Pharmacokinetic and pharmacodynamic analysis of topotecan administered in combination with PS 341 in patients with advanced malignancy

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2033-2033
Author(s):  
M. Tomita ◽  
L. Xin ◽  
B. Freeman ◽  
S. Twomey ◽  
G. Pizzorno ◽  
...  
Keyword(s):  
Topoisomerase I ◽  
Mononuclear Cells ◽  
Day Treatment ◽  
Pharmacokinetic Analysis ◽  
Dna Breaks ◽  
Peripheral Blood Mononuclear ◽  
Advanced Malignancy ◽  
Pharmacodynamic Analysis ◽  
Dose Escalating

2033 Background: In vitro exposure to camptothecin results in down-regulation of the target enzyme, topoisomerase I (topo) via multi-ubiquitination and proteasomal degradation of the protein-linked DNA breaks. To prevent loss of topo, and thus circumvent a possible mechanism of resistance to the topo inhibitors, we conducted a dose escalating phase I study of topotecan in combination with the proteosome inhibitor PS 341. We now report the pharmacokinetic and pharmacodynamic analysis of the trial. Methods: Patients with advanced cancer were treated with topotecan alone at the following dose escalating levels: 0.75, 1.0,1,25 and 1.5 mg/m2 as a 60 min infusion d x 5 during cycle 1. In subsequent cycles (21 days), cohorts of 3–6 patients received PS 341 as a 30 min infusion on days 1, 4, 8 and 11 at the following dose levels: 0.6, 0.8, 1.0 and 1.3 mg/m2. Topo expression was determined by western blot on peripheral blood mononuclear cells (PBMCs) sampled throughout the first 5-day treatment period of cycles #1 and 2. Total topotecan plasma pharmacokinetics were studied with the first doses of topotecan on cycle #1 (topotecan alone) and cycle #2 (topotecan after PS 341). Results: Samples were collected from 22 patients and 38 patient-cycles. In the first week of cycle #1, 9 of 22 (41 %) patients demonstrated a significant decrease in topo expression (range 0.2 - 1 fold) compared with the baseline level. Topo levels did not change (7/22, 32%) or increased (6/22, 27%) in the remaining patients. After administration of PS 341 during cycle #2, PBMC from 10 of 17 patients (59 %) analyzed showed a greater than 0.3 fold increase (range: 0.32 to 63) in topo concentration, and topo levels in 4 patients (23 %) were unchanged. Preliminary pharmacokinetic analysis indicates that PS 341 may interact with topotecan. Conclusions: There is a heterogeneous response in PBMC topo levels following administration of topotecan. However, addition of PS 341 to topotecan stabilized or increased PBMC topo I levels in the majority of patients, suggesting a possible role for PS341 in inhibiting camptothecin-induced topo protein degradation. Further studies combining proteasome inhibitors with topotecan to overcome drug resistance based on topo degradation are warranted. No significant financial relationships to disclose.

Phase I trial of the oral histone deacetylase inhibitor MS-275 administered with food

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13036-13036 ◽  
Author(s):  
E. A. Donovan ◽  
A. Sparreboom ◽  
W. Figg ◽  
J. Trepel ◽  
K. Maynard ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Mononuclear Cells ◽  
Interindividual Variability ◽  
Protein Acetylation ◽  
Hdac Inhibition ◽  
Peripheral Blood Mononuclear ◽  
Advanced Malignancy ◽  
Grade 3

