| Title | Authors | Application Area | Therapeutic Area | Journal | Year | Link | Page | Volume | Issue | PubMed ID | Abstract | Impact Factor | Snippet | Date | DOI |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Automated blood sampling in canine telemetry studies: Enabling enhanced assessments of cardiovascular liabilities and safety margins | Yevgeniya E.Koshman, Amanda S.Wilsey, Brandan M.Bird, Sabine Sadilek, Debra A.Weisbecker, Paige A.Ebert, James S. Polakowski, Gary A.Gintant, Scott W. Mittelstadt, C. Michael Foley | Safety Pharmacology | Cardiovascular Disease | Journal of Pharmacological and Toxicological Methods | 2021 | https://www.sciencedirect.com/science/article/abs/pii/S1056871921001180 | Article 107066 | 109 | May-June 2021 | 33838254 | A successful integration of automated blood sampling (ABS) into the telemetry instrumented canine cardiovascular model is presented in this study. This combined model provides an efficient means to quickly gain understanding of potential effects on key cardiovascular parameters in dog while providing a complete Pharmacokinetic/Pharmacodynamic (PK/PD) profile for discovery compounds without handling artifacts, reducing the need for a separate pharmacokinetic study. | May 2021 | 10.1016/j.vascn.2021.107066 | ||
| Automated Blood Sampling in a Canine Telemetry Cardiovascular Model | Amanda S Wilsey 1, Yevgeniya E Koshman 2, Debra A Weisbecker 3, Brandan M Bird 2, Kuldip K Mirakhur 3, Sabine Sadilek 2, Paige A Ebert 3, James S Polakowski 2, C Michael Foley 2, Chris L Medina 3, Scott W Mittelstadt 2 | Safety Pharmacology | Cardiovascular Disease | Comparative Medicine | 2021 | https://pubmed.ncbi.nlm.nih.gov/33814031/ | 1-8 | 71 | 2 | 33814031 | Successful implementation of automated blood sampling (ABS) into a telemetry instrumented canine cardiovascular model provides simultaneous cardiovascular assessment of novel compounds while collecting multiple blood samples for analysis of drug level, cytokines, and biomarkers. Purpose-bred male Beagle dogs (n = 36) were instrumented with a dual-pressure telemetry transmitter and vascular access port. Modifications to acclimation practices, surgical procedures, and housing were required for implementation of ABS in our established cardiovascular canine telemetry colony. These modifications have increased the use and reproducibility of the model by combining early pharmacokinetic and cardiovascular studies, thus achieving both refinement and reduction from a 3R perspective. In addition, the modified model can shorten timelines and reduce the compound requirement in early stages of drug development. This telemetry-ABS model provides an efficient means to quickly identify potential effects on key cardiovascular parameters in a large animal species and to obtain a more complete pharmacokinetic-pharmacodynamic profile for discovery compounds. | April 2021 | 10.30802/AALAS-CM-20-000083 | ||
| Semi-mechanistic pharmacokinetic/pharmacodynamic modelling of the antinociceptive response in the presence of competitive antagonism: the interaction between tramadol and its active metabolite on micro-opioid agonism and monoamine reuptake inhibition, in the rat | Horst Beier, María J Garrido, Thomas Christoph, Dirk Kasel, Iñaki F Trocóniz | Pharmacokinetics (PK) | Addiction | Pharmaceutical Research | 2008 | https://link.springer.com/article/10.1007%2Fs11095-007-9489-8 | 1789–1797 | 25 | 8 | 18008149 | Purpose: To establish a semi-mechanistic pharmacokinetic/pharmacodynamic (pk/pd) model for racemic tramadol (T) integrating all the components with a significant contribution to T effects in rats, using cold allodynia in the Bennett model of neuropathic pain. | 2007 Nov 16 | 10.1007/s11095-007-9489-8 | ||
