scholarly journals Tumor-Shed Antigen Affects Antibody Tumor Targeting: Comparison of Two 89Zr-Labeled Antibodies Directed against Shed or Nonshed Antigens

2018 ◽  
Vol 2018 ◽  
pp. 1-12 ◽  
Author(s):  
Jae-Ho Lee ◽  
Heejung Kim ◽  
Zhengsheng Yao ◽  
Lawrence P. Szajek ◽  
Luigi Grasso ◽  
...  
Keyword(s):  
Half Life ◽  
Tumor Targeting ◽  
High Dose ◽  
Distribution Profile ◽  
Tumor Penetration ◽  
Lewis Y Antigen ◽  
Tumor Periphery ◽  
Ideal System ◽  
Dose Dependent ◽  
Higher Doses

We investigated the effect of shed antigen mesothelin on the tumor uptake of amatuximab, a therapeutic anti-mesothelin mAb clinically tested in mesothelioma patients. The B3 mAb targeting a nonshed antigen was also analyzed for comparison. The mouse model implanted with A431/H9 tumor, which expresses both shed mesothelin and nonshed Lewis-Y antigen, provided an ideal system to compare the biodistribution and PET imaging profiles of the two mAbs. Our study demonstrated that the tumor and organ uptakes of 89Zr-B3 were dose-independent when 3 doses, 2, 15, and 60 μg B3, were compared at 24 h after injection. In contrast, tumor and organ uptakes of 89Zr-amatuximab were dose-dependent, whereby a high dose (60 μg) was needed to achieve tumor targeting comparable to the low dose (2 μg) of 89Zr-B3, suggesting that shed mesothelin may affect amatuximab tumor targeting as well as serum half-life. The autoradiography analysis showed that the distribution of 89Zr-B3 was nonuniform with the radioactivity primarily localized at the tumor periphery independent of the B3 dose. However, the autoradiography analysis for 89Zr-amatuximab showed dose-dependent distribution profiles of the radiolabel; at 10 μg dose, the radiolabel penetrated toward the tumor core with its activity comparable to that at the tumor periphery, whereas at 60 μg dose, the distribution profile became similar to those of 89Zr-B3. These results suggest that shed antigen in blood may act as a decoy requiring higher doses of mAb to improve serum half-life as well as tumor targeting. Systemic mAb concentration should be at a severalfold molar excess to the shed Ag in blood to overcome the hepatic processing of mAb-Ag complexes. On the other hand, mAb concentration should remain lower than the shed Ag concentration in the tumor ECS to maximize tumor penetration by passing binding site barriers.

Effect of Energy and Dose on Transient-Enhanced Diffusion and Defect Microstructure in Low Energy High Dose As+ Implanted Si

1996 ◽  
Vol 438 ◽  
Author(s):  
V. Krishnamoorthy ◽  
D. Venables ◽  
K. Moeller ◽  
K. S. Jones ◽  
B. Freer
Keyword(s):  
Point Defects ◽  
Surface Recombination ◽  
High Dose ◽  
Enhanced Diffusion ◽  
Projected Range ◽  
Diffusion Enhancement ◽  
Defect Microstructures ◽  
Dose Dependent ◽  
Higher Doses ◽  
Defect Microstructure

Abstract(001) CZ silicon wafers were implanted with arsenic (As+) at energies of 10–50keV to doses of 2×1014 to 5×1015/cm2. All implants were amorphizing in nature. The samples were annealed at 700°C for 16hrs. The resultant defect microstructures were analyzed by XTEM and PTEM and the As profiles were analyzed by SIMS. The As profiles showed significantly enhanced diffusion in all of the annealed specimens. The diffusion enhancement was both energy and dose dependent. The lowest dose implant/annealed samples did not show As clustering which translated to a lack of defects at the projected range. At higher doses, however, projected range defects were clearly observed, presumably due to interstitials generated during As clustering. The extent of enhancement in diffusion and its relation to the defect microstructure is explained by a combination of factors including surface recombination of point defects, As precipitation, As clustering and end of range damage.

