Indirect indicator of transport stress in hematological values in newly acquired cynomolgus monkeys

Kim, Choong-Yong; Han, Jin Soo; Suzuki, Teruo; Han, Sangsoo

doi:10.1111/j.1600-0684.2005.00116.x

Cited by 54 publications

(56 citation statements)

References 28 publications

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“…In the vehicle control group, the average plasma concentration of DBILI was approximately 3-fold lower than UBILI and TBILI. Lower baseline level of DBILI has also been reported by others (Kim et al, 2005) and observed in other independent cynomolgus monkey studies (.300 animals) (unpublished observation) and is within a similar range as in mice (van de Steeg et al, 2012) and humans (unpublished observation). A significant elevation of conjugated, unconjugated, and total bilirubin was observed in both the RIF and RIF/RSV treatment groups as compared with RSV alone and vehicle control groups, respectively.…”

Section: Resultssupporting

confidence: 58%

Evaluation of Cynomolgus Monkeys for the Identification of Endogenous Biomarkers for Hepatic Transporter Inhibition and as a Translatable Model to Predict Pharmacokinetic Interactions with Statins in Humans

et al. 2015

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Inhibition of hepatic transporters such as organic anion transporting polypeptides (OATPs) 1B can cause drug-drug interactions (DDIs). Determining the impact of perpetrator drugs on the plasma exposure of endogenous substrates for OATP1B could be valuable to assess the risk for DDIs early in drug development. As OATP1B orthologs are well conserved between human and monkey, we assessed in cynomolgus monkeys the endogenous OATP1B substrates that are potentially suitable to assess DDI risk in humans. The effect of rifampin (RIF), a potent inhibitor for OATP1B, on plasma exposure of endogenous substrates of hepatic transporters was measured. From the 18 biomarkers tested, RIF (18 mg/kg, oral) caused significant elevation of plasma unconjugated and conjugated bilirubin, which may be attributed to inhibition of cOATP1B1 and cOATP1B3 based on in vitro to in vivo extrapolation analysis. To further evaluate whether cynomolgus monkeys are a suitable translational model to study OATP1B-mediated DDIs, we determined the inhibitory effect of RIF on in vitro transport and pharmacokinetics of rosuvastatin (RSV) and atorvastatin (ATV). RIF strongly inhibited the uptake of RSV and ATV by cOATP1B1 and cOATP1B3 in vitro. In agreement with clinical observations, RIF (18 mg/kg, oral) significantly decreased plasma clearance and increased the area under the plasma concentration curve (AUC) of intravenously administered RSV by 2.8-and 2.7-fold, and increased the AUC and maximum plasma concentration of orally administered RSV by 6-and 10.3-fold, respectively. In contrast to clinical findings, RIF did not significantly increase plasma exposure of either intravenous or orally administered ATV, indicating species differences in the rate-limiting elimination pathways.

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Section: Resultssupporting

confidence: 58%

Evaluation of Cynomolgus Monkeys for the Identification of Endogenous Biomarkers for Hepatic Transporter Inhibition and as a Translatable Model to Predict Pharmacokinetic Interactions with Statins in Humans

et al. 2015

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“…** p<0.05; significant difference between the AAPH-treated group and the no-treated group per genotype. the lymphocytes in the thymus cortex or by extending the neutrophil half-life (18,19). Therefore, to study the correlation between the N/L ratio and corticosterone concentration, the concentration of corticosterone was assayed in the serum from CMV/GFP-hSelM Tg and non-Tg rats using an ELISA kit to coat the specific antibody.…”

Section: Effects Of Selm Overexpression On the Activities Of Gpx And mentioning

confidence: 99%

Overexpression of human selenoprotein M differentially regulates the concentrations of antioxidants and H2O2, the activity of antioxidant enzymes, and the composition of white blood cells in a transgenic rat

Hwang¹,

Sin²,

Kim³

et al. 2008

Int J Mol Med

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Abstract. Selenoprotein is associated with a variety of serious diseases, including infectious diseases, neurodegenerative disorders, cancer and cardiovascular disease. The aim of this study was to produce a new transgenic (Tg) rat expressing human selenoprotein M (SelM) in order to examine the protective function of the antioxidant status in vivo. To achieve this, a new lineage of Tg rats was produced by the microinjection of pCMV/GFP-hSelM constructs into a fertilized rat egg. Several conclusions can be drawn based on the results of the present study. The human SelM gene was successfully expressed at both the transcription and protein levels in the CMV/GFP-hSelM Tg rats. This Tg rat showed a different enzyme activity for the antioxidant protein in the various tissues examined. In response to the 2,2'-azobiz(2-amidinopropane) dihydrochloride (AAPH) injection, the Tg rats showed a lower level of antioxidant and H 2 O 2 concentration as the activity of the antioxidant enzyme was maintained at a higher level in the Tg rats than in the non-Tg rats. Also, the neutrophil-to-lymphocyte ratio was significantly increased in this Tg rat, even though the level of corticosterone remained unchanged in both genotypes. Thus, the results of this study demonstrated that the CMV/GFP-hSelM Tg rat can serve as an animal model for the maintenance of a high level of antioxidant status and can be used to study the biological function of selenoprotein in infectious diseases, cardiovascular disease and cancer.

