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Purpose: Το formulate a methodology for the assessment of bioequivalence using metrics, which are based on the physiologically sound F.A.T., Methods: The equations of the physiologically based finite time pharmacokinetic models for the one-and two-compartment model with one and two input stages of absorption were solved to derive metrics for the extent and rate of absorption. Simulated data were used to study the proper way for the estimation of metrics. A bioequivalence study was analyzed using these metrics., Results: The rate of drug absorption was found to be equal to the slope of the amount absorbed versus time curve. The amount of drug absorbed at the end of the absorption process, corresponding to the blood concentration at F.A.T. is an indicator of the extent of absorption. The plot of the ratio test/reference of the simulated data for the amount absorbed as a function of time becomes constant beyond the end of drug absorption from the formulation exhibiting the longer absorption. The assessment of the bioequivalence study was based on the slope of the amount absorbed versus time curve for the rate of absorption, while the estimate for the constant ratio test/reference for the amount absorbed was used for the assessment of extent of absorption., Conclusions: The assessment of rate in bioequivalence studies can be based on the estimation of slope of the percent absorbed versus time curve while the constant ratio test/reference for the amount of drug absorbed is an indicator of the extent of absorption., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To revise the IVIVC considering the physiologically sound Finite Absorption Time (F.A.T.) and Finite Dissolution Time (F.D.T.) concepts., Methods: The estimates τ and τ d for F.A.T. and F.D.T., respectively are constrained by the inequality τ d  ≤ τ; their relative magnitude is dependent on drug's BCS classification. A modified Levy plot, which includes the time estimates for τ and τ d was developed. IVIVC were also considered in the light of τ and τ d estimates. The modified Levy plot of theophylline, a class I drug, coupled with the rapid (30 min) and very rapid (15 min) dissolution time limits showed that drug dissolution/absorption of Class I drugs takes place in less than an hour. We reanalyzed a carbamazepine (Tegretol) bioequivalence study using PBFTPK models to reveal its complex absorption kinetics with two or three stages., Results: The modified Levy plot unveiled the short time span (~ 2 h) of the in vitro dissolution data in comparison with the duration of in vivo dissolution/absorption processes (~ 17 h). Similar results were observed with the modified IVIVC plots. Analysis of another set of carbamazepine data, using PBFTPK models, confirmed a three stages absorption process. Analysis of steady-state (Tegretol) data from a paediatric study using PBFTPK models, revealed a single input stage of duration 3.3 h. The corresponding modified Levy and IVIVC plots were found to be nonlinear., Conclusions: The consideration of Levy plots and IVIVC in the light of the F.A.T. and F.D.T. concepts allows a better physiological insight of the in vitro and in vivo drug dissolution/absorption processes., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: The Wagner-Nelson and Loo-Riegelman methods developed in the 1960s and used since for the construction of percent of drug absorbed as a function of time as well as in in vitro in vivo correlations are re-considered in the light of the physiologically sound Finite Absorption Time (F.A.T.) concept developed recently., Methods: The classical equations for the percentage of drug absorption as a function of time were modified by taking into account the termination of drug absorption at F.A.T., replacing the parameters associated with the assumption of infinite drug absorption., Results: Mathematical analysis using the relevant Physiologically Based Pharmacokinetic Finite Time (PBFTK) models assuming one- or two-compartment drug disposition, revealed that the modified %absorbed versus time curves are of bilinear type with an ascending limb intersecting the horizontal line at F.A.T. A computer-based methodology is described for the estimation of F.A.T. from experimental data. More than one linear ascending limb is found when more than one absorption phase is operating. Experimental data were analyzed and the estimates for F.A.T were found to be similar to those derived from nonlinear regression analysis using PBFTPK models., Conclusion: These results place an end to the routinely reported exponential %absorbed versus time curves prevailing in biopharmaceutics-pharmacokinetics since their inception in the'60 s. These findings point to the use of the F.A.T. concept in drug absorption research and regulatory guidelines such as deconvolution techniques for the assessment of drug input rate, stochastic mean absorption time calculations, population analyses, in vitro in vivo correlations and bioequivalence guidelines., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background and Objectives: Naloxone for opioid overdose treatment can be administered by intravenous injection, intramuscular injection, or intranasal administration. Published data indicate differences in naloxone pharmacokinetics depending on the route of administration. The aim of this study was to analyze pharmacokinetic data in the same way that we recently successfully applied the concept of the finite absorption time in orally administered drug formulations., Methods: Using the model equations already derived, we performed least squares analysis on 24 sets of naloxone concentration in the blood as a function of time., Results: We found that intramuscular and intranasal administration can be described more accurately when considering zero-order absorption kinetics for finite time compared with classical first order absorption kinetics for infinite time., Conclusions: One-compartment models work well for most cases. Two-compartment models provide better details, but have higher parameter uncertainties. The absorption duration can be determined directly from the model parameters and thus allow an easy comparison between the ways of administration. Furthermore, the precise site of injection for intramuscular delivery appears to make a difference in terms of the duration of the drug absorption., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

