Eisai Hyperbilirubinemic Rat (EHBR) as an Animal Model Affording High Drug-Exposure in Toxicity Studies on Organic Anions

2004 ◽  
Vol 19 (5) ◽  
pp. 339-351 ◽  
Author(s):  
Hiroyasu Naba ◽  
Chitose Kuwayama ◽  
Chihaya Kakinuma ◽  
Shuhei Ohnishi ◽  
Takuo Ogihara
Keyword(s):  
Animal Model ◽  
Drug Exposure ◽  
Organic Anions ◽  
High Drug ◽  
Toxicity Studies ◽  
Eisai Hyperbilirubinemic Rat

scholarly journals Paradoxical Effect of Polymyxin B: High Drug Exposure Amplifies Resistance in Acinetobacter baumannii

2016 ◽  
Vol 60 (7) ◽  
pp. 3913-3920 ◽  
Author(s):  
Brian T. Tsuji ◽  
Cornelia B. Landersdorfer ◽  
Justin R. Lenhard ◽  
Soon-Ee Cheah ◽  
Visanu Thamlikitkul ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Drug Exposure ◽  
Dose Intensity ◽  
Polymyxin B ◽  
Loading Dose ◽  
Paradoxical Effect ◽  
Bacterial Killing ◽  
Unbound Fraction ◽  
Content Type ◽  
High Drug

ABSTRACTAdministering polymyxin antibiotics in a traditional fashion may be ineffective against Gram-negative ESKAPE (Enterococcus faecium,Staphylococcus aureus,Klebsiella pneumoniae,Acinetobacter baumannii,Pseudomonas aeruginosa, andEnterobacterspecies) pathogens. Here, we explored increasing the dose intensity of polymyxin B against two strains ofAcinetobacter baumanniiin the hollow-fiber infection model. The following dosage regimens were simulated for polymyxin B (t1/2= 8 h): non-loading dose (1.43 mg/kg of body weight every 12 h [q12h]), loading dose (2.22 mg/kg q12h for 1 dose and then 1.43 mg/kg q12h), front-loading dose (3.33 mg/kg q12h for 1 dose followed by 1.43 mg/kg q12h), burst (5.53 mg/kg for 1 dose), and supraburst (18.4 mg/kg for 1 dose). Against bothA. baumanniiisolates, a rapid initial decline in the total population was observed within the first 6 h of polymyxin exposure, whereby greater polymyxin B exposure resulted in greater maximal killing of −1.25, −1.43, −2.84, −2.84, and −3.40 log10CFU/ml within the first 6 h. Unexpectedly, we observed a paradoxical effect whereby higher polymyxin B exposures dramatically increased resistant subpopulations that grew on agar containing up to 10 mg/liter of polymyxin B over 336 h. High drug exposure also proliferated polymyxin-dependent growth. A cost-benefit pharmacokinetic/pharmacodynamic relationship between 24-h killing and 336-h resistance was explored. The intersecting point, where the benefit of bacterial killing was equal to the cost of resistance, was anfAUC0–24(area under the concentration-time curve from 0 to 24 h for the free, unbound fraction of drug) of 38.5 mg · h/liter for polymyxin B. Increasing the dose intensity of polymyxin B resulted in amplification of resistance, highlighting the need to utilize polymyxins as part of a combination against high-bacterial-densityA. baumanniiinfections.

Comparison of the Disposition Behavior of Organic anions in an Animal Model for Wilson's Disease (Long-Evans Cinnamon rats) with that in Normal Long-Evans Agouti rats

2004 ◽  
Vol 19 (2) ◽  
pp. 150-154 ◽  
Author(s):  
Shirou Itagaki ◽  
Mitsuru Sugawara ◽  
Michiya Kobayashi ◽  
Katsumi Miyazaki ◽  
Takeshi Hirano ◽  
...  
Keyword(s):  
Animal Model ◽  
Wilson’S Disease ◽  
Wilson's Disease ◽  
Organic Anions ◽  
Long Evans

Assessing drug exposure in rodent toxicity studies without satellite animals

1993 ◽  
Vol 21 (3) ◽  
pp. 323-334 ◽  
Author(s):  
Jerry R. Nedelman ◽  
Ekaterina Gibiansky ◽  
Francis L. S. Tse ◽  
Christine Babiuk
Keyword(s):  
Drug Exposure ◽  
Toxicity Studies

scholarly journals Characterization of Amikacin Drug Exposure and Nephrotoxicity in an Animal Model

2020 ◽  
Vol 64 (9) ◽  
Author(s):  
Katrina Chan ◽  
Kimberly R. Ledesma ◽  
Weiqun Wang ◽  
Vincent H. Tam
Keyword(s):  
Animal Model ◽  
Bacterial Infections ◽  
Drug Exposure ◽  
Area Under The Curve ◽  
Quantitative Relationship ◽  
Multidrug Resistant ◽  
Sprague Dawley ◽  
Blood Samples ◽  
Significant Difference

