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PubMed1991

Microcalorimetric investigation of the complexation between 2-hydroxypropyl-beta-cyclodextrin and amine drugs with the diphenylmethyl functionality.

Solution calorimetry has been employed to evaluate the stability constants and standard-enthalpy changes (delta H degrees) associated with complex formation between 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and a group of amine compounds having the diphenylmethyl functionality in aqueous solution at 298.15 K. Data from microcalorimetric titrations of the compounds were analysed using a nonlinear least-squares method. Of the 12 compounds studied, only terfenadine.HCl formed a 1:2 (compound:HP-beta-CD) complex. All the others formed 1:1 complexes. The standard free energy decrease accompanying the formation of inclusion complexes is generally due to a negative delta H degrees. This exothermic delta H degrees can be interpreted as indicating that the binding forces for complexation include both the hydrophobic effect and strong van der Waals interactions. When a halogen substituent is in the aromatic ring, stability constants are higher and standard-entropy changes (delta S degrees) become positive, suggesting greater hydrophobic interaction. Both adiphenine.HCl and proadifen.HCl form more stable complexes, suggesting that hydrogen bonding to the carbonyl oxygen by the hydroxyl-group on the rim of the CD ring could be an important contributor to the complexation. Substitution on the aliphatic carbon of the diphenylmethyl group was also found to be important in determining the ability of compounds to bind with HP-beta-CD. The independence of the thermodynamic constants on the degree of protonation in the case of bifunctional amines indicates that the amine functional groups do not penetrate into the HP-beta-CD cavity.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed2005

Non-invasive detection of prostate cancer by electromagnetic interaction.

OBJECTIVES: Malignant and normal tissues are known to have different electromagnetic properties, and various attempts have been made to use these information for diagnostic purposes. A nonlinear tuneable oscillator (Trimprob) generating extremely low energy multiple electromagnetic fields has been developed for non-invasive analysis of electromagnetic anisotropy in humans. Objective of this study was to evaluate the feasibility of prostate cancer detection using the TRIMprob and to evaluate its diagnostic accuracy. METHODS: 757 men were evaluated with the TRIMprob between July 2002 and May 2003 in a prostate unit. The TRIMprob was moved over the surface of the patient's perineum while standing, normally dressed, in front of the system receiver. A single operator, blinded to the patient status, conducted the tests. Nonlinear resonance was analysed at 465, 930 and 1395 MHz. RESULTS: Analysis of resonance values at 465 MHz showed a significant difference between controls, patients with benign prostatic hyperplasia and patients with prostate cancer. In our study population, a sensitivity of 95.5% and specificity of 42.7% for the diagnosis of prostate cancer with a positive and negative predictive value of 63.6% and 89.8% was found. CONCLUSIONS: The results of this study confirm the possibility of electromagnetic detection of cancer. An extracorporeal scan by the TRIMprob can identify patients at risk for prostate cancer, and recognise those in whom the risk is extremely low. The results of the present study represent a proof-of-concept, which may open a new field of medicine.

Electromagnetic Phenomena↗

PubMed2006

Prediction of strength and strain of the proximal femur by a CT-based finite element method.

Hip fractures are the most serious complication of osteoporosis and have been recognized as a major public health problem. In elderly persons, hip fractures occur as a result of increased fragility of the proximal femur due to osteoporosis. It is essential to precisely quantify the strength of the proximal femur in order to estimate the fracture risk and plan preventive interventions. CT-based finite element analysis could possibly achieve precise assessment of the strength of the proximal femur. The purpose of this study was to create a simulation model that could accurately predict the strength and surface strains of the proximal femur using a CT-based finite element method and to verify the accuracy of our model by load testing using fresh frozen cadaver specimens. Eleven right femora were collected. The axial CT scans of the proximal femora were obtained with a calibration phantom, from which the 3D finite element models were constructed. Materially nonlinear finite element analyses were performed. The yield and fracture loads were calculated, while the sites where elements failed and the distributions of the principal strains were determined. The strain gauges were attached to the proximal femoral surfaces. A quasi-static compression test of each femur was conducted. The yield loads, fracture loads and principal strains of the prediction significantly correlated with those measured (r=0.941, 0.979, 0.963). Finite element analysis showed that the solid elements and shell elements in undergoing compressive failure were at the same subcapital region as the experimental fracture site.

