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International Journal of Toxicology

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https://read.qxmd.com/read/30852923/evaluation-of-the-toxicity-and-neurological-effects-of-fulranumab-in-adult-cynomolgus-monkeys
#1
Meredith Rocca, Chao Han, Mark Butt, Timothy P Coogan
Fulranumab, an anti-human nerve growth factor antibody, was evaluated in a series of nonclinical toxicology studies. No treatment effects were observed in adolescent cynomolgus monkeys in standard design, repeat-dose toxicology studies of up to 6 months. Adverse effects on the developing nervous system were observed in offspring of pregnant cynomolgus monkeys treated with fulranumab. Subsequent studies including detailed morphologic investigations of the nervous system did reveal fulranumab-related changes in adult cynomolgus monkeys; this article is focused on those findings...
March 10, 2019: International Journal of Toxicology
https://read.qxmd.com/read/30845865/kidney-pathophysiology-toxicology-and-drug-induced-injury-in-drug-development
#2
Zaher A Radi
Anatomically, the kidneys are paired, bean-shaped (in most mammals), excretory organs that lie in the retroperitoneum. High blood flow to the kidneys, together with high oxygen consumption, makes them more vulnerable to exposure, via the circulation, and subsequent injury related to high concentrations of xenobiotics and chemicals. In preclinical drug development and safety assessment of new investigational drugs, changes in kidney structure and/or function following drug administration in experimental laboratory animals need to be put in context with interspecies differences in kidney functional anatomy, physiology, spontaneous pathologies, and toxicopathological responses to injury...
March 7, 2019: International Journal of Toxicology
https://read.qxmd.com/read/30791807/a-global-overview-of-poison-treatment-apps-and-databases
#3
Pooja G Poojari, Girish Thunga, Sreedharan Nair, Vijayanarayana Kunhikatta, Mahadev Rao
Acute poisoning is a serious health problem that is associated with high mortality. Management of acute poisoning cases in the critical care settings is the biggest challenge due to the difficulty in identification of poison involved. Immediate information about the poisoning and its management is crucial in the early diagnosis, treatment, and in the prevention of poisoning complications. Poison information resources, such as various poison apps and databases, are essential for the retrieval of updated and quick information on poisoning...
February 21, 2019: International Journal of Toxicology
https://read.qxmd.com/read/30791754/nonclinical-toxicology-and-toxicokinetic-profile-of-an-oral-lanthionine-synthetase-c-like-2-lancl2-agonist-bt-11
#4
Andrew Leber, Raquel Hontecillas, Victoria Zoccoli-Rodriguez, Marion Ehrich, Jennifer Davis, Jyoti Chauhan, Josep Bassaganya-Riera
BT-11 is an orally active, gut-restricted investigational therapeutic targeting the lanthionine synthetase C-like 2 pathway with lead indications in ulcerative colitis (UC) and Crohn disease (CD), 2 manifestations of inflammatory bowel disease (IBD). In 5 mouse models of IBD, BT-11 is effective at oral doses of 8 mg/kg. BT-11 was also efficacious at nanomolar concentrations in primary human samples from patients with UC and CD. BT-11 was tested under Good Laboratory Practice conditions in 90-day repeat-dose general toxicity studies in rats and dogs, toxicokinetics, respiratory, cardiovascular and central nervous system safety pharmacology, and genotoxicity studies...
February 21, 2019: International Journal of Toxicology
https://read.qxmd.com/read/30791753/language-consideration-and-methodological-transparency-in-systematic-reviews-of-animal-toxicity-studies
#5
Kristine M Alpi, Tram A Vo, David C Dorman
This study evaluated the use of non-English literature (NEL) in systematic reviews (SRs) or meta-analyses (MAs) of animal-based toxicity or communicable disease (CD) studies. A secondary goal was to assess how grant funding, country of primary authorship, or study quality reporting influenced the use of NEL in these reviews. Inclusion criteria and data extraction forms were based on a pilot evaluation of a 10% random sample of reviews that were identified from a PubMed search (2006 to May 2017). This search yielded 111 animal toxicity and 69 CD reviews...
February 21, 2019: International Journal of Toxicology
https://read.qxmd.com/read/30760067/toxicity-of-pexacerfont-a-corticotropin-releasing-factor-type-1-receptor-antagonist-in-rats-and-dogs
#6
Melvin R White, Michael J Graziano, Thomas P Sanderson
Pexacerfont is a corticotropin-releasing factor subtype 1 receptor antagonist that was developed for the treatment of anxiety- and stress-related disorders. This report describes the results of repeat-dose oral toxicity studies in rats (3 and 6 months) and dogs (3 months and 1 year). Pexacerfont was well tolerated in all of these studies at exposures equal to or greater than areas under the curve in humans (clinical dose of 100 mg). Microscopic changes in the liver (hepatocellular hypertrophy), thyroid glands (hypertrophy/hyperplasia and adenomas of follicular cells), and pituitary (hypertrophy/hyperplasia and vacuolation of thyrotrophs) were only observed in rats and were considered adaptive changes in response to hepatic enzyme induction and subsequent alterations in serum thyroid hormone levels...
