A phase I and pharmacokinetic (PK) study of continuous daily administration of P1446A-05, a potent and specific oral Cdk4 inhibitor.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3013-3013 ◽  
Author(s):  
Desiree Hao ◽  
Quincy Chu ◽  
Stephen Welch ◽  
Cindy Y. F. Yau ◽  
Jennifer L. Spratlin ◽  
...  
Keyword(s):  
Phase Ii ◽  
Study Drug ◽  
Multiple Time ◽  
Time Points ◽  
Phase Ii Studies ◽  
Elevated Creatinine ◽  
Multiple Time Points ◽  
Ecog Ps

3013 Background: P1446A-05 is a novel oral inhibitor of Cdk4-D1, Cdk1-B, and Cdk9-T, and has been shown to inhibit tumor growth both in vitro and in vivo. Pharmacodynamic studies demonstrate that activation of Cdk1 reappears within 48 hours after P1446A-05 is withdrawn, suggesting the need for prolonged administration hence, we sought to evaluate the feasibility, safety and tolerability of a continuous daily schedule of P1446A-05 in patients (pts) with advanced malignancies. Methods: P1446A-05 was given at escalating doses of 75, 150, 250, 350 and 500mg. Samples were collected for PK at multiple time points over 24 hours on cycle 1 day 1 and 15, as well as at single time points on cycle 1 day 8, 22 and cycle 2 day 1. Results: Thirty-nine pts (median age=63 years, 51% male, 51% ECOG PS=1) collectively received more than 100 cycles of P1446A-05. The majority of drug-related toxicities were ≤Grade 2, the most common of which were diarrhea (n=54), nausea/vomiting (n=27/17), fatigue (n=22) and anorexia (n=16). Two pts developed study-drug related diarrhea with hypokalemia/elevated creatinine and died during cycle 1. Dose-limiting toxicities (DLT) at 500mg (Table) led to subsequent de-escalation and expansion of the 350mg cohort. A total of 24 pts were treated at 350mg; only one patient experienced dose-limiting diarrhea. PK data are summarized below. Accumulation ratios across dose levels suggest moderate accumulation with continuous dosing. Nine pts achieved stable disease (SD) for at least 2 cycles. One pt with alveolar soft tissue sarcoma, whose disease was progressing at enrollment, remains on treatment with SD after 11 cycles. Conclusions: The recommend phase II dose of P1446A-05 is 350mg. Further phase II studies at this dose will be conducted with potential enrichment strategies. [Table: see text]

First-in-human phase-I pharmacokinetic trial of NS-9, a liposomal poly(I):poly(C), in patients with liver metastases from various primary cancers

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13016-13016
Author(s):  
R. P. Perez ◽  
L. D. Lewis ◽  
G. I. Cohen ◽  
J. Hwang ◽  
S. Malik ◽  
...  
Keyword(s):  
Phase I ◽  
Liver Metastases ◽  
Cationic Liposome ◽  
Dose Escalation Study ◽  
Phase Ii Studies ◽  
Elevated Glucose ◽  
Grade 3 ◽  
Ecog Ps

13016 Background: NS-9 is a complex of poly-inosinate [poly(I)] and poly-cytidylate [poly(C)] in a cationic liposome and is active in vitro and in vivo. Objectives: to determine the tolerability, safety, and maximal tolerated dose (MTD), and pharmacokinetics of NS-9 by 1 hr IV infusion, given daily x5 q 28 days. Methods: A phase I dose escalation study was undertaken in patients with liver metastases from solid tumors. Eligible patients were adults with ECOG PS 0–1 and no recent chemotherapy (≥ 4 wks prior). Dose cohorts studied were 0.1, 0.15, 0.2, 0.3 and 0.4mg/m2. Results: 18 patients were enrolled (13M:5F) median age 58 (range 21 to 77 yrs). Tumor types included neuroendocrine (8), and ocular melanoma (1), gastric (1), GE junction (1), esophageal (2), and colorectal (5) carcinomas. Two of three patients treated at the first dose level (0.4 mg/m2) had grade 3/4 reversible lipase elevation with or without acute pancreatitis, a dose limiting toxicity (DLT). De-escalation to doses ranging from 0.1 to 0.2 mg/m2/day was with no DLT. At 0.3 mg/m2 two of three patients treated had a DLT (neutropenia and thrombocytopenia). The MTD was determined at 0.2 mg/m2. Common toxicities included pyrexia, chills, nausea, fatigue, abdominal pain, myalgia, anorexia, sweating, neutropenia, thrombocytopenia, and elevated glucose, amylase, and LFTs. Pharmacokinetics showed rapid elimination (T1/2 ranged from 2.4 to 5.0 hours) without accumulation after multiple doses. 1 patient (esophageal Ca) had a PR in the target lesions in the liver. Conclusions: The MTD is 0.2 mg/m2/day with a hint of antitumor activity. NS-9 should be pursued in phase-II studies. No significant financial relationships to disclose.