13036 Background: The histone deacetylase (HDAC) inhibitor MS-275, a synthetic benzamide derivative, has demonstrated antitumor activity in vitro & in vivo. After determining maximum tolerable dose (MTD = 2 mg/m2) & dose limiting toxicity (DLT) for MS-275 given to fasting patients (pts) weekly ×4 q6 weeks, we explored toxicity profile, MTD, & pharmacokinetics (PK) of MS-275 when given po on the same schedule with food. Methods: MS-275 at 2, 4, or 6 mg/m2 was administered to pts with advanced malignancy & PS ≤2, LFTs ≤2.5 × normal, adequate hematopoietic & renal function, & normal resting MUGA. PK samples were analyzed by LC-MS. Data for pts in the fed state were compared to data obtained in previous cohorts of pts treated in the fasting state. Protein acetylation assessed by a novel flow cytometric assay & HDAC enzymatic activity were measured in peripheral blood mononuclear cells (PBMC). Results: 16 pts received a median of 2 cycles (1–5) of MS-275 2–6 mg/m2 with food. No DLT occurred on 2 or 6 mg/m2 (n = 3 each), while 1 pt on 4 mg/m2 (n = 10) had a DLT: grade 3 hypophosphatemia. For 2–6 mg/m2 other grade 3 toxicities were neutropenia & lymphopenia. Grade 1–2 toxicities in >1 pt were leucopenia, anemia, thrombocytopenia, fatigue, nausea, vomiting, headache, hypoalbuminemia, hypophosphatemia, hyponatremia, & hypocalcemia. MTD has not been reached; current dose level is 8 mg/m2. Comparing PK for fasting & fed pts on 2–4 mg/m2, there was no difference in Tmax (0.5h); average Cmax & AUC were 35% & 25% lower, respectively, in fed pts; this difference is not statistically significant. Interindividual variability in exposure to MS-275 increased from 52% in fasting pts to 100% in fed pts. PBMC protein acetylation & HDAC inhibition were seen at all dose levels (2–6 mg/m2) in fed pts. Of 9 pts evaluable for response (2–4 mg/m2), 2 of 6 pts on 4 mg/m2 had stable disease. Conclusions: MTD has not yet been established for MS-275 given with food on this schedule but is ≥4 mg/m2 weekly x4 q6 weeks. Interindividual variability in exposure increases with food. Whether intestinal absorption is decreased when MS-275 is given with food requires further evaluation with additional patients. Drug-related protein hyperacetylation & HDAC inhibition were observed. [Table: see text]

Preliminary Report of In vitro and In vivo Effectiveness of Dornase Alfa on SARS-CoV-2 Infection (Preprint)

2020 ◽  
Author(s):  
Hacer Kuzu Okur ◽  
Koray Yalcin ◽  
Cihan Tastan ◽  
Sevda Demir ◽  
Bulut Yurtsever ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Respiratory Tract ◽  
Mononuclear Cells ◽  
Multiple Organ ◽  
Peripheral Blood Mononuclear ◽  
Dornase Alfa ◽  
Tract Infections ◽  
Adult Peripheral Blood

UNSTRUCTURED Dornase alfa, the recombinant form of the human DNase I enzyme, breaks down neutrophil extracellular traps (NET) that include a vast amount of DNA fragments, histones, microbicidal proteins and oxidant enzymes released from necrotic neutrophils in the highly viscous mucus of cystic fibrosis patients. Dornase alfa has been used for decades in patients with cystic fibrosis to reduce the viscoelasticity of respiratory tract secretions, to decrease the severity of respiratory tract infections, and to improve lung function. Previous studies have linked abnormal NET formations to lung diseases, especially to acute respiratory distress syndrome (ARDS). Coronavirus disease 2019 (COVID-19) pandemic affected more than two million people over the world, resulting in unprecedented health, social and economic crises. The COVID-19, viral pneumonia that progresses to ARDS and even multiple organ failure, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). High blood neutrophil levels are an early indicator of SARS-CoV-2 infection and predict severe respiratory diseases. A similar mucus structure is detected in COVID-19 patients due to the accumulation of excessive NET in the lungs. Here, we show our preliminary results with dornase alfa that may have an in-vitro anti-viral effect against SARS-CoV-2 infection in a bovine kidney cell line, MDBK without drug toxicity on healthy adult peripheral blood mononuclear cells. In this preliminary study, we also showed that dornase alfa can promote clearance of NET formation in both an in-vitro and three COVID-19 cases who showed clinical improvement in radiological analysis (2-of-3 cases), oxygen saturation (SpO2), respiratory rate, disappearing of dyspnea and coughing.

scholarly journals Potential Role and Impact of Peripheral Blood Mononuclear Cells in Radiographic Axial Spondyloarthritis-Associated Endothelial Dysfunction

Diagnostics ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 1037
Author(s):  
Patricia Ruiz-Limon ◽  
Maria L. Ladehesa-Pineda ◽  
Clementina Lopez-Medina ◽  
Chary Lopez-Pedrera ◽  
Maria C. Abalos-Aguilera ◽  
...  
Keyword(s):  
Endothelial Dysfunction ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Axial Spondyloarthritis ◽  
Endothelial Injury ◽  
In Vitro Studies ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

