The Relationship Between Internal and External Dose: Some General Results Based on a Generic Compartmental Model

2020 ◽  
Vol 177 (1) ◽  
pp. 60-70 ◽  
Author(s):  
Wout Slob ◽  
Marco J Zeilmaker ◽  
Rudolf T Hoogenveen

Abstract Statements on how the internal-to-external-dose (IED) relationship looks like are often based on qualitative toxicokinetic arguments. For example, the recently proposed kinetically derived maximum dose (KMD) states that the IED relationship must have an inflection point, due to saturation of underlying processes like metabolism or absorption. However, such statements lack a solid quantitative foundation. Therefore, we derived expressions for the IED relationship for a number of scenarios based on a generic compartmental model involving saturation. The scenarios included repeated or single dose, and saturable metabolism or saturable absorption. For some of these scenarios, an explicit expression for the IED relationship can be derived, for others only implicit expressions can be established, which need to be evaluated numerically. The results show that saturable processes will lead to an IED relationship that is nonlinear over the whole dose range, ie, it can be approximated by a linear relationship at the lower end, whereas the approximation will become gradually poorer with increasing doses. The finding that saturation does not lead to an inflection point in the IED relationship, as assumed in the KMD, implies that the KMD is not a valid approach for selecting the top dose in toxicological studies. An additional use of our results is that the derived explicit expressions of the IED relationship can be fitted to IED data, and, possibly, for extrapolation outside the observed dose range.

1996 ◽  
Vol 84 (4) ◽  
pp. 782-788. ◽  
Author(s):  
Heiko Ropcke ◽  
Helmut Schwilden

Background The volatile anesthetic sparing effect of nitrous oxide in clinical studies is less than might be expected from the additivity of minimum alveolar concentration values. Other studies identify nonadditive interactions between isoflurane and nitrous oxide. The aim of this study was to quantify the interaction of isoflurane and nitrous oxide at a constant median electroencephalographic frequency. Methods Twenty-five patients were studied during laparotomies. Nitrous oxide was randomly administered in concentrations of 0, 20, 40, 60, and 75 vol%, to ten patients for each nitrous oxide concentration. Isoflurane vaporizer settings were chosen so that the median electroencephalographic frequency was held between 2 and 3 Hz. The relationship between nitrous oxide concentrations and required isoflurane concentrations was examined with the method of isoboles. Results Nitrous oxide linearly decreased the isoflurane requirement. Addition of every 10 vol% of nitrous oxide decreases the isoflurane requirement by approximately 0.04 vol%. The total anesthetic requirement of isoflurane and nitrous oxide, expressed in terms of previously reported minimum alveolar concentration values, increased significantly with increasing nitrous oxide concentrations. Conclusions The interaction of isoflurane and nitrous oxide in the dose range 0-75 vol% on median electroencephalographic frequency is compatible with additivity. The potency of nitrous oxide as a substitute for isoflurane is less than on a minimum alveolar concentration basis. Maintaining median electroencephalographic frequency more appropriately reflects the clinical usage of isoflurane and nitrous oxide than does maintaining minimum alveolar concentration.