To date, mechanistic modeling of oral drug absorption has been achieved via the use of physiologically based pharmacokinetic (PBPK) modeling, and more specifically, physiologically based biopharmaceutics model (PBBM). The concept of finite absorption time (FAT) has been developed recently and the application of the relevant physiologically based finite time pharmacokinetic (PBFTPK) models to experimental data provides explicit evidence that drug absorption terminates at a specific time point. In this manuscript, we explored how PBBM and PBFTPK models compare when applied to the same dataset. A set of six compounds with clinical data from immediate-release formulation were selected. Both models resulted in absorption time estimates within the small intestinal transit time, with PBFTPK models generally providing shorter time estimates. A clear relationship between the absorption rate and the product of permeability and luminal concentration was observed, in concurrence with the fundamental assumptions of PBFTPK models. We propose that future research on the synergy between the two modeling approaches can lead to both improvements in the initial parameterization of PBPK/PBBM models but to also expand mechanistic oral absorption concepts to more traditional pharmacometrics applications., (© 2022. Merck & Co., Inc., Rahway, NJ, USA and its affiliates under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

The infinite time of oral drug absorption was conceived from the first day of the birth of pharmacokinetics when H. Dost introduced the term pharmacokinetics in his book published in 1953. He adopted the function developed by H. Bateman back in 1908 for the decay of the nuclei isotopes to describe oral drug absorption as a first-order process. We unveiled this false hypothesis relying on common wisdom i.e. drugs are absorbed in finite time. This false assumption had dramatic effects on the evolution of oral pharmacokinetics but most importantly on the bioavailability and bioequivalence concepts and metrics. This work focuses on the finite absorption time (FAT) concept, the relevant Physiologically Based Finite Time (PBFTPK) models developed and their applications in oral pharmacokinetics, bioavailability and bioequivalence. The crux of the matter is that drug absorption from the gastrointestinal tract takes place under sink conditions because of the high blood flow rate in the vena cava. The termination of oral, pulmonary and intranasal drug absorption at a specific time point, calls for regulatory changes in bioavailability and bioequivalence studies in terms of the study design and metrics used for the bioequivalence assessment., (Copyright © 2022. Published by Elsevier B.V.)

