/tratamiento farmacológico , Quinolonas/farmacología , Streptococcus pneumoniae/efectos de los fármacos , Streptococcus pneumoniae/patogenicidad , Administración Oral , Adolescente , Adulto , Antibacterianos/administración & dosificación , Antibacterianos/farmacocinética , Claritromicina/administración & dosificación , Claritromicina/farmacocinética , Estudios Cruzados , Análisis Mutacional de ADN , ADN Bacteriano , Farmacorresistencia Bacteriana , Quimioterapia Combinada , Fluoroquinolonas/administración & dosificación , Fluoroquinolonas/farmacocinética , Gemifloxacina , Humanos , Masculino , Persona de Mediana Edad , Naftiridinas/administración & dosificación , Naftiridinas/farmacocinéticaRESUMEN
In a randomized crossover study, 16 volunteers (8 men, 8 women) received single oral doses of 320 mg of gemifloxacin and 400 mg of ofloxacin on two separate occasions in the fasting state to assess the urinary excretion and urinary bactericidal titers (UBTs) at intervals for up to 144 h. Ofloxacin showed higher concentrations in urine compared with those of gemifloxacin. The median (range) cumulative excretion of gemifloxacin was 29.7% (8.4 to 48.7%) of the parent drug administered, and median (range) cumulative excretion of ofloxacin was 84.3% (46.5 to 95.2%) of the parent drug administered. The UBTs, i.e., the highest twofold dilutions (with antibiotic-free urine as the diluent) of urine that were still bactericidal, were determined for a reference strain and nine uropathogens for which the MICs of gemifloxacin and ofloxacin were as follows: Escherichia coli ATCC 25922, 0.016 and 0.06 microg/ml, respectively; Klebsiella pneumoniae, 0.03 and 0.06 microg/ml, respectively; Proteus mirabilis, 0.125 and 0.125 microg/ml, respectively; Escherichia coli, 0.06 and 0.5 microg/ml, respectively; Pseudomonas aeruginosa, 1 and 4 microg/ml, respectively; Staphylococcus aureus, 0.008 and 0.25 microg/ml, respectively; Enterococcus faecalis, 0.06 and 2 microg/ml, respectively; Staphylococcus aureus, 0.25 and 4 microg/ml, respectively; Enterococcus faecalis, 0.5 and 32 microg/ml, respectively; and Staphylococcus aureus, 2 and 32 microg/ml, respectively. Generally, the UBTs for gram-positive uropathogens were higher for gemifloxacin than for ofloxacin and the UBTs for gram-negative uropathogens were higher for ofloxacin than for gemifloxacin. According to the UBTs, ofloxacin-resistant uropathogens (MICs, >or=4 mg/liter) should also be considered gemifloxacin resistant. Although clinical trials have shown that gemifloxacin is effective for the treatment of uncomplicated urinary tract infections, whether an oral dosage of 320 mg of gemifloxacin once daily is also adequate for the treatment of complicated urinary tract infections has yet to be confirmed.
