38 research outputs found
Population pharmacokinetics of apramycin from first-in-human plasma and urine data to support prediction of efficacious dose
BACKGROUND: Apramycin is under development for human use as EBL-1003, a crystalline free base of apramycin, in face of increasing incidence of multidrug-resistant bacteria. Both toxicity and cross-resistance, commonly seen for other aminoglycosides, appear relatively low owing to its distinct chemical structure.
OBJECTIVES: To perform a population pharmacokinetic (PPK) analysis and predict an efficacious dose based on data from a first-in-human Phase I trial.
METHODS: The drug was administered intravenously over 30â
min in five ascending-dose groups ranging from 0.3 to 30â
mg/kg. Plasma and urine samples were collected from 30 healthy volunteers. PPK model development was performed stepwise and the final model was used for PTA analysis.
RESULTS: A mammillary four-compartment PPK model, with linear elimination and a renal fractional excretion of 90%, described the data. Apramycin clearance was proportional to the absolute estimated glomerular filtration rate (eGFR). All fixed effect parameters were allometrically scaled to total body weight (TBW). Clearance and steady-state volume of distribution were estimated to 5.5â
L/h and 16â
L, respectively, for a typical individual with absolute eGFR of 124â
mL/min and TBW of 70â
kg. PTA analyses demonstrated that the anticipated efficacious dose (30â
mg/kg daily, 30â
min intravenous infusion) reaches a probability of 96.4% for a free AUC/MIC target of 40, given an MIC of 8â
mg/L, in a virtual Phase II patient population with an absolute eGFR extrapolated to 80â
mL/min.
CONCLUSIONS: The results support further Phase II clinical trials with apramycin at an anticipated efficacious dose of 30â
mg/kg once daily
Metabolism of Low-Dose Inorganic Arsenic in a Central European Population: Influence of Sex and Genetic Polymorphisms
BACKGROUND: There is a wide variation in susceptibility to health effects of arsenic, which, in part, may be due to differences in arsenic metabolism. Arsenic is metabolized by reduction and methylation reactions, catalyzed by reductases and methyltransferases. OBJECTIVES: Our goal in this study was to elucidate the influence of various demographic and genetic factors on the metabolism of arsenic. METHODS: We studied 415 individuals from Hungary, Romania, and Slovakia by measuring arsenic metabolites in urine using liquid chromatography with hydride generation and inductively coupled plasma mass spectrometry (HPLC-HG-ICPMS). We performed genotyping of arsenic (+III) methyltransferase (AS3MT), glutathione S-transferase omega 1 (GSTO1), and methylene-tetrahydrofolate reductase (MTHFR). RESULTS: The results show that the M287T (T-->C) polymorphism in the AS3MT gene, the A222V (C-->T) polymorphism in the MTHFR gene, body mass index, and sex are major factors that influence arsenic metabolism in this population, with a median of 8.0 microg/L arsenic in urine. Females C) polymorphism in the AS3MT gene on the methylation capacity was much more pronounced in men than in women. CONCLUSIONS: The factors investigated explained almost 20% of the variation seen in the metabolism of arsenic among men and only around 4% of the variation among women. The rest of the variation is probably explained by other methyltransferases backing up the methylation of arsenic
Impact of Smoking and Chewing Tobacco on Arsenic-Induced Skin Lesions
BACKGROUND: We recently reported that the main reason for the documented higher prevalence of arsenic-related skin lesions among men than among women is the result of less efficient arsenic metabolism. OBJECTIVE: Because smoking has been associated with less efficient arsenic methylation, we aimed to elucidate interactions between tobacco use and arsenic metabolism for the risk of developing skin lesions. METHODS: We used a population-based case-referent study that showed increased risk for skin lesions in relation to chronic arsenic exposure via drinking water in Bangladesh and randomly selected 526 of the referents (random sample of inhabitants > 4 years old; 47% male) and all 504 cases (54% male) with arsenic-related skin lesions to measure arsenic metabolites [methylarsonic acid (MA) and dimethylarsinic acid (DMA)] in urine using high-performance liquid chromatography (HPLC) and inductively coupled plasma mass spectrometry (ICPMS). RESULTS: The odds ratio for skin lesions was almost three times higher in the highest tertile of urinary %MA than in the lowest tertile. Men who smoked cigarettes and bidis (locally produced cigarettes; 33% of referents, 58% of cases) had a significantly higher risk for skin lesions than did nonsmoking men; this association decreased slightly after accounting for arsenic metabolism. Only two women smoked, but women who chewed tobacco (21% of referents, 43% of cases) had a considerably higher risk of skin lesions than did women who did not use tobacco. The odds ratio (OR) for women who chewed tobacco and who had < or = 7.9%MA was 3.8 [95% confidence interval (CI), 1.4-10] compared with women in the same MA tertile who did not use tobacco. In the highest tertile of %MA or %inorganic arsenic (iAs), women who chewed tobacco had ORs of 7.3 and 7.5, respectively, compared with women in the lowest tertiles who did not use tobacco. CONCLUSION: The increased risk of arsenic-related skin lesions in male smokers compared with nonsmokers appears to be partly explained by impaired arsenic methylation, while there seemed to be an excess risk due to interaction between chewing tobacco and arsenic metabolism in women
