Chronic effects of the novel glucocorticosteroid RPR 106541 administered to beagle dogs by inhalation.

Abstract:

:The preclinical safety of RPR 106541, a novel 17-thiosteroid, was evaluated in young adult and mature dogs by inhalation exposure for 26 weeks and 52 weeks, respectively. A dry powder formulation of RPR 106541 in lactose was administered to young adult dogs (approximately 6 months of age at initiation) at doses of 0 (air and placebo controls), 10, 100, or 1,000 microg/kg/d for 26 weeks. A solution-based aerosol formulation was administered to mature dogs (approximately 10 months at initiation) from a pressurized metered dose inhaler at 0 (air and placebo controls), 10, 50, and 150 microg/kg/d for 52 weeks. Clinical evidence of glucocorticosteroid-induced immunosuppression was observed by weeks 20-26 following relatively high dose exposures (100 microg/kg/d and 1,000 microg/kg/d) in young dogs receiving the dry powder formulation for 26 weeks. Classic glucocorticosteroid effects were observed, including adrenocortical atrophy, reduced bone mass with retention of epiphyseal growth plates in long bones, prominence of stromal adipose tissue in bone marrow, and atrophy of lymphoid tissues. Inhalation administration of RPR 106541 to sexually mature dogs facilitated more definitive characterization of endocrine affects of RPR 106541 as compared with administration in younger, sexually immature animals. Significant effects in female reproductive organs included absence of corpora lutea in association with atresia of vesicular follicles within the ovaries, endometrial hyperplasia, and lobular development of mammary tissue. Discordant development of mammary tissue, accumulation of secretory material within hyperplastic endometrial glands, and hypertrophy of uterine lining epithelium in absence of ovulation were consistent with a secondary progestin effect by a potent glucocorticosteroid.

journal_name

Toxicol Pathol

journal_title

Toxicologic pathology

authors

Miller GK,Valerio MG,Pino MV,Larson JL,Viau A,Hamelin N,Labbé R,Banks CM

doi

10.1177/019262330002800202

subject

Has Abstract

pub_date

2000-03-01 00:00:00

pages

226-36

issue

2

eissn

0192-6233

issn

1533-1601

journal_volume

28

pub_type

杂志文章
  • TCDD: an environmental immunotoxicant reveals a novel pathway of immunoregulation--a 30-year odyssey.

    abstract::I was honored to be the keynote speaker at the 30th Annual Society of Toxicologic Pathology Symposium "Toxicologic Pathology and the Immune System." I had the opportunity to reminisce about events in the 1970s that set the stage for the birth and subsequent growth of the field of immunotoxicology and to summarize my r...

    journal_title:Toxicologic pathology

    pub_type: 历史文章

    doi:10.1177/0192623311427710

    authors: Kerkvliet NI

    更新日期:2012-01-01 00:00:00

  • Lipid composition, physical state, and lipid peroxidation of tumor membranes.

    abstract::Studies were carried out on microsomes isolated from the highly differentiated (slow-growing) Morris hepatoma 9618A, on microsomes and plasma membranes from the poorly differentiated (fast-growing) Morris hepatoma 3924A, and rat liver used as control. The lipid composition (phospholipid and cholesterol content, degree...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章

    doi:10.1177/019262338401200404

    authors: Galeotti T,Borrello S,Minotti G,Palombini G,Masotti L,Sartor G,Cavatorta P,Arcioni A,Zannoni C

    更新日期:1984-01-01 00:00:00

  • CDER photosafety guidance for industry.

    abstract::In the Federal Register of January 10, 2000 (65 FR 1399), FDA published a draft guidance entitled "Photosafety Testing." The notice gave interested persons an opportunity to submit comments. As a result of the comments, certain sections of the guidance were reworded to improve clarity. A final guidance was published i...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章

    doi:10.1080/01926230490463821

    authors: Jacobs AC,Brown PC,Chen C,Ellis A,Farrelly J,Osterberg R

    更新日期:2004-07-01 00:00:00

  • Early stellate cell activation and veno-occlusive-disease (VOD)-like hepatotoxicity in dogs treated with AR-H047108, an imidazopyridine proton pump inhibitor.