Endothelial dysfunction (ED) is well known as a process that can lead to atherosclerosis and is frequently presented in radiographic axial spondyloarthritis (r-axSpA) patients. Here, we investigated cellular and molecular mechanisms underlying r-axSpA-related ED, and analyzed the potential effect of peripheral blood mononuclear cells (PBMCs) in promoting endothelial injury in r-axSpA. A total of 30 r-axSpA patients and 32 healthy donors (HDs) were evaluated. The endothelial function, inflammatory and atherogenic profile, and oxidative stress were quantified. In vitro studies were designed to evaluate the effect of PBMCs from r-axSpA patients on aberrant endothelial activation. Compared to HDs, our study found that, associated with ED and the plasma proatherogenic profile present in r-axSpA, PBMCs from these patients displayed a pro-oxidative, proinflammatory, and proatherogenic phenotype, with most molecular changes noticed in lymphocytes. Correlation studies revealed the relationship between this phenotype and the microvascular function. Additional in vitro studies confirmed that PBMCs from r-axSpA patients promoted endothelial injury. Altogether, this study suggests the relevance of r-axSpA itself as a strong and independent cardiovascular risk factor, contributing to a dysfunctional endothelium and atherogenic status by aberrant activation of PBMCs. Lymphocytes could be the main contributors in the development of ED and subsequent atherosclerosis in this pathology.

Differential expression of miRNAs in canine peripheral blood mononuclear cells (PBMC) exposed to Leishmania infantum in vitro

2021 ◽  
Vol 134 ◽  
pp. 58-63
Author(s):  
Matheus Fujimura Soares ◽  
Larissa Martins Melo ◽  
Jaqueline Poleto Bragato ◽  
Amanda de Oliveira Furlan ◽  
Natália Francisco Scaramele ◽  
...  
Keyword(s):  
Differential Expression ◽  
Peripheral Blood Mononuclear Cells ◽  
Peripheral Blood ◽  
Leishmania Infantum ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Blood Mononuclear Cells

scholarly journals Noble Metals for Modern Implant Materials: MOCVD of Film Structures and Cytotoxical, Antibacterial, and Histological Studies

Biomedicines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 851
Author(s):  
Svetlana I. Dorovskikh ◽  
Evgeniia S. Vikulova ◽  
Elena V. Chepeleva ◽  
Maria B. Vasilieva ◽  
Dmitriy A. Nasimov ◽  
...  
Keyword(s):  
Vapor Deposition ◽  
Physical Vapor Deposition ◽  
Noble Metals ◽  
Mononuclear Cells ◽  
Chemical Vapor ◽  
Organic Chemical ◽  
Ti Alloy ◽  
Peripheral Blood Mononuclear ◽  
Histological Studies

This work is aimed at developing the modification of the surface of medical implants with film materials based on noble metals in order to improve their biological characteristics. Gas-phase transportation methods were proposed to obtain such materials. To determine the effect of the material of the bottom layer of heterometallic structures, Ir, Pt, and PtIr coatings with a thickness of 1.4–1.5 μm were deposited by metal–organic chemical vapor deposition (MOCVD) on Ti6Al4V alloy discs. Two types of antibacterial components, namely, gold nanoparticles (AuNPs) and discontinuous Ag coatings, were deposited on the surface of these coatings. AuNPs (11–14 nm) were deposited by a pulsed MOCVD method, while Ag films (35–40 nm in thickness) were obtained by physical vapor deposition (PVD). The cytotoxic (24 h and 48 h, toward peripheral blood mononuclear cells (PBMCs)) and antibacterial (24 h) properties of monophase (Ag, Ir, Pt, and PtIr) and heterophase (Ag/Pt, Ag/Ir, Ag/PtIr, Au/Pt, Au/Ir, and Au/PtIr) film materials deposited on Ti-alloy samples were studied in vitro and compared with those of uncoated Ti-alloy samples. Studies of the cytokine production by PBMCs in response to incubation of the samples for 24 and 48 h and histological studies at 1 and 3 months after subcutaneous implantation in rats were also performed. Despite the comparable thickness of the fibrous capsule after 3 months, a faster completion of the active phase of encapsulation was observed for the coated implants compared to the Ti alloy analogs. For the Ag-containing samples, growth inhibition of S. epidermidis, S. aureus, Str. pyogenes, P. aeruginosa, and Ent. faecium was observed.

scholarly journals Identification of Promiscuous African Swine Fever Virus T-Cell Determinants Using a Multiple Technical Approach

Vaccines ◽  
2021 ◽  
Vol 9 (1) ◽  
pp. 29
Author(s):  
Laia Bosch-Camós ◽  
Elisabet López ◽  
María Jesús Navas ◽  
Sonia Pina-Pedrero ◽  
Francesc Accensi ◽  
...  
Keyword(s):  
T Cell ◽  
Mononuclear Cells ◽  
African Swine Fever Virus ◽  
African Swine Fever ◽  
Cd8 T Cell ◽  
Protective Role ◽  
Full Length ◽  
T Cell Epitopes ◽  
Peripheral Blood Mononuclear