Purpose: To develop physiologically based finite time pharmacokinetic (PBFTPK) models for the analysis of oral pharmacokinetic data., Methods: The models are based on the passive drug diffusion mechanism under the sink conditions principle. Up to three drug successive input functions of constant rate operating for a total time τ are considered. Differential equations were written for all these models assuming linear one- or two-compartment-model disposition. The differential equations were solved and functions describing the concentration of drug as a function of time for the central and the peripheral compartment were derived. The equations were used to generate simulated data and they were also fitted to a variety of experimental literature oral pharmacokinetic data., Results: The simulated curves resemble real life data. The end of the absorption processes τ is either equal to t max or longer than t max at the descending portion of the concentration time curve. Literature oral pharmacokinetic data of paracetamol, ibuprofen, almotriptan, cyclosporine (a total of four sets of data), and niraparib were analyzed using the PBFTPK models. Estimates for τ corresponding to a single or two or three different in magnitude input rates were derived along with the other model parameters for all data analyzed., Conclusions: The PBFTPK models are a powerful tool for the analysis of oral pharmacokinetic data since they rely on the physiologically sound concept of finite absorption time., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To explore the application of the parameters of the physiologically based finite time pharmacokinetic (PBFTPK) models subdivided in first-order (PBFTPK) 1  and zero-order (PBFTPK) 0  models to bioavailability and bioequivalence. To develop a methodology for the estimation of absolute bioavailability, F, from oral data exclusively., Methods: Simulated concentration time data were generated from the Bateman equation and compared with data generated from the (PBFTPK) 1  and (PBFTPK) 0  models. The blood concentration C b (τ) at the end of the absorption process τ, was compared to C max ; the utility of [Formula: see text] and [Formula: see text] in bioequivalence assessment was also explored. Equations for the calculation of F from oral data were derived for the (PBFTPK) 1  and (PBFTPK) 0  models. An estimate for F was also derived from an areas proportionality using oral data exclusively., Results: The simulated data of the (PBFTPK) 0  models exhibit rich dynamics encountered in complex drug absorption phenomena. Both (PBFTPK) 1  and (PBFTPK) 0  models result either in C max  = C b (τ) or C max  > C b (τ) for rapidly- and not rapidly-absorbed drugs, respectively; in the latter case, C b (τ) and τ are meaningful parameters for drug's rate of exposure. For both (PBFTPK) 1  and (PBFTPK) 0  models, [Formula: see text] or portions of it cannot be used as early exposure rate indicators. [Formula: see text] is a useful parameter for the assessment of extent of absorption for very rapidly absorbed drugs. An estimate for F for theophylline formulations was found close to unity., Conclusion: The (PBFTPK) 1  and (PBFTPK) 0  models are more akin to in vivo conditions. Estimates for F can be derived from oral data exclusively., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction  The reaction between susceptible and infected subjects has been studied under the well-mixed hypothesis for almost a century. Here, we present a consistent analysis for a not well-mixed system using fractal kinetics' principles.  Methods  We analyzed COVID-19 data to get insights on the disease spreading in absence/presence of preventive measures. We derived a three-parameter model and show that the "fractal" exponent h of time larger than unity can capture the impact of preventive measures affecting population mobility.  Results  The h=1 case, which is a power of time model, accurately describes the situation without such measures in line with a herd immunity policy. The pandemic spread in four model countries (France, Greece, Italy and Spain) for the first 10 months has gone through four stages: stages 1 and 3 with limited to no measures, stages 2 and 4 with varying lockdown conditions. For each stage and country two or three model parameters have been determined using appropriate fitting procedures. The fractal kinetics model was found to be more akin to real life.  Conclusion  Model predictions and their implications lead to the conclusion that the fractal kinetics model can be used as a prototype for the analysis of all contagious airborne pandemics., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Macheras P et al.)

Films of polar molecules vapour-deposited on sufficiently cold substrates are not only amorphous, but also exhibit charge polarization across their thickness. This is an effect known for 50 years, but it is very poorly understood and no mechanism exists in the literature that can explain and predict it. We investigated this bulk effect for 18 small organic molecules as a function of substrate temperature (30-130 K). We found that, as a rule, alcohol films have the negative end on the vacuum side at all temperatures. Alkyl acetates and toluene showed positive voltages which reached a maximum around the middle of the temperature range investigated. Tetrahydrofuran showed positive voltages which dropped with increasing deposition temperature. Diethyl ether, acetone, propanal, and butanal showed positive film voltages at low temperatures, negative at intermediate temperatures and again positive voltages at higher temperatures. In all cases, film voltages were monitored during heating leading to film evaporation. Film voltages were irreversibly eliminated before film elimination, but voltage profiles during temperature ramps differed vastly depending on compound and deposition temperature. In general, there was a gradual voltage reduction, but propanal, butanal, and diethyl ether showed a change in voltage sign during temperature ramp in films deposited at low temperatures. All these data expand substantially the experimental information regarding spontaneous polarization in vapour-deposited films, but still require complementary measurements as well as numerical simulations for a detailed explanation of the phenomenon.

Vapor-deposited films of neutral polar molecules on cold surfaces exhibit spontaneous electric polarization across the faces of the film. We deposited known amounts of the first five members of the normal monohydroxy alcohols at substrate temperatures in the range of 30-130 K. It is known that voltages measured are proportional to film thickness and that the effect is substrate-independent. The main trend observed was that the voltage per molecule surface density grows with molecule size and drops with deposition temperature. With the exception of some high-temperature methanol depositions, the films had a negative voltage on the vacuum side. Furthermore, the heavier members (1-butanol and 1-pentanol) showed reduced voltages for the lowest temperatures, suggesting that all members of the series could follow this pattern at temperatures below what was experimentally accessible. After deposition, film voltage was monitored during a temperature ramp showing first an increase in the voltage measured, then gradual decay before film evaporation. Initial film voltages are in general agreement with the concept of surface mobility of vapor-deposited molecules and indicate a negative correlation with dipole moment size.

