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At least 1,747 records · Page 97Linked to original sources

PubMed2007

Laser treatment of keloids and hypertrophic scars.

BACKGROUND: Lasers have been used in the treatment of hypertrophic scars and keloids for more than 20 years. Different laser systems have been examined; among them pulsed dye lasers are currently considered the laser of choice in these settings. OBJECTIVES: The purpose of this study is to review the pertinent literature and provide updated information on different laser therapies available for treatment of keloids and hypertrophic scars. METHODS: A Medline literature search was performed for relevant publications. RESULTS: In this review the results of published studies in the treatment and prevention of hypertrophic scars and keloids are presented. Suggested mechanisms of action are reviewed. A review of the optimal laser parameters to modulate treatment outcome will be discussed. Different lasers are effective in not only the treatment but also the prevention of hypertrophic scars and keloids, among them PDL is more promising. Most of the suggested theories are based on the selective photothermolysis in which the light energy emitted from a vascular laser is absorbed by hemoglobin, generating heat and leading to coagulation necrosis, neocollagenesis, collagen fiber heating with dissociation of disulfide bonds and subsequent collagen fiber realignment. CONCLUSION: The optimal laser is currently 585 nm PDL, although the recent results of Q-switched 532 nm frequency-doubled Nd:YAG are promising. Early use of lasers are beneficial, especially in those who are prone to develop these lesions.

Cicatrix, Hypertrophic↗

PubMed2005

Genetically optimized fuzzy decision trees.

In this study, we are concerned with genetically optimized fuzzy decision trees (G-DTs). Decision trees are fundamental architectures of machine learning, pattern recognition, and system modeling. Starting with the generic decision tree with discrete or interval-valued attributes, we develop its fuzzy set-based generalization. In this generalized structure we admit the values of the attributes that are represented by some membership functions. Such fuzzy decision trees are constructed in the setting of genetic optimization. The underlying genetic algorithm optimizes the parameters of the fuzzy sets associated with the individual nodes where they play a role of fuzzy "switches" by distributing a flow of processing completed within the tree. We discuss various forms of the fitness function that help capture the essence of the problem at hand (that could be either of classification nature when dealing with discrete outputs or regression-like when handling a continuous output variable). We quantify a nature of the generalization of the tree by studying an optimally adjusted spreads of the membership functions located at the nodes of the decision tree. A series of experiments exploiting synthetic and machine learning data is used to illustrate the performance of the G-DTs.

Algorithms↗

PubMed2000

Optical-thermal simulation of human tonsillar tissue irradiation: clinical implications.

BACKGROUND AND OBJECTIVE: Mucosa intact laser tonsillar ablation is an alternative to conventional tonsillectomy. The efficacy of this procedure was demonstrated in canines, but establishing the safety of irradiating human tonsils is paramount. STUDY DESIGN/MATERIALS AND METHODS: An optical-thermal simulation of tonsillar tissue irradiation was previously developed, but the effect of varying parameters was not investigated. The tissue response to irradiation at 5-25 watts for 1 minute and 10 watts for 10 seconds to 162 seconds is simulated. RESULTS: At 15 watts and greater, the peak temperature is over 100 degrees C and the mucosal temperature is over 70 degrees C. At the depth of the tonsil, the temperature does not vary significantly. The peak temperature is at 1 mm. The radial temperature profile is not significantly altered by longer irradiation times. CONCLUSIONS: The optimal dosimetry parameters for irradiation of human tonsillar tissue at 805 nm with the MILTA technique is under 15 watts for approximately 1 minute.

Computer Simulation↗

PubMed2002

Substituted 4-(2,2-diphenylethyl)pyridine-N-oxides as phosphodiesterase-4 inhibitors: SAR study directed toward the improvement of pharmacokinetic parameters.

A detailed SAR study directed toward the optimization of pharmacokinetic parameters for analogues of L-791,943 is reported. The introduction of a soft metabolic site on this structure permitted the identification of L-826,141 as a potent phosphodiesterase type 4 (PDE4) inhibitor that is well absorbed and that presents a shorter half-life than L-791,943 in a variety of animal species. The efficacy of L-826,141 is also demonstrated in different in vivo models.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2003

Preclinical and clinical studies on naltrexone: what have they taught each other?

