bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of two Bayesian approaches to dose‐individualization for once‐daily aminoglycoside regimens
Authors: Duffull S. B. , Kirkpatrick C. M. J. , Begg E. J. 
Published: October 2003

Aims Bayesian dose‐individualization methods have been shown to have good predictive performance using minimal data points, and are now used widely in clinical practice. This study was designed to compare two computerised Bayesian dose‐individualization methods, ABBOTTBASE and SeBA‐GEN, in once‐daily dosing of aminoglycosides. Methods ABBOTTBASE uses the maximum a posteriori estimator (MAP) algorithm which analyses all available serum drug concentration data for individual patients simultaneously, while the prior model remains unchanged. SeBA‐GEN analyses each data set sequentially while continually modifying the individual patient's prior model, allowing within‐patient variability to be modelled. One hundred consecutive patients who received once‐daily dosing of aminoglycosides were prospectively dose‐individualized using either of these methods. Retrospectively the alternative dosing method was used to provide comparative data. The ability of the methods to predict subsequent serum aminoglycoside concentration data was assessed in terms of their predictive performance, bias and precision. Results From the 100 patients, 277 serum aminoglycoside concentrations were available. Ninety‐eight patients had serum concentrations available from the first dose and 55 from the second dose. Gentamicin was used in 96 patients. There was no significant bias when predicting peak concentrations from the prior model using either SeBA‐GEN or ABBOTTBASE. The prior model used by ABBOTTBASE did, however, significantly underpredict the mid‐dose concentration (mean bias=−0.79 mg l−1, 95% Confidence Interval [CI]: −1.3 to −0.3). When using the Bayesian algorithms for prediction of the second set of concentrations neither method was biased when predicting the peak concentration. ABBOTTBASE significantly overpredicted the mid‐dose concentration (mean bias=0.38 mg l−1, 95% CI: 0.03 to 0.74). The prior model used by SeBA‐GEN was more precise at predicting both peak and mid‐dose concentrations (P<0.01), indicating better use of covariates. There was no difference between the methods in terms of estimation of the value of volume of distribution, but they differed significantly in the estimation of clearance (mean difference=0.24 l h−1 for SeBA‐GEN‐ABBOTTBASE, 95% CI: 0.05 to 0.43). Conclusions Bayesian techniques appear to work well with once‐daily aminoglycoside dosing. The method of incorporation of individual patient information into the prior model appears to be important in the optimum choice of the first dose. SeBA‐GEN has an advantage in this and in the lack of bias related to predicting low concentrations compared with ABBOTTBASE.
Non‐linear pharmacokinetics of high‐dose intravenous verapamil
Authors: Toffoli G. , Robieux I. , Fantin D. , Gigante M. , Frustaci S. , Nicolosi G. L. , De Cicco M. , Boiocchi M. 
Published: October 2003

Aims In an attempt to reverse multidrug resistance, in a recent trial of verapamil in association with doxorubicin, we used escalating doses of continuous intravenous (i.v.) verapamil under close haemodynamic monitoring. We report the pharmacokinetics of escalating doses of verapamil. Methods We studied nine patients [
seven males, two females; median age 46 years (range, 31–57)] with advanced adenocarcinoma of the colon and normal renal, hepatic, and cardiac functions. After a loading dose (0.15 mg kg−1 followed by 12 h continuous i.v. infusion at 0.20 mg kg−1 h−1 ), the infusion rate (ko) of verapamil was increased every 24 h (0.25, 0.30, 0.35, and 0.40 mg kg−1 h−1 ). The highest rate was maintained for 48 h. Doxorubicin was given as a continuous i.v. infusion from 12 to 108 h (n=4) or 60 to 108 h (n=5). Blood samples and urine collections were taken every 12 h. Verapamil and nor‐verapamil were assayed by high performance liquid chromatography. We calculated systemic clearance of verapamil (CL=ko/Css ) and renal clearance (CLr) of verapamil and nor‐verapamil. The Cssvs rate relationship was fitted to a Michaelis‐Menten equation: Css=ko(Km+Css )/(V Vm ). Results CL was dose‐dependent and in all nine patients a significant reduction in CL was observed over the dose range (mean CL±s.d. were 0.51±0.31, 0.38±0.16, 0.32±0.18, and 0.27±0.11 l h−1 kg−1, respectively, at 0.25, 0.30, 0.35, and 0.40 mg kg−1 h−1; P=0.0001). Css increased more than proportionally to the dose rate and the Cssvs rate relationship was best defined by a Michaelis‐Menten equation (Km=730 &mu;g l−1; V Vm=0.55 mg kg−1 h−1 ), (r=0.994; P=0.006). CLr of verapamil and nor‐verapamil was not saturable but the contribution to the elimination was only 2 to 4% of the dose. Conclusions These findings suggest a non‐linear, capacity‐limited metabolic clearance of high‐dose verapamil. Using escalating infusion rates, high verapamil concentrations (1500–2500 ng ml−1 ) were achieved without major toxicity. Saturable clearance may cause higher bioavailability and slower elimination of verapamil after acute oral overdoses.
Relative dispersion of intravascular transit times during isolated human limb perfusions for recurrent melanoma
Authors: Roberts Michael S. , Wu Zhen Y. , Rivory Laurent P. , Smithers B. Mark , Egerton William S. , Weiss Michael 
Published: October 2003