2021 ◽  
Author(s):  
Jiří Mihola

The monograph develops the theory of production functions and their systematic typology. It looks at the relationship between inputs and outputs as a universal relationship that is used not only in economics but also in other disciplines. In addition to the static production function, special attention is paid to the dynamization of individual quantities and the issue of expressing the effect of changes in these quantities on the change in production. It is explained why in the aggregate production function expressed through aggregate factor input and aggregate factor productivity it is necessary to use a multiplicative relationship, why the multiplicative link is also suitable in terms of total input factor and why the share of weights in labor and capital should be the same. The use of the production function is demonstrated on the development of the economies of the USA, China and India and on the ten largest economies of the world in terms of absolute GDP, on cryptocurrencies and on the so-called farming role.In addition to a comprehensive overview of production functions, the monograph also enriches new ideas that arose during long-term computational and analytical activities of economic and business. Particularly innovative is the generalization of the production function to any system with variable inputs and outputs. The production function can thus be recognized in many identities. The original intention of the research was to examine the intensity of economic development, but it turned out that it is closely related to production functions. The impetus for this research comes from Prof. Ing. František Brabec, DrSc. a genius mathematician, designer, economist and manager, former general director of Škoda in Pilsen and later rector of ČVÚT.The presented typology of production functions is not limited to one area of economics, but goes beyond it. The monograph respects the definition of the static production function as the maximum amount of production that can be produced with a given number of production factors. On this function, which can be effectively displayed using polynomial functions of different orders,significant points can be systematically defined, ie the inflection point, the point of maximum efficiency, the point of maximum profit and the point of maximum production. The purpose is to optimize the number of inserted production factors. The text is preferred the point with the greatest effectiveness. If this quantity does not correspond, for example, to demand, it is possible to choose another technology, which will be reflected in a shift in the static production function. At the same time, the important points of these functions describe the trajectory, which has the nature of a dynamic production function. For a dynamic production function, the crucial question is how the change in individual factors contributes to the overall change in output. If the production function is expressed through inputs and their efficiency, dynamic parameters of extensibility and intensity can be defined, which exactly express the effect of changes in inputs and the effect of changes in efficiency on changes in outputs for all possible situations. Special attention is paid to the aggregate production function. It explains why it should be expressed as the product of the aggregate input factor (TIF) and aggregate factor productivity (TFP), or why the term TIF should be expressed as a weighted product of labor and capital, in which the value of labor and capital weights could be and identical. The monograph here surpasses the traditional additive view of the multi-factor production function by proposing a multiplicative link, which also allows the derivation of growth accounting, but with a new interpretation of weights and (1-), which do not need to be calculated for each subject and each year.The time production function is used to forecast the GDP development of the US, China and India economies until 2030 and 2050, respectively. It is also predicted an increase in the absolute GDP of Indonesia, a stable position of Russia and the loss of the elite position of Japan and Germany.The monograph also deals with the hitherto unresolved question of whether, even in economics, it is also necessary in certain circumstances to take into account a phenomenon called quantization in physics. It turns out that quantization is a common thing in economics, which is documented on specific forms of production functions that respect quantization in economics.The monograph also deals with the relationship between the efficiency of an individual given the use of a certain point on a specific static production function and common efficiency, ie all actors together. These examples assume limited resources. The sum of the outputs of all actors depends on how the actors share these limited resources. It can be expected that there will be at least one method of distribution that will bring the highest sum of outputs (products, crops) of all actors. This result, however, also depends on the shape of the production functions. This is investigated using EDM, i.e.elementary distribution models. EDM for polynomial production functions of the 2nd to 5th order are not yet published in summary. Of the new findings, they are the most interesting. When using two polynomial production functions, the EDM boundary becomes linear if the inflection point is used for both production functions. If we are above the inflection point, the EDM is properly concave. It turned out that the "bending" of the production function in the region of the inflection point can be modeled using a quantity of the order of the respective polynomial. The higher the order of the polynomial, the higher the deflection can be achieved. This proved to be a very important finding in modeling specific production functions. This effect cannot be achieved by combining other parameters.


2021 ◽  
Vol 12 ◽  
Author(s):  
Molly S. Helt ◽  
Taylor M. Sorensen ◽  
Rachel J. Scheub ◽  
Mira B. Nakhle ◽  
Anna C. Luddy