Proceedings of a symposium at the 2002 RSA/ISBRA Meeting in San Francisco, California; organized and co-chaired by Janice C. Froehlich and Stephanie O'Malley. The presentations were (1) Introduction, by Janice C. Froehlich and Stephanie O'Malley; (2) Preclinical studies on naloxone: genetics and site of action, by Petri Hyytiä; (3) Clinical studies on naltrexone for treating hazardous drinkers, by Dena Davidson; (4) Clinical studies on naltrexone and sertraline in the treatment of alcohol dependence, by Conor Farren; and (5) Discussion by Janice D. Froehlich, Stephanie O'Malley, and Rainer Spanagel. Both preclinical and clinical studies are critical in the development of effective pharmacotherapeutic approaches for the treatment of alcoholism. Nowhere has this been more evident than in the development of naltrexone for the treatment of alcohol relapse. As research continues on the optimal use of naltrexone for modifying alcohol intake, a number of factors have emerged that are likely to determine the efficacy of naltrexone as a pharmacotherapeutic agent for the treatment of alcoholism. Some of these factors include dose, frequency and duration of treatment, pattern and severity of alcohol drinking prior to initiation of naltrexone treatment, genetic aspects of responsive subpopulations, degree of alcohol craving, and susceptibility to adverse effects of naltrexone. New, as well as established, animal models are being used to determine the parameters that optimize the ability of naltrexone to modify alcohol drinking in acute and chronic alcohol access paradigms, under conditions of intermittent versus continuous alcohol intake, and in populations that vary in genetic predisposition toward alcohol drinking. Current clinical studies are exploring the ability of naltrexone to alter alcohol drinking when delivered in combination with pharmacotherapeutic agents that act on nonopioid transmitter systems and the difference in efficacy of naltrexone when administered in populations that differ in drinking frequency and intensity, family history of alcoholism, and alcohol craving. This symposium presented new research findings from both preclinical and clinical studies with the aim of facilitating the development of treatment regimens that optimize the therapeutic potential of naltrexone in the treatment of alcoholism.

Alcoholism↗

PubMed2002

3D computer modeling of sitting working place.

Ergonomic contribution to designing and modeling of sitting working place by use of a computer and computer programs have been presented in this work. The influences of modeling working places on regular posture of a man/woman during work have been reconsidered, so that consumption of energy and fatigue are brought down to a minimum. For that purpose a computer program has been made which with input data on various kinds of work, sex and height of a worker determines the optimal ergonomic parameters during the modeling of a sitting working place. By computer visualisation the values of angle of spine curving have been calculated, the manipulation angle of arms and legs for three anthropometric heights of workers (160 cm, 175 cm and 190 cm). The dimensions of manipulative body space have been established by computerised 3D anthropometric analysis of movement as for example, reach of arms, legs, head, back etc positions. In this process the dimensions of machine and working space surrounding it in respect to optimal utilisation have been put in accordance with the anthropometric size of a man/woman.

Anthropometry↗

PubMed2002

Single-pass attenuated total reflection Fourier transform infrared spectroscopy for the prediction of protein secondary structure.

Principal component regression (PCR) was applied to a spectral library of proteins in H2O solution acquired by single-pass attenuated total reflectance (ATR) Fourier transform infrared (FT-IR) spectroscopy. PCR was used to predict the secondary structure content, principally alpha-helical and the beta-sheet content, of proteins within a spectral library. Quantitation of protein secondary structure content was performed as a proof of principle that use of single-pass ATR-FT-IR is an appropriate method for protein secondary structure analysis. The ATR-FT-IR method permits acquisition of the entire spectral range from 700 to 3900 cm(-1) without significant interference from water bands. An "inside model space" bootstrap and a genetic algorithm (GA) were used to improve prediction results. Specifically, the bootstrap was utilized to increase the number of replicates for adequate training and validation of the PCR model. The GA was used to optimize PCR parameters, particularly wavenumber selection. The use of the bootstrap allowed for adequate representation of variability in the amide A, amide B, and C-H stretching regions due to differing levels of sample hydration. Implementation of the bootstrap improved the robustness of the PCR models significantly; however, the use of a GA only slightly improved prediction results. Two spectral libraries are presented where one was better suited for beta-sheet content prediction and the other for alpha-helix content prediction. The GA-optimized PCR method for alpha-helix content prediction utilized 120 wavenumbers within the amide I, II, A, B, and IV and the C-H stretching regions and 18 factors. For beta-sheet content predictions, 580 wavenumbers within the amide I, II, A, and B and the C-H stretching regions and 18 factors were used. The validation results using these two methods yielded an average absolute error of 1.7% for alpha-helix content prediction and an average absolute error of 2.3% for beta-sheet content prediction. After the PCR models were developed and validated, they were used to predict the alpha-helix and beta-sheet content of two unknowns, casein and immunoglobulin G.