| A benzothiophene inhibitor of mitogen-activated protein kinase-activated protein kinase 2 inhibits tumor necrosis factor alpha production and has oral anti-inflammatory efficacy in acute and chronic models of inflammation | Mourey, RJ;Burnette, BL;Brustkern, SJ;Daniels, JS;Hirsch, JL;Hood, WF;Meyers, MJ;Mnich, SJ;Pierce, BS;Saabye, MJ;Schindler, JF;South, SA;Webb, EG;Zhang, J;Anderson, DR; | Pharmacokinetics (PK) | Inflammatory Disease | J. Pharmacol. Exp. Ther. | 2010 | http://jpet.aspetjournals.org/content/333/3/797.short | 797-807 | 333 | 3 | 20237073 | Activation of the p38 kinase pathway in immune cells leads to the transcriptional and translational regulation of proinflammatory cytokines. Mitogen-activated protein kinase-activated protein kinase 2 (MK2), a direct downstream substrate of p38 kinase, regulates lipopolysaccharide (LPS)-stimulated tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) production through modulating the stability and translation of these mRNAs. Developing small-molecule inhibitors of MK2 may yield anti-inflammatory efficacy with a different safety profile relative to p38 kinase inhibitors. This article describes the pharmacologic properties of a benzothiophene MK2 inhibitor, PF-3644022 [(10R)-10-methyl-3-(6-methylpyridin-3-yl)-9,10,11,12-tetrahydro-8H-[1,4]diazepino[5',6':4,5]thieno[3,2-f]quinolin-8-one]. PF-3644022 is a potent freely reversible ATP-competitive compound that inhibits MK2 activity (K(i) = 3 nM) with good selectivity when profiled against 200 human kinases. In the human U937 monocytic cell line or peripheral blood mononuclear cells, PF-3644022 potently inhibits TNFalpha production with similar activity (IC(50) = 160 nM). PF-3644022 blocks TNFalpha and IL-6 production in LPS-stimulated human whole blood with IC(50) values of 1.6 and 10.3 microM, respectively. Inhibition of TNFalpha in U937 cells and blood correlates closely with inhibition of phospho-heat shock protein 27, a target biomarker of MK2 activity. PF-3644022 displays good pharmacokinetic parameters in rats and is orally efficacious in both the rat acute LPS-induced TNFalpha model and the chronic streptococcal cell wall-induced arthritis model. Dose-dependent inhibition of TNFalpha production in the acute model and inhibition of paw swelling in the chronic model is observed with ED(50) values of 6.9 and 20 mg/kg, respectively. PF-3644022 efficacy in the chronic inflammation model is strongly correlated with maintaining a C(min) higher than the EC(50) measured in the rat LPS-induced TNFalpha model. | 3.615 | Male Sprague-Dawley rats weighing 275 to 300 g were purchased from Charles River Laboratories Inc. (Wilmington, MA) and acclimated to their surroundings for approximately 1 week with food and water provided ad libitum. A minimum of 1 day before study, animals were anesthetized with isoflurane (to effect) and then implanted with Culex (BASi, West Lafayette, IN) vascular catheters in the carotid artery. Animals were acclimated in Culex cages overnight before dosing. Patency of the carotid artery catheter was maintained by using the “tend” function of Culex ABS. PF-3644022 was administered dissolved in 70% normal saline/20% polyethylene glycol-400/10% ethanol (intravenously) or suspended in 0.5% hydroxypropylmethylcellulose/0.1% Tween 80 in distilled water (by mouth). Blood collections were obtained from the carotid artery and performed by the Culex at 2 (intravenous only), 5, 15, 30 min and 1, 2, 4, 6, 8 | 2010-06-01 00:00:00 | 10.1124/jpet.110.166173 |
| A nonspecific phosphotyrosine phosphatase inhibitor, bis(maltolato)oxovanadium(IV), improves glucose tolerance and prevents diabetes in Zucker diabetic fatty rats | Winter, CL;Lange, JS;Davis, MG;Gerwe, GS;Downs, TR;Peters, KG;Kasibhatla, B; | Glucose Tolerance Test | Diabetes | Exp. Biol. Med. (Maywood) | 2005 | https://journals.sagepub.com/doi/abs/10.1177/153537020523000307 | 207-216 | 230 | 3 | 15734724 | The molecular basis of insulin resistance, a major risk factor for development of Type II diabetes, involves defective insulin signaling. Insulin-mediated signal transduction is negatively regulated by the phosphotyrosine phosphatase, PTP1B, and numerous studies have demonstrated that organo-vanadium compounds, which are nonselective phosphotyrosine phosphatase inhibitors, have insulin-mimetic properties. However, whether or not vanadium compounds can prevent the transition from insulin resistance to overt diabetes is unknown. We compared the ability