Application of the Convection–Dispersion Equation to Modelling Oral Drug Absorption

Models of systemic drug absorption after oral administration are frequently based on a direct or a delayed first-order rate process. In practice, the use of the first-order approach to predict drug concentrations in blood plasma frequently yields a considerable mismatch between predicted and measured concentration profiles. This is particularly true for the upswing of the plasma concentration after oral administration. The current investigation explores an alternative model to describe the absorption rate based on the convection–dispersion equation describing the transport of chemicals through the GI tract. This equation is governed by two parameters, transport velocity and dispersion coefficient. One solution of this equation for a specific set of initial and boundary conditions was used to model absorption of paracetamol in a 22-year-old man after oral administration. The GI-tract passage rate in this subject was influenced by co-administration of drugs that stimulate or delay gastric emptying. The transport-limited absorption function is more accurate in describing the plasma concentration versus time curve after oral administration than the first-order model. Additionally, it provides a mechanistic explanation for the observed curve through the differences in GI-tract passage rate

Marginal increase of sunitinib exposure by grapefruit juice

Clinical Oncolog

Dutch guideline on total hip prosthesis

Contains fulltext : 97840.pdf (publisher's version ) (Open Access

Population pharmacokinetic analysis for simultaneous determination of Bmax and KD In Vivo by positron emission tomography

Purpose: Changes in GABAA-receptor density and affinity play an important role in many forms of epilepsy. A novel approach, using positron emission tomography (PET) and [C-11]flumazenil ([C-11]FMZ), was developed for simultaneous estimation of GABAA-receptor properties, characterized by Bmax and KD. Procedures: Following an injection of [C-11]FMZ (dose range: 1-2,000 μg) to 21 rats, concentration time curves of FMZ in brain (using PET) and blood (using HPLC-UV) were analyzed simultaneously using a population pharmacokinetic (PK) model, containing expressions to describe the time course of the plasma concentration (including distribution to the body), the brain distribution, and the specific binding within the brain. Results: Application of this method in control rats resulted in estimates of Bmax and K D (14.5 ± 3.7 ng/ ml and 4.68 ± 1.5 ng/ml, respectively). Conclusions: The proposed population PK model allowed for simultaneous estimation of Bmax and KD for a group of animals using single injection PET experiments per animal

Use and Usability Of Custom-Made Knee-Ankle-Foot Orthoses In Polio Survivors with Knee Instability: A Cross-Sectional Survey

OBJECTIVE: To investigate the use of custom-made knee-ankle-foot orthoses in daily life and differences in usability factors of knee-ankle-foot orthoses between users and discontinued users. DESIGN: Cross-sectional survey study. SUBJECTS: A total of 163 polio survivors provided with a knee-ankle-foot orthosis at an outpatient clinic of a university hospital. METHODS: Use and usability of knee-ankle-foot orthoses in daily life were assessed with a postal questionnaire. Usability factors were formulated using the International Organization for Standardization (ISO) 9241-11 standard. RESULTS: A total of 106 respondents (65%) returned the questionnaire. Of these, 98 were eligible for analysis. Seventy-four respondents (76%) reported using their knee-ankle-foot orthosis. Compared with discontinued users (24%), users experienced more limitations when walking without an orthosis (p = 0.001), were more often experienced with wearing a previous orthosis (p < 0.001) and were more often prescribed with a locked rather than a stance-control knee-ankle-foot orthosis (p = 0.015). Furthermore, users reported better effectiveness of their knee-ankle-foot orthosis (p < 0.001), more satisfaction with goals of use and knee-ankle-foot orthosis-related aspects (p < 0.001). CONCLUSION: The majority of polio survivors used their custom-made knee-ankle-foot orthoses in daily life. Factors related to continued use, such as walking ability without orthosis, expectations of the orthosis, previous orthosis experience and type of knee-ankle-foot orthosis provided, should be considered and discussed when prescribing a knee-ankle-foot orthosis in polio survivors

USE AND USABILITY OF CUSTOM-MADE KNEE-ANKLE-FOOT ORTHOSES IN POLIO SURVIVORS WITH KNEE INSTABILITY: A CROSS-SECTIONAL SURVEY

Objective: To investigate the use of custom-made knee-ankle-foot orthoses in daily life and differences in usability factors of knee-ankle-foot orthoses between users and discontinued users. Design: Cross-sectional survey study. Subjects: A total of 163 polio survivors provided with a knee-ankle-foot orthosis at an outpatient clinic of a university hospital. Methods: Use and usability of knee-ankle-foot orthoses in daily life were assessed with a postal questionnaire. Usability factors were formulated using the International Organization for Standardization (ISO) 9241-11 standard. Results: A total of 106 respondents (65%) returned the questionnaire. Of these, 98 were eligible for analysis. Seventy-four respondents (76%) reported using their knee-ankle-foot orthosis. Compared with discontinued users (24%), users experienced more limitations when walking without an orthosis (p = 0.001), were more often experienced with wearing a previous orthosis (p < 0.001) and were more often prescribed with a locked rather than a stance-control knee-ankle-foot orthosis (p = 0.015). Furthermore, users reported better effectiveness of their knee-ankle-foot orthosis (p < 0.001), more satisfaction with goals of use and knee-ankle-foot orthosis-related aspects (p < 0.001). Conclusion: The majority of polio survivors used their custom-made knee-ankle-foot orthoses in daily life. Factors related to continued use, such as walking ability without orthosis, expectations of the orthosis, previous orthosis experience and type of knee-ankle-foot orthosis provided, should be considered and discussed when prescribing a knee-anklefoot orthosis in polio survivors

Nonlinear mixed effects modeling of the diurnal blood pressure profile in a multiracial population

Cardiac and cerebrovascular events in hypertensive patients are related to specific features of the 24-hour diurnal blood pressure (BP) profile (i.e., daytime and nighttime BP, nocturnal dip (ND), and morning surge (MS)). This investigation aimed to characterize 24-hour diurnal systolic BP (SBP) with parameters that correlate directly with daytime and nighttime SBP, ND, and MS using nonlinear mixed effects modeling. Ambulatory 24-hour SBP measurements (ABPM) of 196 nontreated subjects from three ethnic groups were available. A population model was parameterized in NONMEM to estimate and evaluate the parameters baseline SBP (BSL), nadir (minimum SBP during the night), and change (SBP difference between day and night). Associations were tested between these parameters and patient-related factors to explain interindividual variability. The diurnal SBP profile was adequately described as the sum of 2 cosine functions. The following typical values (interindividual variability) were found: BSL = 139 mm Hg (11%); nadir = 122 mm Hg (14%); change = 25 mm Hg (52%), and residual error = 12 mm Hg. The model parameters correlate well with daytime and nighttime SBP, ND, and MS (R (2) = 0.50-0.92). During covariate analysis, ethnicity was found to be associated with change; change was 40% higher in white Dutch subjects and 26.8% higher in South Asians than in blacks. The developed population model allows simultaneous estimation of BSL, nadir, and change for all individuals in the investigated population, regardless of individual number of SBP measurements. Ethnicity was associated with change. The model provides a tool to evaluate and optimize the sampling frequency for 24-hour ABP