Multivariate Analysis↗

PubMed1998

Pharmacodynamics of fluconazole in a murine model of systemic candidiasis.

In this study we defined the pharmacodynamic parameter that optimizes outcome in deep-seated Candida albicans infections treated with fluconazole. Using a murine model of systemic candidiasis, we conducted single-dose dose-ranging studies with fluconazole to determine the dosage of this drug that resulted in a 50% reduction in fungal densities (50% effective dose [ED50]) in kidneys versus the fungal densities in the kidneys of untreated controls. We found that the ED50 of fluconazole given intraperitoneally was 4.56 mg/kg of body weight/day (95% confidence interval, 3.60 to 5.53 mg/kg/day), and the dose-response relationship was best described by an inhibitory sigmoid maximal effect (Emax) curve. To define the pharmacodynamics of fluconazole, we gave dosages lower than, approximating, and higher than the ED50 of fluconazole (range, 3.5 to 5.5 mg/kg/day, equivalent to the ED16 to the ED75) to various groups of infected animals using three dose-fractionation schedules. For each total dose of fluconazole examined, the dose-fractionation schedules optimized the ratio of the area under the concentration-time curve (AUC) to the MIC (the AUC/MIC ratio), the ratio of the maximum concentration of drug in serum (Cmax) to the MIC, and the time that the drug remained above the MIC for the infecting C. albicans isolate. Similar reductions in fungal densities in kidneys were seen between groups that received the same total dose of fluconazole in one, two, or four equally divided doses. Thus, dose-fractionation studies demonstrated that the pharmacodynamic parameter of fluconazole that best predicted outcome was the AUC/MIC ratio.

Animals↗

PubMed2003

Primary human hepatocytes--a valuable tool for investigation of apoptosis and hepatitis B virus infection.

BACKGROUND/AIMS: Apoptosis is a key event in the pathophysiology of many liver diseases. Primary human hepatocytes (PHH) provide a useful model to study physiological and pathophysiological processes in the liver. Our aim was to optimize PHH cultures to allow studies on induction of apoptosis and of hepatitis B virus (HBV) infection. METHODS: PHH were isolated from human liver tissue by two-step collagenase perfusion. PHH and hepatoma cells were treated with different apoptosis-inducing agents in parallel. PHH cultures were infected with wild type HBV and transduced with HBV genomes using adenoviral vectors. RESULTS: PHH were successfully isolated from 40 different tissue samples with high viability and purity. Perfusion time and seeding density turned out to be critical parameters for optimal cell yield and culture conditions, respectively. Serum addition to the medium reduced viability of PHH. PHH allowed reproducible studies of CD95-dependent and -independent apoptosis. Sensitivity towards CD95-mediated apoptosis was markedly higher than in hepatoma cells. PHH could efficiently be infected with HBV, but infection did neither induce apoptosis nor prevent CD95-induced cell death. CONCLUSIONS: Our data show that PHH provide an excellent tool for the investigation of apoptosis induced by agents like death receptor-ligands and hepatotropic viruses.

Apoptosis↗

PubMed2005

2-Step IMAT and 2-Step IMRT in three dimensions.

In two dimensions, 2-Step Intensity Modulated Arc Therapy (2-Step IMAT) and 2-Step Intensity Modulated Radiation Therapy (IMRT) were shown to be powerful methods for the optimization of plans with organs at risk (OAR) (partially) surrounded by a target volume (PTV). In three dimensions, some additional boundary conditions have to be considered to establish 2-Step IMAT as an optimization method. A further aim was to create rules for ad hoc adaptations of an IMRT plan to a daily changing PTV-OAR constellation. As a test model, a cylindrically symmetric PTV-OAR combination was used. The centrally placed OAR can adapt arbitrary diameters with different gap widths toward the PTV. Along the rotation axis the OAR diameter can vary, the OAR can even vanish at some axis positions, leaving a circular PTV. The width and weight of the second segment were the free parameters to optimize. The objective function f to minimize was the root of the integral of the squared difference of the dose in the target volume and a reference dose. For the problem, two local minima exist. Therefore, as a secondary criteria, the magnitude of hot and cold spots were taken into account. As a result, the solution with a larger segment width was recommended. From plane to plane for varying radii of PTV and OAR and for different gaps between them, different sets of weights and widths were optimal. Because only one weight for one segment shall be used for all planes (respectively leaf pairs), a strategy for complex three-dimensional (3-D) cases was established to choose a global weight. In a second step, a suitable segment width was chosen, minimizing f for this global weight. The concept was demonstrated in a planning study for a cylindrically symmetric example with a large range of different radii of an OAR along the patient axis. The method is discussed for some classes of tumor/organ at risk combinations. Noncylindrically symmetric cases were treated exemplarily. The product of width and weight of the additional segment as well as the integral across the segment profile was demonstrated to be an important value. This product was up to a factor of 3 larger than in the 2-D case. Even in three dimensions, the optimized 2-Step IMAT increased the homogeneity of the dose distribution in the PTV profoundly. Rules for adaptation to varying target-OAR combinations were deduced. It can be concluded that 2-Step IMAT and 2-Step IMRT are also applicable in three dimensions. In the majority of cases, weights between 0.5 and 2 will occur for the additional segment. The width-weight product of the second segment is always smaller than the normalized radius of the OAR. The width-weight product of the additional segment is strictly connected to the relevant diameter of the organ at risk and the target volume. The derived formulas can be helpful to adapt an IMRT plan to altering target shapes.

