Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 13 de 13
Filter
Add more filters










Publication year range
1.
Pituitary ; 2024 May 24.
Article in English | MEDLINE | ID: mdl-38787509

ABSTRACT

PURPOSE: To improve the understanding of adherence as one major factor of disease control in acromegaly patients, we systematically assessed patients' motivations to adhere to advised follow-up schedules and recommended medication for acromegaly. METHODS: Cross-sectional, postal questionnaire study on adult patients with acromegaly, operated upon a growth hormone producing pituitary adenoma more than 1 year ago in two tertiary treatment centers. We assessed demographic and clinical characteristics, disease status, adherence to acromegaly medication and/or aftercare, and the five dimensions defined by the World Health Organization influencing adherence. Wherever applicable, we included validated short scales. The answers of 63 patients (33 f, 30 m; mean age 56.1 y) were analyzed. RESULTS: Patients with problems in adherence to aftercare had a significantly lower subjective symptomload than those adherent to aftercare (p = 0.026) and a lower perceived need for treatment (p = 0.045). Patients with adherence problems to medication had a higher subjective symptomload than those without (p = 0.056). They also tended to have shorter consultations, were significantly more often dissatisfied with the duration of their medical consultations (42% vs 4.8%, p = 0.019) and tended to find that their physician explained potential difficulties with adherence less well than patients without adherence problems (p = 0.089). CONCLUSIONS: To our knowledge, this is the first study which explored adherence to medication and aftercare in patients with acromegaly, taking into account potential influencing factors from all areas defined by the WHO model of adherence. Of the modifiable factors of adherence, patient-doctor relationship seemed to play a crucial role and could be one leverage point to improve adherence.

2.
Pflugers Arch ; 2024 May 07.
Article in English | MEDLINE | ID: mdl-38714572

ABSTRACT

Cells of the immune defence, especially leukocytes, often have to perform their function in tissue areas that are characterized by oxygen deficiency, so-called hypoxia. Physiological hypoxia significantly affects leukocyte function and controls the innate and adaptive immune response mainly through transcriptional gene regulation via the hypoxia-inducible factors (HIFs). Multiple pathogens including components of bacteria, such as lipopolysaccharides (LPS) trigger the activation of leukocytes. HIF pathway activation enables immune cells to adapt to both hypoxic environments in physiological and inflammatory settings and modulates immune cell responses through metabolism changes and crosstalk with other immune-relevant signalling pathways. To study the mutual influence of both processes in vivo, we used a human endotoxemia model, challenging participants with an intravenous LPS injection post or prior to a 4-h stay in a hypoxic chamber with normobaric hypoxia of 10.5% oxygen. We analysed changes in gene expression in whole blood cells and determined inflammatory markers to unveil the crosstalk between both processes. Our investigations showed differentially altered gene expression patterns of HIF and target genes upon in vivo treatment with LPS and hypoxia. Further, we found evidence for effects of hypoxic priming upon inflammation in combination with immunomodulatory effects in whole blood cells in vivo. Our work elucidates the complex interplay of hypoxic and inflammatory HIF regulation in human immune cells and offers new perspectives for further clinical research.

3.
Nat Commun ; 14(1): 2483, 2023 Apr 29.
Article in English | MEDLINE | ID: mdl-37120587

ABSTRACT

Despite recent advances in exfoliated vdW ferromagnets, the widespread application of 2D magnetism requires a Curie temperature (Tc) above room temperature as well as a stable and controllable magnetic anisotropy. Here we demonstrate a large-scale iron-based vdW material Fe4GeTe2 with the Tc reaching ~530 K. We confirmed the high-temperature ferromagnetism by multiple characterizations. Theoretical calculations suggested that the interface-induced right shift of the localized states for unpaired Fe d electrons is the reason for the enhanced Tc, which was confirmed by ultraviolet photoelectron spectroscopy. Moreover, by precisely tailoring Fe concentration we achieved arbitrary control of magnetic anisotropy between out-of-plane and in-plane without inducing any phase disorders. Our finding sheds light on the high potential of Fe4GeTe2 in spintronics, which may open opportunities for room-temperature application of all-vdW spintronic devices.

