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Article ; Online: A first-in-human study of BLZ-100 (tozuleristide) demonstrates tolerability and safety in skin cancer patients.

Yamada, Miko / Miller, Dennis M / Lowe, Melinda / Rowe, Casey / Wood, Dominic / Soyer, H Peter / Byrnes-Blake, Kelly / Parrish-Novak, Julia / Ishak, Laura / Olson, James M / Brandt, Gordon / Griffin, Paul / Spelman, Lynda / Prow, Tarl W

Contemporary clinical trials communications

2021 Volume 23, Page(s) 100830

Abstract: BLZ-100 (tozuleristide) is an intraoperative fluorescent imaging agent that selectively detects malignant tissue and can be used in real time to guide tumor resection. The purpose of this study was to assess the safety, tolerability, and pharmacokinetics ...

Abstract	BLZ-100 (tozuleristide) is an intraoperative fluorescent imaging agent that selectively detects malignant tissue and can be used in real time to guide tumor resection. The purpose of this study was to assess the safety, tolerability, and pharmacokinetics of BLZ-100 and to explore the pharmacodynamics of fluorescence imaging of skin tumors. In this first-in-human study, BLZ-100 was administered intravenously to 21 adult patients 2 days before excising known or suspected skin cancers. Doses were 1, 3, 6, 12, and 18 mg, with 3-6 patients/cohort. Fluorescence imaging was conducted before and up to 48 h after dosing. BLZ-100 was well tolerated. There were no serious adverse events, deaths, or discontinuations due to adverse events, and no maximum tolerated dose (MTD) was identified. Headache (n = 2) and nausea (n = 2) were the only BLZ-100 treatment-related adverse events reported for >1 patient. Median time to maximal serum concentration was <0.5 h. Exposure based on maximal serum concentrations increased in a greater than dose-proportional manner. For intermediate dose-levels (3-12 mg), 4 of 5 basal cell carcinomas and 4 of 4 melanomas were considered positive for BLZ-100 fluorescence. BLZ-100 was well tolerated at all dose levels tested and these results support further clinical testing of this imaging agent in surgical oncology settings. Clinicaltrials.gov: NCT02097875.
Language	English
Publishing date	2021-08-04
Publishing country	Netherlands
Document type	Journal Article
ISSN	2451-8654
ISSN (online)	2451-8654
DOI	10.1016/j.conctc.2021.100830
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Article ; Online: A potent peptide-steroid conjugate accumulates in cartilage and reverses arthritis without evidence of systemic corticosteroid exposure.

Cook Sangar, Michelle L / Girard, Emily J / Hopping, Gene / Yin, Chunfeng / Pakiam, Fiona / Brusniak, Mi-Youn / Nguyen, Elizabeth / Ruff, Raymond / Gewe, Mesfin M / Byrnes-Blake, Kelly / Nairn, Natalie W / Miller, Dennis M / Mehlin, Christopher / Strand, Andrew D / Mhyre, Andrew J / Correnti, Colin E / Strong, Roland K / Simon, Julian A / Olson, James M

Science translational medicine

2020 Volume 12, Issue 533

Abstract: On-target, off-tissue toxicity limits the systemic use of drugs that would otherwise reduce symptoms or reverse the damage of arthritic diseases, leaving millions of patients in pain and with limited physical mobility. We identified cystine-dense ... ...

Abstract	On-target, off-tissue toxicity limits the systemic use of drugs that would otherwise reduce symptoms or reverse the damage of arthritic diseases, leaving millions of patients in pain and with limited physical mobility. We identified cystine-dense peptides (CDPs) that rapidly accumulate in cartilage of the knees, ankles, hips, shoulders, and intervertebral discs after systemic administration. These CDPs could be used to concentrate arthritis drugs in joints. A cartilage-accumulating peptide, CDP-11R, reached peak concentration in cartilage within 30 min after administration and remained detectable for more than 4 days. Structural analysis of the peptides by crystallography revealed that the distribution of positive charge may be a distinguishing feature of joint-accumulating CDPs. In addition, quantitative whole-body autoradiography showed that the disulfide-bonded tertiary structure is critical for cartilage accumulation and retention. CDP-11R distributed to joints while carrying a fluorophore imaging agent or one of two different steroid payloads, dexamethasone (dex) and triamcinolone acetonide (TAA). Of the two payloads, the dex conjugate did not advance because the free drug released into circulation was sufficient to cause on-target toxicity. In contrast, the CDP-11R-TAA conjugate alleviated joint inflammation in the rat collagen-induced model of rheumatoid arthritis while avoiding toxicities that occurred with nontargeted steroid treatment at the same molar dose. This conjugate shows promise for clinical development and establishes proof of concept for multijoint targeting of disease-modifying therapeutic payloads.
MeSH term(s)	Adrenal Cortex Hormones ; Animals ; Arthritis, Experimental/drug therapy ; Cartilage ; Humans ; Peptides ; Rats ; Steroids
Chemical Substances	Adrenal Cortex Hormones ; Peptides ; Steroids
Language	English
Publishing date	2020-03-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.aay1041
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Article ; Online: Real-time Visualization of Breast Carcinoma in Pathology Specimens From Patients Receiving Fluorescent Tumor-Marking Agent Tozuleristide.

