| 1. |
- Benjamin, Daniel J., et al.
(författare)
-
Redefine statistical significance
- 2018
-
Ingår i: Nature Human Behaviour. - : Nature Research (part of Springer Nature). - 2397-3374. ; 2:1, s. 6-10
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
|
|
| 2. |
- Bhatt, Deepak L., et al.
(författare)
-
Rationale, design and baseline characteristics of the effect of ticagrelor on health outcomes in diabetes mellitus patients Intervention study
- 2019
-
Ingår i: Clinical Cardiology. - : Wiley. - 0160-9289 .- 1932-8737. ; 42:5, s. 498-505
-
Tidskriftsartikel (refereegranskat)abstract
- In the setting of prior myocardial infarction, the oral antiplatelet ticagrelor added to aspirin reduced the risk of recurrent ischemic events, especially, in those with diabetes mellitus. Patients with stable coronary disease and diabetes are also at elevated risk and might benefit from dual antiplatelet therapy. The Effect of Ticagrelor on Health Outcomes in diabEtes Mellitus patients Intervention Study (THEMIS, NCT01991795) is a Phase 3b randomized, double-blinded, placebo-controlled trial of ticagrelor vs placebo, on top of low dose aspirin. Patients >= 50 years with type 2 diabetes receiving anti-diabetic medications for at least 6 months with stable coronary artery disease as determined by a history of previous percutaneous coronary intervention, bypass grafting, or angiographic stenosis of >= 50% of at least one coronary artery were enrolled. Patients with known prior myocardial infarction (MI) or stroke were excluded. The primary efficacy endpoint is a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety endpoint is Thrombolysis in Myocardial Infarction major bleeding. A total of 19 220 patients worldwide have been randomized and at least 1385 adjudicated primary efficacy endpoint events are expected to be available for analysis, with an expected average follow-up of 40 months (maximum 58 months). Most of the exposure is on a 60 mg twice daily dose, as the dose was lowered from 90 mg twice daily partway into the study. The results may revise the boundaries of efficacy for dual antiplatelet therapy and whether it has a role outside acute coronary syndromes, prior myocardial infarction, or percutaneous coronary intervention.
|
|
| 3. |
- Bohm, Felix, et al.
(författare)
-
FFR-Guided Complete or Culprit-Only PCI in Patients with Myocardial Infarction
- 2024
-
Ingår i: New England Journal of Medicine. - : MASSACHUSETTS MEDICAL SOC. - 0028-4793 .- 1533-4406.
-
Tidskriftsartikel (refereegranskat)abstract
- Background The benefit of fractional flow reserve (FFR)-guided complete revascularization in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease remains unclear.Methods In this multinational, registry-based, randomized trial, we assigned patients with STEMI or very-high-risk non-STEMI (NSTEMI) and multivessel disease who were undergoing primary percutaneous coronary intervention (PCI) of the culprit lesion to receive either FFR-guided complete revascularization of nonculprit lesions or no further revascularization. The primary outcome was a composite of death from any cause, myocardial infarction, or unplanned revascularization. The two key secondary outcomes were a composite of death from any cause or myocardial infarction and unplanned revascularization.Results A total of 1542 patients underwent randomization, with 764 assigned to receive FFR-guided complete revascularization and 778 assigned to receive culprit-lesion-only PCI. At a median follow-up of 4.8 years (interquartile range, 4.3 to 5.2), a primary-outcome event had occurred in 145 patients (19.0%) in the complete-revascularization group and in 159 patients (20.4%) in the culprit-lesion-only group (hazard ratio, 0.93; 95% confidence interval [CI], 0.74 to 1.17; P=0.53). With respect to the secondary outcomes, no apparent between-group differences were observed in the composite of death from any cause or myocardial infarction (hazard ratio, 1.12; 95% CI, 0.87 to 1.44) or unplanned revascularization (hazard ratio, 0.76; 95% CI, 0.56 to 1.04). There were no apparent between-group differences in safety outcomes.Conclusions Among patients with STEMI or very-high-risk NSTEMI and multivessel coronary artery disease, FFR-guided complete revascularization was not shown to result in a lower risk of a composite of death from any cause, myocardial infarction, or unplanned revascularization than culprit-lesion-only PCI at 4.8 years. (Funded by the Swedish Research Council and others; FULL REVASC ClinicalTrials.gov number, NCT02862119.) In a registry-based trial, FFR-guided PCI of nonculprit lesions did not result in a lower risk of a composite of death from any cause, myocardial infarction, or unplanned revascularization than culprit-lesion-only PCI.
|
|
| 4. |
- Böhm, Felix, et al.