Aims We have characterized the relative dispersion of vascular and extravascular markers in the limbs of three patients undergoing isolated limb perfusions with the cytotoxic melphalan for recurrent malignant melanoma both before and after melphalan dosing. Methods A bolus of injectate containing [
51Cr] labelled red blood cells, [14C]‐sucrose and [3H]‐water was injected into an iliac or femoral artery and outflow samples collected at 1 s intervals by a fraction collector. The radioactivity due to each isotype was analysed by either gamma [ 51Cr] or beta [ 14C and 3H] counting. The moments of the outflow fraction‐time profiles were estimated by a nonparametric (numerical integration) method and a parametric model (sum of two inverse Gaussian functions). Results The availability, mean transit time and normalised variance (CV2 ) obtained for labelled red blood cells, sucrose and water were similar before and after melphalan dosing and with the two methods of calculation but varied between the patients. Conclusions The vascular space is not well‐stirred but characterized by a CV2 similar that reported previously for in situ rat hind limb and rat liver perfusions. A flow‐limited blood‐tissue exchange was observed for the permeating indicators. Administration of melphalan did not influence the distribution characteristics of the indicators.
Thiopurine drugs in the treatment of childhood leukaemia: the influence of inherited thiopurine methyltransferase activity on drug metabolism and cytotoxicity
Authors: Lennard L. , Welch J. C. , Lilleyman J. S. 
Published: October 2003

Aims The response to 6‐mercaptopurine (6MP) is highly variable. Its antileukaemic effect can be related to drug derived 6‐thioguanine nucleotides (TGNs). The inherited level of thiopurine methyltransferase (TPMT) activity may be a major factor in the clinical response to 6MP because TPMT forms methylmercaptopurine metabolites (MeMPs) at the expense of TGNs. The aim of this study was to explore the clinical importance of TPMT phenotype. Methods Thiopurine metabolism was studied in a consecutive cohort of children with acute lymphoblastic leukaemia (ALL) treated according to the Medical Research Council trial UK ALL XI. TPMT phenotype was measured in 38 children at diagnosis, and thiopurine metabolites were measured at defined times during 2 years treatment in 29 of these children. Results TPMT activities at diagnosis ranged from 5.5 to 18.5 units ml−1 packed RBCs, no different from the range of activities reported in healthy children. TGNs and MeMPs measured during the first 6MP cycle at 75 mg m−2 ranged from 187 to 594 pmol 6TGNs, median 327, and 0.5 to 22.0 nmol MeMPs, median 4.5, per 8×108 RBCs. TPMT activity was not significantly related to the generation of MeMPs (rs=0.06), but was negatively correlated to 6TGNs (rs=−0.44, P<0.025, n=29). TGNs were related to neutropenia at the point of dose reduction (rs=−0.5, P<0.01). TPMT activity was also inversely related to the duration of cytopenia driven 6MP withdrawal (rs=−0.41, P<0.05). Conclusions These findings support the suggestion that the inherited activity of TPMT in a given individual can modulate the cytotoxic effect of 6MP, and this information may help in clinical management.
Integrated pharmacokinetics and pharmacodynamics of Ro 48–6791, a new benzodiazepine, in comparison with midazolam during first administration to healthy male subjects
Authors: Dingemanse J. , Van Gerven J. M. A. , Schoemaker R. C. , Roncari G. , Oberyé J. J. L. , Van Oostenbruggen M. F. , Massarella J. , Segala P. , Zell M. , Cohen A. F. 
Published: October 2003