Dintzis, Suzanne M / Hansen, Stacey / Harrington, Kristi M / Tan, Lennart C / Miller, Dennis M / Ishak, Laura / Parrish-Novak, Julia / Kittle, David / Perry, Jeff / Gombotz, Carolyn / Fortney, Tina / Porenta, Stephanie / Hales, Lisa / Calhoun, Kristine E / Anderson, Benjamin O / Javid, Sara H / Byrd, David R

Archives of pathology & laboratory medicine

2018 Volume 143, Issue 9, Page(s) 1076–1083

Abstract: Context.—: Resection of breast carcinoma with adequate margins reduces the risk of local recurrence and reoperation. Tozuleristide (BLZ-100) is an investigational peptide-fluorophore agent that may aid in intraoperative tumor detection and margin ... ...

Abstract	Context.—: Resection of breast carcinoma with adequate margins reduces the risk of local recurrence and reoperation. Tozuleristide (BLZ-100) is an investigational peptide-fluorophore agent that may aid in intraoperative tumor detection and margin assessment. In this study, fluorescence imaging was conducted ex vivo on gross breast pathology specimens. Objectives.—: To determine the potential of tozuleristide to detect breast carcinoma in fresh pathology specimens and the feasibility of fluorescence-guided intraoperative pathology assessment of surgical margins. Design.—: Twenty-three patients received an intravenous bolus dose of 6 or 12 mg of tozuleristide at least 1 hour before surgery. Fifteen lumpectomy and 12 mastectomy specimens were evaluated for fluorescence by the site's clinical pathology staff using the SIRIS, an investigational near-infrared imaging device. The breast tissue was then processed per usual procedures. Fluorescent patterns were correlated with the corresponding hematoxylin-eosin-stained sections. Clinical pathology reports were used to correlate fluorescent signal to grade, histotype, prognostic marker status, and margin measurements. Results.—: Tozuleristide fluorescence was readily observed in invasive and in situ breast carcinoma specimens. Most invasive carcinomas were bright and focal, whereas in situ lesions demonstrated a less intense, more diffuse pattern. Tozuleristide was detected in ductal and lobular carcinomas with a similar fluorescent pattern. Fluorescence was detected in high- and low-grade lesions, and molecular marker/hormone receptor status did not affect signal. Fluorescence could be used to identify the relationship of carcinoma to margins intraoperatively. Conclusions.—: Tumor targeting with tozuleristide allowed visual real-time distinction between pathologically confirmed breast carcinoma and normal tissue.
MeSH term(s)	Breast Carcinoma In Situ/diagnostic imaging ; Breast Carcinoma In Situ/pathology ; Breast Carcinoma In Situ/surgery ; Breast Neoplasms/diagnostic imaging ; Breast Neoplasms/surgery ; Carcinoma, Ductal, Breast/diagnostic imaging ; Carcinoma, Ductal, Breast/pathology ; Carcinoma, Ductal, Breast/surgery ; Carcinoma, Lobular/diagnostic imaging ; Carcinoma, Lobular/pathology ; Carcinoma, Lobular/surgery ; Female ; Fluorescent Dyes ; Humans ; Indocyanine Green/analogs & derivatives ; Intraoperative Care/methods ; Margins of Excision ; Mastectomy ; Mastectomy, Segmental ; Neoplasm Invasiveness/diagnostic imaging ; Neoplasm Invasiveness/pathology ; Prognosis ; Scorpion Venoms
Chemical Substances	Fluorescent Dyes ; Scorpion Venoms ; Chlorotoxin (06UV5RFW57) ; tozuleristide (835UH424TU) ; Indocyanine Green (IX6J1063HV)
Language	English
Publishing date	2018-12-14
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	194119-7
ISSN	1543-2165 ; 0363-0153 ; 0096-8528 ; 0003-9985
ISSN (online)	1543-2165
ISSN	0363-0153 ; 0096-8528 ; 0003-9985
DOI	10.5858/arpa.2018-0197-OA
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Article: Peginterferon Lambda-1a, a New Therapeutic for Hepatitis C Infection, from Bench to Clinic.

