Adipose-derived stem cells: a review of osteogenesis differentiation

Second part of manuscript based on osteogenesis differentiation of stem cells. Bones are highly regenerative organs but there are still many problems with therapy of large bone defects. Sometimes there is necessary to make a replacement or expansion new bone tissue. Stem cells might be a good solution for this especially ADSCs which manage differentiate into osteoblast in in vitro and in vivo conditions

Ripretinib in the treatment of patients with advanced gastrointestinal stromal tumors (GIST)

Gastrointestinal stromal tumors (GISTs) are relatively rare in the population (0.4 to 2 cases per 100 000 per year) and account for approximately 1–2% of gastrointestinal cancers. According to the latest 2020 World Health Organization (WHO) classification of sarcomas, all GISTs are malignant, regardless of their size or mitotic index. In the systemic treatment of GIST, KIT tyrosine kinase receptor and platelet-derived growth factor receptor (PDGFRA) inhibitors, such as imatinib, sunitinib, or regorafenib, are used. The effectiveness of imatinib is significantly reduced in the case of secondary mutations in the KIT gene. The latest drug from the group of KIT inhibitors, ripretinib, was the first to show efficacy against most mutations associated with resistance, as well as in wild-type GIST, in which mutations in KIT and PDGFRA are not found. Analysis of the INVICTUS study showed a beneficial effect of ripretinib at the recommended dose of 150 mg/day on progression-free survival (PFS) in patients with advanced or metastatic GIST previously treated with at least three other inhibitors. However, the preliminary results of the phase III INTRIGUE study did not show an improvement in PFS in patients receiving ripretinib compared to sunitinib in the second-line therapy of GIST patients. Ripretinib has a favorable and acceptable safety profile and is recommended for treating patients with advanced GIST in the fourth line of treatment. In this article, we summarize the most essential data on the efficacy and safety of ripretinib in treating GIST patients and the recommendations for its use

The influence of metoclopramide on pharmacokinetics and pharmacodynamics of ticagrelor in patients with unstable angina pectoris receiving concomitant treatment with morphine — a protocol of a randomized trial

Introduction. Nowadays, due to the “morphine effect”, the screening of methods that provide quick and effective platelet inhibition with oral P2Y12 inhibitors administrated simultaneously with morphine in patients with acute coronary syndromes are extensively investigated by numerous scientists. Metoclopramide, which stimulates the motility of gastrointestinal tract, may become a potential method of overcoming the negative morphine effect. The present study was designed to demonstrate the influence of metoclopramide administration on the pharmacokinetic and pharmacodynamic profile of ticagrelor between patients with unstable angina pectoris treated with morphine and crushed ticagrelor. Methods/design. A study was designed as a phase IV, single-centre, randomized, investigator-initiated, parallel-group, open-label, interventional trial. Patients will be randomized in a 1:1 manner into two arms: 1) patients treated with a combination of crushed ticagrelor and morphine and 2) patients treated with a combination of crushed ticagrelor followed by morphine and metoclopramide. Blood sample collection will be scheduled directly before the administration of ticagrelor loading dose and 15, 30, 45, 60, 120, 180, 240, and 360 minutes after the loading dose. Pharmacokinetic and pharmacodynamic assessment of ticagrelor and its active metabolite will be evaluated in all pre-defined time points. Discussion. The current study is, to our knowledge, the first one to provide data on the influence of metoclopramide in patients with acute coronary syndromes, who received intravenous opioid analgesia. It is expected to contribute to the development of contemporary knowledge on the treatment of patients presenting with acute coronary syndromes, and should enable clinicians to implement strategies of quick platelet inhibition

Variability of prasugrel antiplatelet effect in patients with acute coronary syndrome