scholarly journals Near-infrared optogenetic engineering of photothermal nanoCRISPR for programmable genome editing

2020 ◽  
Vol 117 (5) ◽  
pp. 2395-2405 ◽  
Author(s):  
Xiaohong Chen ◽  
Yuxuan Chen ◽  
Huhu Xin ◽  
Tao Wan ◽  
Yuan Ping
Keyword(s):  
Genome Editing ◽  
Near Infrared ◽  
Irradiation Time ◽  
Inducible Promoter ◽  
Local Heat ◽  
Multiple Time ◽  
Precise Control ◽  
Multiple Time Points

We herein report an optogenetically activatable CRISPR-Cas9 nanosystem for programmable genome editing in the second near-infrared (NIR-II) optical window. The nanosystem, termed nanoCRISPR, is composed of a cationic polymer-coated Au nanorod (APC) and Cas9 plasmid driven by a heat-inducible promoter. The APC not only serves as a carrier for intracellular plasmid delivery but also can harvest external NIR-II photonic energy and convert it into local heat to induce the gene expression of the Cas9 endonuclease. Due to high transfection activity, the APC shows strong ability to induce a significant level of disruption in different genomic loci upon optogenetic activation. Moreover, the precise control of genome-editing activity can be simply programmed by finely tuning exposure time and irradiation time in vitro and in vivo and also enables editing at multiple time points, thus proving the sensitivity and inducibility of such an editing modality. The NIR-II optical feature of nanoCRISPR enables therapeutic genome editing at deep tissue, by which treatment of deep tumor and rescue of fulminant hepatic failure are demonstrated as proof-of-concept therapeutic examples. Importantly, this modality of optogenetic genome editing can significantly minimize the off-target effect of CRISPR-Cas9 in most potential off-target sites. The optogenetically activatable CRISPR-Cas9 nanosystem we have developed offers a useful tool to expand the current applications of CRISPR-Cas9, and also defines a programmable genome-editing strategy toward high precision and spatial specificity.

scholarly journals TRAIL signaling is proinflammatory and proviral in a murine model of rhinovirus 1B infection

2017 ◽  
Vol 312 (1) ◽  
pp. L89-L99 ◽  
Author(s):  
Jason L. Girkin ◽  
Luke M. Hatchwell ◽  
Adam M. Collison ◽  
Malcolm R. Starkey ◽  
Philip M. Hansbro ◽  
...  
Keyword(s):  
Apoptotic Cell ◽  
Lavage Fluid ◽  
Airway Epithelial Cells ◽  
Airway Hyperreactivity ◽  
Multiple Time ◽  
Airway Epithelial ◽  
Downstream Signaling ◽  
Multiple Time Points

the aim of this study is to elucidate the role of TRAIL during rhinovirus (RV) infection in vivo. Naïve wild-type and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-deficient ( Tnfsf10 −/−) BALB/c mice were infected intranasally with RV1B. In separate experiments, Tnfsf10 −/− mice were sensitized and challenged via the airway route with house dust mite (HDM) to induce allergic airways disease and then challenged with RVIB or UV-RVIB. Airway hyperreactivity (AHR) was invasively assessed as total airways resistance in response to increasing methacholine challenge and inflammation was assessed in bronchoalveolar lavage fluid at multiple time points postinfection. Chemokines were quantified by ELISA of whole lung lysates and viral load was determined by quantitative RT-PCR and tissue culture infective dose (TCID50). Human airway epithelial cells (BEAS2B) were infected with RV1B and stimulated with recombinant TRAIL or neutralizing anti-TRAIL antibodies and viral titer assessed by TCID50. HDM-challenged Tnfsf10 −/− mice were protected against RV-induced AHR and had suppressed cellular infiltration in the airways upon RV infection. Chemokine C-X-C-motif ligand 2 (CXCL2) production was suppressed in naïve Tnfsf10 −/− mice infected with RV1B, with less RV1B detected 24 h postinfection. This was associated with reduced apoptotic cell death and a reduction of interferon (IFN)-λ2/3 but not IFN-α or IFN-β. TRAIL stimulation increased, whereas anti-TRAIL antibodies reduced viral replication in RV1B-infected BEAS2B cells in vitro. In conclusion, TRAIL promotes RV-induced AHR, inflammation and RV1B replication, implicating this molecule and its downstream signaling pathways as a possible target for the amelioration of RV1B-induced allergic and nonallergic lung inflammation and AHR.