    abstract::Dogs treated with AR-H047108, an imidazopyridine potassium competitive acid blocker (P-CAB), developed clinical signs of hepatic dysfunction as well as morphologically manifest hepatotoxicity in repeat-dose toxicity studies. An investigative one-month study was performed, with interim euthanasia after one and two week...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章

    doi:10.1177/0192623308320802

    authors: Berg AL,Böttcher G,Andersson K,Carlsson E,Lindström AK,Huby R,Håkansson H,Skånberg-Wilhelmsson I,Hellmold H

    更新日期:2008-07-01 00:00:00

  • Carcinogenicity testing of antitumor agents.

    abstract::Carcinogenicity testing of antitumor agents in animal bioassays has been proposed because of the potential for carcinogenicity of this class of agents and the expectation that such testing may indicate prospectively the target organs of any related human oncogenesis. The literature reveals the anticipated confirmation...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章

    doi:10.1177/019262338501300305

    authors: Hottendorf GH

    更新日期:1985-01-01 00:00:00

  • Dermal carcinogenicity in transgenic mice: effect of vehicle on responsiveness of hemizygous Tg.AC mice to phorbol 12-myristate 13-acetate (TPA).

    abstract::The Tg.AC mouse is being evaluated for use in short-term carcinogenicity bioassays. Because the dermal test protocol necessitates dissolving test agents we determined the effects of several solvents on responsiveness of hemizygous mice to dermal applications of the classical skin tumor promoter. phorbol 12-myristate 1...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章

    doi:10.1080/019262301317226339

    authors: Stoll RE,Furst SM,Stoltz JH,Lilly PD,Mennear JH

    更新日期:2001-09-01 00:00:00

  • Lysozyme-containing renal tubular hyaline droplets in F344 rats bearing a rat fibrosarcoma-derived transplantable tumor.

    abstract::Renal tubular hyaline droplets developed in male and female F344 rats bearing a rat fibrosarcoma-derived transplantable tumor (SS). The droplets accumulated exclusively in the proximal renal tubular epithelia as eosinophilic granules of various sizes in hematoxylin and eosin-stained sections. The granules stained brig...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章

    doi:10.1177/019262339802600517

    authors: Yamate J,Iwaki M,Nakatsuji S,Kuwamura M,Kotani T,Sakuma S

    更新日期:1998-09-01 00:00:00

  • Morphological characterization of spindle cell tumors induced in transgenic Tg.AC mouse skin.

    abstract::Transgenic Tg.AC mice carry a v-Ha-ras coding region flanked by a zeta-globin promoter and an SV40 polyadenylation signal sequence. These mice respond to carcinogens by developing epidermal papillomas. In some cases, malignancies develop at the sites of these papillomas. Various patterns of squamous cell differentiati...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章

    doi:10.1177/019262339802600407

    authors: Asano S,Trempus CS,Spalding JW,Tennant RW,Battalora MS

    更新日期:1998-07-01 00:00:00

  • Transplantation of preneoplastic rat hepatocytes by intraportal injection.

    abstract::Hepatocyte suspensions prepared from inbred male Wistar-Kyoto rats were transplanted to the livers of syngeneic recipients by injection into the portal venous system immediately after partial hepatectomy. Donor cells were labelled with 51Cr in vitro before transplantation. Animals were sacrificed 1 hr, 10 hr, 48 hr, o...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章

    doi:10.1177/019262338701500110

    authors: Saeter G,Schwarze PE,Nesland JM,Seglen PO

    更新日期:1987-01-01 00:00:00

  • Early stages of nodular transformation of the B6C3F1 mouse liver induced by choline deficiency.

    abstract::The B6C3F1 strain of mice is prone to develop liver nodules as animals grow older. This spontaneous tumor development is enhanced by dietary lipotrope deficiency. The present studies were performed to evaluate the liver of the B6C3F1 mice in early periods of lipotrope deficiency and before the nodules appear. Mice wer...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章

    doi:10.1177/019262338501300103

    authors: de Camargo JL,Punyarit P,Newberne PM

    更新日期:1985-01-01 00:00:00

  • Effects of Aging in the Striatum and Substantia Nigra of a Parkinson's Disease Animal Model.

