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The aim of this study was to develop a new in vitro–in vivo simulation (IVIVS) approach in order to predict the outcome of a bioequivalence study. The predictability of the IVIVS procedure was evaluated through its application in the development process of a new generic product of amlodipine/irbesartan/hydrochlorothiazide. The developed IVIVS methodology is composed of three parts: (a) mathematical description of in vitro dissolution profiles, (b) mathematical description of in vivo kinetics, and (c) development of joint in vitro–in vivo simulations. The entire programming was done in MATLAB® and all created scripts were validated through other software. The IVIVS approach can be implemented for any number of subjects, clinical design, variability and can be repeated for thousands of times using Monte Carlo techniques. The probability of success of each scenario is recorded and finally, an overall assessment is made in order to select the most suitable batch. Alternatively, if the IVIVS shows reduced probability of BE success, the R&D department is advised to reformulate the product. In this study, the IVIVS approach predicted successfully the BE outcome of the three drugs. During the development of generics, the IVIVS approach can save time and expenses. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.

During the recent COVID-19 outbreak hydroxychloroquine (HCQ) has been proposed as a safe and effective therapeutic option. However, a wide variety of dosing schemes has been applied in the clinical practice and tested in clinical studies. An extended literature survey was performed investigating the pharmacokinetics, the efficacy and safety of HCQ in COVID-19 treatment. Population pharmacokinetic models were retrieved from the literature and after evaluation and assessment one was selected in order to perform simulations. The most commonly applied dosing schemes were explored for patients with different weights and different levels of HCQ clearance impairment. Model-based simulations of HCQ concentrations revealed that high initial doses followed by low and sparse doses may offer significant benefits to patients by decreasing the viral load without reaching levels considered to produce adverse effects. For instance, the dosing scheme proposed for a 70 kg adult with moderate COVID-19 symptoms would be 600 mg upon diagnosis, 400 mg after 12 h, 300 mg after 24 h, 200 mg after 36 h, followed by 200 mg BID for 4 d, followed by 200 mg OD for 5 d. Based on the results from simulations performed and the currently published knowledge regarding HCQ in COVID-19 treatment, this study provides evidence that a high loading dose followed by sparse doses could offer significant benefits to the patients. © 2020 Informa UK Limited, trading as Taylor & Francis Group.

Induction of intestinal drug metabolizing enzymes can complicate the development of new drugs, owing to the potential to cause drug-drug interactions (DDIs) leading to changes in pharmacokinetics, safety and efficacy. The development of a human-relevant model of the adult intestine that accurately predicts CYP450 induction could help address this challenge as species differences preclude extrapolation from animals. Here, we combined organoids and Organs-on-Chips technology to create a human Duodenum Intestine-Chip that emulates intestinal tissue architecture and functions, that are relevant for the study of drug transport, metabolism, and DDI. Duodenum Intestine-Chip demonstrates the polarized cell architecture, intestinal barrier function, presence of specialized cell subpopulations, and in vivo relevant expression, localization, and function of major intestinal drug transporters. Notably, in comparison to Caco-2, it displays improved CYP3A4 expression and induction capability. This model could enable improved in vitro to in vivo extrapolation for better predictions of human pharmacokinetics and risk of DDIs. © Kasendra et al.

Background: Wound healing in liver cirrhosis is known to be impaired possibly due to liver insufficiency and subsequent malnutrition status; however, there is no study to examine healing effectiveness of the tooth socket following an extraction in such patients. Materials and Methods: Irreversible cirrhosiswas induced in 30 Wistar rats by repetitive weekly doses of CCl4 and continuous administration of phenobarbital in a 12-week course was monitored by body weight measurement and ascites development, and was proved histologically. One week later, cirrhotic and control rats were subjected to extractions of two maxillary grinders on each side, one side by simple method, the other by surgical method. Half of the animals of each subgroup were sacrificed on the 10th post-extraction day, whereas the other half on the 30th post-extraction day, and histological sections were examined from all tooth sockets for wound-healing activity. Results: A malnutrition status was detected in cirrhotic rats with significant difference in their body weight. Several histological parameters of socket healing were not statistically different between cirrhotic and control animals. However, a significant delay on epithelialization and cancellous bone formation was detected on the 10th post-extraction day for either simple or surgical extractions in cirrhotic animals. Conclusions: Liver cirrhosis in rats provokes a significant delay on epithelialization and mature cancellous bone formation and consecutively on early socket wound healing after a tooth extraction.