Algorithms↗

PubMed2005

Enhancement of drug delivery in tumors by using interaction of nanoparticles with ultrasound radiation.

Efficacy and safety of cancer chemo- and biotherapy are limited by poor penetration of anti-cancer drugs from blood into tumor cells. Tumor blood vessel wall, slow diffusion in the interstitium, and cancer cell membrane create physiological barriers for anti-cancer drugs, in particular promising macromolecular agents. Recently, we proposed to use selective accumulation of exogenous nano- and microparticles in tumors followed by ultrasound-induced cavitation for safe and efficient drug and gene delivery. In this paper, we first investigated the influence of polystyrene nanoparticles (100 and 280 nm in diameter and concentration up to 0.2% w/w) on cavitation threshold in water at the frequency of 20 kHz. Then, using optimal irradiation parameters found in the first part of this work, we studied efficacy of cancer chemotherapy with this technique. The experiments were performed in athymic nude mice bearing human colon KM20 tumors, which are highly resistant to chemotherapy. Ultrasound with the frequency of 20 kHz in combination with i.v. injected polystyrene nanoparticles was applied to enhance delivery of chemotherapeutic agent 5-fluorouracil. Our studies demonstrated that ultrasound irradiation in combination with the nanoparticle and drug injections significantly decreased tumor volume and resulted in complete tumor regression at optimal irradiation conditions, while the volume of control (non-irradiated) tumors increased despite drug injections. These data suggest that ultrasound-induced drug delivery may improve efficacy of current cancer treatment regimens.

Animals↗

PubMed2005

Genetic algorithm for large-scale maximum parsimony phylogenetic analysis of proteins.

Inferring phylogeny is a difficult computational problem. For example, for only 13 taxa, there are more then 13 billion possible unrooted phylogenetic trees. Heuristics are necessary to minimize the time spent evaluating non-optimal trees. We describe here an approach for heuristic searching, using a genetic algorithm, that can reduce the time required for weighted maximum parsimony phylogenetic inference, especially for data sets involving a large number of taxa. It is the first implementation of a weighted maximum parsimony criterion using amino acid sequences. To validate the weighted criterion, we used an artificial data set and compared it to a number of other phylogenetic methods. Genetic algorithms mimic the natural selection's ability to solve complex problems. We have identified several parameters affecting the genetic algorithm. Methods were developed to validate these parameters, ensuring optimal performance. This approach allows the construction of phylogenetic trees with over 200 taxa in practical time on a regular PC.

Algorithms↗

PubMed2003

Quantitative model of small molecules uptake after in vitro cell electropermeabilization.

Electropermeabilization of the cell membrane is a phenomenon caused by exposure of the cell to electric pulses. Permeabilization depends on pulse duration, pulse amplitude, the number of pulses delivered, and also on other experimental conditions. With these parameters properly chosen, the process of permeabilization is reversible and cells return to their normal physiological state. This article describes the development of a model of diffusion-driven transmembrane transport of small molecules caused by electropermeabilization. The process of permeabilization is divided into a short permeabilizing phase that takes place during the pulse, and a longer resealing phase that begins after the end of the pulse. Because both phases of permeabilization are important for uptake of molecules into cells, most of the effort is focused on the optimization of parameters that influence the flow between intracellular and extracellular space. The model describes well the transmembrane transport caused by electropermeabilization, allowing to study the uptake of molecules as a function of elapsed time, voltage and pulse duration. In addition, our results show that the shapes of the curves of cell permeabilization and survival as functions of pulse amplitude can to a large extent be explained by cell size distribution.