Andersen, Henrik / Meyer, Jeff / Freeman, Jeremy / Doyle, Sean E / Klucher, Kevin / Miller, Dennis M / Hausman, Diana / Hillson, Jan L

Journal of clinical and translational hepatology

2013 Volume 1, Issue 2, Page(s) 116–124

Abstract: Chronic infection with hepatitis C virus (HCV) is estimated to affect approximately 3% of the world's population and cause 350,000 deaths each year. For a number of years, the standard of care has been combination therapy with recombinant alfa ... ...

Abstract	Chronic infection with hepatitis C virus (HCV) is estimated to affect approximately 3% of the world's population and cause 350,000 deaths each year. For a number of years, the standard of care has been combination therapy with recombinant alfa interferons-originally as native proteins but more recently as polyethyleneglycol-modified derivatives-and ribavirin, with the recent addition of an NS3 protease inhibitor for HCV genotype 1. However, therapeutic alfa interferons are associated with a significant burden of treatment-limiting adverse events, including musculoskeletal and influenza-like symptoms, hematologic cytopenias, autoimmune disease, fatigue, and other neurologic events. In 2003, a team at ZymoGenetics (now a fully owned subsidiary of Bristol-Myers Squibb) and a second, independent group simultaneously identified a new class of interferons-the type III lambda interferons-with near-identical activity to the type I alfa interferons in hepatocytes but with an unrelated and less ubiquitous receptor. Subsequent evaluation of the type III interferon system demonstrated antiviral activity against HCV in vitro with limited activity in peripheral blood mononuclear cells and other nonhepatocyte cell types, supporting its development as a potentially better-tolerated therapy for viral hepatitis. Peginterferon lambda-1a (Lambda) is an investigational type III therapeutic agent originally developed at ZymoGenetics that is currently in Phase 3 studies for the treatment of HCV. In this review, we describe the selection of the Lambda molecule and its preclinical and early clinical development, and how the resulting data have helped to establish the differentiated safety profile for Lambda-with fewer influenza-like and musculoskeletal symptoms and less hematologic toxicity than the alfa interferons-that was seen in later studies.
Language	English
Publishing date	2013-12-15
Publishing country	China
Document type	Journal Article ; Review
ZDB-ID	3019822-7
ISSN	2310-8819 ; 2225-0719
ISSN (online)	2310-8819
ISSN	2225-0719
DOI	10.14218/JCTH.2013.00014
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Article ; Online: Phase 1 Safety, Pharmacokinetics, and Fluorescence Imaging Study of Tozuleristide (BLZ-100) in Adults With Newly Diagnosed or Recurrent Gliomas.

Patil, Chirag G / Walker, David G / Miller, Dennis M / Butte, Pramod / Morrison, Beth / Kittle, David S / Hansen, Stacey J / Nufer, Kaitlin L / Byrnes-Blake, Kelly A / Yamada, Miko / Lin, Lynlee L / Pham, Kim / Perry, Jeff / Parrish-Novak, Julia / Ishak, Laura / Prow, Tarl / Black, Keith / Mamelak, Adam N

Neurosurgery

2019 Volume 85, Issue 4, Page(s) E641–E649

Abstract: Background: Fluorescence-guided surgery (FGS) can improve extent of resection in gliomas. Tozuleristide (BLZ-100), a near-infrared imaging agent composed of the peptide chlorotoxin and a near-infrared fluorophore indocyanine green, is a candidate ... ...