    abstract::Aging is a multifactorial process associated with functional deficits, and the brain is more prone to developing chronic degenerative diseases such as Parkinson's disease. Several groups have tried to correlate the age-related ultrastructural alterations to the neurodegeneration process using in vivo pharmacological m...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章

    doi:10.1177/0192623318767065

    authors: Ureshino RP,Costa AJ,Erustes AG,Pereira GJDS,Sinigaglia-Coimbra R,Smaili SS

    更新日期:2018-04-01 00:00:00

  • Differentiation Patterns of Uterine Carcinomas and Precursor Lesions Induced by Neonatal Estrogen Exposure in Mice.

    abstract::Developmental exposure to estrogenic chemicals is an established risk factor for cancer of the female reproductive tract. This increase in risk has been associated with disruption of normal patterns of cellular differentiation during critical stages of morphogenesis. The goal of this study was to document uterine epit...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章

    doi:10.1177/0192623318779326

    authors: Suen AA,Jefferson WN,Williams CJ,Wood CE

    更新日期:2018-07-01 00:00:00

  • Early alterations of lung injury following acute smoke exposure and 21-aminosteroid treatment.

    abstract::In a simulated fire-related smoke exposure protocol, New Zealand white rabbits were utilized to investigate the potential effects of the 21-aminosteroid (lazaroid) analog U75412E on the early events of acute lung injury. Inhalation of a total of 1.6 mg/kg U75412E aerosolized at a rate of 1.53 mg/min at 0.5 hr after sm...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章

    doi:10.1177/019262339902700309

    authors: Wang S,Lantz RC,Robledo RF,Breceda V,Hays AM,Witten ML

    更新日期:1999-05-01 00:00:00

  • High hematocrit resulting from administration of erythropoiesis-stimulating agents is not fully predictive of mortality or toxicities in preclinical species.

    abstract::We conducted a retrospective analysis of publicly available preclinical toxicology studies with erythropoiesis-stimulating agents (ESAs) to examine common adverse events in rats, Beagle dogs, and cynomolgus monkeys. Mortality and/or thrombotic events were reported sporadically in a subset of studies and attributed to ...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章,评审

    doi:10.1177/0192623313486317

    authors: Andrews DA,Pyrah IT,Boren BM,Tannehill-Gregg SH,Lightfoot-Dunn RM

    更新日期:2014-01-01 00:00:00

  • Urinary tract toxicity in rats following administration of beta 3-adrenoceptor agonists.

    abstract::ZD7114, [(S)-4-[2-(2-hydroxy-3 phenoxypropylamine)ethoxy]-N-(2-methoxyethyl) phenoxyacetamide], and ZD2079, [(R)-N-(2-[4- (carboxymethyl)phenoxy]ethyl)-N-(beta-hydroxyphenethyl)ammonium chloride], are beta 3-adrenoceptor stimulants with selectivity for brown adipose tissue. ZD7144 is the hydrochloride salt of the S-en...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章

    doi:10.1177/019262339902700203

    authors: Waghe M,Westwood R,Nunn G,Kalinowski A,Aldridge A

    更新日期:1999-03-01 00:00:00

  • Comparison of histochemical methods for murine eosinophil detection in an RSV vaccine-enhanced inflammation model.

    abstract::A comparative study of histochemical detection of eosinophils in fixed murine tissue is lacking. Five histochemical methods previously reported for eosinophil detection were quantitatively and qualitatively compared in an established murine RSV vaccine-enhanced inflammation model. Nonspecific neutrophil staining was e...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章

    doi:10.1177/0192623308329342

    authors: Meyerholz DK,Griffin MA,Castilow EM,Varga SM

    更新日期:2009-02-01 00:00:00

  • Loss of Immunohistochemical Reactivity in Association With Handling-Induced Dark Neurons in Mouse Brains.

