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Author |
Cheung, C.; Akiyama, T.E.; Ward, J.M.; Nicol, C.J.; Feigenbaum, L.; Vinson, C.; Gonzalez, F.J. |
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Title |
Diminished hepatocellular proliferation in mice humanized for the nuclear receptor peroxisome proliferator-activated receptor alpha |
Type |
Journal Article |
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Year |
2004 |
Publication |
Cancer research |
Abbreviated Journal |
Cancer Res |
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Volume |
64 |
Issue |
11 |
Pages |
3849-3854 |
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Keywords |
Animals; Anticholesteremic Agents/pharmacology; Carcinogens/pharmacology; Cell Division; DNA Replication/drug effects; Fatty Acids/metabolism; Hepatocytes/cytology/drug effects/metabolism/*physiology; Humans; Mice; Mice, Transgenic; Oxidation-Reduction; Peroxisome Proliferators/pharmacology; Pyrimidines/pharmacology; Receptors, Cytoplasmic and Nuclear/genetics/*physiology; Species Specificity; Transcription Factors/genetics/*physiology |
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Abstract |
Lipid-lowering fibrate drugs function as agonists for the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha). Sustained activation of PPARalpha leads to the development of liver tumors in rats and mice. However, humans appear to be resistant to the induction of peroxisome proliferation and the development of liver cancer by fibrate drugs. The molecular basis of this species difference is not known. To examine the mechanism determining species differences in peroxisome proliferator response between mice and humans, a PPARalpha-humanized mouse line was generated in which the human PPARalpha was expressed in liver under control of the tetracycline responsive regulatory system. The PPARalpha-humanized and wild-type mice responded to treatment with the potent PPARalpha ligand Wy-14643 as revealed by induction of genes encoding peroxisomal and mitochondrial fatty acid metabolizing enzymes and resultant decrease of serum triglycerides. However, surprisingly, only the wild-type mice and not the PPARalpha-humanized mice exhibited hepatocellular proliferation as revealed by elevation of cell cycle control genes, increased incorporation of 5-bromo-2'-deoxyuridine into hepatocyte nuclei, and hepatomegaly. These studies establish that following ligand activation, the PPARalpha-mediated pathways controlling lipid metabolism are independent from those controlling the cell proliferation pathways. These findings also suggest that structural differences between human and mouse PPARalpha are responsible for the differential susceptibility to the development of hepatocarcinomas observed after treatment with fibrates. The PPARalpha-humanized mice should serve as models for use in drug development and human risk assessment and to determine the mechanism of hepatocarcinogenesis of peroxisome proliferators. |
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Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA |
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0008-5472 |
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PMID:15172993 |
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no |
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Call Number |
refbase @ user @ |
Serial |
74 |
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Author |
Guo, G.L.; Moffit, J.S.; Nicol, C.J.; Ward, J.M.; Aleksunes, L.A.; Slitt, A.L.; Kliewer, S.A.; Manautou, J.E.; Gonzalez, F.J. |
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Title |
Enhanced acetaminophen toxicity by activation of the pregnane X receptor |
Type |
Journal Article |
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Year |
2004 |
Publication |
Toxicological sciences : an official journal of the Society of Toxicology |
Abbreviated Journal |
Toxicol Sci |
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Volume |
82 |
Issue |
2 |
Pages |
374-380 |
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Keywords |
Acetaminophen/pharmacokinetics/*toxicity; Analgesics, Non-Narcotic/pharmacokinetics/*toxicity; Animals; Aryl Hydrocarbon Hydroxylases/biosynthesis; Biotransformation; Blotting, Northern; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP3A; Membrane Proteins; Mice; Mice, Knockout; Oxidoreductases, N-Demethylating/biosynthesis; Pregnenolone Carbonitrile/pharmacology; Receptors, Cytoplasmic and Nuclear/*drug effects; Receptors, Steroid/*drug effects; Sulfhydryl Compounds/metabolism |
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Abstract |
