1,720,964 research outputs found
Isoniazid and its hydrazine metabolite in patients with tuberculosis
No full textObjective: The serum profiles of isoniazid and its hydrazine metabolite were investigated in patients with tuberculosis in steady-state conditions in the hope of identifying a pharmacokinetic approach that could be useful in the clinical assessment of other patients with the same disease state. Patients and Study Design: Isoniazid was coadministered with the other drugs included in the antitubercular regimen (rifampicin, ethambutol, streptomycin, morinamide). Concentrations of isoniazid and its hydrazine metabolite were measured in the collected serum samples by high performance liquid chromato-graphy. The pharmacokinetic parameters of isoniazid were estimated by WINNONLIN. Since an isoniazid serum concentration of 1.5 mg/L 3 hours after (C3) the administration of the dose (D) was demonstrated to be therapeutically efficacious with minimal neurotoxic adverse effects, the theoretical dosage adjustment (D(a)) required to achieve this optimal concentration in all our patients was calculated according to the inactivator index (I3) method proposed by Vivien et al. [I3 = (C) + 0.6)/D]; [D(a) = 2.1/I3]. Results: A large interindividual pharmacokinetic variability was observed [especially for maximum concentration (C(max)), trough levels, area under the curve (AUC), and hydrazine metabolite production] not only according to the acetylator status as expected, but inside each group as well. The mean D(a) was significantly lower than the mean D in the slow acetylators (2.32 ± 0.78 vs 4.75 ± 0.47 mg/kg; p < 0.00001), while no statistically significant difference was found in the rapid acetylators (4.16 ± 3.07 vs 4.68 ± 0.81 mg/kg; p = 0.53). Conclusion: Our findings suggest that slow acetylators show a mean daily isoniazid exposure (AUC) two-fold higher than rapid acetylators (36.42 ± 11.53 vs 16.50 ± 7.02 mg/L·h; p < 0.0001) when nearly equal isoniazid daily doses are administered (4.75 ± 0.47 vs 4.68 ± 0.81 mg/kg; p = 0.81) and no peculiar pathophysiological conditions affecting isoniazid disposition are present. It might be speculated that slow acetylators may often benefit from reduced doses (< 5 mg/kg), since this strategy could either guarantee efficacy and reach the desired C(max) and C3 levels, or minimise potential toxicity risks lowering isoniazid daily exposure and fluctuations of hydrazine metabolite serum concentrations. However, care should be exercised and therapeutic drug monitoring needs to be performed in all patients, especially when peculiar pathophysiological conditions such its malabsorption - could affect the drug's pharmacokinetics
Isoniazid and its hydrazine metabolite in patients with tuberculosis
No full textObjective: The serum profiles of isoniazid and its hydrazine metabolite were investigated in patients with tuberculosis in steady-state conditions in the hope of identifying a pharmacokinetic approach that could be useful in the clinical assessment of other patients with the same disease state. Patients and Study Design: Isoniazid was coadministered with the other drugs included in the antitubercular regimen (rifampicin, ethambutol, streptomycin, morinamide). Concentrations of isoniazid and its hydrazine metabolite were measured in the collected serum samples by high performance liquid chromato-graphy. The pharmacokinetic parameters of isoniazid were estimated by WINNONLIN. Since an isoniazid serum concentration of 1.5 mg/L 3 hours after (C3) the administration of the dose (D) was demonstrated to be therapeutically efficacious with minimal neurotoxic adverse effects, the theoretical dosage adjustment (D(a)) required to achieve this optimal concentration in all our patients was calculated according to the inactivator index (I3) method proposed by Vivien et al. [I3 = (C) + 0.6)/D]; [D(a) = 2.1/I3]. Results: A large interindividual pharmacokinetic variability was observed [especially for maximum concentration (C(max)), trough levels, area under the curve (AUC), and hydrazine metabolite production] not only according to the acetylator status as expected, but inside each group as well. The mean D(a) was significantly lower than the mean D in the slow acetylators (2.32 ± 0.78 vs 4.75 ± 0.47 mg/kg; p < 0.00001), while no statistically significant difference was found in the rapid acetylators (4.16 ± 3.07 vs 4.68 ± 0.81 mg/kg; p = 0.53). Conclusion: Our findings suggest that slow acetylators show a mean daily isoniazid exposure (AUC) two-fold higher than rapid acetylators (36.42 ± 11.53 vs 16.50 ± 7.02 mg/L·h; p < 0.0001) when nearly equal isoniazid daily doses are administered (4.75 ± 0.47 vs 4.68 ± 0.81 mg/kg; p = 0.81) and no peculiar pathophysiological conditions affecting isoniazid disposition are present. It might be speculated that slow acetylators may often benefit from reduced doses (< 5 mg/kg), since this strategy could either guarantee efficacy and reach the desired C(max) and C3 levels, or minimise potential toxicity risks lowering isoniazid daily exposure and fluctuations of hydrazine metabolite serum concentrations. However, care should be exercised and therapeutic drug monitoring needs to be performed in all patients, especially when peculiar pathophysiological conditions such its malabsorption - could affect the drug's pharmacokinetics
Pharmacokinetic aspects of levofloxacin 500 mg once daily during sequential intravenous/oral therapy in patients with respiratory tract infections
