Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
Toxicology ; 299(2-3): 90-8, 2012 Sep 28.
Article in English | MEDLINE | ID: mdl-22595365

ABSTRACT

RISPERDAL(®) CONSTA(®) is a long-acting, intramuscular formulation of risperidone microspheres for the biweekly treatment of schizophrenia and other psychiatric disorders. In a 24-month carcinogenicity study male and female Wistar Hannover rats received RISPERDAL(®) CONSTA(®) by intramuscular injection at dosages of 5 or 40 mg/kg once every 2 weeks. Bone changes described as "osteodystrophy" were observed by routine microscopic examination at 40 mg/kg in the sternum of female rats after 12 months, and in the sternum and stifle joint of both male and female rats after 24 months of treatment, respectively. To investigate the etiology of these bone changes, a 12-month mechanistic study was conducted in female Wistar Hannover rats at dosages of 5, 20 and 40 mg/kg once every 2 weeks. In addition to routine parameters, this study included bone markers, hormone measurements, and peripheral quantitative computed tomography (pQCT) and dual-energy X-ray absorptiometry (DXA) bone density measurements. It revealed a treatment-related reduction in metaphyseal trabecular bone density of the femur and tibia at 20 and 40 mg/kg, which was evident in the tibia from Week 13 of treatment onwards. There was no convincing evidence for any of the modes of action known to underlie trabecular bone loss in rats including renal, nutritional, or hepatic osteodystrophy, estrogen deficiency, hyperthyroidism or glucocorticoid excess. It is hypothetized that prolonged hyperprolactinemia accompanied by an increase in parathyroid hormone-related protein (PTHrP) levels and a slight hypoestrogenic state could have caused the reduced trabecular bone density in RISPERDAL(®) CONSTA(®)-treated rats. The relevance of this finding in terms of human risk is unknown.


Subject(s)
Antipsychotic Agents/pharmacology , Bone Density/drug effects , Bone Diseases/chemically induced , Risperidone/pharmacology , Absorptiometry, Photon , Alkaline Phosphatase/blood , Animals , Antipsychotic Agents/toxicity , Bone Diseases/blood , Bone Diseases/pathology , Calcitonin/blood , Collagen Type I/blood , Female , Femur/drug effects , Femur/pathology , Follicle Stimulating Hormone/blood , Luteinizing Hormone/blood , Osteocalcin/blood , Parathyroid Hormone/blood , Peptides/blood , Prolactin/blood , Random Allocation , Rats , Rats, Wistar , Risperidone/toxicity , Thyroid Hormones/blood , Tibia/drug effects , Tibia/pathology , Tomography, X-Ray Computed
2.
Toxicol Pathol ; 39(2): 348-60, 2011 Feb.
Article in English | MEDLINE | ID: mdl-21422261

ABSTRACT

After oral gavage dosing of rats, reflux may occur, resulting in serious respiratory effects and mortality. Published information on gavage-related reflux is limited, as it has not yet been a focus of research. Nevertheless, it represents a recurrent challenge in daily toxicology practice of oral gavage dosing. The absence of clear guidance and criteria for the identification and management of reflux-induced effects can limit the ability to properly interpret toxicity study results. The review presented herein includes an overview of experimental data from gavage studies in rats, in which reflux was observed, and provides a comprehensive analysis of the literature on reflux in general and the different potential pathways contributing to gavage-related reflux in rats. The article aims to increase the awareness and understanding of the pathogenesis of gavage-related reflux and provides guidance on identification of potential risk factors, as well as interpretation of histological changes and their toxicological relevance. Furthermore, differentiation of reflux-induced effects from direct compound-related toxicity and from gavage errors is addressed in particular, and the importance of nasal histology is discussed.


Subject(s)
Enteral Nutrition/adverse effects , Gastroesophageal Reflux/pathology , Nasal Cavity/pathology , Administration, Oral , Animals , Dyspnea , Gastric Acid/metabolism , Gastric Emptying , Gastroesophageal Reflux/metabolism , Rats , Risk Factors
SELECTION OF CITATIONS
SEARCH DETAIL
...