Comparison of calculation results of five population pharmacokinetic analysis tools / 中国临床药理学与治疗学

AIM: To compare the results calculated by population pharmacokinetic analysis tools Phoenix NLME, Monolix, R nlmixr package and CPhaMAS cloud platform with the gold standard sofeware NONMEM. METHODS: Fifty sparse sampling data sets based on a one-compartment model and fifty dense sampling data sets based on a two-compartment model were simulated, and the above five analysis tools were used to calculate the population typical value, individual variability and individual pharmacokinetic parameters. RESULTS: The population typical value and individual variability calculated by CPhaMAS and Phoenix NLME had the highest matching degree with NONMEM, followed by nlmixr. Monolix had the lowest matching degree, but Monolix and nlmixr might be more robust. The correspondence between clearance and distribution volume was better than the absorption rate constant. Except the absorption rate constant calculated by Monolix and intercompartmental clearance calculated by nlmixr, the correlation coefficients of individual pharmacokinetic parameters calculated by all analytical tools were greater than 0.99. CONCLUSION: The results calculated by the above four population pharmacokinetic analysis tools are highly correlated with that of NONMEM.

Estimating Brazilian states demands for intensive care unit and clinical hospital beds during the COVID-19 pandemic: development of a predictive model

ABSTRACT BACKGROUND: The fragility of healthcare systems worldwide had not been exposed by any pandemic until now. The lack of integrated methods for bed capacity planning compromises the effectiveness of public and private hospitals' services. OBJECTIVES: To estimate the impact of the COVID-19 pandemic on the provision of intensive care unit and clinical beds for Brazilian states, using an integrated model. DESIGN AND SETTING: Experimental study applying healthcare informatics to data on COVID-19 cases from the official electronic platform of the Brazilian Ministry of Health. METHODS: A predictive model based on the historical records of Brazilian states was developed to estimate the need for hospital beds during the COVID-19 pandemic. RESULTS: The proposed model projected in advance that there was a lack of 22,771 hospital beds for Brazilian states, of which 38.95% were ICU beds, and 61.05% were clinical beds. CONCLUSIONS: The proposed approach provides valuable information to help hospital managers anticipate actions for improving healthcare system capacity.

In vitro rumen biohydrogenation kinetics of mixed linoleic and alfa-linolenic acids / Cinética de biohidrogenación ruminal in vitro de los ácidos linoleico y alfa-linolénico mezclados / Cinética de biohidrogenação ruminal in vitro dos ácidos linoleico e alfa-linolênico misturados

Abstract Background: Dietary linoleic (LA) and alpha-linolenic (LN) acids are extensively isomerized and hydrogenated by rumen microbes, and this activity can further contribute to the fatty acid profile of ruminant- derived food products. Objective: To evaluate the effects of LA:LN ratio in lipid supplements on the rumen biohydrogenation kinetics of LA and LN, as well as on the trans-vaccenic acid (VA) production, using an in vitro system. Methods: Rumen fluid was collected from a fistulated steer, diluted with incubation buffer, and then incubated with 500 mg of kikuyu grass (Cenchrus clandestinus) supplemented with 16.3 mg of different LA:LN mixtures (100:0, 75:25, 50:50, 25:75 or 0:100). Incubations were performed in triplicate for a period of 0, 2, 4, 6, 8 or 16 hours. Differences between treatments were evaluated in a completely randomized design. Alternatively, computational chemistry was used to determine the changes in the Gibbs free energy (ΔGrxn) at 39 °C for the principal steps of LA and LN ruminal biohydrogenation. Results: Partial replacement of LA by LN decreased the VA concentration and its accumulation rate; it also increased the stearic acid concentration and the rates of transfer from LA to conjugated linoleic acid (CLA), and from CLA to VA. The conversion from CLA to VA (ΔGrxn = -2.65 kJ/mol) was more spontaneous than that from trans-11, cis-15 octadecadienoic acid (TA) to VA (ΔGrxn = -0.29 kJ/mol). Conclusion: The LA:LN ratio in lipids can modulate LA and LN biohydrogenation (BH) kinetics, as well as the VA production in the rumen.