ABSTRACT Despite excellent in vitro activity, aminoglycosides are used conservatively to treat multidrug-resistant bacterial infections due to their associated nephrotoxicity. Aminoglycosides are known to accumulate in the kidneys, but the quantitative relationship between drug exposures and nephrotoxicity is not well established. To bridge the knowledge gap, the objective of this study was to develop an animal model with clinically relevant conditions to mimic human disease progression. Single-dose pharmacokinetics were studied in Sprague-Dawley rats dosed either with 100 or 500 mg/kg of body weight of amikacin subcutaneously. Serial blood samples were collected, and serum amikacin concentrations were measured using liquid chromatography tandem mass spectrometry. Rats were also dosed with amikacin once daily for up to 10 days; blood samples were taken at baseline and daily to detect nephrotoxicity (defined as doubling of serum creatinine from baseline). Kidneys from both studies were harvested from selected rats, and amikacin concentrations in renal tissues were measured. A dose-dependent increase in systemic area under the curve (AUC) was observed, which ranged from approximately 1/3 (AUC of 53 mg·h/liter) to 3 times (AUC of 650 mg·h/liter) the expected exposure resulting from standard dosing in humans. Nephrotoxicity was significantly higher in rats given 500 mg/kg (100% versus 30%, P = 0.003). Kaplan-Meier analysis also showed a significant difference in nephrotoxicity onset between the two groups (P = 0.001). Finally, analysis of the renal tissues showed that the accumulation of amikacin could be associated with nephrotoxicity. These results are consistent with clinical observations, which support using this model in the future to investigate an intervention(s) that can be used clinically to alleviate nephrotoxicity.

Ultrastructural investigation of spontaneous pituitary gonadotroph cell adenomas in aging Sprague-Dawley rats

1983 ◽  
Vol 41 ◽  
pp. 702-703
Author(s):  
D. J. McComb ◽  
J. Beri ◽  
F. Zak ◽  
K. Kovacs
Keyword(s):  
Electron Microscopy ◽  
Animal Model ◽  
Epoxy Resin ◽  
Immunoelectron Microscopy ◽  
Tumor Type ◽  
Gonadal Function ◽  
Sprague Dawley ◽  
Male And Female ◽  
Reticulin Fibers ◽  
Sprague Dawley Rats

Gonadotroph cell adenomas of the pituitary are infrequent in human patients and are not invariably associated with altered gonadal function. To date, no animal model of this tumor type exists. Herein, we describe spontaneous gonadotroph cell adenomas in old male and female Sprague-Dawley rats by histology, immunocytology and electron microscopy.The material consisted of the pituitaries of 27 male and 38 female Sprague Dawley rats, all 26 months of age or older, removed at routine autopsy. Sections of formal in-fixed, paraffin-embedded tissue were stained with hematoxylin-phloxine-saffron (HPS), the PAS method and the Gordon-Sweet technique for the demonstration of reticulin fibers. For immunostaining, sections were exposed to anti-rat β-LH, anti-ratβ-TSH, anti-rat PRL, anti-rat GH and anti-rat ACTH 1-39. For electron microscopy, tissue was fixed in 2.5% glutaraldehyde, postfixed in 1% OsO4 and embedded in epoxy-resin. Tissue fixed in 10% formalin, embedded in epoxy resin without osmification, was used for immunoelectron microscopy.

Electron Microscopic Detection and Characterization of Nonhuman Primate Enteric Viruses

1982 ◽  
Vol 40 ◽  
pp. 306-307
Author(s):  
G. C. Smith ◽  
R. L. Heberling ◽  
S. S. Kalter
Keyword(s):  
Electron Microscopy ◽  
Animal Model ◽  
Nonhuman Primate ◽  
Clinical Condition ◽  
Intestinal Tract ◽  
Enteric Viruses ◽  
Electron Microscopic ◽  
Microscopic Detection

A number of viral agents are recognized as and suspected of causing the clinical condition “gastroenteritis.” In our attempts to establish an animal model for studies of this entity, we have been examining the nonhuman primate to ascertain what viruses may be found in the intestinal tract of “normal” animals as well as animals with diarrhea. Several virus types including coronavirus, adenovirus, herpesvirus, and picornavirus (Table I) were detected in our colony; however, rotavirus, astrovirus, and calicivirus have not yet been observed. Fecal specimens were prepared for electron microscopy by procedures reported previously.

Neurofilaments and Paired Helical Filaments

1985 ◽  
Vol 43 ◽  
pp. 740-743
Author(s):  
J. Metuzals
Keyword(s):  
Animal Model ◽  
Posttranslational Modifications ◽  
Posttranslational Modification ◽  
Giant Axon ◽  
Paired Helical Filaments ◽  
Squid Giant Axon ◽  
In Vitro Experiments ◽  
Thin Sections ◽  
Structural Relationships

It has been demonstrated that the neurofibrillary tangles in biopsies of Alzheimer patients, composed of typical paired helical filaments (PHF), consist also of typical neurofilaments (NF) and 15nm wide filaments. Close structural relationships, and even continuity between NF and PHF, have been observed. In this paper, such relationships are investigated from the standpoint that the PHF are formed through posttranslational modifications of NF. To investigate the validity of the posttranslational modification hypothesis of PHF formation, we have identified in thin sections from frontal lobe biopsies of Alzheimer patients all existing conformations of NF and PHF and ordered these conformations in a hypothetical sequence. However, only experiments with animal model preparations will prove or disprove the validity of the interpretations of static structural observations made on patients. For this purpose, the results of in vitro experiments with the squid giant axon preparations are compared with those obtained from human patients. This approach is essential in discovering etiological factors of Alzheimer's disease and its early diagnosis.

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