The pregnane X receptor (PXR) is a ligand-activated transcription factor and member of the nuclear receptor superfamily. Activation of PXR represents an important mechanism for the induction of cytochrome P450 3A (CYP3A) enzymes that can convert acetaminophen (APAP) to its toxic intermediate metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Therefore, it was hypothesized that activation of PXR plays a major role in APAP-induced hepatotoxicity. Pretreatment with the PXR activator, pregnenolone 16alpha-carbonitrile (PCN), markedly enhanced APAP-induced hepatic injury, as revealed by increased serum ALT levels and hepatic centrilobular necrosis, in wild-type but not in PXR-null mice. Further analysis showed that following PCN treatment, PXR-null mice had lower CYP3A11 expression, decreased NAPQI formation, and increased maintenance of hepatic glutathione content compared to wild-type mice. Thus, these results suggest that PXR plays a critical role in APAP-induced hepatic toxicity, probably by inducing CYP3A11 expression and hence increasing bioactivation. |
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Laboratory of Metabolism, CCR, NCI, NIH, Bethesda, Maryland 20892, USA |
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ISSN |
1096-6080 |
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PMID:15456926 |
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Call Number |
refbase @ user @ |
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71 |
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Hodgson, D.; Howe, S.; Jeffcott, L.; Reid, S.; Mellor, D.; Higgins, A. |
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Title |
Effect of prolonged use of altrenogest on behaviour in mares |
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Year |
2005 |
Publication |
Veterinary journal (London, England : 1997) |
Abbreviated Journal |
Vet J |
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Volume |
169 |
Issue |
1 |
Pages |
113-115 |
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Administration, Oral; Anabolic Agents/adverse effects/*pharmacology; Animals; Behavior, Animal/*drug effects; Body Constitution/drug effects; Body Weight/drug effects; *Doping in Sports; Female; Horses/*physiology; Social Behavior; Social Dominance; Time Factors; Trenbolone/adverse effects/*analogs & derivatives/*pharmacology |
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Abstract |
Erratum in:
Vet J. 2005 May;169(3):321.
Corrected and republished in:
Vet J. 2005 May;169(3):322-5.
Oral administration of altrenogest for oestrus suppression in competition horses is believed to be widespread in some equestrian disciplines, and can be administered continuously for several months during a competition season. To examine whether altrenogest has any anabolic or other potential performance enhancing properties that may give a horse an unfair advantage, we examined the effect of oral altrenogest (0.044 mg/kg), given daily for a period of eight weeks, on social hierarchy, activity budget, body-mass and body condition score of 12 sedentary mares. We concluded that prolonged oral administration of altrenogest at recommended dose rates to sedentary mares resulted in no effect on dominance hierarchies, body mass or condition score. |
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Faculty of Veterinary Science, University of Sydney, Private Mailbag 4, Narellan Delivery Centre, Narellan, NSW 2567, Australia. davidh@camden.usyd.edu.au |
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1090-0233 |
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PMID:15683772 |
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Call Number |
refbase @ user @ |
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671 |
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Hada, T.; Ohmura, H.; Mukai, K.; Eto, D.; Takahashi, T.; Hiraga, A. |
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Title |
Utilisation of the time constant calculated from heart rate recovery after exercise for evaluation of autonomic activity in horses |
Type |
Journal Article |
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Year |
2006 |
Publication |
Equine Veterinary Journal. Supplement |
Abbreviated Journal |
Equine Vet J Suppl |
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Volume |
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Issue |
36 |
Pages |
141-145 |
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Keywords |
Animals; Atropine/pharmacology; Autonomic Nervous System/drug effects/*physiology; Exercise Test/veterinary; Female; Heart Rate/*physiology; Horses/*physiology; Male; Oxygen Consumption/*physiology; Parasympatholytics/*pharmacology; Physical Conditioning, Animal/*physiology; Physical Fitness/physiology; Propranolol/pharmacology |
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Abstract |