Aims This study was performed to investigate the pharmacokinetics and pharmacodynamics of ascending doses of Ro 48–6791, compared with midazolam, in healthy subjects during first administration to man studies. Methods The study was double‐blind and five‐way crossover with treatment on 5 consecutive days (three ascending doses, placebo, fixed midazolam dose) in two sequential groups of five healthy male subjects. Ro 48–6791 was administered as a slow i.v. infusion in doses of 0.1–0.3–1 mg in the first group, and 1–2–3 mg in the second. Midazolam was infused at 0.1 mg kg−1. The infusions were stopped after 20 min or if sedation became too strong for proper performance of the tests. Consequently, infusion rates (mg min−1 ) differed considerably among doses. Blood samples were collected frequently for pharmacokinetic determinations (two‐compartment model). Pharmacodynamics were assessed by recording of saccadic eye movements (saccadic peak velocity) and electroencephalography (&bgr;‐power). These parameters were used for pharmacokinetic/pharmacodynamic modelling. Results Ro 48–6791 and midazolam were both well tolerated. Most clinical events were dose‐dependent central depressant effects. The volume of distribution (Vss ) and plasma clearance of Ro 48–6791 were on average markedly larger than those of midazolam (171±65 vs 41±10 l and 2.2±0.9 vs 0.42±0.11 l min−1, respectively). The doses of Ro 48–6791 leading to loss of saccadic eye movements were on average four times lower than that of midazolam. The corresponding predicted effect compartment concentrations differed by a factor of about six. Doses of Ro 48–6791 and midazolam eliciting similar maximum effects had a comparable onset and duration of action for saccadic peak velocity. Midazolam caused a significantly larger (33%, range 17, 55%) increase in &bgr;‐power than Ro 48–6791 at the highest administered dose. Ro 48–6792, a metabolite of Ro 48–6791, showed a considerably longer half‐life than the parent compound. Although there were no indications of a discernable effect of Ro 48–6792 in the present study, the effects of possible accumulation during prolonged administration should be investigated further. Conclusions This first study with Ro 48–6791 in humans has shown that this benzodiazepine is approximately four to six times as potent as midazolam, but has a comparable onset and duration of action.
Integrated pharmacokinetics and pharmacodynamics of Ro 48–8684, a new benzodiazepine, in comparison with midazolam during first administration to healthy male subjects
Authors: Van Gerven J. M. A. , Roncari G. , Schoemaker R. C. , Massarella J. , Keesmaat P. , Kooyman H. , Heizmann P. , Zell M. , Cohen A. F. , Dingemanse J. 
Published: October 2003

Aims This study aimed to investigate the pharmacodynamics and pharmacokinetics of ascending doses of Ro 48–8684, compared with midazolam, in healthy subjects during first administration to man. Methods The study was double‐blind and five‐way crossover (three ascending doses, placebo, fixed midazolam dose), performed in two groups of five males. Ro 48–8684 was infused in doses of 0.1–0.3–1 mg in the first group, and 1–3–10 mg in the second, with different infusion rates (expressed as mg min−1 ) among doses. Midazolam was infused at 0.1 mg−1 kg. Infusions were stopped after 20 min or if sedation became too strong for proper performance of saccadic eye movements. Pharmacokinetics and pharmacodynamics and their relationships were evaluated as described in the companion article. Results Ro 48–8684 caused dose‐dependent sedation. No serious adverse events occurred. The volume of distribution and clearance of Ro 48–8684 were larger than of midazolam (337±114 vs 50±12 l and 2.4±0.5 vs 0.47±0.11 l min−1, resp). The recovery of saccadic eye movements from equal levels of sedation was on average almost half an hour faster for Ro 48–8684 than for midazolam, with considerable interindividual differences (range 2, 55 min). The doses of Ro 48–8684 leading to the same clinical endpoint as midazolam were comparable, but the corresponding predicted effect compartment concentrations of Ro 48–8684 were on average 2.6 times lower (range 1.5, 4.9 times). The slope of the linear concentration–effect‐relationship for saccadic peak velocity was on average 2.2 times steeper for 10 mg Ro 48–8684 than for midazolam (range 1.3, 3.3). The slope decreased on average 4.4‐fold (range 1.6, 7.3 times), with doses of Ro 48–8684 increasing from 1 to 10 mg. The metabolite Ro 61–2466 had a longer half‐life than the parent compound Ro 48–8684. The influence of this metabolite during prolonged administration should be further investigated. Conclusions These results show that Ro 48–8684 has a considerably shorter duration of action than midazolam. There may be a reduction of sensitivity to Ro 48–8684 with repeated administration of rising doses due to as yet undetermined factors.
Mammary epithelial stem cells: transplantation and self‐renewal analysis
Authors: Smith Gilbert H. , Boulanger Corinne A. 
Published: October 2003