Adult↗

PubMed1988

Analysis of steric partition behavior of molecules in membranes using statistical physics. Application to gel chromatography and electrophoresis.

The principles of statistical physics are used to formulate general expressions for the steric partition behavior of molecules in both random and ordered membrane structures that may be applied to any shape of the solute and/or the volume-excluding element of the membrane. These expressions fully define partitioning in terms of the volume excluded to point molecules and to finite-sized molecules. The mean effective exclusion volume for a molecule is calculated as a function of a global interaction energy, which varies with position, conformation, and orientation of the molecule. It allows consideration of electrostatic and other nonsteric factors. To test the model, specific partition functions are derived for several simple geometries describing the membrane and solute. Frequently, the derived expressions agree with past analyses; however, a new expression describing partitioning within an random network of fibers is derived. It agrees with past results only in the limit of low exclusion volumes. With greater volume exclusions, past results greatly overestimate the partition function. It is applied to gel electrophoresis and chromatography and survives testing with available experimental data. Unlike past analyses, it predicts nonlinear Ferguson plots for agarose gel electrophoresis. In addition, an analytical expression predicting the minimum radius of a sphere excluded from a random fiber matrix is derived, tested, and found to agree with experimental data.

Chromatography, Gel↗

PubMed1997

A meta-analysis of 61 sperm count studies revisited.

OBJECTIVE: To re-examine data on sperm counts over time from 61 studies from around the world. DESIGN: Parametric analyses and flexible nonlinear models of the relation between sperm counts and time. MAIN OUTCOME MEASURE(S): Mean sperm concentrations per milliliter and regression coefficients for possible trends of concentrations over time. RESULT(S): A significant decline was found only in U.S. studies. CONCLUSION(S): Studies from specific sites have found declines in sperm counts, but a world-wide decline has not been demonstrated. Rigorous assessment of statistical models should be done before conclusions are drawn. Flexible smoothing models are a useful addition to currently available analytic methods.

Global Health↗

PubMed1997

Stress analysis of halo pin insertion by non-linear finite element modeling.

Halo fixation is associated with a high complication rate. The most common complications are loose pins and pin site infections believed to be exacerbated by loose pins. Although pin designs and the technique of pin insertion have changed little in over 30 years, the pin/skull mechanics are poorly understood. Halo pin insertion was modeled using nonlinear finite element analyses to determine the stress distribution in the human skull underlying and surrounding the point of pin fixation. Model validity was established by comparing pin insertion depth and the profile of the hole generated in the bone to the results of experimental mechanical tests. The region surrounding the pin tip within 1 mm was found to undergo plastic deformation and compressive loading in excess of the compressive yield strength of cortical bone. The implication is that damaged bone in this region is responsible for the high incidence of halo pin loosening. Resorption or migration of bone particles with periodic relief of compression in this region due to daily cyclic forces might result in an enlarged pin site and eventually, a loose pin.

Bone Nails↗

PubMed2002

Kinetics of the IgG antibody response to pertussis toxin after infection with B. pertussis.

We aimed to provide a quantitative description of decay in pertussis antibody levels to aid in finding a serological estimate of the incidence of pertussis. The serum IgG response against pertussis toxin was studied in a group of clinically diagnosed patients. Individual records consisted of repeated serum IgG measurements at irregular intervals for up to 10 years post diagnosis. These data were analysed with a nonlinear regression model taking into account censoring at upper and lower threshold levels, measurement errors, and individual variation in the shape and magnitude of the immune response. There was considerable variation between individual responses, both in strength (amplitude) and duration (shape). The inverse model relating IgG levels to time from infection (diagnosis) can be applied to cross-sectional IgG data to generate distributions of times from infection, which may be used to calculate infection rates and their variation, in populations sampled for cross-sectional IgG data.