REASONS FOR PERFORMING STUDY: Heart rate (HR) recovery immediately after exercise is controlled by autonomic functions and the time constant (T) calculated from HR recovery is thought to be an index of parasympathetic activity in man. OBJECTIVES: To investigate whether it is possible to evaluate autonomic function using the time constant in horses. METHODS: Five Thoroughbred horses were subjected to a standard exercise test. Following pre-medication with saline, atropine and/or propranolol, the horses ran for 2.5 min at a speed of 8 m/sec at a 10% incline and T was calculated from HR after the exercise. Secondly, 7 Thoroughbred horses were then trained for 11 weeks and T and maximal oxygen uptake (VO2max) measured at intervals of 1 or 2 weeks. In 6 horses, T with atropine pre-medication was also measured before and after the whole training period. Furthermore, the HR variability at rest was evaluated by power spectral analysis at intervals of 3 or 4 weeks. RESULTS: Time constant was increased by atropine and/or propranolol pre-medication, decreased with the progress of training and inversely correlated with VO2max during training (r = 0.43, P<0.005). Parasympathetic blockade significantly decreased T only after and not before, the training; however, T was lower in post training than in pretraining, irrespective of parasympathetic blockade. On the other hand, parasympathetic activity at rest was attenuated and sympathetic activity became predominant following the training. CONCLUSION: Heart rate recovery is affected by sympathetic withdrawal and parasympathetic reactivation in horses and suggests that physical training hastened HR recovery by improving the parasympathetic function after exercise with aerobic capacity. However, the effects of other factors need to be considered because the training effect appeared on T even under parasympathetic blockade. The parasympathetic activity at rest is in contrast to that after exercise, suggesting that T does not reflect parasympathetic activity at rest. POTENTIAL RELEVANCE: If demonstrated how HR recovery is controlled after exercise, its analysis will be important in the evaluation of physical fitness in horses. |
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Equine Science Division, Hidaka Training and Research Center, Japan Racing Association, 535-13 Nischicha, Urakawa-cho, Uraakawagun, Hokkaido, Japan |
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PMID:17402409 |
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Equine Behaviour @ team @ |
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4010 |
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Author |
Rietmann, T.R.; Stauffacher, M.; Bernasconi, P.; Auer, J.A.; Weishaupt, M.A. |
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Title |
The association between heart rate, heart rate variability, endocrine and behavioural pain measures in horses suffering from laminitis |
Type |
Journal Article |
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Year |
2004 |
Publication |
Journal of Veterinary Medicine. A, Physiology, Pathology, Clinical Medicine |
Abbreviated Journal |
J Vet Med A Physiol Pathol Clin Med |
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Volume |
51 |
Issue |
5 |
Pages |
218-225 |
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Keywords |
Animals; Anti-Inflammatory Agents, Non-Steroidal/administration & dosage; Autonomic Nervous System; Behavior, Animal; Electrophysiology/*methods; Endocrine System; Female; Heart Rate; Horse Diseases/blood/drug therapy/*physiopathology; Horses; Joint Diseases/physiopathology/*veterinary; Male; Pain/physiopathology/*veterinary; Pain Measurement/*veterinary; Predictive Value of Tests |
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Abstract |
The objective of this study was to compare the stress response of horses suffering from laminitis after short- and long-term treatment with the intent to evaluate power spectral analysis of heart rate variability (HRV) for pain monitoring. Data were collected from 19 horses with acute or chronic exacerbating laminitis without known primary disease before and after treatment with non-steroidal anti-inflammatory drugs (NSAID). Recordings were carried out the day after admission to the equine hospital. Measurements were repeated on day 7 of the treatment. The recorded parameters included a clinical orthopaedic index (OLPI: Obel-grade plus hoof tester score), frequency of weight-shifting between contralateral limbs, mean beat-to-beat interval (R-R) duration, standard deviation of continuous R-R intervals, low- (LF) and high-frequency (HF) components of HRV, sympatho-vagal balance (LF/HF), and plasma concentration of cortisol, adrenalin and noradrenalin. The LF represents mainly sympathetic influences on the heart whereas HF is mediated by the parasympathetic tone. Weight-shifting and OLPI decreased significantly with treatment. The LF normalized units (n.u.) decreased after NSAID from 60.41 +/- 21.42 to 51.12 +/- 19.81 and was 49.33 +/- 22.64 on day 7, whereas HF n.u. increased from 35.07 +/- 20.02 to 43.14 +/- 18.30 and was 45.98 +/- 23.00 on day 7. Hormone levels showed no tendency to change with treatment. The OLPI was only correlated with LF/HF, LF and HF (R = 0.57, 0.55 and -0.54 respectively). Significant negative correlations existed between HFn.u. and weight-shifting frequency (R = -0.37), HFn.u. and adrenalin (R = -0.47), and HFn.u. and noradrenalin (R = 0.33). The LFn.u. only correlated positively with adrenalin. Cortisol levels were poorly associated with the other parameters. Determination of the sympatho-vagal influences on cardiac function may offer complementary information for reliable assessment of pain and may represent a valuable alternative method to catecholamine measurements. |