Recommended from our members
Sexual (Dis)satisfaction and Its Contributors Among People Living with HIV Infection in Sweden
Earlier research reports lower sexual satisfaction among people living with HIV (PLHIV) compared to HIV-negative persons. A number of psychosocial factors directly associated with sexual dissatisfaction have been identified. Little is known about sexual satisfaction and their contributors among PLHIV in Sweden. The aim of this study was to examine direct and indirect effects of variables within sociodemographic, clinical HIV-related, psychological, and sexual domains on sexual(dis)satisfaction among PLHIV in Sweden. Data for this study was derived from a national representative, anonymous survey among PLHIV conducted in 2014 (n=1096). Statistical analysis included four steps: descriptive analyses, identification of variables associated with sexual (dis)satisfaction, identification of variables associated with those contributors of sexual (dis)satisfaction, and a path model integrating all these analyses. A total of 49% of participants reported being sexually dissatisfied and no significant differences were observed when non-heterosexual men, heterosexual men and women were compared. Among women, a negative change in sex life after HIV diagnosis and distress with orgasmic difficulties were directly associated with sexual dissatisfaction. For men, hopelessness, high HIV stigma, sexual inactivity in the last 6 months, and a negative change in sex life after HIV diagnosis were directly associated with sexual dissatisfaction. Path analyses showed in both men and women significant indirect association between not being involved in an intimate relationship, lower self-reported CD4 cell counts, and perceiving obligation to disclose HIV status to sexual partners as a barrier to look for a long-term partner and sexual dissatisfaction. Our results show that despite good treatment outcomes, the HIV diagnosis has a negative bearing on sexual satisfaction. The need for gender-tailored interventions and clinical implications of these findings are discussed
Implementing a critical gender perspective in art history/visual culture
Based on the assumption that female studentsâ academic careers in particular are disadvantaged by canonical art history teaching, the projectâs chief goal was to launch strategies for the implementation of critical gender perspectives in all undergraduate courses in the division of Art History and Visual Studies, Lund University, 2004-2006. These strategies included teaching practices derived from Lindberg (1988) and Wahl (1996); the introduction and implementation of an annual Gender Marathon Day open to the whole department; student involvement in the educational process as well as project management; and fundamental issues, such as collaboration among instructors, including examinations. Advantages to both male and female students included increased professional competence regarding the contemporary as well as the historical art world
Hur barn beter sig i konflikter
Abstract
Titel: Hur barn beter sig i konflikter
Författare: Fristedt, Anna-Lena & Lindberg, Annika
Fristedt, Anna-Lena & Lindberg, Annika (2008). Hur barn beter sig i konflikter. (How children react in a conflict). Malmö: LÀrarutbildningen, Malmö Högskola.
Syftet med studien Àr att undersöka om yngre skolbarns konfliktbeteende förÀndras samt om de Àr medvetna om sitt eget beteende i en konflikt. Vi har studerat konfliktbeteendet genom att intervjua elever och pedagoger.
För att svara pĂ„ den frĂ„gan har vi intervjuat elever om hur de sjĂ€lva anser att de reagerar i en konflikt, samt pedagoger som har haft ansvar för eleverna frĂ„n 2004 - 2007. Vi har under en treĂ„rsperiod trĂ€ffat eleverna under vĂ„r verksamhetesförlagda tid. VĂ„r undersökning utfördes pĂ„ tvĂ„ f â 9 skolor. Intervjuerna genomfördes med elever i skolĂ„r tvĂ„ respektive tre om hur de sjĂ€lva ser pĂ„ konflikter. DĂ€refter valdes tre elever ut frĂ„n vardera skolĂ„r. Valet föll pĂ„ de elever som vi ansĂ„g gav de mest uttömmande och intressanta svaren. PĂ„ skola 1 intervjuade vi förskollĂ€rare pĂ„ elevernas tidigare förskola, förskollĂ€rare i förskoleklass, nuvarande lĂ€rare samt fritidspedagog. PĂ„ skola 2 intervjuades tvĂ„ förskollĂ€rare i förskoleklassen, en förskollĂ€rare som arbetar med eleverna pĂ„ fritids och i idrott samt elevernas nuvarande lĂ€rare. Vi har i vĂ„rt arbete valt en kvalitativ studie genom att anvĂ€nda intervjuer som en metod. I vĂ„r analys har vi tolkat vĂ„rt material med den sociokulturella teorin som utgĂ„ngspunkt. Vi har sammanstĂ€llt en del av det empiriska datamaterialet i schema för att fĂ„ bĂ€ttre översikt, som vi dĂ€refter analyserat. Vi Ă„terger ocksĂ„ pedagogernas svar och analyserar detta. VĂ„r undersökning visar att elevers beteende i en konflikt kan vara förĂ€nderligt och att yttre pĂ„verkan som t.ex. den fysiska miljön och de olika pedagogernas personlighet pĂ„verkar eleverna