4.
Healthcare (Basel) ; 11(6)2023 Mar 08.
Article in English | MEDLINE | ID: mdl-36981454

ABSTRACT

(1) Background: Patients' experiences and satisfaction with their treatment are becoming increasingly important in the context of quality assurance, but the measurement of these parameters is accompanied by several disadvantages such as poor cross-country comparability and methodological problems. The aim of this review is to describe and summarize the process of measuring, publishing, and utilizing patient experience and satisfaction data in countries with highly developed healthcare systems in Europe (Germany, Sweden, Finland, Norway, the United Kingdom) and the USA to identify possible approaches for improvement. (2) Methods: Articles published between 2000 and 2021 that address the topics described were identified. Furthermore, patient feedback in social media and the influence of sociodemographic and hospital characteristics on patient satisfaction and experience were evaluated. (3) Results: The literature reveals that all countries perform well in collecting patient satisfaction and experience data and making them publicly available. However, due to the use of various different questionnaires, comparability of the results is difficult, and consequences drawn from these data remain largely unclear. (4) Conclusions: Surveying patient experience and satisfaction with more unified as well as regularly updated questionnaires would be helpful to eliminate some of the described problems. Additionally, social media platforms must be considered as an increasingly important source to expand the range of patient feedback.

6.
J Med Chem ; 65(4): 3473-3517, 2022 02 24.
Article in English | MEDLINE | ID: mdl-35108001

ABSTRACT

Upregulation of the transcription factor Nrf2 by inhibition of the interaction with its negative regulator Keap1 constitutes an opportunity for the treatment of disease caused by oxidative stress. We report a structurally unique series of nanomolar Keap1 inhibitors obtained from a natural product-derived macrocyclic lead. Initial exploration of the structure-activity relationship of the lead, followed by structure-guided optimization, resulted in a 100-fold improvement in inhibitory potency. The macrocyclic core of the nanomolar inhibitors positions three pharmacophore units for productive interactions with key residues of Keap1, including R415, R483, and Y572. Ligand optimization resulted in the displacement of a coordinated water molecule from the Keap1 binding site and a significantly altered thermodynamic profile. In addition, minor reorganizations of R415 and R483 were accompanied by major differences in affinity between ligands. This study therefore indicates the importance of accounting both for the hydration and flexibility of the Keap1 binding site when designing high-affinity ligands.


Subject(s)
Kelch-Like ECH-Associated Protein 1/antagonists & inhibitors , Macrocyclic Compounds/pharmacology , NF-E2-Related Factor 2/antagonists & inhibitors , Animals , Binding Sites , Hepatocytes/metabolism , Humans , Ligands , Microsomes, Liver/metabolism , Models, Molecular , Molecular Docking Simulation , Rats , Signal Transduction/drug effects , Structure-Activity Relationship
7.
Nano Lett ; 20(6): 4220-4227, 2020 Jun 10.
Article in English | MEDLINE | ID: mdl-32329620

ABSTRACT

Modern-day CMOS-based computation technology is reaching its fundamental limitations. The emerging field of magnonics, which utilizes spin waves for data transport and processing, proposes a promising path to overcome these limitations. Different devices have been demonstrated recently on the macro- and microscale, but the feasibility of the magnonics approach essentially relies on the scalability of the structure feature size down to the extent of a few 10 nm, which are typical sizes for the established CMOS technology. Here, we present a study of propagating spin-wave packets in individual yttrium iron garnet (YIG) conduits with lateral dimensions down to 50 nm. Space and time-resolved microfocused Brillouin-light-scattering (BLS) spectroscopy is used to characterize the YIG nanostructures and measure the spin-wave decay length and group velocity directly. The revealed magnon transport at the scale comparable to the scale of CMOS proves the general feasibility of magnon-based data processing.