Resumen Antecedentes: los ácidos linoleico (LA) y alfa-linolénico (LN) de la dieta son extensivamente isomerizados y biohidrogenados por los microorganismos ruminales, lo cual puede contribuir al perfil de ácidos grasos de los productos derivados de rumiantes. Objetivo: evaluar el efecto de la relación LA:LN en suplementos lipídicos sobre la cinética de biohidrogenación ruminal del LA y LN, como también sobre la producción del ácido trans-vaccénico (VA), usando un sistema in vitro. Métodos: se colectó fluido ruminal de un toro fistulado, el cual fue diluido con buffer de incubación y posteriormente incubado con 500 mg de pasto kikuyo (Cenchrus clandestinus) suplementado con 16,3 mg de diferentes mezclas de LA:LN (100:0, 75:25, 50:50, 25:75, o 0:100). Las incubaciones fueron desarrolladas en triplicado durante 0, 2, 4, 6, 8 o 16 horas. Diferencias entre tratamientos fueron evaluadas mediante un modelo completamente al azar. Alternativamente, se determinaron los cambios en energía libre de Gibbs ( Δ Grxn) a 39 °C para los pasos principales de la biohidrogenación del LA y LN, usando química computacional. Resultados: la sustitución parcial de LA por LN disminuyó la concentración de VA y su tasa de acumulación, como también incrementó la concentración de ácido esteárico y las tasas de transferencia de LA para ácido linoleico conjugado (CLA) y de CLA para VA. La conversión de CLA para VA ( Δ Grxn = -2,65 kJ/mol) fue más espontánea que la conversión del ácido trans-11, cis-15 octadecadienóico (TA) para VA ( Δ Grxn = -0,29 kJ/mol). Conclusiones: la relación LA:LN en lípidos puede modular la cinética de biohidrogenación (BH) del LA y LN y la producción de VA en el rumen.

Resumo Antecedêntes: o ácido linoleico (LA) e alfa-linolênico (LN) da dieta, são extensivamente isomerizados e biohidrogenados pelos microorganismos do rúmen, o que pode contribuir ao perfil de ácidos graxos dos produtos derivados de ruminantes. Objetivo: avaliar o efeito da relação LA:LN em suplementos lipídicos sobre a cinética de biohidrogenação ruminal do LA e LN como também sobre a produção do ácido trans- vaccênico (VA), utilizando um sistema in vitro. Métodos: coletou-se fluido ruminal de um novilho fistulado, o qual foi diluído com tampão de incubação e, em seguida, incubado com 500 mg de pasto kikuyu (Cenchrus clandestinus) suplementado com 16,3 mg de diferentes misturas LA:LN (100:0, 75:25 , 50:50, 25:75 ou 0:100). As incubações foram desenvolvidas em triplicata, durante 0, 2, 4, 6, 8 ou 16 horas. Diferenças entre tratamentos foram avaliadas utilizando-se um delineamento inteiramente casualizado. Alternativamente, foram determinadas as mudanças em energia livre de Gibbs ( Δ Grxn) a 39 °C para as principais etapas da biohidrogenação do LA e LN, utilizando-se química computacional. Resultados: a substituição parcial de LA por LN diminuiu a concentração de VA e sua taxa de acumulação, como também aumentou a concentração de ácido esteárico e as taxas de transferência do LA para o ácido linoleico conjugado (CLA) e do CLA para VA. A conversão do CLA para VA ( Δ Grxn = -2,65 kJ/ mol) foi mais espontânea que a conversão do ácido trans-11, cis-15 octadecadienóico (TA) para VA ( Δ Grxn = -0,29 kJ/mol). Conclusões: a relação LA:LN em lipídeos pode modular a cinética de biohidrogenação (BH) do LA e LN e a produção de VA no rúmen.

Estimation of Pharmacokinetic Parameters Using Nonlinear Fixed Effects One Compartment Open Model.