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Equine Hospital, Faculty of Veterinary Medicine, University of Zurich, Winterthurerstrasse 260, CH-8057 Zurich, Switzerland |
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0931-184X |
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Notes |
PMID:15315700 |
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no |
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Call Number |
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Serial |
1899 |
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Author |
Natalini, C.C.; Robinson, E.P. |
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Title |
Effects of epidural opioid analgesics on heart rate, arterial blood pressure, respiratory rate, body temperature, and behavior in horses |
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Journal Article |
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Year |
2003 |
Publication |
Veterinary Therapeutics : Research in Applied Veterinary Medicine |
Abbreviated Journal |
Vet Ther |
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Volume |
4 |
Issue |
4 |
Pages |
364-375 |
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Keywords |
3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer/administration & dosage/pharmacology; Alfentanil/administration & dosage/pharmacology; Analgesics, Opioid/administration & dosage/*pharmacology; Anesthesia, Epidural/*veterinary; Animals; Behavior, Animal/drug effects; Blood Pressure/drug effects; Body Temperature/drug effects; Butorphanol/administration & dosage/pharmacology; Cross-Over Studies; Female; Heart Rate/drug effects; Horses/*physiology; Injections, Epidural/veterinary; Male; Morphine/administration & dosage/pharmacology; Respiration/drug effects; Tramadol/administration & dosage/pharmacology |
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Abstract |
Heart rate, arterial blood pressures, respiratory rate, body temperature, and central nervous system excitement were compared before and after epidural administration of morphine (0.1 mg/kg), butorphanol (0.08 mg/kg), alfentanil (0.02 mg/kg), tramadol (1.0 mg/kg), the k-opioid agonist U50488H (0.08 mg/kg), or sterile water using an incomplete Latin square crossover design in five conscious adult horses. Treatments were administered into the first intercoccygeal epidural space. Significant (P <.05) reductions in respiratory rate were detected after epidural administration of morphine, alfentanil, U50488H, and sterile water. Additionally, significant (P <.05) head ptosis was observed within the first hour after administration of morphine, U50488H, and tramadol, but neither of these changes appeared to be of clinical significance. No treatment-related changes in motor activity or behavior were observed. |
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Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA 70803, USA |
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ISSN |
1528-3593 |
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Notes |
PMID:15136978 |
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no |
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Call Number |
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Serial |
1902 |
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Author |
Hubbell, J.A.E.; Muir, W.W. |
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Title |
Antagonism of detomidine sedation in the horse using intravenous tolazoline or atipamezole |
Type |
Journal Article |
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Year |
2006 |
Publication |
Equine Veterinary Journal |
Abbreviated Journal |
Equine Vet J |
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Volume |
38 |
Issue |
3 |
Pages |
238-241 |
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Keywords |
Animals; Behavior, Animal/drug effects/physiology; Dose-Response Relationship, Drug; Double-Blind Method; Horses/*physiology; Hypnotics and Sedatives/*antagonists & inhibitors; Imidazoles/*antagonists & inhibitors/*pharmacology; Infusions, Intravenous/veterinary; Kinetics; Safety; Tolazoline/*pharmacology; Videotape Recording |
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Abstract |
