ABSTRACT
Chloroquine (CQ) efficacy was shown in some coronavirus disease 2019 (COVID-19) adult clinical studies. However, its data in children is still limited. Therefore, this study aims to assess the suitability of the dosage regimens from the literature and regimens proposed by the authors for pediatric COVID-19 patients aged 2-12 years old. The efficacy pharmacodynamic (PD) target was calculated for CQ blood concentration based on the literature's successfully treated COVID-19 adult regimen. The safety PD targets were derived from the literature regarding any adverse effects (AEs) and QTc prolongation. The adult pharmacokinetic (PK) parameters were transformed into pediatrics by allometric scaling (AS) method. A 10,000-time Monte Carlo simulation (MCS) was performed to calculate the percentage of probability to target attainment (%PTA). The literature's regimens were not capable of achieving 90%PTA efficacy PD target. The proposed regimens without loading dose (LD) achieved the efficacy target at day 8-10 which was later than the proposed regimens with LD (day 4-7). The 90%PTA below any AEs target was achieved in the first few days of the literature and proposed regimens but was unavoidable thereafter. Nevertheless, the 90%PTA below QTc prolongation target was favorably achieved by all regimens. This study revealed that the proposed regimen with LD seems to be the optimal dosage regimen. Additional studies are needed to validate our proposed regimens, especially among early-stage COVID-19 patients and recent major variants.
ABSTRACT
China’s new-type urbanisation, as a national strategy, is one of the reasons why the leap in development has been made in the last decade. Existing studies mainly focus on the status and outcomes of china’s new-type urbanisation while stressing not enough the overlooked aspects of new-type urbanisation policies that are currently in use. This paper aims at exploring the highlighted and overlooked aspects of policies of three key elements in China’s new-type urbanisation: population, land, and industry and their implementations. The complicated process and contradictions between formulation and implementation of the policies are extracted by analysing set goals and implemented situations of relative indicators from the three elements. The policies drove the population from separation to unity between household registered and actual residences, land from human land allometry to balance, and industry from traditional industrialisation to emerging service. Although these policies had significant achievements in the transitions of formulation, they still needed to be further implemented. Furthermore, this paper discusses corresponding reasons and potential directions to better the adoption of these policies for greater inclusion and systematic efficiency. The findings could not only highlight directions that improve existing policies of China’s new-type urbanisation but also provide guidance for inclusive and sustainable urbanisation practices in China as well as other cities in similar situations all over the world.
ABSTRACT
The primary motive of this study was to examine advantages of allometry scaling strategies for correct prediction of pharmacokinetics of Baricitinib in human from preclinical species. Baricitinib is basically Janus kinase (JAK) inhibitor used for the treatment of rheumatoid arthritis. Currently approved by FDA in combination with remdesivir for treatment of COVID-19 hospitalized patient. The literature published pharmacokinetic parameters (Cl and Vd) of preclinical species (Rat, Dog and monkey) were utilized for the allometry scaling of Baricitinib. The connection among the primary pharmacokinetic parameters [Volume of distribution (Vd) and clearance (Cl)] and body weight (BW) were studied across three preclinical species, we used the double logarithmic plots for prediction of the human pharmacokinetic parameters i.e. Cl and Vd with use of simple allometry and with additional correction factors for better prediction. The dose extrapolation of baricitinib was carried out by FDA guidelines. By application of the allometric scaling methods and principles correlation was found to be satisfactory for the prediction of intravenous human Cl and Vd for baricitinib. The volume of distribution (Vd) predicted by simple allometry (65.3 L) was found to be in agreement with the reported value (75.5 L);clearance (Cl) prediction by simple allometry was found to be at least 1.06 -closer to the reported value (245 mL/min);CF were used to predict the clearance. Both brain weight (B.W) and maximum life span potential (MLP) predicted the Cl with 0.52- and 0.61 -fold difference. The application of monkey liver blood flow predicted Cl with 0.81 fold which was also in close agreement with reported value. The Cl prediction was also extrapolated using LBF (Liver blood flow) method and observed that the higher species (Dog and Monkey) have predicted Cl with better accuracy than rat. Overall, the simple allometry (SA), monkey liver blood flow (MLBF) and application of liver blood flow (LBF) methods showed excellent correlation with human. The time vs. plasma concentration simulated graph also showed the similar closeness with human profile. The inclusion of plasma protein binding factor didn't improve the prediction accuracy. The FIH dose extrapolation were showed that PK guided approach and exponent for BSA based approach was found closer to actual human dose of 4.0 mg/Kg. Oriental Scientific Publishing Company
ABSTRACT
This article presents an overview of the dynamics of the human heart and the main goal is the discussion of its fluid mechanic features. We will see, however, that the flow in the heart can not be fully described without considering its electrophysiology and elastomechanics as well as the interaction with the systemic and pulmonary circulations with which it is strongly connected. Biologically, the human heart is similar to that of all warm-blooded mammals and it satisfies the same allometric laws. Since the Paleolithic Age, however, humans have improved their living conditions, have modified the environment to satisfy their needs and, more recently, have developed advanced medical knowledge which has allowed triple the number of heartbeats with respect to other mammals. In the last century, effective diagnostic tools, reliable surgical procedures and prosthetic devices have been developed and refined leading to substantial progress in cardiology and heart surgery with routine clinical practice which nowadays cures many disorders, once lethal. Pulse duplicators have been built to reproduce the pulsatile flow and ‘blood analogues’, have been realized. Heart phantoms, can attain deformations similar to the real heart although the active contraction and the tissue anisotropy still can not be replicated. Numerical models have also become a viable alternative for cardiovascular research: they do not suffer from limitations of material properties and device technologies, thus making possible the realization of truly digital twins. Unfortunately, a high-fidelity model for the whole heart consists of a system of coupled, nonlinear partial differential equations with a number of degrees of freedom of the order of a billion and computational costs become the bottleneck. An additional challenge comes from the inherent human variability and the uncertainty of the heart parameters whose statistical assessment requires a campaign of simulations rather than a single deterministic calculation;reduced and surrogate models can be employed to alleviate the huge computational burden and all possibilities are currently being pursued. In the era of big data and artificial intelligence, cardiovascular research is also advancing by exploiting the latest technologies: equation-based augmented reality, virtual surgery and computational prediction of disease progression are just a few examples among many that will become standard practice in the forthcoming years.