Adolescent↗

PubMed1996

Neighborhood deterioration and self-rated health in later life.

This study examined the relationship between the physical living environment and self-rated health in later life. It is hypothesized that older adults who reside in deteriorated neighborhoods will report more physical health problems than elderly people who live in better physical environments. However, it is further predicted that these effects will only emerge in the most dilapidated living conditions. Data from a nationwide survey of older adults provide support for this complex nonlinear relationship. Further analyses reveal that part of the effect can be attributed to friendship strains that arise in deteriorated neighborhood environments.

Aged↗

PubMed2000

Effect of renal function on risedronate pharmacokinetics after a single oral dose.

AIMS: To determine the relationship between risedronate pharmacokinetics and renal function. METHODS: Risedronate was administered to adult men and women (n=21) with various degrees of renal function (creatinine clearance 15-126 ml min-1 ) as a single oral dose of 30 mg. Serum samples were obtained for 72 h after dosing, and urine samples were collected for 72 h after dosing and then periodically for 6 weeks. Risedronate concentrations were determined using an enzyme-linked immunosorbent assay (ELISA). Risedronate serum concentration-time and urinary excretion rate-time profiles were analysed simultaneously using nonlinear regression. RESULTS: Renal clearance and volume of distribution were linearly related to creatinine clearance (r2=0.854, P<0.001; and r2=0.317, P<0.01, respectively). Decreases in predicted renal clearance and volume of distribution of 82 and 69%, respectively, were observed when creatinine clearance decreased from 120 to 20 ml min-1. A 64% decrease in predicted oral clearance was observed when creatinine clearance decreased from 120 to 20 ml min-1 (P=0.064). Iohexol clearance, a predictor of renal function, produced similar results to those observed with creatinine clearance. Risedronate was well tolerated by the study population. CONCLUSIONS: Risedronate renal clearance was significantly related to a decrease in renal function. There was a consistent reduction in oral clearance with a decrease in creatinine clearance. However, based on the regression analysis, generally no dosage adjustment appears to be necessary for most patients with mild or moderate renal impairment (creatinine clearance >20 ml min-1 ).

Administration, Oral↗

PubMed2000

A model for size and age changes in the pharmacokinetics of paracetamol in neonates, infants and children.

AIMS: The aims of this study were to describe paracetamol pharmacokinetics in neonates and infants. METHODS: Infants in their first 3 months of life (n = 30) were randomised to sequentially receive one of three paracetamol formulations (dose 30-40 mg kg-1) over a 2 day period. The formulations were (a) elixir, (b) glycogelatin capsule suppository and (c) triglyceride base suppository. Approximately six blood samples were taken after each dose over the subsequent 10-16 h. Data were analysed using a nonlinear mixed effect model. These neonatal and infant data were then included with data from four published studies of paracetamol pharmacokinetics (n = 221) and age-related pharmacokinetic changes investigated. RESULTS: Population pharmacokinetic parameter estimates and their coefficients of variation (CV%) for a one compartment model with first order input, lag time and first order elimination were volume of distribution 69.9 (18%) l and clearance 13.0 (41%) l h-1 (standardized to a 70 kg person). The volume of distribution decreased exponentially with a half-life of 1.9 days from 120 l 70 kg-1 at birth to 69.9 l 70 kg-1 by 14 days. Clearance increased from birth (4.9 l h-1 70 kg-1) with a half-life of 3.25 months to reach 12.4 l h-1 70 kg-1 by 12 months. The absorption half-life (tabs) for the oral preparation was 0.13 (154%) h with a lag time (tlag) of 0.39 h (31%). Absorption parameters for the triglyceride base and capsule suppositories were tabs 1.34 (90%) h, tlag 0.14 h (31%) and tabs 0.65 (63%) h, tlag 0.54 h (31%), respectively. The tabs for elixir and capsule suppository in children under 3 months were 3.68 and 1.51 times greater than children over 3 months. The relative bioavailability of rectal formulations compared with elixir were 0.67 (30%) and 0.61 (23%) for the triglyceride base and capsule suppositories, respectively. CONCLUSIONS: Total body clearance of paracetamol at birth is 62% and volume of distribution 174% that of older children. A target concentration above 10 mg l-1 in approximately 50% subjects can be achieved by a dose from 45 mg kg-1 day-1 at birth and up to 90 mg kg-1 day-1 in 5-year-old children. A reduced dose of 75 mg kg-1 day-1 in an 8-year-old child is sufficient because clearance is a nonlinear function of weight.