Films of 1-butanol were vapor deposited under vacuum conditions at cryogenic temperatures on a polycrystalline platinum foil. Kelvin probe measurements showed the generation of a large negative voltage on the vacuum side of the film relative to its back side in contact with the platinum foil. Voltages across vapor deposited films, which are known to require molecules with an electric dipole moment, were confirmed to be proportional to the amount of gas deposited at a given temperature. Voltages of several hundreds of volts were recorded for films that were a few thousand monolayers thick. As deposition temperature was reduced from 120 K, the film voltage was found to increase almost linearly from 0 V until a little below 38 K, where the trend was reversed. Ramping up the sample temperature after deposition at 15 K/min exhibited an initial increase in absolute magnitude and then a gradual elimination of the voltage as the temperature of 120 K was reached. Both the initial increase and the subsequent decrease were found to be irreversible and indicate structural changes in the amorphous film. The elimination of the film voltage is associated with small rearrangements of the deposited molecules which are facilitated by the gradual increase of the temperature and the cumulative electric field of the surrounding molecules.

The β-cyclodextrin (β-CD) polyiodide inclusion complex (β-CD)(2)·Co(0.5)·I(7)·21H(2)O has been synthesized, characterized and further investigated via FT-Raman spectroscopy in the temperature range of 30-120°C. The experimental results point to the coexistence of I(-)(7) units (I(2)·I(-)(3)·I(2)) that seem not to interact with the Co(2+) ions and I(-)(7) units that display such interactions. The former units exhibit a disorder-order transition of both their I(2) molecules above 60°C due to a symmetric charge-transfer interaction with the central I(-)(3) [I(2)←I(-)(3)→I(2)], whereas in the latter units only one of the two I(2) molecules becomes well-ordered above 30°C. The other I(2) molecule remains disordered presenting no charge-transfer phenomena. The Co(2+) ion induces a considerable asymmetry on the geometry of the I(-)(3) anion and a significant modification of its Lewis base character. Complementary dielectric measurements suggest no important involvement of H···I contacts in the observed modification of the I(-)(3) electron-transfer properties., (Copyright © 2011 Elsevier B.V. All rights reserved.)

The electron affinity of GaN and Ga2N as well as the geometries and the dissociation energies of the ground states of gallium nitrides GaN, GaN(-), Ga2N, and Ga2N(-) were systematically studied by employing the coupled cluster method, RCCSD(T), in conjunction with a series of basis sets, (aug-)cc-pVxZ(-PP), x=D, T, Q, and 5 and cc-pwCVxZ(-PP), x=D, T, and Q. The calculated dissociation energy and the electron affinity of GaN are 2.12 and 1.84 eV, respectively, and those of Ga2N are 6.31 and 2.53 eV. The last value is in excellent agreement with a recent experimental value for the electron affinity of Ga2N of 2.506+/-0.008 eV. For such quality in the results to be achieved, the Ga 3d electrons had to be included in the correlation space. Moreover, when a basis set is used, which has not been developed for the number of the electrons which are correlated in a calculation, the quantities calculated need to be corrected for the basis set superposition error.

The electronic structure of the heavy diatomic molecule BaI has been examined for the first time by ab initio multiconfigurational configuration interaction (MRCI) and coupled cluster (RCCSD(T)) methods. The effects of special relativity have been taken into account through the second-order Douglas-Kroll-Hess approximation. The construction of Omega(omega,omega) potential energy curves allows for the estimation of "experimental" dissociation energies (De) of the first few excited states by exploiting the accurately known De experimental value of the X2Sigma+ ground state. All states examined are of ionic character with a Mulliken charge transfer of 0.5 e- from Ba to I, and this is reflected to large dipole moments ranging from 6 to 11 D. Despite the inherent difficulties of a heavy system like BaI, our results are encouraging. With the exception of bond distances that on the average are calculated 0.05 A longer than the experimental ones, common spectroscopic parameters are in fair agreement with experiment, whereas De values are on the average 10 kcal/mol smaller.

A 53-year-old Caucasian with keloid formation on the palmar surface of the hand following Dupuytren's contracture release is presented. Only two other cases of keloid formation on the hand have been found in English literature, both on black patients. This is the first known case with association of Dupuytren's disease to be reported. Surgical excision of the keloid with intraoperative injection of triamcinolone of the wound edges resulted in clinical cure., (Copyright 1999 The British Association of Plastic Surgeons.)

A renal transplant recipient with necrotizing fasciitis due to Pseudomonas aeruginosa is presented. Only three other cases of necrotizing fasciitis due to this organism have been found in the literature. This is the first case of P. aeruginosa necrotizing fasciitis in a renal transplant patient to be reported. Prompt diagnosis, enabling treatment with appropriate antibiotics and early surgical intervention, was the key factor in his recovery.