No full textLevofloxacin is considered an effective antibiotic in the treatment of community-acquired lower respiratory tract infections (LRTIs). A study was carried out on 17 in-patients to assess the pharmacokinetics of a 500 mg once-daily switch intravenous (iv)/oral regimen of levofloxacin in the treatment of LRTI patients. Blood samples were collected under steady-state conditions at appropriate intervals. Levofloxacin plasma concentrations were analysed by means of HPLC and pharmacokinetic parameters were estimated using the WinNonlin pharmacokinetic software package. A lower clearance of levofloxacin (<2 mL/min/kg), conditioning both a longer elimination half-life (∼9 h) and a larger AUCO0-τ (∼80 mg/Lh), was observed for both routes in our patients than in healthy volunteers. These differences may be explained considering that levofloxacin is excreted mainly as unchanged drug by the renal route, and most of our patients (71%) were very elderly subjects whose renal function physiologically declines with age. The almost complete (≥99%) absolute oral bioavailability suggests that a comparable exposure to the iv regimen may be achieved after oral administration. The overall clinical success rate was 94.1%
Ciprofloxacin disposition in elderly patients with LRTI being treated with sequential therapy (200 mg intravenously twice daily followed by 500 mg per os twice daily): Comparative pharmacokinetics and the role of therapeutic drug monitoring
No full textCiprofloxacin is a fluoroquinolone antibiotic effective in the treatment of lower respiratory tract infections (LRTI). The aim of this study was to assess the pharmacokinetic appropriateness of a standard switch iv/os regimen of ciprofloxacin (200 mg iv bid for 3 to 5 days followed by 500 mg os bid for 7 to 10 days) frequently used in routine clinical practice in the treatment of elderly patients with mild to moderate LRTI. The pharmacokinetic study was performed on a cohort of 17 elderly inpatients. Blood samples were collected in steady state conditions at appropriate intervals. Ciprofloxacin serum concentrations were analyzed using an HPLC method and pharmacokinetic parameters were estimated using the WinNonlin software package. The pharmacokinetic data were at least partially different from those obtained by other authors in elderly patients (lower C(max) after iv administration and higher CL both after iv and oral administration). C(max) after a 1-hour 200-mg infusion were similar to those observed during the 500 mg bid peroral regimen (2.1 ± 0.9 mg/L vs 2.6 ± 1.0 mg/L; p = 0.054). The absolute oral bioavailability (84.1%) allowed a total body exposure 2.1-fold greater after 500 mg bid oral administration than after 200 mg bid iv administration (AUC(0-τ) 11.4 ± 4.3 mg/L · h vs 5.5 ± 1.8 mg/L · h). The results show that in malabsorption-free elderly patients a regimen of 500 mg os bid may be considered a valid therapeutic approach from the beginning of therapy for mild to moderate LRTI caused by sensitive microrganisms (MIC < 0.1 mg/L). In fact, because the peak serum level to MIC ratio (C(max)/MIC) and the area under the inhibitory serum concentration-time curve (AUIC24 = AUC(24h)/MIC) are actually considered major pharmacodynamic determinants for the outcome of treatment with fluoroquinolones, this regimen could guarantee both a better pharmacokinetic exposure than the 200 mg iv bid regimen and a cost-effective treatment of LRTI. However, because of the great pharmacokinetic interindividual variability observed a normalized dosage per kg (3 mg/kg/12h iv and 8 mg/kg/12h os) should be considered, especially for body weight >90 kg and, whenever possible, TDM of AUC(0-τ) or at least of C(max) should be performed to individualize therapy in this subpopulation
Pharmacokinetic and pharmacodynamic aspects of oral moxifloxacin 400 mg/day in elderly patients with acute exacerbation of chronic bronchitis
No full textObjective: To assess the pharmacokinetic and pharmacodynamic behaviour of Abstract moxifloxacin in 15 consecutive elderly patients with acute exacerbation of chronic bronchitis (AECB) treated with the fixed oral moxifloxacin 400 mg/day regimen with the intent of verifying which degree of exposure may be ensured by this standard regimen against AECB pathogens. Methods: This was an open-label, observational, pharmacokinetic-pharmacodynamic study. Blood samples were collected at steady state at appropriate intervals. Moxifloxacin plasma concentrations were analysed by means of high-performance liquid chromatography. Standard pharmacokinetic parameters and pharmacodynamic determinants (peak concentration [Cmax]/minimum inhibitory concentration [MIC], area under the plasma concentration-time curve during the 24-hour observational period [AUC24]/MIC, pharmacodynamic breakpoints [PDBPs]) were assessed. Results: The mean estimated pharmacokinetic parameters (Cmax 4.40 mg/L at 1.4 hours, AUC24 42.67 mg·h/L, elimination half-life 12.55 hours, total body clearance 0.16 L/h/kg) were generally similar to those observed in both young and elderly historic controls (except for higher-dose normalised Cmax and lower volume of distribution of the central compartment). Median Cmax/MIC and AUC24/MIC ratios for moxifloxacin in the fully assessable cases were, respectively, 67.5 and 823.9 against Streptococcus pneumoniae, 25 and 310.2 against Moraxella catharralis and 416.5 and 3647.5 against Haemophilus influenzae. Mean estimates of PDBP for achieving Cmax/MIC values of 12.2 and AUC24/MIC values of 125 were 0.36 and 0.35 mg/L, respectively. Conclusion: In patients with AECB the pharmacokinetic behaviour of moxifloxacin is not significantly altered by aging processes. This is consistent with moxifloxacin being metabolised mainly by means of phase II hepatic reactions, the activity of which was shown not to decline with age. Both the pharmacokinetic and pharmacodynamic analyses suggest that moxifloxacin 400 mg/day may be a valid therapeutic approach in the treatment of AECB in the elderly. Of note, the unmodified pharmacokinetic behaviour with no need for age-related dosage adjustments combined with the once-daily administration favouring compliance and the low potential for drug-drug pharmacokinetic interactions in case of polytherapy, make moxifloxacin particularly attractive in the treatment of elderly subpopulations at a very high risk of AECB. © 2006 Adis Data Information BV. All rights reserved
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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