Animals↗

PubMed2002

Textural profiling and statistical optimization of crosslinked calcium-alginate-pectinate-cellulose acetophthalate gelisphere matrices.

A 2(5) factorial design was employed to statistically evaluate the textural properties of a crosslinked calcium-alginate-pectinate-cellulose acetophthalate gelisphere system. In accordance with the factorial matrix, gelispheres were formulated by titrating a combination polymeric solution comprised of sodium alginate, pectin and/or cellulose acetophthalate into an inducer solution (crosslinking agent) consisting of calcium and/or acetate ions. A Texture Analyzer was used to profile the gelisphere matrices for their resilience in the unhydrated and hydrated states, the fracture energy involved in matrix rupture, and the matrix hardness achieved with different levels of crosslinking. Significantly different textural properties were found among the crosslinked formulations. In particular, the unhydrated matrix resilience was selected as a parameter for optimization of the gelisphere formulation because of its large impact on drug release modulation, matrix integrity, and sensitivity to the crosslinking process. Resilience increased with increasing polymer concentration, irrespective of the polymer combination. Furthermore, resilience was not significantly influenced by the concentration of the crosslinking agents, but rather by the application of a higher polymer concentration in the crosslinking reaction; again irrespective of the polymer combination. In addition to the use of a factorial design, artificial neural modeling was employed to predict the textural properties based on the factorial matrix as a statistically suitable data source. Neural networks appeared to be a strong competitor of factorial regression for the prediction of textural data.

Alginates↗

PubMed1999

Laser therapy of spider leg veins: clinical evaluation of a new long pulsed alexandrite laser.

BACKGROUND: The response of spider leg veins to laser or intense pulsed light therapy has generally been characterized by varying degrees of success and frequently inconsistent clinical response rates. OBJECTIVE: The purpose of this study was to examine the effectiveness of the 755 nm long pulsed infrared alexandrite (LPA) laser for the treatment of leg telangiectasias. METHODS: This study was constructed in four phases. Phase I examined 28 patients with variable sized telangiectasias using 5 treatment parameters (15 J/cm2 x 1 pulse, 20 J/cm2 x 1 pulse, 20 J/cm2 x 2 pulses, 20 J/cm2 x 3 pulses, or 30 J/cm2 x 1 pulse). Each patient received 3 treatments at 4 week intervals with the LPA. Patient diaries were obtained to examine the effects of the treatments. Subjective grading was performed at each follow-up visit by the investigators. Blinded objective grading was performed at the conclusion of the study by trained observers. Phase II examined the effects of these treatment parameters on varying vessel diameters. Vessels were grouped into small (<0.4 mm), intermediate (0.4-1.0 mm), and large (1.0-3.0 mm) subsets. Phase III examined the effects of a combination of LPA treatment followed by 23.4% hypertonic saline sclerotherapy. Subjective and blinded objective grading was used to determine improvement after a single treatment with the LPA at 20 J/cm2, single pulsed with a pulse duration of 5 or 10 msec followed by treatment with 23.4% hypertonic saline injected 3, 7, 14, or 28 days after laser therapy. Phase IV involved biopsies after LPA treatment alone at time intervals of immediately posttreatment and 5 and 21 days posttreatment. RESULTS: These evaluations revealed that the optimal treatment parameters for LPA therapy alone appeared to be 20 J/cm2, double pulsed at a repetition rate of one Hz. After 3 treatments at 4 week intervals, subjective grading indicated a 63% reduction in leg telangiectasias. Medium diameter vessels responded best with small vessel diameters responding poorly, if at all. The addition of 23.4% hypertonic saline sclerotherapy performed 3 to 7 days after laser therapy (LPA at 20 J/cm2, single pulsed with a pulse duration of 5 msec) produced 87% reduction in leg telangiectasias. Biopsies after LPA treatment revealed vessel wall endothelial cell necrosis at 5 days with fibrosis occurring at 3 weeks. The optimal clinical "window" for sclerotherapy seems to coincide with the period of endothelial cell necrosis. CONCLUSION: LPA therapy is most effective for leg telangiectasias 0.4-3.0 mm in diameter. This LPA technique is significantly improved with the addition of sclerotherapy.

