6,262 research outputs found
Theoretical studies on thiophene based alternating donor-acceptor conjugated polymers and their model compounds
No full textIncreased PAI-1 plasma levels and risk of death from dengue: no association with the 4G/5G promoter polymorphism
Full text linkBackground: Dengue virus infected patients have high plasminogen activator inhibitor type I (PAI-1) plasma concentrations. Whether the insertion/deletion (4G/5G) polymorphism in the promotor region of the PAI-1 gene is associated with increased PAI-1 plasma concentrations and with death from dengue is unknown. We, therefore, investigated the relationship between the 4G/5G polymorphism and PAI-1 plasma concentrations in dengue patients and risk of death from dengue.
Methods: A total of 194 patients admitted to the Dr. Kariadi Hospital in Semarang, Indonesia, with clinical suspected severe dengue virus infection were enrolled. Blood samples were obtained on day of admission, days 1, 2 and 7 after admission and at a 1-month follow-up visit. Plasma concentrations of PAI-1 were measured using a sandwich ELISA kit. The PAI-1 4G/5G polymorphism was typed by allele-specific PCR analysis.
Results: Concentrations of PAI-1 on admission and peak values of PAI-1 during admission were higher than the values measured in healthy controls. Survival was significantly worse in patients with PAI-1 concentrations in the highest tertile (at admission: OR 4.7 [95% CI 0.9–23.8], peak value during admission: OR 6.3 [95%CI 1.3–30.8]). No association was found between the PAI-1 4G/5G polymorphism, and PAI-1 plasma concentrations, dengue disease severity and mortality from dengue.
Conclusion: These data suggest that the 4G/5G polymorphism has no significant influence on PAI-1 concentrations in dengue virus infected patients and is not associated with the risk of death from dengue. Other factors contributing to the variability of PAI-1 plasma concentrations in patients with dengue need to be explored
Doxorubicin delivery by polyamidoamine dendrimer conjugation and photochemical internalization for cancer therapy.
No full textEnhanced cytotoxicity of saporin by polyamidoamine dendrimer conjugation and photochemical internalization
No full textPharmacokinetics and Pharmacodynamics of Continuous Infusion Meropenem in Overweight, Obese, and Morbidly Obese Patients with Stable and Unstable Kidney Function: A Step Toward Dose Optimization for the Treatment of Severe Gram-Negative Bacterial Infections
No full textBACKGROUND:
Meropenem is an anti-Gram-negative antimicrobial, the time-dependent activity of which may be maximized through administration by continuous infusion.
OBJECTIVES:
The objectives of this study were to characterize the pharmacokinetics of continuous infusion meropenem in relation to body size and Cockcroft-Gault estimated creatinine clearance (CLCR) in overweight and obese patients with stable and unstable kidney function with the intent of creating a nomogram for optimal dosing.
PATIENTS AND METHODS:
Patients from a single institution with a body mass index ≥25 kg/m(2) receiving meropenem by continuous infusion with measurement of meropenem steady-state concentrations (C ss) were identified. Individual Bayesian estimates of meropenem volume of distribution of the central compartment (V c) and clearance (CL) were calculated and relationships to body size descriptors and CLCR estimated using these body size descriptors were defined by regression. Kidney function stability was defined based on median absolute deviation, stratification by the ratio of maximum to minimum serum creatinine (SCr) and individual patient-level regression of SCr over time. The influence of kidney function stability on meropenem CL estimation by CLCR was tested.
RESULTS:
A total of 375 patients (77.9 % male) with 846 C ss values (62.4 % of patients with ≥2 measurements) were identified. The median daily dose of meropenem and frequency of infusion bag changes were 2000 mg/day and four times per day, respectively. The meropenem C ss values were ≥16, ≥8, ≥4, and ≥2 mg/L for 41.1, 76.1, 97.4, and 99.9 % of observations, respectively. The median (range) age, weight, and BMI were 66 (24-90) years, 90 (70-250) kg, and 30.8 (25.1-81.6) kg/m(2), respectively. The mean [standard deviation (SD)] serum creatinine at baseline was 1.57 (1.37) mg/dL. The mean (SD) V c was 28.1 (1.36) L and not related to body size, while CL was 8.85 (6.40) L/h and best related to CLCR estimated using adjusted body weight (ABW). The meropenem CL to CLCR relationship was not significantly impacted by the presence or absence of kidney function stability. The user-friendly dosing nomogram based on CLCR estimated using ABW showed that optimal drug exposure [Css ≥ minimum inhibitory concentration (MIC)] may be obtained even against multi-drug resistant (MDR) pathogens when considering dosages up to 1250 mg every 6 h by continuous infusion.
CONCLUSIONS:
Meropenem CL is best estimated using CLCR with ABW in patients with a BMI ≥25 kg/m(2) and this relationship is not altered by unstable kidney function. Application of our dosing nomogram may improve the care of overweight and obese patients with severe MDR Gram-negative infections treated with meropenem by continuous infusion
Considerations for higher doses of daptomycin in critically ill patients with methicillin-resistant Staphylococcus aureus bacteremia.