Abstract	Background: Fluorescence-guided surgery (FGS) can improve extent of resection in gliomas. Tozuleristide (BLZ-100), a near-infrared imaging agent composed of the peptide chlorotoxin and a near-infrared fluorophore indocyanine green, is a candidate molecule for FGS of glioma and other tumor types. Objective: To perform a phase 1 dose-escalation study to characterize the safety, pharmacokinetics, and fluorescence imaging of tozuleristide in adults with suspected glioma. Methods: Patients received a single intravenous dose of tozuleristide 3 to 29 h before surgery. Fluorescence images of tumor and cavity in Situ before and after resection and of excised tissue ex Vivo were acquired, along with safety and pharmacokinetic measures. Results: A total of 17 subjects received doses between 3 and 30 mg. No dose-limiting toxicity was observed, and no reported adverse events were considered related to tozuleristide. At doses of 9 mg and above, the terminal serum half-life for tozuleristide was approximately 30 min. Fluorescence signal was detected in both high- and low-grade glial tumors, with high-grade tumors generally showing greater fluorescence intensity compared to lower grade tumors. In high-grade tumors, signal intensity increased with increased dose levels of tozuleristide, regardless of the time of dosing relative to surgery. Conclusion: These results support the safety of tozuleristide at doses up to 30 mg and suggest that tozuleristide imaging may be useful for FGS of gliomas.
MeSH term(s)	Adult ; Aged ; Brain Neoplasms/diagnostic imaging ; Brain Neoplasms/metabolism ; Brain Neoplasms/surgery ; Dose-Response Relationship, Drug ; Female ; Fluorescent Dyes/administration & dosage ; Fluorescent Dyes/pharmacokinetics ; Glioma/diagnostic imaging ; Glioma/metabolism ; Glioma/surgery ; Humans ; Indocyanine Green/administration & dosage ; Indocyanine Green/analogs & derivatives ; Indocyanine Green/pharmacokinetics ; Injections, Intravenous ; Male ; Middle Aged ; Neoplasm Recurrence, Local/diagnostic imaging ; Neoplasm Recurrence, Local/metabolism ; Neoplasm Recurrence, Local/surgery ; Optical Imaging/methods ; Scorpion Venoms/administration & dosage ; Scorpion Venoms/pharmacokinetics
Chemical Substances	Fluorescent Dyes ; Scorpion Venoms ; tozuleristide (835UH424TU) ; Indocyanine Green (IX6J1063HV)
Language	English
Publishing date	2019-05-08
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article ; Multicenter Study ; Research Support, Non-U.S. Gov't
ZDB-ID	135446-2
ISSN	1524-4040 ; 0148-396X
ISSN (online)	1524-4040
ISSN	0148-396X
DOI	10.1093/neuros/nyz125
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Zs.A 1424: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Pharmacokinetics and pharmacodynamics of pegylated interferon lambda-1 in cynomolgus monkeys.

Byrnes-Blake, Kelly A / Pederson, Susan / Klucher, Kevin M / Anderson-Haley, Monica / Miller, Dennis M / Lopez-Talavera, Juan Carlos / Freeman, Jeremy A

Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research

2012 Volume 32, Issue 5, Page(s) 198–206

Abstract: Type III lambda interferons (IFNs) have activity similar to type I IFNs, but a more restricted receptor distribution. A pegylated human IFN lambda-1 (pegIFNλ) is under development for chronic hepatitis C. Induction of receptor signaling (STAT1 ... ...

