During pre-clinical pharmacokinetic research, it is not easy to gather complete pharmacokinetic data in each animal. In some cases, an animal can only provide a single observation. Under this circumstance, it is not c...During pre-clinical pharmacokinetic research, it is not easy to gather complete pharmacokinetic data in each animal. In some cases, an animal can only provide a single observation. Under this circumstance, it is not clear how to utilize this data to estimate the pharmacokinetic parameters effectively. This study was aimed at comparing a new method to handle such single-observation-per-animal type data with the conventional method in estimating pharmacokinetic parameters. We assumed there were 15 animals within the study receiving a single dose by intravenous injection. Each animal provided one observation point. There were five time points in total, and each time point contained three measurements. The data were simulated with a one-compartment model with first-order elimination. The inter-individual variabilities （ⅡV） were set to 10%, 30% and 50% for both clearance （CL） and apparent volume of distribution （V）. A proportional model was used to describe the residual error, which was also set to 10%, 30% and 50%. Two methods （conventional method and the finite msampling method） to handle with the simulated single-observation-per-animal type data in estimating pharmacokinetic parameters were compared. The conventional method （MI） estimated pharmacokinetic parameters directly with original data, i.e., single-observation-per-animal type data. The finite resampling method （M2） was to expand original data to a new dataset by resampling original data with all kinds of combinations by time. After resampling, each individual in the new dataset contained complete pharmacokinetic data, i.e., in this study, there were 243 （C3^1×C3^1×C3^1×C3^1×C3^1） kinds of possible combinations and each of them was a virtual animal. The study was simulated 100 times by the NONMEM software. According to the results, parameter estimates of CL and V by M2 based on the simulated dataset were closer to their true values, though there was a small difference among different combinations of ⅡVs and the residual errors. In general, M2 was less advantageous over M1 when the residual error increased. It was also influenced by the levels of ⅡV as higher levels of IIV could lead to a decrease in the advantage of M2. However, M2 had no ability to estimate the ⅡV of parameters, nor did M1. The finite resampling method could provide more reliable results compared to the conventional method in estimating pharmacokinetic parameters with single-observation-per-animal type data. Compared to the inter-individual variability, the results of estimation were mainly influenced by the residual error.展开更多
The double wave theory (DWT), sometimes called the“non_statistical quantum mechanics” by its proposer, describes the state of each single particle in an ensemble with two wave functions which have a parameter corres...The double wave theory (DWT), sometimes called the“non_statistical quantum mechanics” by its proposer, describes the state of each single particle in an ensemble with two wave functions which have a parameter corresponding to the particle. However the basic postulates of the DWT show that this theory can hardly describe any quantum rules of the microscopic world. In the double wave descriptions, the wave feature of the behavior of microscopic particles and the discontinuity characteristic of energy almost disappear. The discussions on several problems of the radiation atoms made by the DWT's proposer on the basis of this theory are either mathematically incorrect or inconsistent with experiments and the usual theory.展开更多
Motions of single poly（c-caprolactone） （PCL） molecules during the formation of the dendrite crystals in ultrathin films are captured by single molecule fluorescence microscopy. The relationship of single molecule ...Motions of single poly（c-caprolactone） （PCL） molecules during the formation of the dendrite crystals in ultrathin films are captured by single molecule fluorescence microscopy. The relationship of single molecule diffusion coefficient with the crystal growth rate, together with radius curvature, side-branch spacing of dendrite crystal and morphology are examined. The results support Mullins-Sekerka （MS） instability as the origin of lamellar branching induced by a diffusion field generated by a gradient of polymer segment density ahead of the crystal. Further analysis of the molecular trajectories has recognized different types of motions, depending on the distance to the crystal front： Fickian diffusion in regions far away from the crystal, sub-diffusion in regions adjacent to the crystal, and directed motion between these two regions. Anti-correlation of successive steps is discovered accompanying the sub-diffusion, providing a clear signature of macromolecule crowding at the crystal growth front. This anomalous diffusion process in polymer ultrathin films presents a new insight into the understanding of the retarded dynamics of interfacial mass transport towards the crystal front. It is considered to play a decisive role in controlling the crystal growth and evolution of crystal morphology.展开更多