(författare)
-
FFR-Guided Complete or Culprit-Only PCI in Patients with Myocardial Infarction
- 2024
-
Ingår i: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 390:16, s. 1481-1492
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The benefit of fractional flow reserve (FFR)-guided complete revascularization in patients with ST-segment elevation myocardial infarction (STEMI) and multivessel coronary artery disease remains unclear. METHODS: In this multinational, registry-based, randomized trial, we assigned patients with STEMI or very-high-risk non-STEMI (NSTEMI) and multivessel disease who were undergoing primary percutaneous coronary intervention (PCI) of the culprit lesion to receive either FFR-guided complete revascularization of nonculprit lesions or no further revascularization. The primary outcome was a composite of death from any cause, myocardial infarction, or unplanned revascularization. The two key secondary outcomes were a composite of death from any cause or myocardial infarction and unplanned revascularization. RESULTS: A total of 1542 patients underwent randomization, with 764 assigned to receive FFR-guided complete revascularization and 778 assigned to receive culprit-lesion-only PCI. At a median follow-up of 4.8 years (interquartile range, 4.3 to 5.2), a primary-outcome event had occurred in 145 patients (19.0%) in the complete-revascularization group and in 159 patients (20.4%) in the culprit-lesion-only group (hazard ratio, 0.93; 95% confidence interval [CI], 0.74 to 1.17; P = 0.53). With respect to the secondary outcomes, no apparent between-group differences were observed in the composite of death from any cause or myocardial infarction (hazard ratio, 1.12; 95% CI, 0.87 to 1.44) or unplanned revascularization (hazard ratio, 0.76; 95% CI, 0.56 to 1.04). There were no apparent between-group differences in safety outcomes. CONCLUSIONS: Among patients with STEMI or very-high-risk NSTEMI and multivessel coronary artery disease, FFR-guided complete revascularization was not shown to result in a lower risk of a composite of death from any cause, myocardial infarction, or unplanned revascularization than culprit-lesion-only PCI at 4.8 years. (Funded by the Swedish Research Council and others; FULL REVASC ClinicalTrials.gov number, NCT02862119.).
|
|
| 5. |
- Böhm, Felix, et al.
(författare)
-
The Full Revasc (Ffr-gUidance for compLete non-cuLprit REVASCularization) Registry-based randomized clinical trial
- 2021
-
Ingår i: American Heart Journal. - : Elsevier. - 0002-8703 .- 1097-6744. ; 241, s. 92-100
-
Tidskriftsartikel (refereegranskat)abstract
- Background Complete revascularization in ST elevation myocardial infarction (STEMI) patients with multivessel disease has resulted in reduction in composite clinical endpoints in medium sized trials. Only one trial showed an effect on hard clinical endpoints, but the revascularization procedure was guided by angiographic evaluation of stenosis severity. Consequently, it is not clear how Fractional Flow Reserve (FFR)-guided percutaneous coronary intervention (PCI) affects hard clinical endpoints in STEMI. Methods and Results The Ffr-gUidance for compLete non-cuLprit REVASCularization (FULL REVASC) - is a pragmatic, multicenter, international, registry-based randomized clinical trial designed to evaluate whether a strategy of FFR-guided complete revascularization of non-culprit lesions, reduces the combined primary endpoint of total mortality, non-fatal MI and unplanned revascularization. 1,545 patients were randomized to receive FFR-guided PCI during the index hospitalization or initial conservative management of non-culprit lesions. We found that in angiographically severe non-culprit lesions of 90-99% severity, 1 in 5 of these lesions were re-classified as non-flow limiting by FFR. Considering lesions of intermediate severity (70%-89%), half were re-classified as non-flow limiting by FFR. The study is event driven for an estimated follow-up of at least 2.75 years to detect a 9.9%/year >7.425%/year difference (HR = 0.74 at 80% power (alpha = .05)) for the combined primary endpoint. Conclusion This large randomized clinical trial is designed and powered to evaluate the effect of complete revascularization with FFR-guided PCI during index hospitalization on total mortality, non-fatal MI and unplanned revascularization following primary PCI in STEMI patients with multivessel disease. Enrollment completed in September 2019 and follow-up is ongoing.
