| 1. |
- Gabrielsson, Johan
(författare)
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Dose-response-time data analysis involving nonlinear dynamics, feedback and delay
- 2014
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 59, s. 36-48
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Tidskriftsartikel (refereegranskat)abstract
- This paper offers dose-response-time data analysis of four different case studies where the pharmacological response (neuronal ACh-release, tail-flick response, locomotor activity, NEFA) was modelled by a biophase-driven turnover model. The analysis uses a mathematical/analytical perspective in which analytic properties of the models involved are exploited in order to address the dual challenge of extracting information from these time-series about (i) the biophase kinetics following different routes of administration and (ii) pharmacodynamic issues such as transduction, saturation, and adaptation, and more specifically, parameter identifiability, such as correct estimation of potency (SD50 or ID50). It is shown how many of these estimates can be obtained by analytical means, giving considerable insight in the dynamics involved. (C) 2014 Elsevier B.V. All rights reserved.
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| 2. |
- Gabrielsson, Johan
(författare)
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Mixture dynamics: Dual action of inhibition and stimulation
- 2013
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Ingår i: European Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0928-0987 .- 1879-0720. ; 50, s. 215-226
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Tidskriftsartikel (refereegranskat)abstract
- The impact of a drug, or of multiple drugs, on different receptors usually results in a combination of responses. They may be either opposing or reinforcing one another and can lead to complex response versus drug-concentration relations. In this paper, complexity and synergy of multiple drug actions are studied on the basis of four data sets: two involving opposing actions and two resulting from synergistic actions. It is shown that turnover models can be successfully fitted to these data, offer a mechanism for dissecting complex response versus drug-concentration curves, for understanding and quantifying amplification of dual drug actions and elucidate the role of potencies and other parameters related to the different drugs. (C) 2013 Elsevier B.V. All rights reserved.
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| 3. |
- Gennemark, Peter, 1974, et al.
(författare)
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Modeling energy intake by adding homeostatic feedback and drug intervention
- 2015
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 42:1, s. 79-96
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Tidskriftsartikel (refereegranskat)abstract
- Energy intake (EI) is a pivotal biomarker used in quantification approaches to metabolic disease processes such as obesity, diabetes, and growth disorders. Eating behavior is however under both short-term and long-term control. This control system manifests itself as tolerance and rebound phenomena in EI, when challenged by drug treatment or diet restriction. The paper describes a model with the capability to capture physiological counter-regulatory feedback actions triggered by energy imbalances. This feedback is general as it handles tolerance to both increases and decreases in EI, and works in both acute and chronic settings. A drug mechanism function inhibits (or stimulates) EI. The deviation of EI relative to a reference level (set-point) serves as input to a non-linear appetite control signal which in turn impacts EI in parallel to the drug intervention. Three examples demonstrate the potential usefulness of the model in both acute and chronic dosing situations. The model shifts the predicted concentration-response relationship rightwardly at lower concentrations, in contrast to models that do not handle functional adaptation. A fourth example further shows that the model may qualitatively explain differences in rate and extent of adaptation in observed EI and its concomitants in both rodents and humans.
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| 4. |
- Hansson, Elisabeth, 1955, et al.
(författare)
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Therapeutic innovation: Inflammatory-reactive astrocytes as targets of inflammation
- 2016
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Ingår i: IBRO Reports. - : Elsevier BV. - 2451-8301. ; 1, s. 1-9
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Tidskriftsartikel (refereegranskat)abstract
- This study aimed to test pharmaceutical compounds targeting astrocytes showing inflammatory dysregulation. The primary rat brain cultures were treated with different batches of serum with or without microglia added to make the cells inflammatory-reactive. Lipopolysaccharide (LPS) and tryptase were used as inflammatory inducers. Expression levels of Toll-like receptor 4 (TLR4), Na+/K+-ATPase, and matrix metalloprotease-13 (MMP-13), as well as actin filament organization, pro-inflammatory cytokines, and intracellular Ca2+ release, were evaluated. LPS combined with tryptase upregulated TLR4 expression, whereas Na+/K+-ATPase expression was downregulated, ATP-evoked Ca2+ transients were increased, actin filaments were reorganized and ring structures instead of stress fibers were observed. Other aims of the study were to prevent astrocytes from becoming inflammatory-reactive and to restore inflammatory dysregulated cellular changes. A combination of the μ-opioid antagonist (−)-naloxone in ultra-low concentrations, the non-addictive μ-opioid agonist (−)-linalool, and the anti-epileptic agent levetiracetam was examined. The results indicated that this drug cocktail prevented the LPS- and tryptase-induced inflammatory dysregulation. The drug cocktail could also restore the LPS- and tryptase-treated cells back to a normal physiological level in terms of the analyzed parameters. © 2016 The Author(s)
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| 5. |
- Nilsson, Mats F., et al.