Abstract.  An entire mammary epithelial outgrowth, capable of full secretory differentiation, may be comprised of the progeny of a single cellular antecedent. This conclusion is based upon the maintenance of retroviral insertion sites within the somatic DNA of successive transplant generations derived from a single mammary fragment. In addition, dissociation of these clonal dominant glands and implantation of dispersed cells at limiting dilution demonstrated that both duct‐limited and lobule‐limited outgrowths were developed, as well as complete, fully differentiated glands. Thus, transplantation has revealed three distinct mammary epithelial progenitors in the mouse. Similar studies have extended this observation to rat mammary tissue. Recently, using cre‐lox conditional activation of reporter genes, a new epithelial progenitor, specific for mammary secretory epithelium in postlactation females has been uncovered. In situ, these cells were shown to regenerate secretory lobules upon successive pregnancies. In transplant studies, they demonstrated the capacity for self‐renewal and contributed to the new generation of all of the known epithelial cell types among mammary epithelium. In limiting dilution, the parity‐induced progenitors were capable of engendering lobule‐limited and duct‐limited outgrowths in their entirety, but not completely developed glands. Serial transplant studies indicate that these progenitors have a significant but limited capacity for self‐renewal.
Rhinitis in pre‐school children: prevalence, association with allergic diseases and risk factors
Authors: Peroni D. G. , Piacentini G. L. , Alfonsi L. , Zerman L. , Di Blasi P. , Visona' G. , Nottegar F. , Boner A. L. 
Published: October 2003

SummaryBackground
The aim of our study was to assess the prevalence of rhinitis, sneezing, runny or blocked nose apart from colds in a pre‐school children population and to evaluate the risk factors and relationship with allergic diseases and sensitization.Methods
Eighteen nursery schools were randomly selected. The International Study of Asthma and Allergies in Childhood (ISAAC) written questionnaire (WQ) was distributed and filled by parents of pre‐school children (3–5 years). The allergic sensitization to common aeroallergens and foods was evaluated by skin prick test (SPT). χ2 tests were used to compare proportions between rhinitic and non‐rhinitic children.Results
One thousand four hundred and two (92%) valuable questionnaires were returned. Prevalence of rhinitis in the last 12 months was 16.8%. Rhinitic children compared to non‐rhinitic children presented a significant increase of diagnosed asthma (20.8% vs. 6.2%, P<0.001), lifetime wheezing (43.2% vs. 21.6%, P<0.001), wheezing in the last 12 months (25.0% vs. 9.4%, P<0.001), atopic dermatitis (22.9% vs. 13.9%, P<0.001) and allergic sensitization (29.9% vs. 13.7%, P<0.001). Sensitization to grass pollen and house dust mites were significant risk factors for rhinitis (P<0.01). A family history of atopy, having pets at home, male gender and greater age were significant risk factors for rhinitis, but not smoking exposure, sharing a bedroom or breastfeeding.Conclusions
In pre‐school children rhinitis has a strong association with wheezing symptoms, asthma and atopic dermatitis. Allergic sensitization is a risk factor for rhinitis and should be evaluated even in pre‐school children.
Intake of unsaturated fatty acids and HDL cholesterol levels are associated with manifestations of atopy in adults
Authors: Schäfer T. , Ruhdorfer S. , Weigl L. , Wessner D. , Heinrich J. , Döring A. , Wichmann H.‐E. , Ring J. 
Published: October 2003