Background. Many reports have demonstrated excessive variability in response to clopidogrel, the most commonly used P2Y12 receptor antagonist. Clopidogrel resistant patients are at increased risk of cardiovascular (CV) events. Prasugrel is a new P2Y12 inhibitor that provides greater and faster platelet inhibition and reduces CV events more effectively than clopidogrel. The aim of this study was to evaluate the variability and efficacy of prasugrel antiplatelet activity in patients presenting with acute coronary syndrome (ACS). Materials and methods. The study was designed as a prospective, single-center, non-randomized, observational trial. Platelet reactivity (PR) was assessed with the VeryfyNow assay three times during hospitalization in forty-two patients undergoing percutaneous coronary intervention (PCI) for ACS and treated with standard doses of prasugrel. Results. Platelet aggregation with prasugrel displayed relatively high variability. The platelet aggregation was lowest on the 3rd day of the treatment at 4 p.m. and was significantly different from the measurements obtained on the 3rd and 4th day in the morning (6.0 v. 8.5 U; p = 0.0005 and 6.0 v. 36.5 U; p < 0.00001, respectively), with the latter two differing significantly from each other (p = 0.002). All participants were successfully treated with prasugrel achieving PR < 208 PRU in each measurement, whereas 42.9–80.9% (depending on sampling point) of patients presented very low platelet activity. The subgroups of stable and persistent low PR included a higher percentage of active smokers (73.3 v. 40.7%; p = 0.04 and 80.0 v. 43.8%; p = 0.04, respectively). Conclusions. Prasugrel treatment is associated with high variability of PR. Nonetheless, prasugrel is a highly effective antiplatelet drug. Active smoking may predispose to strong and stable on-prasugrel platelet inhibition.

Pro Libris: Lubuskie Pismo Literacko-Kulturalne, nr 4 (2010)

145 s. : il., portr.

Saliva as Blood Alternative in Therapeutic Monitoring of Teriflunomide—Development and Validation of the Novel Analytical Method

Therapeutic drug monitoring (TDM) is extremely helpful in individualizing dosage regimen of drugs with narrow therapeutic ranges. It may also be beneficial in the case of drugs characterized by serious side effects and marked interpatient pharmacokinetic variability observed with leflunomide and its biologically active metabolite, teriflunomide. One of the most popular matrices used for TDM is blood. A more readily accessible body fluid is saliva, which can be collected in a much safer way comparing to blood. This makes it especially advantageous alternative to blood during life-threatening SARS-CoV-2 pandemic. However, drug’s saliva concentration is not always a good representation of its blood concentration. The aim of this study was to verify whether saliva can be used in TDM of teriflunomide. We also developed and validated the first reliable and robust LC-MS/MS method for quantification of teriflunomide in saliva. Additionally, the effect of salivary flow and swab absorptive material from the collector device on teriflunomide concentration in saliva was evaluated. Good linear correlation was obtained between the concentration of teriflunomide in plasma and resting saliva (p p p = 0.198) or type of swab in the Salivette device on saliva’s teriflunomide concentration was detected. However, to reduce variability the use of stimulated saliva and synthetic swabs is advised

DNA methylation: gene expression regulation

Epigenetic modifications are responsible for the modulation of gene expression without affecting the nucleotide sequence. The observed changes in transcriptional activity of genes in tumor tissue compared to normal tissue, are often the result of DNA methylation within the promoter sequences of these genes. This modification by attaching methyl groups to cytosines within CpG islands results in silencing of transcriptional activity of the gene, which in the case of tumor suppressor genes is manifested by abnormal cell cycle, proliferation and excessive destabilization of the repair processes. Further studies of epigenetic modifications will allow a better understanding of mechanisms of their action, including the interdependence between DNA methylation and activity of proteins crucial to the structure of chromatin and gene activity. Wider knowledge of epigenetic mechanisms involved in the process of malignant transformation and pharmacological regulation of the degree of DNA methylation provides an opportunity to improve the therapeutic actions in the fight against cancer

Biological and Physico-Chemical Characteristics of Arginine-Rich Peptide Gemini Surfactants with Lysine and Cystine Spacers

Ultrashort cationic lipopeptides (USCLs) and gemini cationic surfactants are classes of potent antimicrobials. Our recent study has shown that the branching and shortening of the fatty acids chains with the simultaneous addition of a hydrophobic N-terminal amino acid in USCLs result in compounds with enhanced selectivity. Here, this approach was introduced into arginine-rich gemini cationic surfactants. l-cystine diamide and l-lysine amide linkers were used as spacers. Antimicrobial activity against planktonic and biofilm cultures of ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) strains and Candida sp. as well as hemolytic and cytotoxic activities were examined. Moreover, antimicrobial activity in the presence of human serum and the ability to form micelles were evaluated. Membrane permeabilization study, serum stability assay, and molecular dynamics were performed. Generally, critical aggregation concentration was linearly correlated with hydrophobicity. Gemini surfactants were more active than the parent USCLs, and they turned out to be selective antimicrobial agents with relatively low hemolytic and cytotoxic activities. Geminis with the l-cystine diamide spacer seem to be less cytotoxic than their l-lysine amide counterparts, but they exhibited lower antibiofilm and antimicrobial activities in serum. In some cases, geminis with branched fatty acid chains and N-terminal hydrophobic amino acid resides exhibited enhanced selectivity to pathogens over human cells