|
|
| 6. |
- Erlinge, David, et al.
(författare)
-
Rationale and design of INFINITY-SWEDEHEART : A registry-based randomized clinical trial comparing clinical outcomes of the sirolimus-eluting DynamX bioadaptor to the zotarolimus-eluting Resolute Onyx stent
- 2024
-
Ingår i: American Heart Journal. - : Elsevier. - 0002-8703 .- 1097-6744. ; 277, s. 1-10
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Modern drug-eluting stents have seen significant improvements, yet still create a rigid cage within the coronary artery. There is a 2% to 4% annual incidence of target lesion failure (TLF) beyond 1 year, and half of the patients experience angina after 5 years. The DynamX bioadaptor is a sirolimus-eluting, thin (71 µm) cobalt-chromium platform with helical strands that unlock and separate after in vivo degradation of the bioresorbable polymer coating. This allows the vessel to return to normal physiological function and motion, along with compensatory adaptive remodeling, which may reduce the need for reintervention and alleviate angina following percutaneous coronary intervention (PCI).METHODS: The INFINITY-SWEDEHEART trial is a single-blind, registry-based randomized clinical trial (R-RCT) to evaluate the safety and effectiveness of the DynamX bioadaptor compared to the Resolute Onyx stent in the treatment of patients with ischemic heart disease with de novo native coronary artery lesions. The R-RCT framework allows for recruitment, randomization, and pragmatic data collection of baseline demographics, medications, and clinical outcomes using existing national clinical registries integrated with the trial database. The primary objective is to demonstrate noninferiority in terms of freedom from TLF (cardiovascular death, target vessel myocardial infarction, or ischemia-driven target lesion revascularization) at 1 year. Powered secondary endpoints will be tested sequentially for superiority from 6 months to the end of follow-up (5 years) for the following: 1) TLF in all subjects, 2) target vessel failure in all subjects, and 3) TLF in subjects with acute coronary syndrome (ACS). Subsequent superiority testing will be performed at a time determined depending on the number of events, ensuring sufficient statistical power. Change in angina-related symptoms, function and quality of life will be assessed using the Seattle Angina Questionnaire-short version. Predefined sub-groups will be analyzed. In total, 2400 patients have been randomized at 20 sites in Sweden. Available baseline characteristic reveal relatively old age (68 years) and a large proportion of ACS patients including 25% STEMI and 37% NSTEMI patients.SUMMARY: The INFINITY-SWEDEHEART study is designed to evaluate the long-term safety and efficacy of the DynamX bioadaptor compared to the Resolute Onyx stent in a general PCI patient population.
|
|
| 7. |
- Gustafsson, Johan, 1976, et al.
(författare)
-
Sources of variation in cell-type RNA-Seq profiles
- 2020
-
Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:9
-
Tidskriftsartikel (refereegranskat)abstract
- Cell-type specific gene expression profiles are needed for many computational methods operating on bulk RNA-Seq samples, such as deconvolution of cell-type fractions and digital cytometry. However, the gene expression profile of a cell type can vary substantially due to both technical factors and biological differences in cell state and surroundings, reducing the efficacy of such methods. Here, we investigated which factors contribute most to this variation. We evaluated different normalization methods, quantified the variance explained by different factors, evaluated the effect on deconvolution of cell type fractions, and examined the differences between UMI-based single-cell RNA-Seq and bulk RNA-Seq. We investigated a collection of publicly available bulk and single-cell RNA-Seq datasets containing B and T cells, and found that the technical variation across laboratories is substantial, even for genes specifically selected for deconvolution, and this variation has a confounding effect on deconvolution. Tissue of origin is also a substantial factor, highlighting the challenge of using cell type profiles derived from blood with mixtures from other tissues. We also show that much of the differences between UMI-based single-cell and bulk RNA-Seq methods can be explained by the number of read duplicates per mRNA molecule in the single-cell sample. Our work shows the importance of either matching or correcting for technical factors when creating cell-type specific gene expression profiles that are to be used together with bulk samples.