Both individuals with diagnosed with Autism Spectrum Disorder (ASD) and individuals high in psychopathic traits show reduced susceptibility to contagious yawning; that is, yawning after seeing or hearing another person yawn. Yet it is unclear whether the same underlying processes (e.g., reduced eye gaze) are responsible for the relationship between reduced contagion and these very different types of clinical traits. College Students (n = 97) watched videos of individuals yawning or scratching (a form of contagion not reliant on eye gaze for transmission) while their eye movements were tracked. They completed the Interpersonal Reactivity Index (IRI), the Autism-Spectrum Quotient (AQ), the Psychopathy Personality Inventory-Revised (PPI-R), and the Adolescent and Adult Sensory Processing Disorder Checklist. Both psychopathic traits and autistic traits showed an inverse relationship to contagious yawning, consistent with previous research. However, the relationship between autistic (but not psychopathic) traits and contagious yawning was moderated by eye gaze. Furthermore, participants high in autistic traits showed typical levels of contagious itching whereas adults high in psychopathic traits showed diminished itch contagion. Finally, only psychopathic traits were associated with lower overall levels of empathy. The findings imply that the underlying processes contributing to the disruptions in contagious yawning amongst individuals high in autistic vs. psychopathic traits are distinct. In contrast to adults high in psychopathic traits, diminished contagion may appear amongst people with high levels of autistic traits secondary to diminished attention to the faces of others, and in the absence of a background deficit in emotional empathy.


Author(s):  
Mingliang Zhao ◽  
Fangyi Liu ◽  
Wei Sun ◽  
Xin Tao

Promoting the coordinated development of industrialization and the environment is a goal pursued by all of the countries of the world. Strengthening environmental regulation (ER) and improving green total factor productivity (GTFP) are important means to achieving this goal. However, the relationship between ER and GTFP has been debated in the academic circles, which reflects the complexity of this issue. This paper empirically tested the relationship between ER and GTFP in China by using panel data and a systematic Gaussian Mixed Model (GMM) of 177 cities at the prefecture level. The research shows that the relationship between ER and GTFP is complex, which is reflected in the differences and nonlinearity between cities with different monitoring levels and different economic development levels. (1) The relationship between ER and GTFP is linear and non-linear in different urban groups. A positive linear relationship was found in the urban group with high economic development level, while a U-shaped nonlinear relationship was found in other urban groups. (2) There are differences in the inflection point value and the variable mean of ER in different urban groups, which have different promoting effects on GTFP. In key monitoring cities and low economic development level cities, the mean value of ER had not passed the inflection point, and ER was negatively correlated with GTFP. The mean values of ER variables in the whole sample, the non-key monitoring and the middle economic development level cities had all passed the inflection point, which gradually promoted the improvement of GTFP. (3) Among the control variables of the different city groups, science and technology input and the financial development level mainly had positive effects on GTFP, while foreign direct investment (FDI) and fixed asset investment variables mainly had negative effects.


2019 ◽  
Vol 30 ◽  
pp. v662-v663
Author(s):  
S. Kajiura ◽  
S. Chikaoka ◽  
T. Yokota ◽  
A. Kadota ◽  
S. Fukai ◽  
...  

2020 ◽  
Vol 318 (1) ◽  
pp. H135-H142
Author(s):  
Takamitsu Nakamura ◽  
Takeo Horikoshi ◽  
Kiyotaka Kugiyama

Coronary arteries with advanced atherosclerosis do not necessarily have greater contractile responses than those with early atherosclerosis. This study aimed to clarify the relationship between thickness of the medial layer and the contractile response to acetylcholine (ACh) in coronary artery using optical coherence tomography (OCT). The OCT and the vasomotor response to ACh in the left anterior descending coronary artery were assessed in 32 patients with previous myocardial infarction. The intimal and medial layer areas were measured by planimetric analysis of the OCT images. The coronary contractile response to ACh had a positive linear relationship with medial area ( r = 0.61, P < 0.001). In contrast, the relationship between the coronary contractile response to ACh and intimal area was described by an inverted U-shaped curve that was fitted to a quadratic regression model ( R2 = 0.35, P = 0.002, y-axis, contraction; x-axis, intimal area). The contractile response increased as the intimal layer thickened up to the inflection point; thereafter, the contractile response declined. The relationship between medial area and intimal area was also described by an inverted U-shaped curve that was fitted to a quadratic regression model ( R2 = 0.41, P < 0.01, y-axis, medial area; x-axis, intimal area). The medial area increased as the intimal area thickened up to the inflection point; thereafter, the medial area thinned. In conclusion, the thinned medial layer was associated with the attenuated contractile response in a coronary artery with greater atherosclerosis. NEW & NOTEWORTHY This is the first clinical study to show the relationship between the contractile response and the thickness of medial smooth muscle layer in coronary artery of patients with previous myocardial infarction using OCT. The contractile response to acetylcholine was attenuated, and medial layer area was thinned in coronary artery with greater atherosclerosis compared with those in coronary artery with mild or moderate atherosclerosis. The coronary contractile response was positively correlated with thickness of the medial layer in coronary arteries with either mild or greater atherosclerosis. Thus, coronary arteries with advanced atherosclerosis do not necessarily have greater contractile responses than those with early atherosclerosis, which could be related to the thinned medial layer.