New Method to Quantify Angiogenesis in vivo Using Multi-photon Imaging

2009 ◽  
Vol 17 (5) ◽  
pp. 24-27 ◽  
Author(s):  
B. J. Herron ◽  
J. S. Smith ◽  
R. W. Cole
Keyword(s):  
Inflammatory Responses ◽  
Experimental Manipulation ◽  
Multiple Time ◽  
Experimental Animals ◽  
Time Points ◽  
Surgical Methods ◽  
Vessel Growth ◽  
Environmental Variations ◽  
Multiple Time Points

Efforts to understand the basic mechanisms of angiogenesis, that is, the formation of new blood vessels from existing vasculature, have been limited by the methods that are currently used to measure vessel growth. Although in vivo assays provide the best environment in which to track angiogenesis, inherent difficulties in obtaining reproducible data limit the power of this approach. Limitations include: environmental variations between experimental animals, induction of inflammatory responses by surgical methods, and labor-intensive blood vessel quantification procedures. A better assay would measure vessel growth in one animal at multiple time points and would focus on minimization of artifacts induced by experimental manipulation.

scholarly journals Alternative Strategies for Proof-of-Principle Studies of Antibacterial Agents

2014 ◽  
Vol 58 (8) ◽  
pp. 4257-4263 ◽  
Author(s):  
Axel Dalhoff ◽  
Andrej Weintraub ◽  
Carl Erik Nord
Keyword(s):  
Phase Ii ◽  
Antibacterial Agent ◽  
Study Drug ◽  
Indicator Organisms ◽  
Study Program ◽  
Alternative Strategies ◽  
Investigational Agent ◽  
Proof Of Principle

ABSTRACTThe proof that a new antibacterial agent is not only activein vitrobut also effectivein vivounder clinically relevant conditions is currently provided (i) by using appropriate nonclinical models of infection and pharmacokinetic-pharmacodynamic (PK-PD) analysis providing evidence of the likelihood of clinical efficacy and (ii) by examining the study drug in exploratory clinical trials, as well as dose and schedule finding during phase II of clinical development. This approach is both time-consuming and costly. Furthermore, PK-PD targets for any novel antibacterial agent cannot be derived from studies with experimental animals. Therefore, alternative strategies have to be identified to prove the principle that a novel antibacterial agent is active under clinically relevant conditions. This review summarizes evidence that the quantitative analysis of shifts in the viable counts of pathogens in infected patients or the evaluation of the PD effect of an investigational agent on indicator organisms of the human resident microflora or colonizers of healthy volunteers, if paralleled with PK monitoring of serum and the target site, provides an alternative to a classical proof-of-principle study in the course of a phase II study program.

Comparison of Pharmacokinetic Properties of Two VWF/FVIII Concentrates In Subjects with Inherited Von Willebrand Disease (VWD)- Results of a Prospective, Randomized, Crossover Study.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3672-3672 ◽  
Author(s):  
Craig M. Kessler ◽  
Jerry Powell ◽  
Bruce A. Schwartz
Keyword(s):  
Study Drug ◽  
Von Willebrand Disease ◽  
Multiple Time ◽  
Active Components ◽  
Open Label ◽  
Fviii Activity ◽  
Multiple Time Points ◽  
Type 3 ◽  
Von Willebrand