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Antiinfecciosos/farmacología , Antiinfecciosos/orina , Fluoroquinolonas , Naftiridinas/farmacología , Naftiridinas/orina , Ofloxacino/farmacología , Ofloxacino/orina , Orina/microbiología , Adolescente , Adulto , Antiinfecciosos/efectos adversos , Calibración , Estudios Cruzados , Femenino , Gemifloxacina , Humanos , Concentración de Iones de Hidrógeno , Masculino , Pruebas de Sensibilidad Microbiana , Naftiridinas/efectos adversos , Ofloxacino/efectos adversos , Control de CalidadRESUMEN
PURPOSE: To assess whether topical ketoprofen, which has been reported to provide analgesic effects in clinical studies, reaches predictable tissue concentrations high enough to account for the reported analgesia. Intramuscular ketoprofen was used as positive control. METHODS: Muscle and subcutaneous tissue concentrations were assessed by microdialysis. Plasma and tissue concentrations after intramuscular injection were described using a three-compartment population pharmacokinetic model. The prediction performance of the model was assessed by superimposing tissue concentrations of 12 subjects that did not participate in the present study. RESULTS: Most dialysate concentrations after topical dosing of ketoprofen (100 mg) were below the quantification limit of 0.47 ng/ml. Plasma concentrations increased slowly and reached an apparent plateau of 7-40 ng/ml at 10-12h. No decline was observed up to 16 h. Tissue concentrations after intramuscular injection (100 mg) were about 10 times higher than those after topical dosing. Tissue concentrations measured in the majority of the 12 subjects that did not participate in the present study were found within the range of two-thirds of the predicted concentrations. CONCLUSION: Predictable and cyclooxygenase-inhibiting concentrations of ketoprofen were achieved in subcutaneous and muscle tissue after intramuscular but not after topical dosing. Thus, the tissue concentrations of ketoprofen after topical administration can hardly explain the reported clinical efficacy of topical ketoprofen.
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Antiinflamatorios no Esteroideos/farmacología , Cetoprofeno/farmacocinética , Administración Tópica , Adulto , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/sangre , Área Bajo la Curva , Estudios Cruzados , Soluciones para Diálisis/metabolismo , Humanos , Inyecciones Intramusculares , Cetoprofeno/administración & dosificación , Cetoprofeno/sangre , Masculino , Microdiálisis/métodos , Músculos/metabolismo , Perfusión , Distribución Aleatoria , Distribución Tisular/fisiologíaRESUMEN
Urine bactericidal titers (UBTs) against Escherichia coli ATCC 25922 and Staphylococcus saprophyticus ATCC 1970 were determined after the administration of single oral doses of gemifloxacin at 320 mg and trovafloxacin at 200 mg to healthy volunteers. Gemifloxacin presented significantly lower experimental versus mathematically predicted UBTs over 72 h, due to the effect of urine on the susceptibility of the E. coli strain. Experimental UBTs were significantly higher for gemifloxacin than trovafloxacin against both strains over 72 h.
Asunto(s)
Antiinfecciosos/farmacocinética , Escherichia coli/efectos de los fármacos , Fluoroquinolonas , Naftiridinas/farmacocinética , Staphylococcus/efectos de los fármacos , Administración Oral , Adulto , Antiinfecciosos/sangre , Antiinfecciosos/farmacología , Antiinfecciosos/orina , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Gemifloxacina , Humanos , Masculino , Pruebas de Sensibilidad Microbiana , Naftiridinas/sangre , Naftiridinas/farmacología , Naftiridinas/orinaRESUMEN
Gatifloxacin (GTX), a new fluoroquinolone with extended antibacterial activity, is an interesting candidate for the treatment of chronic bacterial prostatitis (CBP). Besides the antibacterial spectrum, the concentrations in the target tissues and fluids are crucial for the treatment of CBP. Thus, it was of interest to investigate its penetration into prostatic and seminal fluid. GTX concentrations in plasma, urine, ejaculate, prostatic and seminal fluid, and sperm cells were determined by a high-performance liquid chromatography method after oral intake of a single 400-mg dose in 10 male Caucasian volunteers in the fasting state. Simultaneous application of the renal contrast agent iohexol was used to estimate the maximal possible contamination of ejaculate and prostatic and seminal fluid by urine. GTX was well tolerated. The means (standard deviations) for the following parameters were as indicated: time to maximum concentration of drug in serum, 1.66 (0. 91) h; maximum concentration of drug in serum, 2.90 (0.39) microg/ml; area under the concentration-time curve from 0 to 24 h, 25.65 microg. h/ml; and half life, 7.2 (0.90) h. Within 12 h about 50% of the drug was excreted unchanged into the urine. The mean renal clearance was 169 ml/min. The gatifloxacin concentrations in ejaculate, seminal fluid, and prostatic fluid were in the range of the corresponding plasma concentrations which were 1.92 (0.27) microg/ml at approximately the same time point (4 h after drug intake). The concentrations in sperm cells (0.195, 0.076, and 0.011 microg/ml) could be determined in three subjects. The good penetration into prostatic and seminal fluid, the good tolerance, and the previously reported broad antibacterial spectrum suggest that GTX may be a good alternative for the treatment of chronic bacterial prostatitis. Clinical studies should be performed to confirm this assumption.