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“…All standard clinical chemistry and CBC parameters were collected for all samples, but for the purposes of this report, only the subset of parameters that were thought to be of clinical/experimental relevance and that seemed likely to be affected by transport, relocation and acclimatization (Bergeron et al, 2002; Kagira et al, 2007; Kim et al, 2005; Landi et al, 1982; McGlone et al, 1993; Schapiro, 2002; van Ruiven et al, 1998) were analyzed. These included, for clinical chemistry, levels of Alanine Aminotransferase (ALT), Alkaline Phosphatase (ALK Phos), Blood Urea Nitrogen (BUN), Cholesterol, Creatinine, Glucose, Lactate Dehydrogenase (LDH), Potassium, Total Protein, and Triglycerides.…”

Section: Materials Methods and Ethical Approvalmentioning

confidence: 99%

“…Koban and colleagues (Koban et al, 2010), Kim and colleagues (Kim et al, 2005), Honess and colleagues (Honess et al, 2004), and Watson and colleagues (Watson et al, 2005), have presented behavioral and/or physiological data on the effects of transport on cynomolgus macaques, rhesus macaques, and Garnett's bushbabies, respectively. The responses of all three species were indicative of negative changes in welfare state as a function of the transportation episode.…”

Section: Introductionmentioning

confidence: 99%

Physiological and welfare consequences of transport, relocation, and acclimatization of chimpanzees (Pan troglodytes)

Schapiro

Lambeth

Jacobsen

et al. 2012

Applied Animal Behaviour Science

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Manipulations of the environments of captive nonhuman primates often have welfare consequences to the animals, including behavioral effects, and for certain manipulations, physiological effects as well. The processes of transporting, relocating, and acclimatizing nonhuman primates across facilities represent manipulations that are likely to have welfare, behavioral, and physiological consequences to the relocated animals. Seventy-two chimpanzees were relocated from the Primate Foundation of Arizona (PFA) in Arizona to the Keeling Center (KCCMR) in Texas. Animals were transported for approximately 21 h in single cages in a USDA-approved, climate-controlled trailer. Chimpanzees were weighed, anesthetized, and blood samples were collected 1) immediately prior to departure from PFA, 2) immediately upon arrival at the KCCMR, and 3) at additional time point(s) between 3 and 12 weeks after arrival at the KCCMR. Chimpanzees were quarantined in familiar pairs or social groups for 60-90 days at the KCCMR. Blood samples were analyzed for hematological and clinical chemistry parameters and compared across time points. In addition, samples from a subset of animals were assayed for cell-mediated immune parameters. Comparisons of the data obtained just prior to transport, to the data obtained immediately upon arrival, revealed numerous statistically significant differences in hematological, clinical chemistry, and immunological parameters. Some of these were indicative of stress, and thus, changes in welfare state, although many remained within the published normal ranges for chimpanzees. Additional analyses showed that many of the clinical chemistry values collected 3 to 12 weeks after arrival at the KCCMR had returned to pre-transport values. In contrast, of the cell-mediated immune parameters that were affected by transport and relocation, few had returned to pre-transport levels 8 weeks after transport, and three of the four hematology variables analyzed had not returned to pre-transport levels 12 weeks after transport. Comparisons of body weights before and immediately after transport revealed that animals lost an average of 2.5 kg during the 21-h transport, a statistically significant reduction that some animals never regained. These results demonstrate that transport and relocation affect a variety of physiological parameters with potential welfare implications and that some of these effects last as long as 3 months. These findings have important implications for the welfare and use of recently transported nonhuman primates, especially chimpanzees, in biomedical research. In order to allow animals to adapt to their new surroundings and to prevent unwanted confounds from influencing experiments, sufficient time must be provided after transport for chimpanzees to acclimatize.

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Indirect indicator of transport stress in hematological values in newly acquired cynomolgus monkeys

Cited by 54 publications

References 28 publications

Evaluation of Cynomolgus Monkeys for the Identification of Endogenous Biomarkers for Hepatic Transporter Inhibition and as a Translatable Model to Predict Pharmacokinetic Interactions with Statins in Humans

Evaluation of Cynomolgus Monkeys for the Identification of Endogenous Biomarkers for Hepatic Transporter Inhibition and as a Translatable Model to Predict Pharmacokinetic Interactions with Statins in Humans

Overexpression of human selenoprotein M differentially regulates the concentrations of antioxidants and H2O2, the activity of antioxidant enzymes, and the composition of white blood cells in a transgenic rat

Physiological and welfare consequences of transport, relocation, and acclimatization of chimpanzees (Pan troglodytes)

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