Abstract	Type III lambda interferons (IFNs) have activity similar to type I IFNs, but a more restricted receptor distribution. A pegylated human IFN lambda-1 (pegIFNλ) is under development for chronic hepatitis C. Induction of receptor signaling (STAT1 phosphorylation) and expression of interferon-stimulated genes (ISGs) by pegIFNλ were assessed in, respectively, cynomolgus monkey leukocyte subsets and hepatocytes stimulated in vitro. ISG induction by pegIFNλ or IFNα was also assessed in peripheral leukocytes and liver biopsies after single and repeat (x3) dosing of pegIFNλ (0.03, 0.3, 3.0 mg/kg) or unpegylated IFNα-2b (10(7) IU/kg). Single-dose pharmacokinetics of pegIFNλ were evaluated. Strong ISG induction occurred in cultured hepatocytes and liver biopsies with both pegIFNλ and IFNα. However, STAT1 phosphorylation, MHC class 1 upregulation, and ISG induction in leukocytes only occurred with IFNα. Serum neopterin was unaffected by pegIFNλ; however, β-2-microglobulin was elevated at all doses. The terminal half-life of pegIFNλ was 23 h with a 59 mL/kg volume of distribution, consistent with other pegylated IFNs. Serum exposure was dose-proportional across the dosing range. These data demonstrate the suitability of cynomolgus monkeys for the preclinical evaluation of pegIFNλ. Additionally, the absence of pegIFNλ pharmacologic activity in leukocytes is consistent with its low receptor expression in blood.
MeSH term(s)	Animals ; Cells, Cultured ; Drug Evaluation, Preclinical ; Gene Expression Regulation ; Hepatitis C, Chronic/drug therapy ; Hepatitis C, Chronic/immunology ; Hepatocytes/drug effects ; Hepatocytes/immunology ; Humans ; Immunotherapy ; Interferons ; Interleukins/administration & dosage ; Interleukins/chemistry ; Interleukins/pharmacokinetics ; Leukocytes, Mononuclear/drug effects ; Leukocytes, Mononuclear/immunology ; Macaca fascicularis ; Phosphorylation/drug effects ; Polyethylene Glycols/chemistry ; STAT1 Transcription Factor/genetics ; STAT1 Transcription Factor/metabolism ; Signal Transduction/drug effects
Chemical Substances	interferon-lambda, human ; Interleukins ; STAT1 Transcription Factor ; Polyethylene Glycols (3WJQ0SDW1A) ; Interferons (9008-11-1)
Language	English
Publishing date	2012-01-26
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1226675-9
ISSN	1557-7465 ; 1079-9907
ISSN (online)	1557-7465
ISSN	1079-9907
DOI	10.1089/jir.2011.0075
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Article ; Online: Preclinical safety, pharmacokinetics, and pharmacodynamics of recombinant human interleukin-21 in cynomolgus macaques (Macaca fascicularis).

Waggie, Kimberly S / Holdren, Matthew S / Byrnes-Blake, Kelly / Pedersen, Susan / Ponce, Rafael / Hughes, Steven / Miller, Dennis M

International journal of toxicology

2012 Volume 31, Issue 4, Page(s) 303–316

Abstract: Interleukin-21 (IL-21), a pleiotropic immunostimulatory type I cytokine, has anticancer effects in animal models. Preclinical studies designed to assess the safety of recombinant human IL-21 (rIL-21) for use in phase I oncology studies are described. The ...

Abstract	Interleukin-21 (IL-21), a pleiotropic immunostimulatory type I cytokine, has anticancer effects in animal models. Preclinical studies designed to assess the safety of recombinant human IL-21 (rIL-21) for use in phase I oncology studies are described. The rIL-21 (≤3.0 mg/kg per dose) was given intravenously to cynomolgus monkeys (Macaca fascicularis) once daily for 5 days, followed by 9 nondosing days (1 cycle) for ≤4 cycles. The rIL-21 pharmacokinetics was dose-dependent. Accumulation was not observed after repeated dosing, consistent with the short elimination half-life (t (1/2,λz); 0.4-0.8 hours). Safety findings included cyclical anemia and thrombocytopenia, clinical pathology changes consistent with acute-phase response, leukocyte infiltrates in hepatic sinusoids, and sporadic serum transaminase elevations (typically <3 times upper-limit of normal); all were reversible upon cessation of treatment. Decreased pharmacodynamic responses with time corresponded to the development of anti-rIL-21 antibodies; effects varied among individuals and were dose-dependent. These studies demonstrated rIL-21 to be generally well-tolerated when administered to cynomolgus monkeys, and all adverse effects were reversible upon treatment cessation. However, development of anti-rIL-21 antibodies may limit the use of this species in long-term studies.
MeSH term(s)	Acute-Phase Reaction/drug therapy ; Animals ; Dose-Response Relationship, Drug ; Drug Evaluation, Preclinical ; Escherichia coli/genetics ; Escherichia coli/metabolism ; Female ; Half-Life ; Humans ; Interleukins/blood ; Interleukins/pharmacokinetics ; Interleukins/pharmacology ; Macaca fascicularis ; Male ; Phosphorylation ; Recombinant Proteins/pharmacokinetics ; Recombinant Proteins/pharmacology ; STAT3 Transcription Factor/metabolism
Chemical Substances	Interleukins ; Recombinant Proteins ; STAT3 Transcription Factor ; interleukin-21
Language	English
Publishing date	2012-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1379845-5
ISSN	1092-874X ; 1091-5818
ISSN (online)	1092-874X
ISSN	1091-5818
DOI	10.1177/1091581812449661
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Article ; Online: Nonclinical Profile of BLZ-100, a Tumor-Targeting Fluorescent Imaging Agent.