Effect of Energy and Dose on Transient-Enhanced Diffusion and Defect Microstructure in Low Energy High Dose As+ Implanted Si

1996 ◽  
Vol 439 ◽  
Author(s):  
V. Krishnamoorthy ◽  
D. Venables ◽  
K. Moeller ◽  
K. S. Jones ◽  
B. Freer
Keyword(s):  
Point Defects ◽  
Surface Recombination ◽  
High Dose ◽  
Enhanced Diffusion ◽  
Projected Range ◽  
Diffusion Enhancement ◽  
Defect Microstructures ◽  
Dose Dependent ◽  
Higher Doses ◽  
Defect Microstructure

Abstract(001) CZ silicon wafers were implanted with arsenic (As+) at energies of 10–50keV to doses of 2x 1014 to 5x1015/cm2. All implants were amorphizing in nature. The samples were annealed at 700°C for 16hrs. The resultant defect microstructures were analyzed by XTEM and PTEM and the As profiles were analyzed by SIMS. The As profiles showed significantly enhanced diffusion in all of the annealed specimens. The diffusion enhancement was both energy and dose dependent. The lowest dose implant/annealed samples did not show As clustering which translated to a lack of defects at the projected range. At higher doses, however, projected range defects were clearly observed, presumably due to interstitials generated during As clustering. The extent of enhancement in diffusion and its relation to the defect microstructure is explained by a combination of factors including surface recombination of point defects, As precipitation, As clustering and end of range damage.

scholarly journals Dose-dependent Effects of Smoked Cannabis on Capsaicin-induced Pain and Hyperalgesia in Healthy Volunteers

2007 ◽  
Vol 107 (5) ◽  
pp. 785-796 ◽  
Author(s):  
Mark Wallace ◽  
Gery Schulteis ◽  
J Hampton Atkinson ◽  
Tanya Wolfson ◽  
Deborah Lazzaretto ◽  
...  
Keyword(s):  
Healthy Volunteers ◽  
Drug Exposure ◽  
Pain Perception ◽  
Experimental Pain ◽  
High Dose ◽  
Significant Difference ◽  
Pain State ◽  
Double Blinded ◽  
Dose Dependent ◽  
Higher Doses

Background Although the preclinical literature suggests that cannabinoids produce antinociception and antihyperalgesic effects, efficacy in the human pain state remains unclear. Using a human experimental pain model, the authors hypothesized that inhaled cannabis would reduce the pain and hyperalgesia induced by intradermal capsaicin. Methods In a randomized, double-blinded, placebo-controlled, crossover trial in 15 healthy volunteers, the authors evaluated concentration-response effects of low-, medium-, and high-dose smoked cannabis (respectively 2%, 4%, and 8% 9-delta-tetrahydrocannabinol by weight) on pain and cutaneous hyperalgesia induced by intradermal capsaicin. Capsaicin was injected into opposite forearms 5 and 45 min after drug exposure, and pain, hyperalgesia, tetrahydrocannabinol plasma levels, and side effects were assessed. Results Five minutes after cannabis exposure, there was no effect on capsaicin-induced pain at any dose. By 45 min after cannabis exposure, however, there was a significant decrease in capsaicin-induced pain with the medium dose and a significant increase in capsaicin-induced pain with the high dose. There was no effect seen with the low dose, nor was there an effect on the area of hyperalgesia at any dose. Significant negative correlations between pain perception and plasma delta-9-tetrahydrocannabinol levels were found after adjusting for the overall dose effects. There was no significant difference in performance on the neuropsychological tests. Conclusions This study suggests that there is a window of modest analgesia for smoked cannabis, with lower doses decreasing pain and higher doses increasing pain.

Stiffness of targeted layer-by-layer nanoparticles impacts elimination half-life, tumor accumulation, and tumor penetration

2021 ◽  
Vol 118 (42) ◽  
pp. e2104826118
Author(s):  
Stephanie M. Kong ◽  
Daniel F. Costa ◽  
Anna Jagielska ◽  
Krystyn J. Van Vliet ◽  
Paula T. Hammond
Keyword(s):  
Drug Delivery ◽  
Half Life ◽  
Tumor Targeting ◽  
Layer By Layer ◽  
Elimination Half Life ◽  
Tumor Penetration ◽  
Anticancer Drug Delivery ◽  
Elimination Half ◽  
Tumor Accumulation