Acetaminophen↗

PubMed2003

Population pharmacokinetics of levosimendan in patients with congestive heart failure.

AIMS: The aim of this study was to characterize the population pharmacokinetics of levosimendan in patients with heart failure (NYHA grades III and IV) and its relationship to demographic factors, disease severity and concomitant use of digoxin and beta-blocking agents. METHODS: Data from two efficacy studies with levosimendan administered by intravenous infusion were combined (190 patients in total). The data were analysed using a nonlinear mixed-effects modelling approach as implemented in the NONMEM program. The model development was done in three sequential steps. First the best structural model was determined (e.g. a one-, two- or three-compartment pharmacokinetic model). This was followed by the identification and incorporation of important covariates into the model. Lastly the stochastic part of the model was refined. RESULTS: A two-compartment model best described levosimendan pharmacokinetics. Clearance and the central volume of distribution were found to increase linearly with bodyweight. No other covariates, including concomitant use of digoxin and beta-blocking agents, influenced the pharmacokinetics. In the final model, a 76-kg patient was estimated to have a clearance +/- s.e. of 13.3 +/- 0.4 l h-1 and a central volume of distribution of 16.8 +/- 0.79 l. The interindividual variability was estimated to be 39% and 60% for clearance and central volume of distribution, respectively. Weight changed clearance by 1.5% [95% confidence interval (CI) 0.9%, 2.1%] and the central volume of distribution by 0.9% (95% CI 0.5%, 1.3%) per kg. CONCLUSIONS: The population pharmacokinetics parameters of levosimendan in this patient group were comparable to those obtained by traditional methods in healthy volunteers and patients with mild heart failure. Bodyweight influenced the clearance and the central volume of distribution, which in practice is accounted for by weight adjusting doses. None of the other covariates, including digoxin and beta-blocking agents, significantly influenced the pharmacokinetics of levosimendan.

Adrenergic beta-Antagonists↗

PubMed2003

Population pharmacokinetics of imipenem in burn patients.

The interindividual variability of imipenem pharmacokinetic parameters in burn patients suggest that these parameters have to be estimated with a large number of patients. The aim of this study is (i) to estimate these parameters with a population pharmacokinetic approach, and (ii) to test the influence of factors on pharmacokinetics parameters. Data are provided by therapeutic drug monitoring (n = 47,118 samples) and analysed by a nonlinear mixed effect modelling method. Among the tested covariates (age, gender, body weight, height, size of burn and creatinine plasma level) creatinine plasma level affects imipenem pharmacokinetic parameters substantially. The best fit is obtained with a two-compartment model integrating a linear-inverse relationship between imipenem clearance and creatinine plasma level. The estimates of imipenem clearance (16.37 +/- 0.204 L/h) and of the distribution volume of the central compartment (0.376 +/- 0.039 L/kg) are higher in the population of burn patients than the estimates in healthy subjects. This result is connected with high values of glomerule filtration rate and confirms the interest of therapeutic drug monitoring of imipenem in burn patients and particularly for patients with extreme values of creatinine clearance.

Burns↗

PubMedDate not supplied

Short-run associations between medical care expenditures and adherence to clinical practice guideline-based measures for diabetes.