February 13, 2019: International Journal of Toxicology
https://read.qxmd.com/read/30739550/cder-experience-with-juvenile-animal-studies-for-cns-drugs
#7
J Edward Fisher, Arippa Ravindran, Ikram Elayan
A survey was undertaken to evaluate juvenile animal studies conducted for drug applications reviewed by the Center for Drug Evaluation and Research between 2009 and 2014. Some conclusions about the nonclinical pediatric safety assessment based on studies performed in support of central nervous system-active compounds are presented here. A total of 44 completed studies from 32 New Drug Applications submitted to the Divisions of Psychiatry and Neurology Products were evaluated. Data on animal species and age range used, endpoints evaluated, and outcomes included in labeling were analyzed...
February 10, 2019: International Journal of Toxicology
https://read.qxmd.com/read/30739549/lipoxygenase-protein-expression-and-its-effect-on-oxidative-stress-caused-by-benzidine-in-normal-human-urothelial-cell-lines
#8
Yun Huang, Shaoling Huang, Yue Wu, Minlan Peng, Xinge Zhang, Jing Wang, Jianan Hu
Metabolic activation of indirect-acting carcinogens in the target organ is an effective mechanism of carcinogenesis. Lipoxygenase (LOX) can co-oxidize the bladder carcinogen benzidine (BZ). However, it is not entirely clear whether BZ is activated and which enzyme is involved in its activation in bladder epithelial cells. Our results showed that BZ induced 5-LOX protein expression but had no significant influence on the expression of 15-LOX-2, CYP1B1, and CYP2E1 in SV-40 immortalized human uroepithelial SV-HUC-1 cells...
February 10, 2019: International Journal of Toxicology
https://read.qxmd.com/read/30673360/investigating-the-value-of-urine-volume-creatinine-and-cystatin-c-for-urinary-biomarkers-normalization-for-drug-development-studies
#9
Adeyemi O Adedeji, Tony Pourmohamad, Yafei Chen, Jennifer Burkey, Catherine J Betts, Susan J Bickerton, Manisha Sonee, James E McDuffie
Novel urinary protein biomarkers have recently been identified and qualified in rats for the early detection of renal injury in drug development studies. However, there seems to be no standardized normalization method for analyzing these urinary biomarkers, as some users normalize with urinary creatinine (uCr), urine volume (uVol), or leave biomarker un-normalized. More recently, urinary cystatin C is also emerging as a urinary biomarker normalizer, given some of its characteristics as a glomerular filtration marker...
January 23, 2019: International Journal of Toxicology
https://read.qxmd.com/read/30663459/%C3%AE-n-methylamino-l-alanine-inhibits-human-catalase-activity-possible-implications-for-neurodegenerative-disease-development
#10
Rianita van Onselen, Tim G Downing
The naturally produced, nonprotein amino acid β- N-methylamino-l-alanine (BMAA) has been proposed as a significant contributor to sporadic neurodegenerative disease development worldwide. However, the existing hypothesized mechanisms of toxicity do not adequately explain the role of BMAA in neurodegenerative disease development. There is evidence for BMAA-induced enzyme inhibition, but the effect of BMAA on human stress response enzymes has received little attention, despite the well-described role of oxidative stress in neurodegenerative disease development...
January 20, 2019: International Journal of Toxicology
https://read.qxmd.com/read/30663453/safety-study-of-single-dose-intravenously-administered-dota-siglec-9-peptide-in-sprague-dawley-rats
#11
Paulina Chrusciel, Emrah Yatkin, Xiang-Guo Li, Ulla-Marjut Jaakkola, Juhani Knuuti, Sirpa Jalkanen, Anne Roivainen
The peptide-based radioactive compound [68 Ga]Ga-DOTA-Siglec-9 is a novel agent for imaging of inflammation with positron emission tomography. The drug target of [68 Ga]Ga-DOTA-Siglec-9 is vascular adhesion protein 1. Previous studies have obtained promising results with [68 Ga]Ga-DOTA-Siglec-9 in experimental animals. However, before taking this novel imaging agent into clinical trials, safety and toxicological studies need to be performed with the nonradioactive precursor compound DOTA-Siglec-9. This extended single-dose toxicity study was designed to provide information on the major toxic effects of DOTA-Siglec-9 and to indicate possible target organs after a single intravenous (iv) injection in rats...
January 20, 2019: International Journal of Toxicology
https://read.qxmd.com/read/30791847/editor-s-note
#12
Mary Beth Genter
No abstract text is available yet for this article.
January 2019: International Journal of Toxicology
https://read.qxmd.com/read/30567462/a-proof-of-concept-evaluation-of-jtpc-and-tp-tec-as-proarrhythmia-biomarkers-in-preclinical-species-a-retrospective-analysis-by-an-hesi-sponsored-consortium
#13
Emmanuel Boulay, Matthew M Abernathy, Ray Chu, Gregory S Friedrichs, Nicolas Gendron-Parra, Andrea Greiter-Wilke, Jean-Michel Guillon, John E Koerner, Ariane Menard, Jill Steidl-Nichols, Jennifer Pierson, Michael K Pugsley, Eric I Rossman, David Strauss, Eric Troncy, Jean-Pierre Valentin, Todd Wisialowski, Simon Authier
INTRODUCTION: Based on the ICH S7B and E14 guidance documents, QT interval (QTc) is used as the primary in vivo biomarker to assess the risk of drug-induced torsades de pointes (TdP). Clinical and nonclinical data suggest that drugs that prolong the corrected QTc with balanced multiple ion channel inhibition (most importantly the l-type calcium, Cav1.2, and persistent or late inward sodium current, Nav1.5, in addition to human Ether-à-go-go-Related Gene [hERG] IKr or Kv11.1) may have limited proarrhythmic liability...