2020 ◽  
Author(s):  
Sophie-Charlotte Lappe ◽  
Georg Winkens ◽  
Joerg Persson ◽  
Shibabrata Nandi ◽  
Oleg Petracic

&lt;p&gt;Paleomagnetic measurements provide very important methods to study the evolution of and variations in the Earth&amp;#8217;s magnetic field throughout time. A vital tool used in paleomagnetism are natural magnetic minerals, such as the titanomagnetite (&lt;em&gt;TM&lt;/em&gt;) solid solution series (Fe&lt;sub&gt;3-&lt;em&gt;x&lt;/em&gt;&lt;/sub&gt;Ti&lt;em&gt;&lt;sub&gt;x&lt;/sub&gt;&lt;/em&gt;O&lt;sub&gt;4&lt;/sub&gt;, 0 &amp;#8804; &lt;em&gt;x&lt;/em&gt; &amp;#8804; 1). The main source of magnetic information in &lt;em&gt;TM&lt;/em&gt;s is the thermal remanent magnetisation (&lt;em&gt;TRM&lt;/em&gt;) they retain whilst being cooled below their Curie temperature (&lt;em&gt;T&lt;sub&gt;C&lt;/sub&gt;&lt;/em&gt;) during their formation.&lt;/p&gt;&lt;p&gt;The key factor determining the &lt;em&gt;T&lt;sub&gt;C&lt;/sub&gt;&amp;#160; &lt;/em&gt;is the composition. However, recent studies on natural and synthetic TM powders [1,2,3] have shown that their &lt;em&gt;T&lt;sub&gt;C&lt;/sub&gt;&amp;#160; &lt;/em&gt;is also heavily influenced by their thermal history. Annealing various natural and synthetic &lt;em&gt;TM&lt;/em&gt; powders at temperatures between 300&amp;#176;C and 425&amp;#176;C for timescales of hours to months resulted in changes in their &lt;em&gt;T&lt;sub&gt;C&lt;/sub&gt;&amp;#160; &lt;/em&gt;of up to 150&amp;#176;C.&lt;/p&gt;&lt;p&gt;The accuracy of many paleomagnetic measuring techniques, such as geomagnetic paleointensity estimates and paleomagnetic paleothermometry, depends on the exact knowledge of the Curie temperature. Changes in &lt;em&gt;T&lt;sub&gt;C&lt;/sub&gt;&amp;#160; &lt;/em&gt;of such a considerable extend could deeply impact those techniques or even render them doubtable. So far, vacancy-mediated chemical clustering at the octahedral site of the &lt;em&gt;TM&lt;/em&gt; structure has been postulated as the mechanism causing this phenomenon [2,3]. To further investigate the underlying processes, we synthesised a large (~6.5 mm diameter;&amp;#160; ~27 mm length) &lt;em&gt;TM&lt;/em&gt; single crystal using an optical floating zone furnace. Via SEM-EDX techniques it was established that the crystal was homogenous over its whole length with a composition of&amp;#160; Fe&lt;sub&gt;2.64&lt;/sub&gt;Ti&lt;sub&gt;0.36&lt;/sub&gt;O&lt;sub&gt;4&lt;/sub&gt;. Using a Physical Properties Measurement System (&lt;em&gt;PPMS&lt;/em&gt;) the Curie temperatures of several pieces of the crystal were determined after different annealing treatments. For the first time it has been possible to detect systematic changes in &lt;em&gt;T&lt;sub&gt;C&lt;/sub&gt;&amp;#160; &lt;/em&gt;with annealing in a &lt;em&gt;TM&lt;/em&gt; single crystal.&lt;/p&gt;&lt;p&gt;Additionally within the scope of this project it was possible to determine the relationship between the extend of change in &lt;em&gt;T&lt;sub&gt;C&lt;/sub&gt;&amp;#160; &lt;/em&gt;and the microstructure for polycrystalline samples.&lt;/p&gt;&lt;p&gt;&amp;#160;&lt;/p&gt;&lt;p&gt;[1] Bowles, J. A., Jackson, M. J., Berqu&amp;#243;, T. S., Solheid, P. A. and Gee, J. S. (2013), Nature Communications, 4, 1916. https://doi:10.1038/ncomms2938&lt;/p&gt;&lt;p&gt;[2] Jackson, M. J., and Bowles, J. A. (2018), J. Geophys. Res., 123, 1-20. https://doi:10.1002/2017JB015193&lt;/p&gt;&lt;p&gt;[3] Bowles, J. A., Lappe, S.&amp;#8208;C. L. L., Jackson, M. J., Arenholz, E., &amp; van der Laan, G. (2019). Geochem. Geophy. Geosy. 20. https://doi.org/10.1029/2019GC008217&lt;/p&gt;