OBJECTIVES: To estimate relationships between medical care expenditures in 1996 and adherence to seven guideline-based measures for diabetes. METHODS AND DATA: Nonlinear exponential regression analyses were used to estimate relationships between medical care expenditures in 1996 and adherence to guideline-based measures that year, adjusting for differences in patients' demographics, location, plan type, and severity of illness. Adherence to criteria regarding physician visits, eye exams, blood sugar tests, urinalysis, triglyceride tests, total cholesterol tests, and HDL cholesterol tests was studied for 18,403 patients in 35 health plans. RESULTS: Average total medical expenditures would be $713 higher if all patients were treated according to the guideline-based measures in 1996, compared to what expenditures would be if no patients were treated that way. Average diabetes-related expenditures would be about $322 higher. Two important exceptions to this pattern were for adherence to the suggested frequency of hemoglobin A1c blood sugar tests and ophthalmology visits for dilated eye exams. Having the recommended number of these tests was associated with significantly lower total expenditures. CONCLUSIONS: In general, adherence to clinical practice guideline-based measures was more costly than deviating from those criteria, in the short-run. Perhaps expenditures should be higher for many patients who are not treated according to guidelines. Randomized studies with more years of follow-up should be conducted to assess whether short-term investments in guideline adherence pay off with lower medical expenditures and greater levels of health in the long term.

Databases, Factual↗

PubMed1992

Coronary heart disease risk scales and reactivity in a prevention program assessment: failure to show positive relationships.

This study was designed to evaluate relationships among the Jenkins Activity Survey, the Cook-Medley Hostility Scale, and cardiovascular reactivity measured during a semistructured interview in a hospital setting. Subjects were 201 business persons participating in a cardiovascular risk assessment interview component of a fitness program. Correlation analysis showed little evidence of significant positive relationships between self-report scores and reactivity in the total sample and among subjects with high resting blood pressures. Graphic analysis of total sample bivariate distributions, however, demonstrated patterns suggestive of nonlinear relationships. Evaluation of scatterplots and residual plots in conjunction with nonlinear and weighted least squares regression analyses nonetheless failed to reveal significant nonlinear relationships. The authors discuss implications of these findings.

Adult↗

PubMed2005

Are the acute effects of particulate matter on mortality in the National Morbidity, Mortality, and Air Pollution Study the result of inadequate control for weather and season? A sensitivity analysis using flexible distributed lag models.

Time-series studies have linked daily variations in nonaccidental deaths with daily variations in ambient particulate matter air pollution, while controlling for qualitatively larger influences of weather and season. Although time-series analyses typically include nonlinear terms for weather and season, questions remain as to whether models to date have completely controlled for these important predictors. In this paper, the authors use two flexible versions of distributed lag models to control extensively for the confounding effects of weather and season. One version builds on the current approach to controlling for weather, while the other version offers a new approach. The authors conduct a comprehensive sensitivity analysis of the particulate matter-mortality relation by applying these methods to the recently updated National Morbidity, Mortality, and Air Pollution Study database that comprises air pollution, weather, and mortality time series from 1987 to 2000 for 100 US cities. They combine city-specific estimates of the short-term effects of particulate matter on mortality using a Bayesian hierarchical model. They conclude that, within the broad classes of models considered, national average estimates of particulate matter relative risk are consistent with previous estimates from this study and are robust to model specification for weather and seasonal confounding.

Aged↗

PubMed2002

Dynamics of climate and ecosystem coupling: abrupt changes and multiple equilibria.