of bis(maltolato)oxovanadium(IV) (BMOV), an orally bioavailable organo-vanadium compound, and rosiglitazone maleate (RSG), a known insulin sensitizer, to prevent development of diabetes in Zucker diabetic fatty (ZDF) rats. Treatment began at 6 weeks of age when animals are insulin resistant and hyperinsulinemic, but not yet hyperglycemic, and ended at 12 weeks of age, which is 4 weeks after ZDF rats typically develop overt diabetes. BMOV-treated ZDF rats did not develop hyperglycemia, showed significant improvement in insulin sensitivity, and retained normal pancreatic islet morphology and endocrine cell distribution, similar to RSG-treated animals. BMOV and RSG treatment also prevented the hyper-phagia and polydipsia present in untreated ZDF rats; however, BMOV-treated ZDF rats gained much less weight than did RSG-treated animals. Circulating levels of adiponectin decreased in untreated ZDF rats compared to lean controls, but these levels remained normal in BMOV-treated ZDF rats. In contrast, in RSG-treated ZDF rats, plasma adiponectin levels were nearly 4-fold higher than in lean control rats, primarily as a result of a large increase in the amount of low-molecular weight forms of adiponectin in circulation. These data demonstrate that phosphatase inhibition offers a new approach to diabetes prevention, one that may have advantages over current approaches. | At the end of the 6-week treatment period, a jugular vein catheter was surgically implanted, and the rats were allowed to recover for 24 hrs. Following a 16-hr fast, an oral glucose tolerance test was performed. Glucose was administered via oral gavage at a dose of 2 g/kg of body weight. Blood was sampled at 0, 30, 60,90, and 120 min using a Culex automated blood sampler from Bioanalytical Systems (West Lafayette, IN). The blOod was collected in sodium heparin tubes, centrifuged, and the plasma was analyzed for glucose levels using a Yellow Springs, Inc. (YSI) 2700 (Yellow Springs, OH) blOod glucose analyzer. The remaining plasma was frozen at -80°C for insulin analysis | 2005-03-01 00:00:00 | 10.1177/153537020523000307 | |
| A novel autotaxin inhibitor reduces lysophosphatidic acid levels in plasma and the site of inflammation | Gierse, J;Thorarensen, A;Beltey, K;Bradshaw-Pierce, E;Cortes-Burgos, L;Hall, T;Johnston, A;Murphy, M;Nemirovskiy, O;Ogawa, S;Pegg, L;Pelc, M;Prinsen, M;Schnute, M;Wendling, J;Wene, S;Weinberg, R;Wittwer, A;Zweifel, B;Masferrer, J; | PK/PD | Inflammatory Disease | J. Pharmacol. Exp. Ther. | 2010 | http://jpet.aspetjournals.org/content/334/1/310.short | 310-317 | 334 | 1 | 20392816 | Autotaxin is the enzyme responsible for the production of lysophosphatidic acid (LPA) from lysophosphatidyl choline (LPC), and it is up-regulated in many inflammatory conditions, including but not limited to cancer, arthritis, and multiple sclerosis. LPA signaling causes angiogenesis, mitosis, cell proliferation, and cytokine secretion. Inhibition of autotaxin may have anti-inflammatory properties in a variety of diseases; however, this hypothesis has not been tested pharmacologically because of the lack of potent inhibitors. Here, we report the development of a potent autotaxin inhibitor, PF-8380 [6-(3-(piperazin-1-yl)propanoyl)benzo[d]oxazol-2(3H)-one] with an IC(50) of 2.8 nM in isolated enzyme assay and 101 nM in human whole blood. PF-8380 has adequate oral bioavailability and exposures required for in vivo testing of autotaxin inhibition. Autotaxin's role in producing LPA in plasma and at the site of inflammation was tested in a rat air pouch model. The specific inhibitor PF-8380, dosed orally at 30 mg/kg, provided >95% reduction in both plasma and air pouch LPA within 3 h, indicating autotaxin is a major source of LPA during inflammation. At 30 mg/kg PF-8380 reduced inflammatory hyperalgesia with the same efficacy as 30 mg/kg naproxen. Inhibition of plasma autotaxin activity correlated with inhibition of autotaxin at the site of inflammation and in ex vivo whole blood. Furthermore, a close pharmacokinetic/pharmacodynamic relationship was observed, which suggests that LPA is