REASONS FOR PERFORMING STUDY: The ability to shorten the duration of sedation would potentially improve safety and utility of detomidine. OBJECTIVES: To determine the effects of tolazoline and atipamezole after detomidine sedation. HYPOTHESIS: Administration of tolazoline or atipamezole would not affect detomidine sedation. METHODS: In a randomised, placebo-controlled, double-blind, descriptive study, detomidine (0.02 mg/kg bwt i.v.) was administered to 6 mature horses on 4 separate occasions. Twenty-five mins later, each horse received one of 4 treatments: Group 1 saline (0.9% i.v.) as a placebo control; Group 2 atipamezole (0.05 mg/kg bwt i.v.); Group 3 atipamezole (0.1 mg/kg bwt i.v.); and Group 4 tolazoline (4.0 mg/kg bwt i.v.). Sedation, muscle relaxation and ataxia were scored by 3 independent observers at 9 time points. Horses were led through an obstacle course at 7 time points. Course completion time was recorded and the ability of the horse to traverse the course was scored by 3 independent observers. Horses were videotaped before, during and after each trip through the obstacle course. RESULTS: Atipamezole and tolazoline administration incompletely antagonised the effects of detomidine, but the time course to recovery was shortened. CONCLUSIONS AND POTENTIAL RELEVANCE: Single bolus administration of atipamezole or tolazoline produced partial reversal of detomidine sedation and may be useful for minimising detomidine sedation. |
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Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Ohio State University, 601 Tharp Street, Columbus, Ohio 43210, USA |
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0425-1644 |
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Notes |
PMID:16706278 |
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Call Number |
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Serial |
1869 |
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Author |
Grubb, T.L.; Foreman, J.H.; Benson, G.J.; Thurmon, J.C.; Tranquilli, W.J.; Constable, P.D.; Olson, W.O.; Davis, L.E. |
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Title |
Hemodynamic effects of calcium gluconate administered to conscious horses |
Type |
Journal Article |
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Year |
1996 |
Publication |
Journal of veterinary internal medicine / American College of Veterinary Internal Medicine |
Abbreviated Journal |
J Vet Intern Med |
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Volume |
10 |
Issue |
6 |
Pages |
401-404 |
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Keywords |
Animals; Blood Pressure/drug effects/physiology; Calcium/blood; Calcium Gluconate/administration & dosage/*pharmacology; Cardiac Output/drug effects/physiology; Consciousness/*physiology; Dose-Response Relationship, Drug; Female; Heart Rate/drug effects/physiology; Hemodynamic Processes/*drug effects/physiology; Horses/blood/*physiology; Infusions, Intravenous; Male; Myocardial Contraction/drug effects/physiology; Respiration/drug effects/physiology; Stroke Volume/drug effects/physiology; Time Factors |
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Abstract |
Calcium gluconate was administered to conscious horses at 3 different rates (0.1, 0.2, and 0.4 mg/kg/min for 15 minutes each). Serum calcium concentrations and parameters of cardiovascular function were evaluated. All 3 calcium administration rates caused marked increases in both ionized and total calcium concentrations, cardiac index, stroke index, and cardiac contractility (dP/dtmax). Mean arterial pressure and right atrial pressure were unchanged; heart rate decreased markedly during calcium administration. Ionized calcium concentration remained between 54% and 57% of total calcium concentration throughout the study. We conclude that calcium gluconate can safely be administered to conscious horses at 0.1 to 0.4 mg/kg/min and that administration will result in improved cardiac function. |
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Department of Veterinary Clinical Medicine, University of Illinois at Urbana-Champaign, USA |
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0891-6640 |
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Notes |
PMID:8947873 |
Approved |
no |
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Call Number |
refbase @ user @ |
Serial |
97 |
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Author |
Aronson, L. |
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Title |
Animal behavior case of the month. Aggression directed toward other horses |
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Journal Article |
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Year |
1998 |
Publication |
Journal of the American Veterinary Medical Association |
Abbreviated Journal |
J Am Vet Med Assoc |
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Volume |
213 |
Issue |
3 |
Pages |
358-359 |
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Keywords |
*Aggression; Animals; *Behavior, Animal; Follow-Up Studies; Horse Diseases/*diagnosis/drug therapy/psychology; Horses/*psychology; Housing, Animal; Hypothyroidism/diagnosis/drug therapy/*veterinary; Male; Physical Examination/veterinary; Thyroxine/blood/therapeutic use |