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Antiinfecciosos/farmacocinética , Fluoroquinolonas , Próstata/metabolismo , Semen/metabolismo , Espermatozoides/metabolismo , Adolescente , Adulto , Antiinfecciosos/sangre , Antiinfecciosos/orina , Área Bajo la Curva , Cromatografía Líquida de Alta Presión , Medios de Contraste/análisis , Gatifloxacina , Semivida , Humanos , Yohexol/análisis , MasculinoRESUMEN
BACKGROUND AND OBJECTIVES: Pefloxacin is reported to cause clinically relevant inhibition of theophylline metabolism in vivo, but in vitro pefloxacin was only a weak inhibitor of the cytochrome P450 CYP1A2, mediating main theophylline biotransformation. We therefore further characterized the interaction between pefloxacin and CYP1A2. METHODS: A randomized 3-period change-over study was conducted in 12 healthy young volunteers on the steady-state interactions between pefloxacin or enoxacin (400 mg twice a day) with caffeine (183 mg once daily), a validated marker of CYP1A2. Caffeine pharmacokinetics were estimated after its fifth dose. Studies in human liver microsomes were carried out to measure the effect of pefloxacin and norfloxacin on caffeine 3-demethylation, an in vitro CYP1A2 probe, and to identify the enzyme(s) that mediate pefloxacin N-4'-demethylation with selective inhibitors. RESULTS: For the in vivo study, ANOVA-based point estimates (90% confidence intervals [CI]) for the ratios of caffeine pharmacokinetics with and without pefloxacin coadministration were 1.11 for maximal steadystate plasma concentrations (Cmax,ss; 90% CI, 0.99 to 1.26), 0.53 for total clearance (CLt,ss; 90% CI, 0.49 to 0.58), and 1.04 for the beta-phase distribution volume (Vdbeta; 90% CI, 0.96 to 1.13). The values for enoxacin were 1.99 for Cmax,ss (90% CI, 1.77 to 2.23), 0.17 for CLt,ss (90% CI, 0.16 to 0.19), and 1.01 for Vdbeta (90% CI, 0.90 to 1.13). Thus pefloxacin caused a 2-fold decrease in caffeine clearance, and enoxacin caused a 6-fold decrease in caffeine clearance. In vitro, norfloxacin and pefloxacin competitively inhibited CYP1A2, with inhibition constant (Ki) values of 0.1 and 1 mmol/L, respectively, and CYP1A2 was the only enzyme with a relevant contribution (approximately 50%) to pefloxacin N-4'-demethylation. CONCLUSIONS: Enoxacin and to a lesser extent pefloxacin may cause clinically relevant interactions with further CYP1A2 substrates. The data suggest that the pefloxacin interaction is partly mediated by its major metabolite norfloxacin.