Parrish-Novak, Julia / Byrnes-Blake, Kelly / Lalayeva, Narine / Burleson, Stefanie / Fidel, Janean / Gilmore, Rhonda / Gayheart-Walsten, Pamela / Bricker, Gregory A / Crumb, William J / Tarlo, K S / Hansen, Stacey / Wiss, Valorie / Malta, Errol / Dernell, William S / Olson, James M / Miller, Dennis M

International journal of toxicology

2017 Volume 36, Issue 2, Page(s) 104–112

Abstract: BLZ-100 is a single intravenous use, fluorescent imaging agent that labels tumor tissue to enable more complete and precise surgical resection. It is composed of a chlorotoxin peptide covalently bound to the near-infrared fluorophore indocyanine green. ... ...

Abstract	BLZ-100 is a single intravenous use, fluorescent imaging agent that labels tumor tissue to enable more complete and precise surgical resection. It is composed of a chlorotoxin peptide covalently bound to the near-infrared fluorophore indocyanine green. BLZ-100 is in clinical development for intraoperative visualization of human tumors. The nonclinical safety and pharmacokinetic (PK) profile of BLZ-100 was evaluated in mice, rats, canines, and nonhuman primates (NHP). Single bolus intravenous administration of BLZ-100 was well tolerated, and no adverse changes were observed in cardiovascular safety pharmacology, PK, and toxicology studies in rats and NHP. The single-dose no-observed-adverse-effect-levels (NOAELs) were 7 mg (28 mg/kg) in rats and 60 mg (20 mg/kg) in NHP, corresponding to peak concentration values of 89 400 and 436 000 ng/mL and area-under-the-curve exposure values of 130 000 and 1 240 000 h·ng/mL, respectively. Based on a human imaging dose of 3 mg, dose safety margins are >100 for rat and monkey. BLZ-100 produced hypersensitivity reactions in canine imaging studies (lethargy, pruritus, swollen muzzle, etc). The severity of the reactions was not dose related. In a follow-up study in dogs, plasma histamine concentrations were increased 5 to 60 minutes after BLZ-100 injection; this coincided with signs of hypersensitivity, supporting the conclusion that the reactions were histamine based. Hypersensitivity reactions were not observed in other species or in BLZ-100 human clinical studies conducted to date. The combined imaging, safety pharmacology, PK, and toxicology studies contributed to an extensive initial nonclinical profile for BLZ-100, supporting first-in-human clinical trials.
MeSH term(s)	Animals ; Complement System Proteins/analysis ; Dogs ; Drug Hypersensitivity/blood ; Female ; Fluorescent Dyes/pharmacokinetics ; Fluorescent Dyes/toxicity ; HEK293 Cells ; Histamine/blood ; Humans ; Indocyanine Green/analogs & derivatives ; Indocyanine Green/pharmacokinetics ; Indocyanine Green/toxicity ; Macaca fascicularis ; Male ; Mice ; Neoplasms/diagnostic imaging ; Neoplasms/metabolism ; Rats, Sprague-Dawley ; Scorpion Venoms/blood ; Scorpion Venoms/pharmacokinetics ; Scorpion Venoms/toxicity
Chemical Substances	Fluorescent Dyes ; Scorpion Venoms ; Histamine (820484N8I3) ; tozuleristide (835UH424TU) ; Complement System Proteins (9007-36-7) ; Indocyanine Green (IX6J1063HV)
Language	English
Publishing date	2017-03-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	1379845-5
ISSN	1092-874X ; 1091-5818
ISSN (online)	1092-874X
ISSN	1091-5818
DOI	10.1177/1091581817697685
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Article ; Online: Interferon lambda as a potential new therapeutic for hepatitis C.

Miller, Dennis M / Klucher, Kevin M / Freeman, Jeremy A / Hausman, Diana F / Fontana, David / Williams, Doug E

Annals of the New York Academy of Sciences

2009 Volume 1182, Page(s) 80–87

Abstract: Interferon lambdas (IFN-lambda) are Type III interferons with biological activity, including induction of antiviral genes, similar to Type I IFNs, but signal through a distinct receptor complex. The expression pattern for the IFN-lambda receptor is more ... ...