Nanoparticle (NP) stiffness has been shown to significantly impact circulation time and biodistribution in anticancer drug delivery. In particular, the relationship between particle stiffness and tumor accumulation and penetration in vivo is an important phenomenon to consider in optimizing NP-mediated tumor delivery. Layer-by-layer (LbL) NPs represent a promising class of multifunctional nanoscale drug delivery carriers. However, there has been no demonstration of the versatility of LbL systems in coating systems with different stiffnesses, and little is known about the potential role of LbL NP stiffness in modulating in vivo particle trafficking, although NP modulus has been recently studied for its impact on pharmacokinetics. LbL nanotechnology enables NPs to be functionalized with uniform coatings possessing molecular tumor-targeting properties, independent of the NP core stiffness. Here, we report that the stiffness of LbL NPs is directly influenced by the mechanical properties of its underlying liposomal core, enabling the modulation and optimization of LbL NP stiffness while preserving LbL NP outer layer tumor-targeting and stealth properties. We demonstrate that the stiffness of LbL NPs has a direct impact on NP pharmacokinetics, organ and tumor accumulation, and tumor penetration—with compliant LbL NPs having longer elimination half-life, higher tumor accumulation, and higher tumor penetration. Our findings underscore the importance of NP stiffness as a design parameter in enhancing the delivery of LbL NP formulations.

lmmunotoxicological Investigation of SCMF, a New Pyrethroid Pesticide in Mice

1994 ◽  
Vol 13 (5) ◽  
pp. 337-343 ◽  
Author(s):  
Olga Siroki ◽  
L. Institoris ◽  
E. Tatar ◽  
I. Desi
Keyword(s):  
Oral Treatment ◽  
Dose Range ◽  
High Dose ◽  
Experimental Conditions ◽  
Cell Content ◽  
Pyrethroid Pesticide ◽  
Dose Dependent Decrease ◽  
Dose Dependent ◽  
Higher Doses ◽  
Femoral Bone Marrow

The toxicity of a new pyrethroid pesticide Supercypermethrin Forte (SCMF) was studied in male CFLP mice using classic toxicological (body weight, organ weights) and haematological (white blood cell count, haematocrit, nucleated cell content of femoral bone marrow) methods and immune function tests (PFC assay, DTH reaction). Four weeks of oral treatment in a 5 days per week system at doses of 1/10, 1/20, or 1/40 x LD50 did not cause evaluable changes in the measured parameters. When single calculated LD20, LD10, or LD5 doses of SCMF were administered on different days before termination to different groups of mice the two higher doses caused a time- and dose-dependent decrease in the splenic PCF number, Apart from some temporary toxic signs and an increase of haematocrit at the top dose the other examined parameters did not show evaluable changes. Under these experimental conditions toxic changes appeared only at the high dose range and, of those applied, the PFC assay proved to be the most sensitive method for detecting the toxicity of SCMF.

The Embryotoxic and Immunodepressive Effects of Gossypol

1986 ◽  
Vol 14 (03n04) ◽  
pp. 110-115 ◽  
Author(s):  
G.M. Sein ◽  
M. Phil
Keyword(s):  
Parent Compound ◽  
Lymphocyte Transformation ◽  
Immunological Response ◽  
High Dose ◽  
Intragastric Administration ◽  
Humoral Immune ◽  
Pregnant Mice ◽  
Dose Levels ◽  
Dose Dependent ◽  
Higher Doses

The effects of gossypol acetic on pregnancy, embryofoetal development and on some selected parameters of immunological response in mice were studied. Daily intragastric administration of gossypol (50 or 75 mg/kg/day) during day 1-15 of gestation in mice produced a dose-dependent embroyocidal effect (37.8% and 94.5% respectively) of non-viable foetuses. There was a significant reduction in foetal bodyweight when pregnant mice were treated with gossypol, although no foetal abnormalities were observed. Lymphocyte transformation induced by mitogen concanavalin A, was not inhibited by pretreatment with gossypol (25, 50 or 75 mg/kg/day) for 10 weeks. However, both plaque-forming cells to sheep red blood cell immunisation and the total spleen cell population were significantly depressed by higher doses (50 or 75 mg/kg/day) of gossypol. The results of the present study indicate that gossypol is not teratogenic, but exerts embryocidal and a selective depression humoral immune response at high dose levels (50 or 75 mg/kg/day). It is not clear, whether the dose-dependent embryocidal and/or immunodepressive effects of gossypol are mediated by the parent compound or its metabolites, or whether these findings have any clinical relevance.

scholarly journals Pharmacokinetic study of isoquercitrin in rat plasma after intravenous administration at three different doses