(författare)
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Improved methodology for identifying the teratogenic potential in early drug development of hERG channel blocking drugs
- 2010
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Ingår i: Reproductive Toxicology. - : Elsevier. - 0890-6238 .- 1873-1708. ; 29:2, s. 156-163
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Tidskriftsartikel (refereegranskat)abstract
- Drugs blocking the potassium current IKr of the heart (via hERG channel-inhibition) have the potential to cause hypoxia-related teratogenic effects. However, this activity may be missed in conventional teratology studies because repeat dosing may cause resorptions. The aim of the present study was to investigate an alternative protocol to reveal the teratogenic potential of IKr-blocking drugs. The IKr blocker astemizole, given as a single dose (80mg/kg) on gestation day (GD) 13 to pregnant rats caused digital defects. In whole rat embryo culture (2h) on GD 13, astemizole caused a decrease in embryonic heart rate at 20nM, and arrhythmias at 200-400nM. Cetirizine, without IKr-blocking properties, did not affect the rat embryonic heart in vitro. The present study shows that single dose testing on sensitive days of development, together with whole embryo culture, can be a useful methodology to better characterize the teratogenic potential of IKr-blocking drugs.
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| 6. |
- Cardilin, Tim, 1989, et al.
(författare)
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Modeling long-term tumor growth and kill after combinations of radiation and radiosensitizing agents
- 2019
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Ingår i: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 83:6, s. 1159-1173
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: Radiation therapy, whether given alone or in combination with chemical agents, is one of the cornerstones of oncology. We develop a quantitative model that describes tumor growth during and after treatment with radiation and radiosensitizing agents. The model also describes long-term treatment effects including tumor regrowth and eradication. Methods: We challenge the model with data from a xenograft study using a clinically relevant administration schedule and use a mixed-effects approach for model-fitting. We use the calibrated model to predict exposure combinations that result in tumor eradication using Tumor Static Exposure (TSE). Results: The model is able to adequately describe data from all treatment groups, with the parameter estimates taking biologically reasonable values. Using TSE, we predict the total radiation dose necessary for tumor eradication to be 110 Gy, which is reduced to 80 or 30 Gy with co-administration of 25 or 100 mg kg −1 of a radiosensitizer. TSE is also explored via a heat map of different growth and shrinkage rates. Finally, we discuss the translational potential of the model and TSE concept to humans. Conclusions: The new model is capable of describing different tumor dynamics including tumor eradication and tumor regrowth with different rates, and can be calibrated using data from standard xenograft experiments. TSE and related concepts can be used to predict tumor shrinkage and eradication, and have the potential to guide new experiments and support translations from animals to humans.
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| 7. |
- Tapani, Sofia, 1982, et al.
(författare)
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Joint feedback analysis modeling of nonesterified fatty acids in obese zucker rats and normal sprague-dawley rats after different routes of administration of nicotinic acid
- 2014
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Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549 .- 1520-6017. ; 103:8, s. 2571-2584
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Tidskriftsartikel (refereegranskat)abstract
- Data were pooled from several studies on nicotinic acid (NiAc) intervention of fatty acid turnover in normal Sprague-Dawley and obese Zucker rats in order to perform a joint PKPD of data from more than 100 normal Sprague-Dawley and obese Zucker rats, exposed to several administration routes and rates. To describe the difference in pharmacodynamic parameters between obese and normal rats, we modified a previously published nonlinear mixed effects model describing tolerance and oscillatory rebound effects of NiAc on nonesterified fatty acids plasma concentrations. An important conclusion is that planning of experiments and dose scheduling cannot rely on pilot studies on normal animals alone. The obese rats have a less-pronounced concentration-response relationship and need higher doses to exhibit desired response. The relative level of fatty acid rebound after cessation of NiAc administration was also quantified in the two rat populations. Building joint normal-disease models with scaling parameter(s) to characterize the "degree of disease" can be a useful tool when designing informative experiments on diseased animals, particularly in the preclinical screen. Data were analyzed using nonlinear mixed effects modeling, for the optimization, we used an improved method for calculating the gradient than the usually adopted finite difference approximation.