Interactions between subunits of the global climate-biosphere system (e.g. atmosphere, ocean, biosphere and cryosphere) often lead to behaviour that is not evident when each subunit is viewed in isolation. This newly evident behaviour is an emergent property of the coupled subsystems. Interactions between thermohaline circulation and climate illustrate one emergent property of coupling ocean and atmospheric circulation. The multiple thermohaline circulation equilibria that result caused abrupt climate changes in the past and may cause abrupt climate changes in the future. Similarly, coupling between the climate system and ecosystem structure and function produces complex behaviour in certain regions. For example, atmosphere-biosphere interactions in the Sahel region of West Africa lead to multiple stable equilibria. Either wet or dry climate equilibria can occur under otherwise identical forcing conditions. The equilibrium reached is dependent on past history (i.e. initial conditions), and relatively small perturbations to either climate or vegetation can cause switching between the two equilibria. Both thermohaline circulation and the climate-vegetation system in the Sahel are prone to abrupt changes that may be irreversible. This complicates the relatively linear view of global changes held in many scientific and policy communities. Emergent properties of coupled socio-natural systems add yet another layer of complexity to the policy debate. As a result, the social and economic consequences of possible global changes are likely to be underestimated in most conventional analyses because these nonlinear, abrupt and irreversible responses are insufficiently considered.

Climate↗

PubMed2004

Population pharmacokinetics of total and unbound plasma cisplatin in adult patients.

AIMS: To investigate the pharmacokinetics of unbound (ultrafilterable) and total plasma platinum using a population approach and to identify patient characteristics that may influence the disposition of the drug. METHODS: Pharmacokinetic and demographic data were collected from adult patients treated with 30-min daily infusions of cisplatin for various malignancies. Unbound and total platinum concentration-time data were analysed using a nonlinear mixed effects model. RESULTS: Data from 43 patients were available for analysis. A linear two-compartment model best described total and unbound platinum plasma concentration-time data. The mean population estimates for total and unbound drug were, respectively, 0.68 and 35.5 l h(-1) for clearance and 21.1 and 23.4 l for central distribution volume (V(1)). Unbound clearance (CL) was dependent on body surface area (BSA) and creatinine clearance, and V(1) was dependent on BSA. The elimination rate constant for plasma-bound platinum (modelled as metabolite formation) was 0.014 h(-1). The pharmacokinetic parameter, f(m)/V(m), a measure of the clearance of unbound platinum due to irreversible plasma binding, was related to serum protein concentration and to the inverse of dose per m(2). The covariate modelling of CL, V(1) and f(m)/V(m) improved the intersubject variabilities associated with these parameters. The final pharmacokinetic models were validated using 200 bootstrap samples from the original datasets. CONCLUSIONS: The results support the conventional dose adjustment of cisplatin based on BSA. They also support the need for a dose reduction in case of renal insufficiency.

Adult↗

PubMed2006

Population pharmacokinetics of darbepoetin alfa in healthy subjects.

AIM: To develop and evaluate a population pharmacokinetic (PK) model of the long-acting erythropoiesis-stimulating protein, darbepoetin alfa in healthy subjects. METHODS: PK profiles were obtained from 140 healthy subjects receiving single intravenous and/or single or multiple subcutaneous doses of darbepoetin alfa (0.75-8.0 microg kg(-1), or either 80 or 500 microg). Data were analysed by a nonlinear mixed-effects modelling approach using NONMEM software. Influential covariates were identified by covariate analysis emphasizing parameter estimates and their confidence intervals, rather than stepwise hypothesis testing. The model was evaluated by comparing simulated profiles (obtained using the covariate model) to the observed profiles in a test dataset. RESULTS: The population PK model, including first-order absorption, two-compartment disposition and first-order elimination, provided a good description of data. Modelling indicated that for a 70-kg human, the observed nearly twofold disproportionate dose-exposure relationship at the 8.0 microg kg(-1)-dose relative to the 0.75 microg kg(-1)-dose may reflect changing relative bioavailability, which increased from approximately 48% at 0.75 microg kg(-1) to 78% at 8.0 microg kg(-1). The covariate analysis showed that increasing body weight may be related to increasing clearance and central compartment volume, and that the absorption rate constant decreased with increasing age. The full covariate model performed adequately in a fixed-effects prediction test against an external dataset. CONCLUSION: The developed population PK model describes the inter- and intraindividual variability in darbepoetin alfa PK. The model is a suitable tool for predicting the PK response of darbepoetin alfa using clinically untested dosing regimens.

Darbepoetin alfa↗