Asunto(s)
Antiinfecciosos/farmacología , Cafeína/farmacocinética , Estimulantes del Sistema Nervioso Central/farmacocinética , Inhibidores del Citocromo P-450 CYP1A2 , Enoxacino/farmacología , Microsomas Hepáticos/efectos de los fármacos , Pefloxacina/farmacología , Adulto , Área Bajo la Curva , Estudios Cruzados , Citocromo P-450 CYP1A2/metabolismo , Interacciones Farmacológicas , Femenino , Humanos , Masculino , Metilación/efectos de los fármacos , Microsomas Hepáticos/enzimología , Valores de ReferenciaRESUMEN
Several quinolone antibacterial agents are known to inhibit the metabolism of theophylline, with the potential to cause adverse events due to raised theophylline concentrations during coadministration. A randomized crossover study was therefore conducted with 12 healthy male volunteers (ages, 23 to 34 years; body weight, 64 to 101 kg) to evaluate a possible interaction between rufloxacin and theophylline. Both drugs were administered at steady state. Following the administration of an oral loading dose of 400 mg on day 1, rufloxacin was given orally at 200 mg once daily on days 2 to 7 during one period only. During both periods, 146 mg of theophylline was administered orally twice daily for 3 days (which were days 4 to 6 of the rufloxacin coadministration period) and intravenously once the next morning to test for an interaction. Theophylline and rufloxacin concentrations were measured by reversed-phase high-pressure liquid chromatography, the pharmacokinetics of theophylline at steady state following administration of the last dose were calculated by compartment-model-independent methods. To compare the treatments, analysis of variance-based point estimates and 90% confidence intervals (given in parentheses) were calculated for the mean ratios of the pharmacokinetic parameters from the test (rufloxacin coadministration) over those from the reference (theophylline without rufloxacin) period. These were as follows: maximum concentration at steady state, 1.01 (0.96 to 1.07); area under the concentration-time curve from 0 to 12 h, 0.98 (0.94 to 1.02); half-life, 0.99 (0.95 to 1.03); total clearance at steady state, 1. 02 (0.99 to 1.06); and volume of distribution in the elimination phase, 1.01 (0.97 to 1.05). In conclusion, rufloxacin did not affect theophylline pharmacokinetics at steady state. Therefore, therapeutic coadministration of rufloxacin and theophylline is not expected to cause an increased incidence of theophylline-related adverse events.
Asunto(s)
Antiinfecciosos/farmacología , Fluoroquinolonas , Quinolonas/farmacología , Teofilina/farmacocinética , Adulto , Estudios Cruzados , Interacciones Farmacológicas , Humanos , MasculinoRESUMEN
The broad antibacterial spectrum and the low incidence of seizures in meropenem-treated patients qualifies meropenem for therapy of bacterial meningitis. The present study evaluates concentrations in ventricular cerebrospinal fluid (CSF) in the absence of pronounced meningeal inflammation. Patients with occlusive hydrocephalus caused by cerebrovascular diseases, who had undergone external ventriculostomy (n = 10, age range 48 to 75 years), received 2 g of meropenem intravenously over 30 min. Serum and CSF were drawn repeatedly and analyzed by liquid chromatography-mass spectroscopy. Pharmacokinetics were determined by noncompartmental analysis. Maximum concentrations in serum were 84.7 +/- 23.7 microg/ml. A CSF maximum (CmaxCSF) of 0.63 +/- 0.50 microg/ml (mean +/- standard deviation) was observed 4.1 +/- 2.6 h after the end of the infusion. CmaxCSF and the area under the curve for CSF (AUCCSF) depended on the AUC for serum (AUCS), the CSF-to-serum albumin ratio, and the CSF leukocyte count. Elimination from CSF was considerably slower than from serum (half-life at beta phase [t1/2beta] of 7.36 +/- 2.89 h in CSF versus t1/2beta of 1.69 +/- 0.60 h in serum). The AUCCSF/AUCS ratio for meropenem, as a measure of overall CSF penetration, was 0.047 +/- 0.022. The AUCCSF/AUCS ratio for meropenem was similar to that for other beta-lactam antibiotics with a low binding to serum proteins. The concentration maxima of meropenem in ventricular CSF observed in this study are high enough to kill fully susceptible pathogens. They may not be sufficient to kill bacteria with a reduced sensitivity to carbapenems, although clinical success has been reported for patients with meningitis caused by penicillin-resistant pneumococci and Pseudomonas aeruginosa.