Pharmacokinetics (PK) is the science of the kinetics of drug absorption, distribution and elimination. Statistical methods are usually used for PK parameter estimation producing nonlinear responses where drug effect mechanism is modeled using compartmental approach. In the present study, PK parameters were estimated with nonlinear fixed effects one compartment open model where drug dose and sampling time are covariates and the plasma drug concentration is dependent variable. The PK parameters namely absorption rate constant (a), elimination rate constant (b) and apparent volume of distribution (V) were estimated using nonlinear least square method for each individual separately and for all individuals collectively with longitudinal or multiple response plasma drug concentration-time data obtained from 24 healthy human volunteers with reference drug product of Atorvastatin. The estimates for combined data were â =0.13±0.13hr-1, 􀜾􀷡 =0.49±0.13hr-1, 􀜸􀷡 =248±0.05L. All the individuals were again stratified into three categories based on Body Mass Index (BMI) and the PK parameters were estimated for each stratum accordingly (stratum-normal: â=0.12±0.17hr-1, 􀜾 􀷠 =0.47±0.17hr-1, 􀜸 􀷠 =250.24±0.07L; stratum-overweight: â =0.15±0.24hr-1, 􀜾􀷡 =0.47±0.25hr-1, 􀜸􀷡 =267.25±0.09L; stratumunderweight: â =0.13±0.13hr-1, 􀜾 􀷠 =0.49±0.13hr-1, 􀜸 􀷠=245±0.05L).

Evaluation of Myocardial Oxygen Consumption with 11C-Acetate and 3D PET/CT: By Applying Recirculation Correction Method and Modified One-Compartmental Tracer Kinetic Modeling / 핵의학분자영상

PURPOSE: We intended to evaluate myocardial oxygen consumption (MVO2) by applying recirculation correction and modified one-compartment model to have a reference range of MVO2 in normal young population and to reveal the effect of recirculation on time-activity curve (TAC). Materials and METHODS: In nine normal male volunteers with mean age of 26.3+/-4.0, MVO2 was estimated with 925 MBq (25mCi) of 11C-Acetate (Neuroscience Research Institute, Gachon University of Medicine and Science, Incheon, Korea) and PET/CT (Biograph 6, Siemens Medical Solution, Germany). Analysis software such as MATLAB(R) v7.1 (Mathworks, Inc., United States), Excel(R) 2007 (Microsoft, United States), and SPSS(R) v12.0 (Apache Software Foundation, United States) were used. Twenty three frames were of 12 x 10, 5 x 60, 3 x 120, 2 x 300's duration, respectively. The modified one-compartmental model and the recirculation correction method were applied. Statistical analysis was performed by using Test of Normality, ANOVA and Post-Hoc (Scheffe's) analysis, and p-value less than 0.05 was considered as significant. RESULTS: The normal reference ranges of MVO2 were presented as 3.18-4.64 x 10(-4) ml/g/sec, 1.91-3.94 x 10(-4) ml/g/sec, 4.31-6.40 x 10(-4) ml/g/sec, 2.84-4.53 x 10(-4) ml/g/sec and 3.42-5.00 x 10(-4) ml/g/sec in the septum, the inferior wall, the lateral wall, the anterior wall and the entire wall, respectively. In addition, it was noted that the dual exponentiality of the clearance curve is due to the recirculation effect and that the characteristic of the curve is essentially mono-exponential. CONCLUSION: 11C-Acetate is a radiotracer worthwhile to assess MVO2. Re-circulated 11C can influence TAC of 11C in myocadia and so the recirculation correction must be considered when measuring MVO2.

Establishment of a network pharmacokinetic model for multiple component drugs and parameter analyses / 中国临床药理学与治疗学

AIM:To establish a network pharmacoki- netic model for studying multiple drug components and analyzing their parameters.METHODS:A model has been set up based on the compartment and linear kinetic theories,and the solutions have been obtained by Laplace transform method.The relations between the whole comp- artment model and network model for multiple component have been comparatively studied and their kinetic parame- ters have also been estimated and analyzed.RESULTS: The multiple component network pharmacokinetics follow a first order linear mammillary model.C_i is a polynomial of power index number e,which is similar to the whole compartment model.Various parameters(transit constant) were calculated by the expression of matrix consisting of?_i and the compartment parameters.Its kinetic parameters can be obtained on the basis of the whole compartment model.CONCLUSION:The multiple component net- work pharmacokinetic parameters can be obtained and an- alyzed similarly as the whole compartment model.