December 19, 2018: International Journal of Toxicology
https://read.qxmd.com/read/30453808/percutaneous-hepatic-perfusion-with-filtered-melphalan-for-localized-treatment-of-metastatic-hepatic-disease-a-risk-assessment
#14
Pauline E McEwan, Lynn Bailey, David Trost, Christopher Scull, John H Keating, Misty Williams, Robert J Guttendorf
Regional therapies for metastatic liver disease have garnered interest in recent years due to technological advances in drug delivery. A percutaneous hepatic perfusion (PHP) using a newly developed generation 2 (GEN2) filtration system was designed to mitigate systemic toxicity and cardiovascular risk associated with hepatic blood filtration during hepatic artery infusion of the chemotherapy drug melphalan. The GEN2 system was evaluated in healthy swine, and plasma samples were assessed for clinical chemistry, melphalan toxicokinetics (TK), inflammatory cytokines, catecholamines, hematological, and cardiac biomarkers...
November 19, 2018: International Journal of Toxicology
https://read.qxmd.com/read/30526174/ernest-hodgson-1932-2018
#15
(no author information available yet)
No abstract text is available yet for this article.
November 2018: International Journal of Toxicology
https://read.qxmd.com/read/30380967/toxicity-and-mutagenicity-evaluation-following-risug-contraception-reversal-in-rats
#16
Abdul S Ansari, Mubarik Hussain, Sadi Rehan Khan, Ayesha Badar, N K Lohiya
Reestablishment of fertility, after a male contraceptive method, is of great concern. In this context, RISUG (Reversible Inhibition of Sperm Under Guidance) has been evaluated for its mutagenicity following reversibility with dimethyl sulfoxide (DMSO)/sodium bicarbonate (NaHCO3 ) in Wistar albino rats. Animals were divided into 7 groups, namely, sham-operated control, vas occlusion with RISUG for 90 and 360 days, reversal with DMSO and NaHCO3 after 90 and 360 days, respectively. The testis, cauda epididymis, cauda epididymal spermatozoa, and serum were evaluated for apoptosis and hormonal status through various assays...
November 1, 2018: International Journal of Toxicology
https://read.qxmd.com/read/30373422/long-term-systemic-treatment-with-methamphetamine-causes-retinal-damage-in-cd1-mice
#17
Haojiang Yang, Liming Tao, Lin Li
As a powerful psychostimulant with high potential for abuse, methamphetamine (Meth) could cause long-lasting abnormalities in retinas. The purpose of this study was to investigate the effects of systemic administration of Meth at low dose on retinal damage and understand the underlying mechanisms of pathology. CD1 mice were treated with 0.5 mg/kg or 1 mg/kg Meth by intraperitoneal injection daily for 2 months, mice treated with saline were used as negative control. Electroretinography (ERG) reflects the mass response of photoreceptor cells and was used to test the outer retinal function after Meth treatment...
October 29, 2018: International Journal of Toxicology
https://read.qxmd.com/read/30282506/embracing-transparency-through-data-sharing
#18
Stéphanie Boué, Michael Byrne, A Wallace Hayes, Julia Hoeng, Manuel C Peitsch
Low rates of reproducibility and translatability of data from nonclinical research have been reported. Major causes of irreproducibility include oversights in study design, failure to characterize reagents and protocols, a lack of access to detailed methods and data, and an absence of universally accepted and applied standards and guidelines. Specific areas of concern include uncharacterized antibodies and cell lines, the use of inappropriate sampling and testing protocols, a lack of transparency and access to raw data, and deficiencies in the translatability of findings to the clinic from studies using animal models of disease...
October 3, 2018: International Journal of Toxicology
https://read.qxmd.com/read/30244632/-not-everything-that-shakes-is-a-seizure-making-the-determination-of-test-article-induced-convulsions-in-toxicology-studies
#19
David V Gauvin, Zachary J Zimmermann, Joshua Yoder, Theodore J Baird
Spontaneous unexpected events occasionally develop during the course of rodent preclinical toxicology studies. The presentation of serious adverse events on animal studies may require notification of these events to the Food and Drug Administration if the events are most likely the direct result of test article administration. Classical conditioning of emotional responses may occur over the course of a repeat-dose study and clinical observation calls of "convulsions" are reported to the study director and/or staff veterinarians...
September 24, 2018: International Journal of Toxicology
https://read.qxmd.com/read/30236031/editor-s-note
#20
Mary Beth Genter
No abstract text is available yet for this article.
September 2018: International Journal of Toxicology
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