    abstract::The handling-induced dark neuron is a histological artifact observed in brain samples handled before fixation with aldehydes. To explore associations between dark neurons and immunohistochemical alterations in mouse brains, we examined protein products encoded by Cav3 (neuronal perikarya/neurites), Rbbp4 (neuronal nuc...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章

    doi:10.1177/0192623319896263

    authors: Soontornniyomkij V,Chang RC,Soontornniyomkij B,Schilling JM,Patel HH,Jeste DV

    更新日期:2020-04-01 00:00:00

  • Longevity, body weight, and neoplasia in ad libitum-fed and diet-restricted C57BL6 mice fed NIH-31 open formula diet.

    abstract::Groups of C57BL6 mice of each sex were assigned to one of 2 dietary regimens, ad libitum (AL) or dietary restriction (DR), to study effects of food restriction on body weight, survival, and neoplasia. The AL and DR groups were subdivided into a scheduled sacrifice group for examination at 6-mo intervals, and a lifetim...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章

    doi:10.1177/019262339502300503

    authors: Blackwell BN,Bucci TJ,Hart RW,Turturro A

    更新日期:1995-09-01 00:00:00

  • Brainstem axonal degeneration in mice with deletion of selenoprotein p.

    abstract::Selenoprotein P is an abundant extracellular protein that is expressed in liver, brain, and other tissues. Studies in mice with the selenoprotein P gene deleted (Sepp-/- mice) have implicated the protein in maintaining brain selenium. Sepp-/- mice fed a normal or low selenium diet develop severe motor impairment and d...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章

    doi:10.1080/01926230500243045

    authors: Valentine WM,Hill KE,Austin LM,Valentine HL,Goldowitz D,Burk RF

    更新日期:2005-01-01 00:00:00

  • Morphologic changes associated with intrathecal catheters for direct delivery to the central nervous system in preclinical studies.

    abstract::A retrospective analysis of microscopic evaluation data from control (device and/or saline-treated) animals in intrathecal studies in monkeys, dogs, sheep, and rats was conducted. The studies were performed by multiple testing facilities. All slide preparation and microscopic evaluation were conducted in the laborator...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章

    doi:10.1177/0192623310391679

    authors: Butt MT

    更新日期:2011-01-01 00:00:00

  • Flow cytometry in the preclinical development of biopharmaceuticals.

    abstract::Novel biomarkers are often required in the preclinical development of biopharmaceuticals in order to characterize pharmacologic and toxicologic effects and to establish pharmacodynamic and pharmacokinetic relationships. Flow cytometry is uniquely suited for measurement of these biomarkers. Large numbers of single cell...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章,评审

    doi:10.1177/019262339902700107

    authors: Gossett KA,Narayanan PK,Williams DM,Gore ER,Herzyk DJ,Hart TK,Sellers TS

    更新日期:1999-01-01 00:00:00

  • Cross Talk from Tubules to Glomeruli.

    abstract::Tubular injury sensitizes glomeruli to injury. We review potential mechanisms of this tubuloglomerular cross talk. In the same nephron, tubular injury can cause stenosis of the glomerulotubular junction and finally result in atubular glomeruli. Tubular injury also affects glomerular filtration function through tubulog...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章,评审

    doi:10.1177/0192623318796784

    authors: Wang J,Zhong J,Yang HC,Fogo AB

    更新日期:2018-12-01 00:00:00

  • An overview of current cytochrome P450 technology for assessing the safety and efficacy of new materials.

    abstract::Studies of xenobiotic biotransformation by in vitro techniques are destined to play an increasingly important role in assessing the safety and efficacy of drugs and other new chemical entities. The first part of this article summarizes some of the in vitro techniques that have been developed to evaluate xenobiotics as...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章,评审

    doi:

    authors: Parkinson A

    更新日期:1996-01-01 00:00:00

  • Congenital intrahepatic arteriovenous fistulae in a young beagle dog.