The development of subunit vaccines against African swine fever (ASF) is mainly hindered by the lack of knowledge regarding the specific ASF virus (ASFV) antigens involved in protection. As a good example, the identity of ASFV-specific CD8+ T-cell determinants remains largely unknown, despite their protective role being established a long time ago. Aiming to identify them, we implemented the IFNγ ELISpot as readout assay, using as effector cells peripheral blood mononuclear cells (PBMCs) from pigs surviving experimental challenge with Georgia2007/1. As stimuli for the ELISpot, ASFV-specific peptides or full-length proteins identified by three complementary strategies were used. In silico prediction of specific CD8+ T-cell epitopes allowed identifying a 19-mer peptide from MGF100-1L, as frequently recognized by surviving pigs. Complementarily, the repertoire of SLA I-bound peptides identified in ASFV-infected porcine alveolar macrophages (PAMs), allowed the characterization of five additional SLA I-restricted ASFV-specific epitopes. Finally, in vitro stimulation studies using fibroblasts transfected with plasmids encoding full-length ASFV proteins, led to the identification of MGF505-7R, A238L and MGF100-1L as promiscuously recognized antigens. Interestingly, each one of these proteins contain individual peptides recognized by surviving pigs. Identification of the same ASFV determinants by means of such different approaches reinforce the results presented here.

scholarly journals The Effect of the Clenbuterol—β2-Adrenergic Receptor Agonist on the Peripheral Blood Mononuclear Cells Proliferation, Phenotype, Functions, and Reactive Oxygen Species Production in Race Horses In Vitro

Cells ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 936
Author(s):  
Olga Witkowska-Piłaszewicz ◽  
Rafał Pingwara ◽  
Jarosław Szczepaniak ◽  
Anna Winnicka
Keyword(s):  
Reactive Oxygen Species ◽  
Acute Exercise ◽  
Mononuclear Cells ◽  
Anabolic Steroids ◽  
Reactive Oxygen ◽  
Oxygen Species ◽  
Peripheral Blood Mononuclear ◽  
Adrenoceptor Agonist ◽  
Race Horses

Clenbuterol, the β2-adrenoceptor agonist, is gaining growing popularity because of its effects on weight loss (i.e., chemical liposuction). It is also popular in bodybuilding and professional sports, due to its effects that are similar to anabolic steroids. However, it is prohibited by anti-doping control. On the other hand, it is suggested that clenbuterol can inhibit the inflammatory process. The cells from 14 untrained and 14 well-trained race horses were collected after acute exercise and cultured with clenbuterol. The expressions of CD4, CD8, FoxP3, CD14, MHCII, and CD5 in PBMC, and reactive oxygen species (ROS) production, as well as cell proliferation, were evaluated by flow cytometry. In addition, IL-1β, IL-4, IL-6, IL-10, IL-17, INF-γ and TNF-α concentrations were evaluated by ELISA. β2-adrenoceptor stimulation leads to enhanced anti-inflammatory properties in well-trained horses, as do low doses in untrained animals. In contrast, higher clenbuterol doses create a pro-inflammatory environment in inexperienced horses. In conclusion, β2-adrenoceptor stimulation leads to a biphasic response. In addition, the immune cells are more sensitive to drug abuse in inexperienced individuals under physical training.

scholarly journals A non-human primate in vitro functional assay for the early evaluation of TB vaccine candidates

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Rachel Tanner ◽  
Andrew D. White ◽  
Charelle Boot ◽  
Claudia C. Sombroek ◽  
Matthew K. O’Shea ◽  
...  
Keyword(s):  
Growth Inhibition ◽  
Mononuclear Cells ◽  
Functional Assay ◽  
Intermediate Precision ◽  
Peripheral Blood Mononuclear ◽  
Growth Inhibition Assay ◽  
Early Evaluation ◽  
Human Primate

AbstractWe present a non-human primate mycobacterial growth inhibition assay (MGIA) using in vitro blood or cell co-culture with the aim of refining and expediting early tuberculosis vaccine testing. We have taken steps to optimise the assay using cryopreserved peripheral blood mononuclear cells, transfer it to end-user institutes, and assess technical and biological validity. Increasing cell concentration or mycobacterial input and co-culturing in static 48-well plates compared with rotating tubes improved intra-assay repeatability and sensitivity. Standardisation and harmonisation efforts resulted in high consistency agreements, with repeatability and intermediate precision <10% coefficient of variation (CV) and inter-site reproducibility <20% CV; although some systematic differences were observed. As proof-of-concept, we demonstrated ability to detect a BCG vaccine-induced improvement in growth inhibition in macaque samples, and a correlation between MGIA outcome and measures of protection from in vivo disease development following challenge with either intradermal BCG or aerosol/endobronchial Mycobacterium tuberculosis (M.tb) at a group and individual animal level.

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