2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 818-818
Author(s):  
Shinya Kajiura ◽  
Shingo Chikaoka ◽  
Ayaka Kadota ◽  
Sakie Fukai ◽  
Takako Matsushita ◽  
...  

818 Background: Opioid-induced constipation (OIC) is the most common side effect of opioid therapy. Laxatives are usually used as a first-line treatment for OIC. Treatment options for OIC are switching to other opioids associated with less frequent OIC, such as Fentanyl. Naldemedine is an orally active peripherally acting µ-opioid receptor antagonists that was approved in Japan from 2017 for management of cancer-related OIC. The aim of this study is to investigate the relationship between Naldemedine administration and the maximum dose of oral Oxycodone which is the most frequently used oral opioids at our hospital. Methods: During June 2017 and December 2018, a total of 217 patients with cancer-related pain received Oxycodone at our institution. The first group of the patients concurrently received Naldemedine 0.2 mg daily (group A, n = 101), and the second group didn’t receive it (group B, n = 116) for cancer-related OIC reduction. We compared the maximum Oxycodone dose between two groups by medical record retrospectively. Results: The median age of group A was 69 y.o. (range 20-87 y.o.), and the median age of group B was 67 y.o. (range 27-88y.o.). There was no significant difference in common patient background between group A and B. The median dose of maximum Oxycodone dose of group A was 40 mg/day (range 10-480 mg/day), and that of group B was 20 mg/day (range 10-320 mg/day). There was a significant difference in the median dose of maximum Oxycodone between group A and B (Mann-Whitney U test, P < 0.0001). In Group A, the administration was started in 31 patient Naldemedine and Oxycodone at the same time. As for 70 remaining patients, the administration was started when they had constipation after oxycodone was administrated. In those patients, the median days was 19 days from the Oxycodone administration starting date to the Naldemedine administration starting date. Conclusions: Naldemedine administration in patients with cancer-related OIC may increase the maximum dose of oral Oxycodone.


2004 ◽  
Vol 22 (5) ◽  
pp. 935-942 ◽  
Author(s):  
Bin Peng ◽  
Michael Hayes ◽  
Debra Resta ◽  
Amy Racine-Poon ◽  
Brian J. Druker ◽  
...  