2013 ◽  
Vol 49 (3) ◽  
pp. 435-441 ◽  
Author(s):  
Hefei Xue ◽  
Yuzhong Li ◽  
Wenjie Zhang ◽  
Dongrui Lu ◽  
Yinghui Chen ◽  
...  
Keyword(s):  
Half Life ◽  
Internal Standard ◽  
Rat Plasma ◽  
Hplc Method ◽  
Pharmacokinetic Parameters ◽  
Linear Pharmacokinetics ◽  
Dose Dependent ◽  
Higher Doses ◽  
Compartment Open Model ◽  
Different Doses

The aim of this study is to develop a simple and specific HPLC method using vitexin as the internal standard to investigate the pharmacokinetics of isoquercitrin (ISOQ) after three different doses administrated intravenously to rats. The pharmacokinetic parameters were calculated by both compartmental and non-compartmental approaches. The results showed that ISOQ fitted a three-compartment open model. The values of AUC increased proportionally within the range of 5-10 mg·kg-1. Moreover, a half-life, b half-life, ªCL, MRT0-t and MRT0→∞ of ISOQ in rats showed significant differences between 20 mg·kg-1 and other doses, indicating that ISOQ presented dose-dependent pharmacokinetics in the range of 5-10 mg·kg-1 and non-linear pharmacokinetics at higher doses.

A Nova EPO-Fusion Protein with Prolonged Half-Life in Circulation and Enhanced Activity In Vivo.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1301-1301
Author(s):  
Haitao Wang ◽  
Yong Du ◽  
Rui Zhang ◽  
Jin Xu ◽  
Longbin Liu
Keyword(s):  
Fusion Protein ◽  
Half Life ◽  
Structural Changes ◽  
Renal Anemia ◽  
Surgical Removal ◽  
Pharmacokinetic Studies ◽  
Functional Activities ◽  
Dose Dependent ◽  
Higher Doses

Abstract Clinical practice merits the search of long-lasting erythropoietic proteins that reduce the injection requirements. Darbepoietin, the first long-lasting EPO, was created by replacing two amino acids of EPO molecule to increase the sugar contents. Darbepoietin has a half-life of about 24 hours and enhanced functional activities. However, the structural changes of EPO molecules may increase the potential of antibody production in logn-term application. With our NovaFusion technology, we successfully created a nova EPO-fusion protein that contains two identical molecules of natural human EPO sequences and a fragment of another human protein(Nova-EPO). We produced recombinant Nova-EPO protein by CHO cells and then conducted extensive laboratory and anemial studies. Pharmacokinetic studies in primates showed that the half-life of Nova-EPO was about 35 hours comparing to about 8 hours of that of recombinant EPO. In pharmacodynamic studies, we compared, on the same molar basis, the erythropoietic effects of Nova-EPO, recombinant EPO and Darbepoietin in normal mice or rats with experimental renal anemia. The experimental renal anemia was created by the surgical removal of 5/6 renal tissues in rats. Five doses (0.1, 0.5, 2.5, 12.5 or 62.5 ug/kg), two administration methods (subcutaneouly or intravenously) and three administration intervials(three injections per week, one injection per week or one injection per two weeks) were selected in different combinations. With three injections per week, both Nova-EPO and EPO induced dose-dependent elevation of hemoglobulin (HB) levels in normal mice. Lower doses of Nova-EPO increased the HB levels to the extent only achived by the higher doses of EPO, and the highest elevation of HB levels was induced by Nova-EPO. With one injection per week in normal mice, the dose-dependent elevation of HB levels was more significant in the Nova-EPO groups than in the EPO groups, and 12.5ug/kg of Nova-EPO induced the increase of HB levels to the same extent by 62.5ug/kg of EPO. The elevation of HB levels in Nova-EPO groups also remained longer than that in EPO groups after the termination of treatment. These data demonstrated that Nova-EPO has functional activities in vivo and stimulates stronger erythropoiesis. The erythropoietic properties of Nova-EPO were further eveluated in rats with experimental anemia, and compared with EPO and Darbepoietin. When administrated once per week, Nova-EPO, EPO and Darbepoietin all induced the increase of HB levels and corrected the anemia. The levels of HB in Nova-EPO and Darbepoietin groups, however, were higher and decreased more slowly than those in EPO groups. The highest HB levels were observed in Nova-EPO groups. After reducing the injection to once per two weeks, Nova-EPO and Darbepoietin still induced satisfactory elevation of HB levels. Similarly, Nova-EPO induced stronger erythropoietic responses than Darbepoietin. In immunogenisis studies in primates, injection of 5ug/kg of Nova-EPO three times per week for four weeks failed to produce antibodies against Nova-EPO molecules. Acute toxic studies in mice showed that injection of up to 13mg/kg of Nova-EPO intravenously did not result in pathologic changes. Collectively these data indicated that Nova-EPO has significantly prolonged half-life in vivo and enhanced erythropoietic activities. With no immunogenisis in primates, Nova-EPO has the potential to become a better alternative than the long-lasting erythropoietic therapeutics on the market and is justified to be further evaluated in clinical studies.