No full textBackground. Higher daptomycin doses are advocated for select methicillin-resistant Staphylococcus aureus (MRSA)-related infections, but the probabilities of target attainment (PTA) and toxicity of these doses have not been characterized in critically ill patients. Methods. We evaluated the plasma pharmacokinetics (PK) and clinical outcomes of a cohort of critically ill patients treated with daptomycin 6-8 mg/kg/day for primarily Staphylococcus species-related infections. Daptomycin concentrations were measured intensively over the initial 96-hour dosing period. Data were modeled by population PK analyses, and Monte Carlo simulation was used to estimate the probabilities of effect and toxicity with standard and alternate dosing regimens. Results. Fifty patients with a mean (SD) age of 69.7 (12.2) years, weight 74.5 (20.3) kg, and creatinine clearance 56.8 (38.2) mL/minute were enrolled with measurements of 12 (2.2) daptomycin samples per patient. Significantly lower daptomycin exposures were observed despite comparable doses in a subset of patients (n = 13) with augmented clearance (CL). No covariates of CL were identified, but this subset was significantly more likely to be in severe sepsis or septic shock, have higher Sequential Organ Failure Assessment scores, and MRSA bacteremia. In-hospital mortality was significantly higher (30.7% vs 10.8%) in patients with augmented daptomycin CL. Use of an empiric fixed dose of 750 mg of daptomycin is predicted to achieve a comparable PTA with a lower probability of toxicity as compared to the use of 10 mg/kg in critically ill patients. Conclusions. A reappraisal of current daptomycin dosing recommendations is needed to improve the PTA and reduce toxicity among critically ill patients. © The Author 2013.BACKGROUND:
Higher daptomycin doses are advocated for select methicillin-resistant Staphylococcus aureus (MRSA)-related infections, but the probabilities of target attainment (PTA) and toxicity of these doses have not been characterized in critically ill patients.
METHODS:
We evaluated the plasma pharmacokinetics (PK) and clinical outcomes of a cohort of critically ill patients treated with daptomycin 6-8 mg/kg/day for primarily Staphylococcus species-related infections. Daptomycin concentrations were measured intensively over the initial 96-hour dosing period. Data were modeled by population PK analyses, and Monte Carlo simulation was used to estimate the probabilities of effect and toxicity with standard and alternate dosing regimens.
RESULTS:
Fifty patients with a mean (SD) age of 69.7 (12.2) years, weight 74.5 (20.3) kg, and creatinine clearance 56.8 (38.2) mL/minute were enrolled with measurements of 12 (2.2) daptomycin samples per patient. Significantly lower daptomycin exposures were observed despite comparable doses in a subset of patients (n = 13) with augmented clearance (CL). No covariates of CL were identified, but this subset was significantly more likely to be in severe sepsis or septic shock, have higher Sequential Organ Failure Assessment scores, and MRSA bacteremia. In-hospital mortality was significantly higher (30.7% vs 10.8%) in patients with augmented daptomycin CL. Use of an empiric fixed dose of 750 mg of daptomycin is predicted to achieve a comparable PTA with a lower probability of toxicity as compared to the use of 10 mg/kg in critically ill patients.
CONCLUSIONS:
A reappraisal of current daptomycin dosing recommendations is needed to improve the PTA and reduce toxicity among critically ill patients
ESTIMATING CALORIC EXPENDITURE USING THE PHYSICAL ACTIVITY INDEX (PAI) IN CHILDREN AND ADOLESCENTS PERFORMING A MULTISTAGE MAXIMAL EXERCISE TEST
Full text linkPURPOSE: The primary purposes of this investigation were (a) to examine the validity of the PAI, (b) to develop a statistical model to predict cumulative Kcal expenditure using PAI as the predictor variable and (c) to develop a statistical model to predict total Kcal expenditure using PAItotal and selected physiological and behavioral measures as the predictor variables for children and adolescents performing load incremented maximal treadmill exercise. The secondary purpose of the study was to develop a prediction model to estimate total Kcal expenditure using the PAI (session) alone and in combination with selected physiological measures as the predictor variables. METHODS: Eighty-four children and adolescents (12.5±2.4 yrs) performed a maximal Bruce treadmill (TM) protocol. During TM, heart rate (HR), oxygen consumption (VO2), rating of perceived exertion (RPE-overall), pedometer step count, and Kcal expenditure were measured. Post-TM, RPE-session was obtained and a physical activity questionnaire administered. The PAI, PAItotal, and PAI (session) were calculated as:
PAI = Cumulative step count x RPE-overall
PAItotal = Total step count x RPE-overall at test termination
PAI (session) = Total step count x RPE-session
RESULTS: Multiple regression analyses revealed a strong, positive relation between the PAI score and VO2 in L.min-1(r=0.607, p<0.05), VO2 in mL.kg-1.min-1 (r=0.725, p<0.05) and HR in beats.min-1 (r=0.755, p<0.05). These findings established a high level of concurrent validity for the PAI. The following models to predict Kcal expenditure were developed:
Model I : Cumulative Kcal = 21.632 + 0.006(PAI) p<0.05, SEE=17.59, r=0.74, r2=0.54.