|
|
| 8. |
- Held, Felix, et al.
(författare)
-
Bayesian hierarchical model of oscillatory cortisol response during drug intervention
- 2018
-
Ingår i: 27th meeting of the Population Approach Group in Europe Montreux, Switzerland, 2018-05-29 - 2018-06-01.
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Oscillating biomarker response-time courses challenge modelling of drug intervention. A periodically recurring pattern is typically seen for the stress hormone cortisol. This pattern can be captured by mechanism-based turnover models. However, analysing experimental data requires new mathematical techniques. Bayesian hierarchical modelling allows for full quantification of parameter uncertainty while also capturing the population aspects typical to nonlinear mixed effects modelling. Inter-occasion variability (IOV) is incorporated in addition to inter-individual variability (IIV). Objectives: - Propose a model based workflow for oscillating baseline turnover models including IIV and IOV. - Apply the workflow to cortisol- and dexamethasone time-series data obtained from horses. - An additional aim was to predict test performance of a two-sample dexamethasone suppression test-protocol (DST-protocol) [1, 2] in horses. Methods: Cortisol- and dexamethasone time courses were collected [1]. Four different doses of dexamethasone were given (no drug and 0.1, 1, 10 µg/kg bolus + 0.07, 0.7, 7 µg/kg infusion over three hours). The pharmacokinetic/pharmacodynamic model was adapted from [1]. Cortisol was described by a turnover model with oscillating turnover rate (average baseline kavg, amplitude α, phase-shift t0) and fractional turnover rate kout. Drug intervention was modelled with Hill-type suppression (maximum inhibition Imax, potency IC50, hill coefficient n). Dexamethasone exposure was described by a two-compartment model. The model was then extended to a population model by introduction of inter-individual and inter-occasion effects. The final model was inferred from data using a Bayesian framework with the Hamiltonian Monte Carlo algorithm in Stan [3]. Ordinary differential equations were solved analytically for the case of constant drug exposure. The performance of the two-sample DST-protocol was studied by calculation of the specificity of the test. Specificity was predicted by Monte Carlo simulations and compared to two previously published experimental results. Results: The proposed model described the data well. Estimated ranges for pharmacodynamic parameters were estimated as median (95% credible intervals): kavg = 12.7 (6.44, 23.5) µg L-1 h-1, α = 5.40 (1.38, 17.9) µg L-1 h-1, t0 = -3.71 (-7.54, 0.494) h, kout = 0.315 (0.221, 0.493) h-1, Imax = 0.923 (0.874, 0.965), IC50 = 0.0298 (0.00490, 0.155) µg L-1, n = 1.57 (1.03, 2.61 ). Low precision was found in the standard deviations of the random effect parameters. IIV and IOV present in the data were captured by the model. The average cortisol response level and its amplitude are suppressed with respect to magnitude and variability with increasing exposure to dexamethasone. The maximum and minimum levels of cortisol response were also suppressed by increasing exposure to dexamethasone. Mathematical expressions were derived describing cortisol oscillations with inhibition and were consistent with experimental data. Dependence of predicted specificity on drug administration time and time until measurement was observed. Different levels of variability (IIV and IOV) led to a fraction of healthy subjects with positive test results. The oscillatory behaviour of cortisol response led to an oscillatory pattern in predicted specificity. Conclusions: - New techniques were developed for graphical analysis of the oscillatory cortisol response - These were successfully applied to equine cortisol data after dexamethasone intervention - Oscillatory behaviour and level of variability had great impact on the sparse-sample DST-design
|
|
| 9. |
- Held, Felix, et al.