scholarly journals A dose-dependent plasma signature of the safety and immunogenicity of the rVSV-Ebola vaccine in Europe and Africa

2017 ◽  
Vol 9 (385) ◽  
pp. eaaj1701 ◽  
Author(s):  
Angela Huttner ◽  
Christophe Combescure ◽  
Stéphane Grillet ◽  
Mariëlle C. Haks ◽  
Edwin Quinten ◽  
...  
Keyword(s):  
Critical Role ◽  
Vaccine Dose ◽  
High Dose ◽  
Vaccine Response ◽  
African Countries ◽  
Tnf Α ◽  
Vesicular Stomatitis ◽  
Dose Dependent ◽  
Higher Doses ◽  
Site Pain

The 2014–2015 Ebola epidemic affected several African countries, claiming more than 11,000 lives and leaving thousands with ongoing sequelae. Safe and effective vaccines could prevent or limit future outbreaks. The recombinant vesicular stomatitis virus–vectored Zaire Ebola (rVSV-ZEBOV) vaccine has shown marked immunogenicity and efficacy in humans but is reactogenic at higher doses. To understand its effects, we examined plasma samples from 115 healthy volunteers from Geneva who received low-dose (LD) or high-dose (HD) vaccine or placebo. Fifteen plasma chemokines/cytokines were assessed at baseline and on days 1, 2 to 3, and 7 after injection. Significant increases in monocyte-mediated MCP-1/CCL2, MIP-1β/CCL4, IL-6, TNF-α, IL-1Ra, and IL-10 occurred on day 1. A signature explaining 68% of cytokine/chemokine vaccine-response variability was identified. Its score was higher in HD versus LD vaccinees and was associated positively with vaccine viremia and negatively with cytopenia. It was higher in vaccinees with injection-site pain, fever, myalgia, chills, and headache; higher scores reflected increasing severity. In contrast, HD vaccinees who subsequently developed arthritis had lower day 1 scores than other HD vaccinees. Vaccine dose did not influence the signature despite its influence on specific outcomes. The Geneva-derived signature associated strongly (ρ = 0.97) with that of a cohort of 75 vaccinees from a parallel trial in Lambaréné, Gabon. Its score in Geneva HD vaccinees with subsequent arthritis was significantly lower than that in Lambaréné HD vaccinees, none of whom experienced arthritis. This signature, which reveals monocytes’ critical role in rVSV-ZEBOV immunogenicity and safety across doses and continents, should prove useful in assessments of other vaccines.

Involvement of 5-Hydroxytryptamine in Platelet Aggregation In Vivo in Rats and Guinea Pigs

1989 ◽  
Vol 61 (03) ◽  
pp. 463-467 ◽  
Author(s):  
G M Smith
Keyword(s):  
Platelet Count ◽  
Guinea Pigs ◽  
Platelet Adhesion ◽  
Adenosine Diphosphate ◽  
Rate Of Return ◽  
Low Doses ◽  
Dose Dependent ◽  
Higher Doses ◽  
Rat Platelets

SummaryIn this study, 5-hydroxytryptamine (5-HT) caused a dose- dependent fall in the circulating platelet count suggesting that 5-HT receptors are activated in rat platelets to cause platelet adhesion and aggregation. When low doses of adenosine diphosphate (ADP) were simultaneously injected with 5-HT, there was a significant potentiation of the responses to ADR Ketanserin significantly reduced the potentiated responses. When higher doses of ADP were infused with bolus injections of 5-HT there was no potentiation and ketanserin did not reduce these responses. Ketanserin did not inhibit the collagen-induced fall in circulating platelet count, but did significantly increase the rate of return to the basal platelet count compared with control. 5-HT did not cause a fall in platelet count in guinea-pigs

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