8.
J Clin Pharmacol ; 60(4): 528-539, 2020 04.
Article in English | MEDLINE | ID: mdl-31701537

ABSTRACT

Upadacitinib (ABT-494) is a selective Janus kinase (JAK)1 inhibitor being developed for treatment of several inflammatory disorders. A population pharmacokinetic model was developed for upadacitinib using 11,658 plasma concentrations from 1145 subjects from 4 phase 1 and 5 phase 2 studies in healthy subjects and subjects with rheumatoid arthritis, Crohn's disease, ulcerative colitis, or atopic dermatitis. A 2-compartment model with first-order absorption and lag time for the immediate-release formulation and mixed zero- and first-order absorption with lag time for the extended-release formulation, and linear elimination adequately described upadacitinib plasma concentration-time profiles. The oral bioavailability of upadacitinib extended-release formulation was estimated to be approximately 80% relative to the immediate-release formulation. Covariates included in the final model were creatinine clearance, subject population (healthy subjects vs subjects with atopic dermatitis, ulcerative colitis, or Crohn's disease vs subjects with rheumatoid arthritis) and sex on apparent oral clearance and sex and body weight on apparent volume of distribution of the central compartment. Female subjects had 21% higher upadacitinib steady-state area under the plasma concentration-time curve (AUC) compared to male subjects. Compared to healthy subjects, subjects with atopic dermatitis, ulcerative colitis, or Crohn's disease had 21% higher upadacitinib steady-state AUC, while subjects with rheumatoid arthritis had 35% higher steady-state AUC. Subjects with mild or moderate renal impairment were estimated to have 10% or 22% higher AUC, respectively, compared to subjects with normal renal function. Based on final model parameter estimates, effects of the tested covariates are not expected to result in clinically relevant changes in upadacitinib steady-state exposures.


Subject(s)
Arthritis, Rheumatoid/metabolism , Colitis, Ulcerative/metabolism , Crohn Disease/metabolism , Dermatitis, Atopic/metabolism , Heterocyclic Compounds, 3-Ring/adverse effects , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Janus Kinase Inhibitors/adverse effects , Janus Kinase Inhibitors/pharmacokinetics , Adolescent , Adult , Aged , Aged, 80 and over , Area Under Curve , Arthritis, Rheumatoid/drug therapy , Biological Availability , Clinical Trials, Phase I as Topic , Clinical Trials, Phase II as Topic , Colitis, Ulcerative/drug therapy , Computer Simulation , Crohn Disease/drug therapy , Delayed-Action Preparations/pharmacokinetics , Dermatitis, Atopic/drug therapy , Female , Healthy Volunteers , Heterocyclic Compounds, 3-Ring/administration & dosage , Heterocyclic Compounds, 3-Ring/blood , Humans , Janus Kinase Inhibitors/administration & dosage , Janus Kinase Inhibitors/blood , Male , Middle Aged , Models, Biological , Young Adult
9.
Hematol Oncol ; 37(4): 464-473, 2019 Oct.
Article in English | MEDLINE | ID: mdl-31251400

ABSTRACT

The objective of this research was to characterize the venetoclax exposure-efficacy and exposure-safety relationships and determine its optimal dose in elderly patients with newly diagnosed acute myeloid leukemia (AML) receiving venetoclax in combination with low intensity therapies (hypomethylating agent [HMA; azacitidine or decitabine] or low-dose cytarabine [LDAC]). A total of 212 patients from the HMA study and 92 patients from the LDAC study were included in the exposure-safety analyses. Those who received at least one dose of venetoclax and had at least one measurable response (201 and 83 in the HMA and LDAC studies, respectively) were included in the exposure-efficacy analyses. The probability of response based on International Working Group (IWG) for AML response criteria, adverse events of grade 3 or worse neutropenia or infection or a serious adverse event was modeled using logistic regression analyses to characterize the venetoclax exposure-response relationships. In combination with an HMA, increasing concentrations of venetoclax, up to those associated with a less than or equal to 400-mg once daily (QD) dose, were associated with a higher probability of response, with a trend for flat or decreasing probabilities of response thereafter. In combination with LDAC, increasing concentrations of venetoclax were associated with higher probabilities of response, with no plateau observed. Increasing concentrations of venetoclax were not associated with increasing probability of any safety event except for a slight increase in grade 3 or worse infections with HMAs; however, tolerability issues were observed at doses of greater than or equal to 800 mg QD in each study. Exposure-response analyses support the use of venetoclax 400 mg QD in combination with an HMA and 600 mg QD in combination with LDAC (ie, the next highest dose evaluated below 800 mg in each combination) to safely maximize the probability of response in elderly patients with newly diagnosed AML.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Bridged Bicyclo Compounds, Heterocyclic/administration & dosage , Leukemia, Myeloid, Acute/drug therapy , Sulfonamides/administration & dosage , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Azacitidine/administration & dosage , Azacitidine/adverse effects , Bridged Bicyclo Compounds, Heterocyclic/adverse effects , Bridged Bicyclo Compounds, Heterocyclic/pharmacokinetics , Clinical Trials, Phase I as Topic/statistics & numerical data , Cytarabine/administration & dosage , Cytarabine/adverse effects , DNA Methylation/drug effects , Decitabine/administration & dosage , Decitabine/adverse effects , Dose-Response Relationship, Drug , Humans , Molecular Targeted Therapy , Remission Induction , Sulfonamides/adverse effects , Sulfonamides/pharmacokinetics , Treatment Outcome
10.
Clin Pharmacokinet ; 58(8): 1045-1058, 2019 08.
Article in English | MEDLINE | ID: mdl-30945116