Abstract	Interferon lambdas (IFN-lambda) are Type III interferons with biological activity, including induction of antiviral genes, similar to Type I IFNs, but signal through a distinct receptor complex. The expression pattern for the IFN-lambda receptor is more cell specific than the widely distributed IFN-alpha receptor, suggesting in vivo, IFN-lambda may have fewer side effects than IFN-alpha, such as less hematologic toxicities. A PEGylated form of IFN-lambda (PEG-rIL-29) was well tolerated in animals and did not result in hematologic toxicity. Clinical data from initial studies of PEG-rIL-29 has demonstrated antiviral effects in patients with hepatitis C without producing hematologic toxicity. These preclinical and early clinical data support PEG-rIL-29 as a potential new therapeutic agent for treatment of patients with hepatitis C.
MeSH term(s)	Animals ; Hepatitis C/drug therapy ; Hepatitis C/pathology ; Humans ; Interleukins/adverse effects ; Interleukins/metabolism ; Interleukins/therapeutic use ; Polyethylene Glycols/metabolism ; Recurrence ; Signal Transduction/drug effects
Chemical Substances	Interleukins ; Polyethylene Glycols (30IQX730WE)
Language	English
Publishing date	2009-12
Publishing country	United States
Document type	Journal Article
ZDB-ID	211003-9
ISSN	1749-6632 ; 0077-8923
ISSN (online)	1749-6632
ISSN	0077-8923
DOI	10.1111/j.1749-6632.2009.05241.x
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Article: Interleukin-21 signaling: functions in cancer and autoimmunity.

Davis, Ian D / Skak, Kresten / Smyth, Mark J / Kristjansen, Paul E G / Miller, Dennis M / Sivakumar, Pallavur V

Clinical cancer research : an official journal of the American Association for Cancer Research

2007 Volume 13, Issue 23, Page(s) 6926–6932

Abstract: Interleukin-21 (IL-21) is a cytokine with structural and sequence homology to IL-2 and IL-15, yet possesses several biological properties distinct from these cytokines. IL-21 is produced mainly by activated CD4(+) T cells and natural killer T cells and ... ...

Abstract	Interleukin-21 (IL-21) is a cytokine with structural and sequence homology to IL-2 and IL-15, yet possesses several biological properties distinct from these cytokines. IL-21 is produced mainly by activated CD4(+) T cells and natural killer T cells and mediates its activity by binding to the IL-21 receptor (IL-21R), consisting of an IL-21-specific alpha chain (IL-21Ralpha; JAK/STAT) that heterodimerizes with the common gamma chain (CD132). Intracellular signaling occurs through the Janus-activated kinase/signal transducer and activator of transcription pathways. Physiologic expression of IL-21R is restricted to lymphoid tissues and peripheral blood mononuclear cells; however, other tissues such as epithelium, synovium, or transformed cells can acquire expression of both components of IL-21R heterodimer. IL-21 has complex activities on a wide variety of cell types, leading to enhancement of adaptive T-cell immunity, antibody production, activation of natural killer cell subtypes, and opposition to suppressive effects mediated by regulatory T cells. Functionally, these activities promote immune responses and point to a physiologic role of IL-21 in autoimmunity and immune enhancement. Therapeutic manipulation of IL-21 activity may allow improved immunotherapy for cancer as well as insights into autoimmune disease. Recently conducted phase 1 trials in metastatic melanoma and renal cell carcinoma have shown that recombinant IL-21 has a favorable safety profile and support its continued investigation as a potential anticancer drug.
MeSH term(s)	Animals ; Autoimmunity/physiology ; Humans ; Interleukins/immunology ; Interleukins/metabolism ; Interleukins/therapeutic use ; Neoplasms/immunology ; Neoplasms/metabolism ; Neoplasms/therapy ; Receptors, Interleukin-21/immunology ; Receptors, Interleukin-21/metabolism ; Signal Transduction
Chemical Substances	Interleukins ; Receptors, Interleukin-21 ; interleukin-21
Language	English
Publishing date	2007-12-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-07-1238
Database	MEDical Literature Analysis and Retrieval System OnLINE

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