    abstract::Congenital intrahepatic arteriovenous fistulae, a rare hepatic vascular anomaly, in an 8-mo-old female beagle dog was investigated. The animal showed anorexia, repeated vomiting, hemorrhagic diarrhea, and jaundice for approximately 2 wk. There was mild to severe increase of serum alkaline phosphatase, glutamic-oxalace...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章

    doi:10.1177/019262339702500511

    authors: Yoshizawa K,Oishi Y,Matsumoto M,Fukuhara Y,Makino N,Noto T,Fujii T

    更新日期:1997-09-01 00:00:00

  • Indoor air pollution from biomass burning activates Akt in airway cells and peripheral blood lymphocytes: a study among premenopausal women in rural India.

    abstract::Biomass burning is a major source of indoor air pollution in rural India. The authors investigated in this study whether cumulative exposures to biomass smoke cause activation of the serine/threonine kinase Akt in airway cells and peripheral blood lymphocytes (PBL). For this, the authors enrolled 87 premenopausal (med...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章

    doi:10.1177/0192623310385139

    authors: Mondal NK,Roy A,Mukherjee B,Das D,Ray MR

    更新日期:2010-12-01 00:00:00

  • Enzymic pattern of preneoplastic and neoplastic lesions induced in the kidney of CBA mice by 1,2-dimethylhydrazine.

    abstract::Mouse renal cell tumors (RCTs) were induced in male CBA mice by 5 subcutaneous injections of 8 mg 1,2-dimethylhydrazine (DMH)/kg body weight once a week. After a lag period of 2 yr kidneys were removed, and serial cryostat sections of the kidneys were histochemically analyzed for the following parameters: glycogen con...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章

    doi:10.1177/019262339402200407

    authors: Ahn YS,Chemeris GY,Turusov VS,Bannasch P

    更新日期:1994-07-01 00:00:00

  • Toxicologic Pathology Forum Opinion Paper*: Recommendations for a Tiered Approach to Nonclinical Mechanistic Nephrotoxicity Evaluation.

    abstract::Nephrotoxicity is one of the more common causes of attrition in nonclinical drug development. Like most tissues, the kidney has a limited number of ways of responding to toxicological insults from diverse mechanistic pathways, which can limit the ability to determine mechanisms of renal injury using the assays routine...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章

    doi:10.1177/0192623318788302

    authors: Ennulat D,Ringenberg M,Frazier KS

    更新日期:2018-08-01 00:00:00

  • Occurrence of Pineal Gland Tumors in Combined Chronic Toxicity/Carcinogenicity Studies in Wistar Rats.

    abstract::Pineal gland tumors are very rare brain lesions in rats as well as in other species including humans. A total of 8 (out of 1,360 examined) Wistar rats from 3 different combined chronic toxicity/carcinogenicity or mere carcinogenicity studies revealed pineal gland tumors. The tumors were regarded to be spontaneous and ...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章

    doi:10.1177/0192623315572700

    authors: Treumann S,Buesen R,Gröters S,Eichler JO,van Ravenzwaay B

    更新日期:2015-08-01 00:00:00

  • Sequential alteration of apoptosis, p53 expression, and cell proliferation in the rat pancreas treated with 4-hydroxyaminoquinoline 1-oxide.

    abstract::Changes in p53 expression, apoptosis and cell proliferation after treatment with 4-hydroxyaminoquinoline 1-oxide (4HAQO) were investigated in the rat pancreas and liver, target and nontarget organs for tumorigenesis, respectively. Male rats were given a single intravenous injection of 4HAQO at a dose of 20 mg/kg body ...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章

    doi:10.1080/01926230390241855

    authors: Imazawa T,Nishikawa A,Toyoda K,Furukawa F,Mitsui M,Hirose M

    更新日期:2003-11-01 00:00:00

  • Hylan G-F 20 induces delayed foreign body inflammation in Guinea pigs and rabbits.

    abstract::Recent clinical evidence suggests that hylan, a modified hyaluronan, and related products potentially elicit foreign body granulomatous inflammation in human soft tissue. We investigated the biocompatibility of hylan G-F 20 (Synvisc) for up to 28 days after intradermal injection in guinea pigs and intramuscular inject...

    journal_title:Toxicologic pathology

    pub_type: 杂志文章

    doi:10.1080/01926230390204360

    authors: Sasaki M,Miyazaki Y,Takahashi T

    更新日期:2003-05-01 00:00:00