Adult↗

PubMed2006

The use of protonated Sargassum muticum as biosorbent for cadmium removal in a fixed-bed column.

The protonated Sargassum muticum seaweed was studied as a possible biosorbent for cadmium removal in a fixed-bed column. The experiments were conducted in order to determine the effect of flow rate (0.42, 5, 10 and 20 mL min(-1)) and bed height (0.6 and 15.3 cm for the lowest flow rate or 7.4, 13 and 16.6 cm for the others) on breakthrough curves behaviour. The determined breakthrough and exhaustion times increased with the diminution in flow rate and with the increase in bed height. The maximum cadmium uptake capacity, obtained from the area below adsorbed cadmium concentration versus time curves, was found to remain practically constant with bed depth and flow rate. The bed depth service time (BDST) model was applied to analyse experimental data, determining the characteristic process parameters. The optimal lowest sorbent usage rate was evaluated at 2 min contact time and the minimum bed height values necessary to prevent the effluent solution concentration from exceeding 0.02 mg L(-1) at zero time were 5.3, 6.9 and 7.5 cm for flow rates of 5, 10 and 20 mL min(-1), respectively. Several empirical models proposed in the literature (Bohart-Adams, Yan, Belter and Chu models) were investigated in order to obtain the best fit of column data, describing in a simple manner the breakthrough curves. A correlation between model parameters and the variables implied in the process was attempted.

Adsorption↗

PubMed2002

Noninvasive reduction of open-book pelvic fractures by circumferential compression.

OBJECTIVES: To determine the efficacy and optimal application parameters of circumferential compression to reduce external rotation-type pelvic fractures. DESIGN: Biomechanical investigation on human cadaveric specimens. SETTING: Biomechanics laboratory. INTERVENTION: Partially stable and unstable external rotation injuries of the pelvic ring (OTA classification 61-B1 and 61-C1) were created in seven human cadaveric specimens. A prototype pelvic strap was applied subsequently at three distinct transverse levels around the pelvis. Circumferential pelvic compression was induced by gradual tensioning of the strap to attempt complete reduction of the symphysis diastasis. MAIN OUTCOME MEASUREMENTS: Pelvic reduction was evaluated with respect to strap tension and the strap application site. The effect of circumferential compression on intraperitoneal pressure and skin-strap interface pressure was measured. RESULTS: A successive increase in circumferential compression consistently induced a gradual decrease in symphysis diastasis. An optimal strap application site was determined, at which circumferential compression most effectively yielded pelvic reduction. The minimum strap tension required to achieve complete reduction of symphysis diastasis was determined to be 177 +/- 44 Newtons and 180 +/- 50 Newtons in the partially stable and unstable pelvis, respectively. CONCLUSIONS: Application of circumferential compression to the pelvic soft tissue envelope with a pelvic strap was an efficient means to achieve controlled reduction of external rotation-type pelvic fractures. This study derived application parameters with direct clinical implication for noninvasive emergent management of traumatic pelvic ring disruptions.

Aged↗

PubMed1994

Application of optimal sampling theory to the determination of metacycline pharmacokinetic parameters: effect of model misspecification.

Use of optimal sampling theory (OST) in pharmacokinetic studies allows the number of sampling times to be greatly reduced without loss in parameter estimation precision. OST has been applied to the determination of the bioavailability parameters (area under the curve (AUC), maximal concentration (Cmax), time to reach maximal concentration (Tmax), elimination half-life (T1/2), of metacycline in 16 healthy volunteers. Five different models were used to fit the data and to define the optimal sampling times: one-compartment first-order, two-compartment first-order, two-compartment zero-order, two-compartment with Michaelis-Menten absorption kinetics, and a stochastic model. The adequacy of these models was first evaluated in a 6-subject pilot study. Only the stochastic model with zero-order absorption kinetics was adequate. Then, bioavailability parameters were estimated in a group of 16 subjects by means of noncompartmental analysis (with 19 samples per subject) using each optimal sampling schedule based procedure (with 6 to 9 samples depending on the model). Bias (PE) and precision (RMSE) of each bioavailability parameter estimation were calculated by reference to noncompartmental analysis, and were satisfactory for the 3 adequate models. The most relevant criteria for discrimination of the best model were the coefficient of determination, the standard deviation, and the mean residual error vs. time plot. Additional criteria were the number of required sampling times and the coefficient of variation of the estimates. In this context, the stochastic model was superior and yielded very good estimates of the bioavailability parameters with only 8 samples per subject.

Adult↗