rapidly formed and degraded in vivo. PF-8380 can serve as a tool compound for elucidating LPA's role in inflammation. | 3.615 | Male Lewis rats weighing 275 to 300 g were purchased from Charles River Laboratories, Inc. (Wilmington, MA) and acclimated to their surroundings for approximately 1 week with food and water provided ad libitum. A minimum of 1 day before study, animals were anesthetized with isoflurane (to effect) and implanted with Culex (BASi, West Lafayette, IN) vascular catheters in the carotid artery. Animals were acclimated in Culex cages overnight before dosing. Patency of the carotid artery catheter was maintained by using the “tend” function of the Culex automated blood sampler. Animals were dosed with PF-8380 at 1, 3, 10, 30, and 100 mg/kg by oral gavage after an overnight fast. Blood collections were obtained from the carotid artery and performed by the Culex automated blood sampler at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 h after administration. Blood was centrifuged, and plasma was collected for analysis of PF-8380 and LPA concentrations | 2010-07-01 00:00:00 | 10.1124/jpet.110.165845 |
| AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-beta peptide metabolism | Vingtdeux, V;Giliberto, L;Zhao, H;Chandakkar, P;Wu, Q;Simon, JE;Janle, EM;Lobo, J;Ferruzzi, MG;Davies, P;Marambaud, P; | PK/PD | Alzheimers | J. Biol. Chem. | 2010 | http://www.jbc.org/content/285/12/9100.short | 9100-9113 | 285 | 12 | 20080969 | Alzheimer disease is an age-related neurodegenerative disorder characterized by amyloid-beta (Abeta) peptide deposition into cerebral amyloid plaques. The natural polyphenol resveratrol promotes anti-aging pathways via the activation of several metabolic sensors, including the AMP-activated protein kinase (AMPK). Resveratrol also lowers Abeta levels in cell lines; however, the underlying mechanism responsible for this effect is largely unknown. Moreover, the bioavailability of resveratrol in the brain remains uncertain. Here we show that AMPK signaling controls Abeta metabolism and mediates the anti-amyloidogenic effect of resveratrol in non-neuronal and neuronal cells, including in mouse primary neurons. Resveratrol increased cytosolic calcium levels and promoted AMPK activation by the calcium/calmodulin-dependent protein kinase kinase-beta. Direct pharmacological and genetic activation of AMPK lowered extracellular Abeta accumulation, whereas AMPK inhibition reduced the effect of resveratrol on Abeta levels. Furthermore, resveratrol inhibited the AMPK target mTOR (mammalian target of rapamycin) to trigger autophagy and lysosomal degradation of Abeta. Finally, orally administered resveratrol in mice was detected in the brain where it activated AMPK and reduced cerebral Abeta levels and deposition in the cortex. These data suggest that resveratrol and pharmacological activation of AMPK have therapeutic potential against Alzheimer disease. | 4.125 | Resveratrol Pharmacokinetics and Brain Accumulation in Rodents— All animal procedures were approved by the Purdue Animal Care and Use Committee. Sprague-Dawley rats were dosed orally by gavage with resveratrol in a dose escalation schedule and after an oral 400- mg/kg dose. Blood sampling was obtained in the CulexTM automated system (Bioanalytical Systems, West Lafayette, IN). Rats were then fasted for 8 h, dosed orally with 400 mg/kg resveratrol, and sacrificed 1 h postdose | 2010-03-19 00:00:00 | |
| An acute rat in vivo screening model to predict compounds that alter blood glucose and/or insulin regulation | Brott, DA;Diamond, M;Campbell, P;Zuvich, A;Cheatham, L;Bentley, P;Gorko, MA;Fikes, J;Saye, J; | Glucose Tolerance Test | Diabetes | J Pharmacol Toxicol Methods | 2013 | https://www.sciencedirect.com/science/article/pii/S105687191300275X | 190-196 | 68 | 2 | Drug-induced glucose dysregulation and insulin resistance have been associated with weight gain and potential induction and/or exacerbation of diabetes mellitus in the clinic suggesting they may be safety biomarkers when developing antipsychotics. Glucose and insulin have also been suggested as potential