Abstract Abstract 3672 Objective: Understanding pharmacokinetic (PK) profiles of von Willebrand Factor (VWF)/Factor VIII (FVIII) concentrates is important in the treatment of VWD. This prospective, randomized, open-label, crossover trial investigated the PK characteristics of two plasma-derived (pd) VWF/FVIII concentrates (Wilate® [high-purity (HP)] and Humate-P® [intermediate-purity (IP)]) in subjects with inherited VWD. Methods: After a wash-out period, twenty-two subjects (Type 1, n=6; Type 2, n=9 [6 Type 2A, 1 Type 2B, and 2 Type 2M]; and Type 3, n=7) were randomized in a prospective, controlled, open-labeled, 2-arm crossover, to receive 40 IU VWF:RCo/kg of Wilate® or Humate-P® followed by another washout period and administration of the other study drug. Blood samples were taken at multiple time-points over 72hrs for PK evaluations. Results: A non compartmental statistical model was used to analyze the data. The mean VWF:RCo half-life for Type-3 subjects was similar for the HP product (9.1 hours [±2.6]) and IP product (10.2 hours [±2.1]. For all study participants there were no significant differences in incremental in-vivo recoveries (≂f2.0 IU VWF:RCo/dL per IU/kg), or in clearance. Bioequivalence between the two products was shown for the main VWF PK parameters. The decay-curves for VWF:RCo and FVIII:C in the HP product showed a parallel decay, while the IP product did not and showed an unusually sustained FVIII plateau over the initial decay time period. The data showed an almost a 2 fold decrease in clearance between the two products. The chromogenic FVIII:C terminal half live for the two products were similar (16.1hrs [SD=3.1] HP product and 20.5 hrs [SD=7.6] IP product), although the average half lives were quite different (13 hrs [SD=4.1] HP product and 37.7 hrs [SD=6.4] IP product). This was in spite of the much higher initial FVIII concentration profile of the 1:1 VWF/FVIII HP product. The 2.4:1 VWF/FVIII IP product showed an expected lower mean FVIII:C peak value due to the excess of VWF:RCo activity in the product that was based on VWF:RCo unit dosing, but similar both products had a similar dose adjusted IVR. Conclusions: This study confirms the similarity of the VWF PK properties of the two licensed VWF products. However, the analysis of FVIII activity, in the two products revealed some differences in their PK profiles. With the similar PK-properties for VWF:RCo and FVIII:C, Wilate showed a more parallel course for the two active components. A more predictable PK profile for both VWF and FVIII in a product may facilitate both more accurate dosing and laboratory monitoring of VWF replacement in VWD treatment. A parallel PK profile together with an equal ratio for FVIII and VWF activities may help avoid over or under dosing of either of the two critical coagulation parameters. Disclosures: Kessler: Grifols S.A.: Research Funding. Schwartz:Octapharma: Employment.

The pharmacokinetic diversity of two von Willebrand factor (VWF)/ factor VIII (FVIII) concentrates in subjects with congenital von Willebrand disease

2011 ◽  
Vol 106 (08) ◽  
pp. 279-288 ◽  
Author(s):  
Craig M. Kessler ◽  
Friedman Ken ◽  
Bruce A. Schwartz ◽  
Joan C. Gill ◽  
Jerry S. Powell ◽  
...  
Keyword(s):  
Factor Viii ◽  
Von Willebrand Factor ◽  
Coagulation Factor ◽  
Study Drug ◽  
Von Willebrand Disease ◽  
Multiple Time ◽  
Multiple Time Points ◽  
Von Willebrand ◽  
Willebrand Factor

SummaryThe pharmacokinetic (PK) profiles of von Willebrand factor (VWF) /factor VIII (FVIII) concentrates are important for treatment efficacy and safety of von Willebrand disease (VWD) patients. This prospective, head-to-head, randomised crossover study compared the PK profile of a new, high purity, human plasma-derived (pd)VWF/FVIII concentrate, Wilate®, with the PK profile of an intermediate purity (pd)VWF/FVIII concentrate, Humate-P¯, in VWD patients. Subjects with inherited VWD were randomised to a single intravenous dose (40 IU/kg VWF ristocetin cofactor activity [VWF:RCo]) of Wilate® or Humate-P¯ in Period 1, and switched to the other study drug in Period 2. Each period was preceded by a washout time of ≥7 days. Coagulation factor parameters were analysed at multiple time-points. Of 22 randomised subjects, 20 had evaluable PK profiles, which indicated comparability for VWF antigen and VWF:RCo between Wilate® and Humate-P¯. The reported VWF:RCo average and terminal t1/2 of 10.4 and 15.8 hours (h), respectively, for Wilate® and 9.3 h and 12.8 h for Humate-P®, were not statistically different. Also, the mean VWF:RCo in vivo recoveries (Wilate® 1.89, Humate-P® 1.99 IU/dl per IU/kg) were similar between the two replacement therapies. Wilate® showed parallel decay curves for VWF:RCo and FVIII clotting activity (FVIII:C) over time, while FVIII:C of Humate-P® displayed a plateau between 0 and 12–24 h. This study demonstrated bioequivalent PK properties for VWF between Wilate® and Humate-P®. The PK profile of Wilate®, combined with the 1:1 VWF/FVIII ratio, theoretically should facilitate dosing and laboratory monitoring of VWF replacement to prevent bleeding in individuals with VWD.

scholarly journals Use of TanDEM-X and SRTM-C Data for Detection of Deforestation Caused by Bark Beetle in Central European Mountains