(författare)
-
Challenge model of TNFα turnover at varying LPS and drug provocations
- 2019
-
Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 46:3, s. 223-240
-
Tidskriftsartikel (refereegranskat)abstract
- A mechanism-based biomarker model of TNF α -response, including different external provocations of LPS challenge and test compound intervention, was developed. The model contained system properties (such as k t , k out ), challenge characteristics (such as k s , k LPS , K m,LPS , S max , SC 50 ) and test-compound-related parameters (I max , IC 50 ). The exposure to test compound was modelled by means of first-order input and Michaelis–Menten type of nonlinear elimination. Test compound potency was estimated to 20nM with a 70% partial reduction in TNF α -response at the highest dose of 30mg·kg −1 . Future selection of drug candidates may focus the estimation on potency and efficacy by applying the selected structure consisting of TNF α system and LPS challenge characteristics. A related aim was to demonstrate how an exploratory (graphical) analysis may guide us to a tentative model structure, which enables us to better understand target biology. The analysis demonstrated how to tackle a biomarker with a baseline below the limit of detection. Repeated LPS-challenges may also reveal how the rate and extent of replenishment of TNF α pools occur. Lack of LPS exposure-time courses was solved by including a biophase model, with the underlying assumption that TNF α -response time courses, as such, contain kinetic information. A transduction type of model with non-linear stimulation of TNF α release was finally selected. Typical features of a challenge experiment were shown by means of model simulations. Experimental shortcomings of present and published designs are identified and discussed. The final model coupled to suggested guidance rules may serve as a general basis for the collection and analysis of pharmacological challenge data of future studies. © 2019, The Author(s).
|
|
| 10. |
|
|
| 11. |
- Held, Felix, et al.
(författare)
-
Investigation of sparse clinical sampling in light of baseline oscillations and between‐individual variability using pharmacokinetic/pharmacodynamic modelling
- 2018
-
Ingår i: Journal of Veterinary Pharmacology and Therapeutics. Special Issue 14th International Congress of the European Association for Veterinary Pharmacology and Toxicology, Wroclaw, Poland, June 24‐27, 2018, pp146-148. - : Wiley. - 1365-2885.
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Cortisol exhibits a circadian rhythm in horses. It is a well‐known biomarker that is suppressed by dexamethasone. A sampling protocol of cortisol with one pre‐ and one post drug administration sample is used in dexamethasone suppression tests. However, diurnal fluctuation and inter‐individual variation may hamper the utility of test results. The aim of this study was to quantify the determinants of baseline fluctuation and between‐individual and between‐occasion variability for guidance of an improved test protocol.
|
|
| 12. |
- Held, Felix, 1990
(författare)
-
Modelling of drug-effect on time-varying biomarkers
- 2018
-
Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Model-based quantification of drug effect is an efficient tool during pre-clinical and clinical phases of drug trials. Mathematical modelling can lead to improved understanding of the underlying biological mechanisms, help in finding shortcomings of experimental design and suggest improvements, or be an effective tool in simulation-based analyses. This thesis addresses the modelling of time-varying biomarkers both with and without drug-treatment. Pharmacokinetic/pharmacodynamic models were used to describe observed drug concentrations and biomarkers. These are modelled in the framework of compartmental modelling described by ordinary differential equations. This thesis contains two papers in manuscript-form. In the first paper, a metaanalysis was performed of an existing model and previously published data for the stress-hormone cortisol and the drug dexamethasone. Cortisol exhibits a circadian rhythm, resembling oscillations, and is therefore a time-varying target for treatment. The aim was to utilize the model for prediction of the outcome of a medical test used in veterinary treatments on horses. In addition to model parameters, inter-individual variability was modelled and estimated in a Bayesian framework. This allowed simulation of test outcomes for the whole population, which in turn were used to evaluate available test protocols and suggest improvements. In the second paper, an improved model was constructed for the cytokine TNFα after challenge with LPS in addition to intervention treatment. TNFα is not measurable in healthy subjects but release into blood plasma can be provoked by challenge with LPS. The result is a short-lived turnover of TNFα. A test compound targeting intervention of TNFα release was included in the study. Comprehensive experimental data from two studies was available and allowed to model features of TNFα release, that were not addressed in previously published models. The final model was then used to analyse the current experimental design and correlations between LPS challenge and test compound effectiveness. The paper provides suggestions for future experimental designs.
|
|
| 13. |
- Held, Felix, et al.