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| 8. |
- Held, Felix, et al.
(författare)
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Modelling of oscillatory cortisol response in horses using a Bayesian population approach for evaluation of dexamethasone suppression test protocols
- 2019
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Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 46:1, s. 75-87
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Tidskriftsartikel (refereegranskat)abstract
- Cortisol is a steroid hormone relevant to immune function in horses and other species and shows a circadian rhythm. The glucocorticoid dexamethasone suppresses cortisol in horses. Pituitary pars intermedia dysfunction (PPID) is a disease in which the cortisol suppression mechanism through dexamethasone is challenged. Overnight dexamethasone suppression test (DST) protocols are used to test the functioning of this mechanism and to establish a diagnosis for PPID. However, existing DST protocols have been recognized to perform poorly in previous experimental studies, often indicating presence of PPID in healthy horses. This study uses a pharmacokinetic/pharmacodynamic (PK/PD) modelling approach to analyse the oscillatory cortisol response and its interaction with dexamethasone. Two existing DST protocols were then scrutinized using model simulations with particular focus on their ability to avoid false positive outcomes. Using a Bayesian population approach allowed for quantification of uncertainty and enabled predictions for a broader population of horses than the underlying sample. Dose selection and sampling time point were both determined to have large influence on the number of false positives. Advice on pitfalls in test protocols and directions for possible improvement of DST protocols were given. The presented methodology is also easily extended to other clinical test protocols.
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| 9. |
- Stryamets, Natalya, et al.
(författare)
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From economic survival to recreation: contemporary uses of wild food and medicine in rural Sweden, Ukraine and NW Russia
- 2015
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Ingår i: Journal of Ethnobiology and Ethnomedicine. - : Springer Science and Business Media LLC. - 1746-4269. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Background: There are many ethnobotanical studies on the use of wild plants and mushrooms for food and medicinal treatment in Europe. However, there is a lack of comparative ethnobotanical research on the role of non-wood forest products (NWFPs) as wild food and medicine in local livelihoods in countries with different socio-economic conditions. The aim of this study was to compare the present use of wild food and medicine in three places representing different stages of socio-economic development in Europe. Specifically we explore which plant and fungi species people use for food and medicine in three selected rural regions of Sweden, Ukraine and the Russian Federation.Methods: We studied the current use of NWFPs for food and medicine in three rural areas that represent a gradient in economic development (as indicated by the World Bank), i. e., Smaland high plain (south Sweden), Roztochya (western Ukraine), and Kortkeros (Komi Republic in North West Russia). All areas were characterised by (a) predominating rural residency, (b) high forest coverage, and (c) free access to NWFPs. A total of 205 in-depth semi-structured interviews were conducted with local residents in the three study areas. The collected NWFPs data included (1) the species that are used; (2) the amount harvested, (3) uses and practices (4) changes over time, (5) sources of knowledge regarding the use of NWFPs as wild food and medicine and (6) traditional recipes.Results: In Sweden 11 species of wild plant and fungi species were used as food, and no plant species were used for medicinal purposes. In Ukraine the present use of NWFPs included 26 wild foods and 60 medicinal species, while in Russia 36 food and 44 medicinal species were reported.Conclusions: In the economically less developed rural areas of Ukraine and Russia, the use of NWFPs continues to be an important part of livelihoods, both as a source of income and for domestic use as food and medicine. In Sweden the collection of wild food has become mainly a recreational activity and the use of medicinal plants is no longer prevalent among our respondents. This leads us to suggest that the consumption of wild food and medicine is influenced by the socio-economic situation in a country.
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| 10. |
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