efficacy biomarkers for some oncology compounds. The objective of this study was to qualify a medium throughput rat _in vivo_ acute Intravenous Glucose Tolerance Test (IVGTT) for predicting compounds that will induce altered blood glucose and/or insulin levels. | 2.679 | Cannulas were externalized at the nape of the neck, and the animals allowed at least 4 days of recovery, prior to the IVGTT. The day prior to the experiment, rats were jacketed, tethered and housed individually in the Culex® (BASi, West Lafayette, IN) system ;and 2) clozapine increased the basal glucose level in the male mouse (Dwyer & compound risk for inducing clinical weight gain, 3) determine if different rat strains/substrains experiment, rats were jacketed, tethered and housed individually in the Culex® (BASi, West Lafayette | 2013-07-05 00:00:00 | 10.1016/j.vascn.2013.06.003 | |
| An automated blood sampler for simultaneous sampling of systemic blood and brain microdialysates for drug absorption, distribution, metabolism, and elimination studies | Gunaratna, PC;Kissinger, PT;Kissinger, CB;Gitzen, JF; | ADME | Method Development | J Pharmacol Toxicol Methods | 2004 | https://www.sciencedirect.com/science/article/pii/S1056871903000583 | 57-64 | 49 | 1 | 14670694 | A major problem in preclinical drug development where blood sampling from small animals is a routine practice is the time and labor involved in the serial sampling of small blood volumes from small animals such as rats for the duration of pharmacokinetic/pharmacodynamic (PK/PD) studies. The traditional method of manually drawing blood from the animal requires the animal to be anesthetized or restrained with some device, both of which cause stress to the animal. An automated blood sampler (ABS) was developed to simultaneously collect blood and brain microdialysate samples at preprogrammed time points from awake and freely moving animals. The samples are delivered to fraction collectors and stored at 4 degrees C until use. The lost blood volume during collection is replaced with sterile saline to prevent fluid loss from the animal. In addition, the system is capable of collecting urine and feces for metabolism studies and monitoring the animal activity for behavioral studies. In the present study, blood samples were collected for 24 h after dosing rats orally with a 5 mg/kg dose of olanzapine (OLAN). Brain dialysates were collected for the same duration from a microdialysis probe implanted in the striatum. The pharmacokinetic parameters, obtained after an oral dose, are in good agreement with reported values in literature. The pharmacodynamic information obtained from brain dialysates data show that OLAN elevates the concentration of dopamine (DA) in the brain and remains in the brain even after it is cleared from the plasma. The ABS described here is a very useful tool in drug development to accelerate the pace of preclinical in vivo studies and to simultaneously provide pharmacodynamic and physiological information. | 2.679 | and a BAS Sample Sentinel autosampler with a 20-μl injection loop (Bioanalytical Systems, West Lafayette During the 24-h postsurgery recovery period in the Culex ABS, the catheter patency was temperature on a microbore ODS column (150×1.0 mm, 3 μm) (BAS Unijet) using | 2004-12-13 00:00:00 | 10.1016/S1056-8719(03)00058-3 |
| An initial investigation into the effects of isolation and enrichment on the welfare of laboratory pigs housed in the PigTurn® system, assessed using tear staining, behaviour, physiology and haematology | DeBoer, S;Garner, J;McCain, R;Lay Jr, D;Eicher, S;Marchant-Forde, J; | Stress Hormones | Method Development | anim welf | 2015 | http://dx.doi.org/10.7120/09627286.24.1.015 | 15-27 | 24 | 1 | 1.522 | 2-m catheter extension fixed to the automatic sampling system (Culex-L, BASi, West Lafayette 1 ml of heparinised (10 units ml-1) saline into the pig to maintain Automated blood collection was controlled by an automated sampling system (Culex, BioAnalytical Systems Inc, West | 2015-02-15 00:00:00 | 10.7120/09627286.24.1.015 |
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