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Department of Surgery, School of Veterinary Medicine, Tufts University, North Grafton, MA 01536, USA |
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0003-1488 |
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Notes |
PMID:9702222 |
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Call Number |
refbase @ user @ |
Serial |
1935 |
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Author |
Carroll, G.L.; Matthews, N.S.; Hartsfield, S.M.; Slater, M.R.; Champney, T.H.; Erickson, S.W. |
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Title |
The effect of detomidine and its antagonism with tolazoline on stress-related hormones, metabolites, physiologic responses, and behavior in awake ponies |
Type |
Journal Article |
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Year |
1997 |
Publication |
Veterinary surgery : VS : the official journal of the American College of Veterinary Surgeons |
Abbreviated Journal |
Vet Surg |
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Volume |
26 |
Issue |
1 |
Pages |
69-77 |
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Keywords |
Adrenergic alpha-Antagonists/administration & dosage/*pharmacology; Animals; Behavior, Animal/drug effects/physiology; Blood Glucose/metabolism; Blood Pressure/drug effects/physiology; Consciousness/physiology; Dose-Response Relationship, Drug; Drug Interactions; Epinephrine/blood; Fatty Acids, Nonesterified/blood; Female; Heart Rate/drug effects/physiology; Horse Diseases/metabolism/physiopathology/psychology; Horses/blood/metabolism/*physiology; Hydrocortisone/blood; Hypnotics and Sedatives/administration & dosage/*pharmacology; Imidazoles/administration & dosage/*pharmacology; Injections, Intravenous; Male; Norepinephrine/blood; Receptors, Adrenergic, alpha/drug effects/*physiology; Stress/metabolism/physiopathology/veterinary; Time Factors; Tolazoline/administration & dosage/*pharmacology |
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Abstract |
Six ponies were used to investigate the effect of tolazoline antagonism of detomidine on physiological responses, behavior, epinephrine, norepinephrine, cortisol, glucose, and free fatty acids in awake ponies. Each pony had a catheter inserted into a jugular vein 1 hour before beginning the study. Awake ponies were administered detomidine (0.04 mg/kg intravenously [i.v.]) followed 20 minutes later by either tolazoline (4.0 mg/kg i.v.) or saline. Blood samples were drawn from the catheter 5 minutes before detomidine administration (baseline), 5 minutes after detomidine administration, 20 minutes before detomidine administration which was immediately before the administration of tolazoline or saline (time [T] = 0), and at 5, 30, and 60 minutes after injections of tolazoline or saline (T = 5, 30, and 60 minutes, respectively). Compared with heart rate at T = 0, tolazoline antagonism increased heart rate 45% at 5 minutes. There was no difference in heart rate between treatments at 30 minutes. Blood pressure remained stable after tolazoline, while it decreased over time after saline. Compared with concentrations at T = 0, tolazoline antagonism of detomidine in awake ponies resulted in a 55% increase in cortisol at 30 minutes and a 52% increase in glucose at 5 minutes. The change in free fatty acids was different for tolazoline and saline over time. Free fatty acids decreased after detomidine administration. Free fatty acids did not change after saline administration. After tolazoline administration, free fatty acids increased transiently. Tolazoline tended to decrease sedation and analgesia at 15 and 60 minutes postantagonism. Antagonism of detomidine-induced physiological and behavioral effects with tolazoline in awake ponies that were not experiencing pain appears to precipitate a stress response as measured by cortisol, glucose, and free fatty acids. If antagonism of an alpha-agonist is contemplated, the potential effect on hormones and metabolites should be considered. |
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Address |
Department of Small Animal Medicine and Surgery, Texas A&M University, College Station, USA |
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Language |
English |
Summary Language |
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Original Title |
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Series Title |
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Series Volume |
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Series Issue |
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Edition |
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ISSN |
0161-3499 |
ISBN |
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Notes |
PMID:9123816 |
Approved |
no |
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Call Number |
refbase @ user @ |
Serial |
96 |
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