SummaryBackground
The increase in allergic diseases is still unexplained. It was hypothesized that the intake of unsaturated fatty acids is a contributing cause of this development. We investigated the relationship between serum cholesterol levels, intake of polyunsaturated fatty acids (PUFA) and manifestations of atopy in a population‐based setting.Methods
A nested case–control study was performed within the population of the 3rd MONICA survey in Augsburg (Germany). The serum levels of total, high‐density lipoprotein (HDL) and low‐density lipoprotein (LDL) cholesterol of 1537 adults (aged 28–78 years, response 61.4%) and the estimated intake of PUFA in a subset of 139 men were compared with the frequency of a doctor's diagnosis of asthma, allergic rhinoconjunctivitis (AR), atopic eczema (AE) and allergic sensitization as measured by skin prick and Radio Allergo Sorbent Test.Findings
In bivariate analyses, we obtained a negative linear association between total and LDL cholesterol levels and the frequency of AR and sensitization, which was no longer significant after adjustment for important confounders. In contrast, positive linear associations were found between HDL cholesterol levels and AR and AE and, furthermore, between the intake of PUFA and allergic sensitization in men (P<0.01). After adjustment, an increasing risk for atopic diseases with increasing levels of HDL cholesterol and an increasing risk for allergic sensitization with increasing intakes of PUFA remained statistically significant.Interpretation
There is indication that HDL cholesterol also plays a role in the complex interaction of fat intake, metabolism and the manifestation of atopy in adults. These findings may contribute to the understanding of time trends and regional differences of allergies.
Changes in body composition in men and women with advanced nonsmall cell lung cancer (NSCLC) undergoing chemotherapy
Authors: Harvie M. N. , Campbell I. T. , Thatcher N. , Baildam A. 
Published: October 2003

AbstractBackground  Men with nonsmall cell lung cancer (NSCLC) are more susceptible to weight loss than women. The composition and aetiology of these gender specific weight changes are not known.Methods  Measurements of body mass, body composition and energy balance (resting energy expenditure and energy intake) were made in 15 men and six women before and after chemotherapy for NSCLC.Results  Over the course of chemotherapy minimal weight change was observed in both men and women. Men increased body fat from 25.0 ± 5.5 to 27.9 ± 7.9% (P < 0.05) whereas fat free mass (FFM) tended to decrease (P = 0.063). There was no change in body fat or FFM in the women. In the men resting energy expenditure decreased over the course of chemotherapy from 113.2 ± 15.9 to 105.1 ± 10.1% of the value predicted from the Harris Benedict equation (P < 0.05). In the women resting energy expenditure (REE) did not alter.Conclusion  Over the course of chemotherapy for NSCLC, men and women appear to have different patterns of change in body composition and in energy expenditure.
Disparities in food habits in Europe: systematic review of educational and occupational differences in the intake of fat
Authors: López‐Azpiazu I. , Sánchez‐Villegas A. , Johansson L. , Petkeviciene J. , Prättälä R. , Martínez‐González M. A. ,   for the FAIR‐97‐3096 Project
Published: October 2003

AbstractBackground A higher socio‐economic level is associated with healthier dietary habits. Nevertheless, socio‐economic differences in the intake of fat have not consistently been reported in Europe. The objective of our study was to systematically assess differences in total fat (TF) intake and saturated fat (SF) intake across social groups.Methods Representative samples from nine European countries were used to perform a meta‐analysis of surveys between 1985–1999, including both published and nonpublished results.Results Because important heterogeneity was found and the estimates for TF from Spain and Estonia were different from all others, we calculated the differences in intake excluding these two countries. We found a lower TF intake in the highest (versus the lowest) occupational level both for men (difference: −1.1% of total energy intake; 95% CI: −1.3 to −0.8%) and women (difference: −0.9%; 95% CI: −1.2 to −0.6%) when Estonia and Spain were excluded.Conclusion European surveys indicate that people in the lowest category of occupation consume more fat and SF than people in the highest category.