2021 ◽  
Vol 13 (15) ◽  
pp. 3042
Author(s):  
Kateřina Gdulová ◽  
Jana Marešová ◽  
Vojtěch Barták ◽  
Marta Szostak ◽  
Jaroslav Červenka ◽  
...  
Keyword(s):  
Bark Beetle ◽  
Synergistic Effects ◽  
Canopy Height ◽  
Surface Model ◽  
Multiple Time ◽  
Central European ◽  
Time Points ◽  
Bohemian Forest ◽  
Multiple Time Points ◽  
Surrounding Areas

The availability of global digital elevation models (DEMs) from multiple time points allows their combination for analysing vegetation changes. The combination of models (e.g., SRTM and TanDEM-X) can contain errors, which can, due to their synergistic effects, yield incorrect results. We used a high-resolution LiDAR-derived digital surface model (DSM) to evaluate the accuracy of canopy height estimates of the aforementioned global DEMs. In addition, we subtracted SRTM and TanDEM-X data at 90 and 30 m resolutions, respectively, to detect deforestation caused by bark beetle disturbance and evaluated the associations of their difference with terrain characteristics. The study areas covered three Central European mountain ranges and their surrounding areas: Bohemian Forest, Erzgebirge, and Giant Mountains. We found that vertical bias of SRTM and TanDEM-X, relative to the canopy height, is similar with negative values of up to −2.5 m and LE90s below 7.8 m in non-forest areas. In forests, the vertical bias of SRTM and TanDEM-X ranged from −0.5 to 4.1 m and LE90s from 7.2 to 11.0 m, respectively. The height differences between SRTM and TanDEM-X show moderate dependence on the slope and its orientation. LE90s for TDX-SRTM differences tended to be smaller for east-facing than for west-facing slopes, and varied, with aspect, by up to 1.5 m in non-forest areas and 3 m in forests, respectively. Finally, subtracting SRTM and NASA DEMs from TanDEM-X and Copernicus DEMs, respectively, successfully identified large areas of deforestation caused by hurricane Kyril in 2007 and a subsequent bark beetle disturbance in the Bohemian Forest. However, local errors in TanDEM-X, associated mainly with forest-covered west-facing slopes, resulted in erroneous identification of deforestation. Therefore, caution is needed when combining SRTM and TanDEM-X data in multitemporal studies in a mountain environment. Still, we can conclude that SRTM and TanDEM-X data represent suitable near global sources for the identification of deforestation in the period between the time points of their acquisition.

Meta-analysis of effect sizes reported at multiple time points: A multivariate approach

2012 ◽  
Vol 9 (5) ◽  
pp. 610-620 ◽  
Author(s):  
Thomas A Trikalinos ◽  
Ingram Olkin
Keyword(s):  
Random Effects ◽  
Treatment Effects ◽  
Multivariate Analyses ◽  
Meta Analysis ◽  
Effect Sizes ◽  
Multiple Time ◽  
Time Points ◽  
Fixed And Random Effects ◽  
Multiple Time Points ◽  
Meta Analyses

Background Many comparative studies report results at multiple time points. Such data are correlated because they pertain to the same patients, but are typically meta-analyzed as separate quantitative syntheses at each time point, ignoring the correlations between time points. Purpose To develop a meta-analytic approach that estimates treatment effects at successive time points and takes account of the stochastic dependencies of those effects. Methods We present both fixed and random effects methods for multivariate meta-analysis of effect sizes reported at multiple time points. We provide formulas for calculating the covariance (and correlations) of the effect sizes at successive time points for four common metrics (log odds ratio, log risk ratio, risk difference, and arcsine difference) based on data reported in the primary studies. We work through an example of a meta-analysis of 17 randomized trials of radiotherapy and chemotherapy versus radiotherapy alone for the postoperative treatment of patients with malignant gliomas, where in each trial survival is assessed at 6, 12, 18, and 24 months post randomization. We also provide software code for the main analyses described in the article. Results We discuss the estimation of fixed and random effects models and explore five options for the structure of the covariance matrix of the random effects. In the example, we compare separate (univariate) meta-analyses at each of the four time points with joint analyses across all four time points using the proposed methods. Although results of univariate and multivariate analyses are generally similar in the example, there are small differences in the magnitude of the effect sizes and the corresponding standard errors. We also discuss conditional multivariate analyses where one compares treatment effects at later time points given observed data at earlier time points. Limitations Simulation and empirical studies are needed to clarify the gains of multivariate analyses compared with separate meta-analyses under a variety of conditions. Conclusions Data reported at multiple time points are multivariate in nature and are efficiently analyzed using multivariate methods. The latter are an attractive alternative or complement to performing separate meta-analyses.

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