文摘During pre-clinical pharmacokinetic research, it is not easy to gather complete pharmacokinetic data in each animal. In some cases, an animal can only provide a single observation. Under this circumstance, it is not clear how to utilize this data to estimate the pharmacokinetic parameters effectively. This study was aimed at comparing a new method to handle such single-observation-per-animal type data with the conventional method in estimating pharmacokinetic parameters. We assumed there were 15 animals within the study receiving a single dose by intravenous injection. Each animal provided one observation point. There were five time points in total, and each time point contained three measurements. The data were simulated with a one-compartment model with first-order elimination. The inter-individual variabilities （ⅡV） were set to 10%, 30% and 50% for both clearance （CL） and apparent volume of distribution （V）. A proportional model was used to describe the residual error, which was also set to 10%, 30% and 50%. Two methods （conventional method and the finite msampling method） to handle with the simulated single-observation-per-animal type data in estimating pharmacokinetic parameters were compared. The conventional method （MI） estimated pharmacokinetic parameters directly with original data, i.e., single-observation-per-animal type data. The finite resampling method （M2） was to expand original data to a new dataset by resampling original data with all kinds of combinations by time. After resampling, each individual in the new dataset contained complete pharmacokinetic data, i.e., in this study, there were 243 （C3^1×C3^1×C3^1×C3^1×C3^1） kinds of possible combinations and each of them was a virtual animal. The study was simulated 100 times by the NONMEM software. According to the results, parameter estimates of CL and V by M2 based on the simulated dataset were closer to their true values, though there was a small difference among different combinations of ⅡVs and the residual errors. In general, M2 was less advantageous over M1 when the residual error increased. It was also influenced by the levels of ⅡV as higher levels of IIV could lead to a decrease in the advantage of M2. However, M2 had no ability to estimate the ⅡV of parameters, nor did M1. The finite resampling method could provide more reliable results compared to the conventional method in estimating pharmacokinetic parameters with single-observation-per-animal type data. Compared to the inter-individual variability, the results of estimation were mainly influenced by the residual error.
文摘The double wave theory (DWT), sometimes called the“non_statistical quantum mechanics” by its proposer, describes the state of each single particle in an ensemble with two wave functions which have a parameter corresponding to the particle. However the basic postulates of the DWT show that this theory can hardly describe any quantum rules of the microscopic world. In the double wave descriptions, the wave feature of the behavior of microscopic particles and the discontinuity characteristic of energy almost disappear. The discussions on several problems of the radiation atoms made by the DWT's proposer on the basis of this theory are either mathematically incorrect or inconsistent with experiments and the usual theory.
基金supported by the National Natural Science Foundation of China (51573197)the National Basic Research Program of China (2014CB643601)
文摘Motions of single poly（c-caprolactone） （PCL） molecules during the formation of the dendrite crystals in ultrathin films are captured by single molecule fluorescence microscopy. The relationship of single molecule diffusion coefficient with the crystal growth rate, together with radius curvature, side-branch spacing of dendrite crystal and morphology are examined. The results support Mullins-Sekerka （MS） instability as the origin of lamellar branching induced by a diffusion field generated by a gradient of polymer segment density ahead of the crystal. Further analysis of the molecular trajectories has recognized different types of motions, depending on the distance to the crystal front： Fickian diffusion in regions far away from the crystal, sub-diffusion in regions adjacent to the crystal, and directed motion between these two regions. Anti-correlation of successive steps is discovered accompanying the sub-diffusion, providing a clear signature of macromolecule crowding at the crystal growth front. This anomalous diffusion process in polymer ultrathin films presents a new insight into the understanding of the retarded dynamics of interfacial mass transport towards the crystal front. It is considered to play a decisive role in controlling the crystal growth and evolution of crystal morphology.