Simultaneous measurements of DNA cell phase cycle distributions and in vivo 31P NMR spectroscopy were performed on 40 RIF-1 murine tumors irradiated with 14 Gy of X-radiation. Diploid and tetraploid tumor populations were observed. The cells blocked in G2/M phase were measured as a function of the ratios of tetraploid cell number in G2/M phase versus total cell population measured. The G2/M population reached a maximum at 32 h post irradiation, dropping to control values by 72 h, while the ratio of inorganic phosphate to beta-nucleotide triphosphate dropped significantly at 32 h and remained significantly lower than control up to 72 h post irradiation. Measurements of PME, PDE, PCr, and pH showed no significant variations at any time point. No significant change in host cell population could be observed. Since the measured G2/M population never increased to more than 3% of the total cell population, the change observed in the 31P NMR spectra were not simply the result of possible differences in NMR profiles of the different cell phase populations but were more likely due to a change in the metabolic characteristics or environment of a majority of the cells.

Adiponectin, a hormone secreted by adipose tissue, circulates at high concentrations in human plasma. Paradoxically, plasma levels of adiponectin are approximately 50% lower in obese than in lean subjects. An association between low plasma levels of adiponectin and higher risk of developing breast and other cancers was recently reported. Obesity and overweight have also been associated with increased mortality from cancer. To test the hypothesis that adiponectin exerts direct anti proliferative and/or pro-apoptotic effects on cancer cells, we used the MCF7 human breast adenocarcinoma cell line. The proliferation rate of the MCF7 cells was measured using the MTT method, while apoptosis was examined by quantifying the DNA fragmentation using an ELISA assay. In addition, adiponectin receptor 1 (AdipoR1) and AdipoR2 mRNA expression was detected using RT-PCR. Adiponectin diminished the proliferation rate of MCF7 cells; this effect was significant after 48-96 hours of treatment. The presence of receptor expression suggested that the effect of adiponectin on cell proliferation was most likely specific and adiponectin receptor-mediated. Adiponectin induced no apoptosis of MCF7 cells over 48 hours. We conclude that adiponectin inhibits proliferation but causes no apoptosis of MCF7 breast cancer cells. These data suggest that adiponectin may represent a direct hormonal link between obesity and cancer.

This paper reports on initial investigations into appropriate calibration models for and the reliability and stability of the calibration of the Kodak DC200 series cameras. Results of test of different types of digital still cameras are compared, in general, to the DC200 series and then various calibration test of a DC265 camera are presented and analyzed. Block- and photo-invariant camera calibration models are compared to ascertain their suitability for the physical variability of the cameras. In conclusion, this paper makes some recommendations on the potential reliability and stability of the Kodak DC265 camera.© (2000) COPYRIGHT SPIE--The International Society for Optical Engineering. Downloading of the abstract is permitted for personal use only.

In the summer of 1996, the Chicago Dietetic Association sent 1490 salary surveys to Chicagoland area dietitians. 493 surveys were returned yielding a 33% response rate and of those 84% were available for analysis. 99% of the respondents were female and 1% male. 58.6% had a BS or BA degree as their highest degree. Although there were only six men in the sample, there was a statistically significant difference between their salaries and those of the women in the sample (p=.010). No statistically significant differences were found between whites, Asians, or African Americans with respect to salary (p=.82). A statistically significant difference was found between primary job roles with respect to salary (p 2-21} were found between salary and age group, highest degree earned, years as a practicing dietitian and years in primary job role/position. A statistically significant difference was found between primary job roles and satisfaction with pay (p=.006). The percentages who felt that they were paid adequately for the primary job roles are: business/industry(70%), food service(55%), community dietetics(51%), management(45%), clinical dietetics(43%), consulting/private practice(57%) and education research(30%). As expected, respondents who felt that they were paid adequately had higher salaries than those who did not feel that they were paid adequately (p=.001).

In situ phosphorous MRS was employed to study the metabolites of normal and cancerous breasts, and the alterations of tumor response to therapy. In a group of 7 normal volunteers and 12 patients, the total mobile phosphate content of breast carcinomas was found to be at least two to three times higher than that of the normal breast measured off menstruation. The metabolite profiles of normal and tumorous breasts are coarsely similar. In both cases the intracellular pH (pHi) was either neutral or slightly alkaline (pH greater than 7.0). Prior to treatments, the metabolite levels of phosphoryl monoester-to-ATP ratio of breast neoplasms were higher than those of the controls and decreased after the patients received a few treatments while the pHi fluctuated at a value greater than 7.0. The phosphoryl diester-to-ATP ratio also demonstrated to a lesser extent a decreasing trend in response to therapy.

To investigate the effect of long term hashish use on T-lymphocytes we have measured the incorporation of14C-thymidine by peripheral blood lymphocytes, unstimulated and stimulated by phytohemagglutinin, as well as the proportion and number of E-rosettes in 12 healthy male chronic users of the drug before and after a smoking session, and in 15 control subjects. The results show that hashish smoking does not impair the response of lymphocytes to PHA, at least at the concentration of PHA used. Furthermore there is a possibility that among chronic users a hashish smoking session may have a slight stimulatory effect. © 1978 Springer-Verlag.