(författare)
-
Modelling of oscillatory cortisol response in horses using a Bayesian population approach for evaluation of dexamethasone suppression test protocols
- 2019
-
Ingår i: Journal of Pharmacokinetics and Pharmacodynamics. - : Springer Science and Business Media LLC. - 1567-567X .- 1573-8744. ; 46:1, s. 75-87
-
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.
|
|
| 14. |
- Larsson, Ida, et al.
(författare)
-
Reconstructing the regulatory programs underlying the phenotypic plasticity of neural cancers
- 2024
-
Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Nervous system cancers contain a large spectrum of transcriptional cell states, reflecting processes active during normal development, injury response and growth. However, we lack a good understanding of these states' regulation and pharmacological importance. Here, we describe the integrated reconstruction of such cellular regulatory programs and their therapeutic targets from extensive collections of single-cell RNA sequencing data (scRNA-seq) from both tumors and developing tissues. Our method, termed single-cell Regulatory-driven Clustering (scRegClust), predicts essential kinases and transcription factors in little computational time thanks to a new efficient optimization strategy. Using this method, we analyze scRNA-seq data from both adult and childhood brain cancers to identify transcription factors and kinases that regulate distinct tumor cell states. In adult glioblastoma, our model predicts that blocking the activity of PDGFRA, DDR1, ERBB3 or SOX6, or increasing YBX1-activity, would potentiate temozolomide treatment. We further perform an integrative study of scRNA-seq data from both cancer and the developing brain to uncover the regulation of emerging meta-modules. We find a meta-module regulated by the transcription factors SPI1 and IRF8 and link it to an immune-mediated mesenchymal-like state. Our algorithm is available as an easy-to-use R package and companion visualization tool that help uncover the regulatory programs underlying cell plasticity in cancer and other diseases.
|
|
| 15. |
- Loryan, Irena, 1977-, et al.
(författare)
-
Quantitative Assessment of Drug Delivery to Tissues and Association with Phospholipidosis: A Case Study with Two Structurally Related Diamines in Development
- 2017
-
Ingår i: Molecular Pharmaceutics. - : American Chemical Society (ACS). - 1543-8384 .- 1543-8392. ; 14:12, s. 4362-4373
-
Tidskriftsartikel (refereegranskat)abstract
- Drug induced phospholipidosis (PLD) may be observed in the preclinical phase of drug development and pose strategic questions. As lysosomes have a central role in pathogenesis of PLD, assessment of lysosomal concentrations is important for understanding the pharmacokinetic basis of PLD manifestation and forecast of potential clinical appearance. Herein we present a systematic approach to provide insight into tissue-specific PLD by evaluation of unbound intracellular and lysosomal (reflecting acidic organelles) concentrations of two structurally related diprotic amines, GRT1 and GRT2. Their intratissue distribution was assessed using brain and lung slice assays. GRT1 induced PLD both in vitro and in vivo. GRT1 showed a high intracellular accumulation that was more pronounced in the lung, but did not cause cerebral PLD due to its effective efflux at the blood-brain barrier. Compared to GRT1, GRT2 revealed higher interstitial fluid concentrations in lung and brain, but more than 30-fold lower lysosomal trapping capacity. No signs of PLD were seen with GRT2. The different profile of GRT2 relative to GRT1 is due to a structural change resulting in a reduced basicity of one amino group. Hence, by distinct chemical modifications, undesired lysosomal trapping can be separated from desired drug delivery into different organs. In summary, assessment of intracellular unbound concentrations was instrumental in delineating the intercompound and intertissue differences in PLD induction in vivo and could be applied for identification of potential lysosomotropic compounds in drug development.
|
|