Model II : Total Kcal = -11.59+0.002(PAItotal)+27.245(VO2max) p<0.05, SEE=15.37, r=0.86, r2=0.739.
Model V : Total Kcal = 38.6 + 0.004(PAIsession), p<0.05, SEE=24.23, r=0.36, r2=0.13.
Model VI : Total Kcal = -64.759+26.998(VO2max)+0.305(HRmax)+0.001 (PAIsession) p<0.05, SEE=10.46, r = 0.918 , r2 = 0.842.
In comparison to the PAI (session), PAI was a stronger predictor of Kcal expenditure during a load incremented treadmill protocol in a sample of children and adolescents. CONCLUSIONS: The PAI has public health implications, provides an easy tool to estimate total physical activity load (i.e. volume x intensity) and predicts Kcal expenditure in children and adolescents performing standard treadmill exercise protocols. Generalizability of findings is limited to healthy children and adolescents performing load incremented maximal treadmill exercise
Levofloxacin dosing regimen in severely morbidly obese patients (BMI ≥40 kg/m2) should be guided by creatinine clearance estimates based on ideal body weight and optimized by therapeutic drug monitoring
No full textBACKGROUND:
Levofloxacin is a commonly prescribed antimicrobial where recommendations exist to reduce doses for renal impairment but not to increase doses for augmented renal function. Morbidly obese patients are increasing in prevalence, and represent a population that can have augmented renal function requiring higher-than-standard doses.
OBJECTIVE:
The current investigation was performed to characterize the pharmacokinetics (PK) and evaluate the influence of alternate body size descriptors and renal function as predictors of levofloxacin clearance (CL) and the area under the curve over 24 h (AUC24).
METHODS:
A database of patients undergoing levofloxacin therapeutic drug monitoring (TDM) were queried to identify patients ≥18 years of age with a body mass index ≥40 kg/m(2). A maximum a posteriori probability Bayesian approach using a two-compartment linear PK model was used to estimate individual PK parameters and AUC24.
RESULTS:
A total of 394 concentration-time data points (peaks and trough) from 68 patients between 98 and 250 kg were evaluated. The median (5th, 95th percentile) daily dose and AUC24 was 1,000 (250, 1,500) mg and 90.7 (44.4, 228) mg·h/L, respectively. Levofloxacin CL was significantly (p 90 % probability of achieving an AUC24 of 50-150 mg·h/L in morbidly obese patients. Subsequent application of TDM and integration with pathogen-specific information could then be applied to tailor the levofloxacin regimen.
CONCLUSIONS:
The proposed approach serves as a relevant alternative to the current fixed-dosing paradigm of levofloxacin in the morbidly obese
Open access self-archiving: An author study
No full textThis, our second author international, cross-disciplinary study on open access had 1296 respondents. Its focus was on self-archiving. Almost half (49%) of the respondent population have self-archived at least one article during the last three years. Use of institutional repositories for this purpose has doubled and usage has increased by almost 60% for subject-based repositories. Self-archiving activity is greatest amongst those who publish the largest number of papers. There is still a substantial proportion of authors unaware of the possibility of providing open access to their work by self-archiving. Of the authors who have not yet self-archived any articles, 71% remain unaware of the option. With 49% of the author population having self-archived in some way, this means that 36% of the total author population (71% of the remaining 51%), has not yet been appraised of this way of providing open access. Authors have frequently expressed reluctance to self-archive because of the perceived time required and possible technical difficulties in carrying out this activity, yet findings here show that only 20% of authors found some degree of difficulty with the first act of depositing an article in a repository, and that this dropped to 9% for subsequent deposits. Another author worry is about infringing agreed copyright agreements with publishers, yet only 10% of authors currently know of the SHERPA/RoMEO list of publisher permissions policies with respect to self-archiving, where clear guidance as to what a publisher permits is provided. Where it is not known if permission is required, however, authors are not seeking it and are self-archiving without it. Communicating their results to peers remains the primary reason for scholars publishing their work; in other words,
researchers publish to have an impact on their field. The vast majority of authors (81%) would willingly comply with a mandate from their employer or research funder to deposit copies of their articles in an institutional or subject-based repository. A further 13% would comply reluctantly; 5% would not comply with such a mandate
Atypical findings in three patients with Pai syndrome and literature review
No full textPai syndrome is a rare disorder characterized by congenital nasal or facial polyp, midline cleft lip, pericallosal lipoma, ocular anomalies, and normal neuropsychological development. Here, we report on three patients with Pai syndrome and atypical findings: temporal triangular alopecia, posterior lenticonus, bilateral palatal pits, bifid uvula, hypospadias, sacral dimple, true tracheal bronchus, and epilepsy. Thirty-three cases of Pai syndrome have been described so far. We present a review of the previously reported cases and suggest modified diagnostic criteria for Pai syndrome. © 2012 Wiley Periodicals, Inc.sponsorship: Grant sponsor: Fonds Marguerite-Marie Delacroix. (Fonds Marguerite-Marie Delacroix, National Institute for Health Research|CL-2010-01-002)status: Publishe
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