Purpose To evaluate the basic pharmacokinetic (PK) characteristics of imatinib mesylate and assess the relationship between the PK and pharmacodynamic (PD) properties of the drug. Patients and Methods The PK and PD properties of imatinib were investigated during a phase I trial that included 64 adult patients with Philadelphia chromosome–positive leukemias. Patients received imatinib orally once or twice daily. PK parameters of imatinib, derived from the plasma concentration–time curves, were determined. PD response, defined as the WBC after 1 month of treatment with imatinib, was used to develop an efficacy model. A maximum inhibition–effect model was used to describe the relationship between reduction in WBC and drug exposure parameters. Results Imatinib exposure was dose proportional after oral administration for the dose range of 25 to 1,000 mg. There was a 1.5- to three-fold drug accumulation after repeated once-daily dosing. Mean plasma trough concentration was 0.57 μg/mL (approximately 1 μmol/L) 24 hours after administration of 350 mg of imatinib at steady-state, which exceeds the 50% inhibitory concentration required to inhibit proliferation of Bcr-Abl–positive leukemic cells. Analysis of PK/PD relationships indicates that the initial hematologic response depends on the administered dose for patients with chronic myeloid leukemia. Conclusion Drug exposure (area under the concentration-time curve) is dose proportional for the dose range of 25 to 1,000 mg, and there is a 1.5- to three-fold drug accumulation at steady-state after once-daily dosing. Analysis of the relationship between PD (WBC reduction) and PK parameters at steady-state indicates that a dose of 400 mg or greater is required for maximal PD effect.


2021 ◽  
Author(s):  
Fan Yang ◽  
Xiaohan Ding ◽  
Zhuangsen Chen ◽  
Yan Liao ◽  
Miaoling Chen ◽  
...  

Abstract BackgroundThe triglyceride glucose-body mass index (TyG-BMI) has been proposed as a marker of insulin resistance (IR). However, evidence for the relationship between TyG-BMI and the incidence of diabetes mellitus remains limited. This study investigated the association between TyG-BMI and diabetes occurrence in Chinese individuals.MethodsThis retrospective study included a cohort of 204978 non-diabetic individuals using data from healthy screening program data in China between 2010 and 2016. The independent and dependent variables are TyG-BMI and incident of diabetes, respectively. Cox proportional hazards regression analysis was used to evaluate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the relationship between TyG-BMI and incident diabetes. Generalized additive models were used to identify non-linear relationships. Subgroup analysis helped better understand other factors that may affect the association between TyG-BMI and diabetes to identify potential special populations. And the data were downloaded from the DATADRYAD website.ResultOur study indicated that the incidence of diabetes increases with the rise of TyG-BMI (HR = 1.023, 95%CI(1.022, 1.024) ) after adjusting age, gender, SBP, DBP, TC, HDL, LDL, ALT, AST, Scr, smoking status, drinking status, family history. There was a nonlinear relationship between TyG-BMI and the incidence of diabetes, and the inflection point was 232.416. The effect size and confidence interval of the left and right sides of the inflection point were 1.029 (1.027, 1.031), 1.016 (1.014, 1.018), P for interaction < 0.0001. Subgroup analysis showed that the correlation was stronger in the population aged 20–30 (P for interaction < 0.0001, HR 1.029, 95%CI:1.024 to 1.035),and the same trend was found in the following populations: age 30–40(HR = 1.032), age 40–50(HR = 1.029), HDL (high group) (HR = 1.024 ), SBP<140(HR = 1.025), DBP<90(HR = 1.024), current drinker(HR = 1.031), and ever drinker(HR = 1.032).ConclusionThis study demonstrated that increased TyG-BMI was positively correlated with incident diabetes in Chinese. TyG-BMI and incident diabetes had non-linear relationship. Before and after TyG-BMI equals 232.416, the risk of diabetes increased by 2.9% and 1.6%, respectively, when TyG-BMI increased one unit.


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