ABSTRACT

BACKGROUND AND OBJECTIVES: Upadacitinib is a selective Janus kinase (JAK) 1 inhibitor being developed as an orally administered treatment for patients with moderate to severe rheumatoid arthritis (RA) and other autoimmune disorders. These analyses characterized the population pharmacokinetics of upadacitinib across phase I-III clinical trials using data for immediate-release (IR) and extended-release (ER) formulations. METHODS: Pharmacokinetic data from 4170 subjects taking IR doses of 1-48 mg and ER doses of 7.5-30 mg across 12 studies spanning phase I-III clinical trials, with a total of 29,372 upadacitinib plasma concentrations, were analyzed using non-linear mixed-effects modeling. The model was evaluated using bootstrap analyses and visual predictive checks. RESULTS: A two-compartment model with first-order absorption with lag time for the IR formulation, mixed zero- and first-order absorption with lag time for the ER formulation, and linear elimination, adequately described upadacitinib plasma concentration-time profiles. Population estimates of upadacitinib apparent oral clearance and steady-state volume of distribution in healthy volunteers for the ER formulation were 53.7 L/h and 294 L, respectively. The relative bioavailability of the ER formulation compared with the IR formulation was estimated to be 76.2%. Statistically significant covariates were patient population (RA subjects vs. healthy subjects), creatinine clearance, and baseline bodyweight on apparent clearance (CL/F) and bodyweight on volume of distribution of the central compartment (Vc/F). The intersubject variability for upadacitinib CL/F and Vc/F were estimated to be 21% and 24%, respectively, in the phase I studies, and 37% and 53%, respectively, in the phase II/III studies. Upadacitinib area under the concentration-time curve (AUC) was estimated to be only 5% higher or lower for RA patients who were < 60 or > 100 kg, respectively, relative to subjects with a bodyweight of 60-100 kg. RA subjects with mild or moderate renal impairment had 13% and 26% higher AUC, respectively, compared with RA subjects with normal renal function. Sex, race, concomitant use of pH-modifying drugs, moderate cytochrome P450 3A inhibitors, or methotrexate use had no effect on upadacitinib exposure. CONCLUSIONS: A robust population pharmacokinetic model was developed for upadacitinib using a large dataset from phase I-III clinical trials in healthy volunteers and subjects with RA. None of the identified covariates had a clinically meaningful effect on upadacitinib exposures. The model is appropriate to use for simulations and to evaluate the exposure-response relationship of upadacitinib.


Subject(s)
Arthritis, Rheumatoid/drug therapy , Delayed-Action Preparations/pharmacokinetics , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Janus Kinase Inhibitors/pharmacokinetics , Administration, Oral , Adult , Aged , Antirheumatic Agents/therapeutic use , Biological Availability , Case-Control Studies , Female , Healthy Volunteers , Heterocyclic Compounds, 3-Ring/blood , Heterocyclic Compounds, 3-Ring/therapeutic use , Humans , Janus Kinase Inhibitors/blood , Janus Kinase Inhibitors/therapeutic use , Male , Methotrexate/therapeutic use , Middle Aged
11.
J Clin Pharmacol ; 59(9): 1225-1235, 2019 09.
Article in English | MEDLINE | ID: mdl-30990907

ABSTRACT

Depatuxizumab mafodotin (depatux-m) is an antibody-drug conjugate (ADC) designed for the treatment of tumors expressing epidermal growth factor receptor (EGFR), consisting of a veneered "humanized" recombinant IgG1κ antibody that has binding properties specific to a unique epitope of human EGFR with noncleavable maleimido-caproyl linkers each attached to a potent antimitotic cytotoxin, monomethyl auristatin F. We aimed to describe the development and comparison of 2 population pharmacokinetic modeling approaches. Data from 2 phase 1 studies enrolling patients with glioblastoma multiforme or advanced solid tumors were included in the analysis. Patients in these studies received doses of depatux-m ranging from 0.5 to 4.0 mg/kg as monotherapy, in combination with temozolomide, or radiation plus temozolomide depending on the study and/or arm. First, an integrated ADC model to simultaneously describe the concentration-time data for ADC, total antibody, and cys-mafodotin was built using a 2-compartment model for ADC for each drug-to-antibody ratio. Then, 3 individual models were developed for ADC, total antibody, and cys-mafodotin separately using 2-compartment models for ADC and total antibody and a 1-compartment model for cys-mafodotin. Visual predictive checks suggested accurate model fitting across a range of concentrations. The analysis showed that both an integrated complex ADC model and the individual models that have shorter computational time would result in similar outcomes.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacokinetics , Glioblastoma/metabolism , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/therapeutic use , ErbB Receptors/metabolism , Female , Glioblastoma/drug therapy , Humans , Immunoconjugates/pharmacokinetics , Immunoconjugates/therapeutic use , Male , Middle Aged , Temozolomide/pharmacokinetics , Temozolomide/therapeutic use , Young Adult
12.
Ecotoxicol Environ Saf ; 164: 548-553, 2018 Nov 30.
Article in English | MEDLINE | ID: mdl-30149353

ABSTRACT

Throughout evolutionary history bees have developed complex communication systems. For social bees, communication is important for both the individual and the development of the colony. Successful communication helps bees to recognize relatives, defend the colony, and promote recruitment to optimize foraging of floral resources. Bees' contribution to pollination is of broad environmental and economic importance. However, studies have reported that anthropogenic actions, such as the use of pesticides, negatively affect bee survival and behavior. We tested the effect of a commercially available pesticide mix containing two pesticide classes, a neonicotinoid and a pyrethroid, on the social behavior of the stingless bee, Melipona quadrifasciata (Lepeletier, 1863). After determining a sublethal dose of the pesticides, we tested the effect of an acute dose on antennation and trophallaxis behaviors of worker bees. Our results showed a drastic reduction in the communication and social interactions of bees.


Subject(s)
Bees/drug effects , Behavior, Animal/drug effects , Pesticides/toxicity , Pyrethrins/toxicity , Social Behavior , Animal Communication , Animals , Environmental Exposure , Pollination
13.
Curr Opin Cell Biol ; 21(2): 237-44, 2009 Apr.
Article in English | MEDLINE | ID: mdl-19230642

ABSTRACT

During S phase, eukaryotic cells unwind and duplicate a tremendous amount of DNA, generating structures that are very sensitive to both endogenous and exogenous insults. The collision of DNA polymerases with damaged DNA or other obstructions to fork progression generates replication stress, which can evolve into fork collapse if the replisome components are not stabilized. To ensure genome integrity, stalled replication forks are recognized by a checkpoint, whose central player is the human kinase ATR or Mec1 in S. cerevisiae. This review will discuss recent findings revealing roles of the ATR/Mec1 kinase: both in stabilizing the replisome directly and in activating the checkpoint response to regulate origin firing, DNA repair, fork restart, and cell cycle progression.


Subject(s)
Cell Cycle Proteins/metabolism , DNA Repair , DNA Replication , Genomic Instability , Intracellular Signaling Peptides and Proteins/metabolism , Protein Serine-Threonine Kinases/metabolism , Saccharomyces cerevisiae Proteins/metabolism , Animals , Ataxia Telangiectasia Mutated Proteins , Cell Cycle/physiology , Cell Cycle Proteins/genetics , Checkpoint Kinase 1 , Checkpoint Kinase 2 , DNA Damage , Enzyme Activation , Humans , Intracellular Signaling Peptides and Proteins/genetics , Protein Kinases/genetics , Protein Kinases/metabolism , Protein Serine-Threonine Kinases/genetics , Saccharomyces cerevisiae/genetics , Saccharomyces cerevisiae Proteins/genetics
SELECTION OF CITATIONS
SEARCH DETAIL
...