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1.
J Pharmacol Toxicol Methods ; 128: 107528, 2024.
Article de Anglais | MEDLINE | ID: mdl-38852684

RÉSUMÉ

INTRODUCTION: In preclinical cardiovascular safety pharmacology studies, statistical analysis of the rate corrected QT interval (QTc) is the focus for predicting QTc interval changes in the clinic. Modeling of a concentration/QTc relationship, common clinically, is limited due to minimal pharmacokinetic (PK) data in nonclinical testing. It is possible, however, to relate the average drug plasma concentration from sparse PK samples over specific times to the mean corrected QTc. We hypothesize that averaging drug plasma concentration and the QTc-rate relationship over time provides a simple, accurate concentration-QTc relationship bridging statistical and concentration/QTc modeling. METHODS: Cardiovascular telemetry studies were conducted in non-human primates (NHP; n = 48) and canines (n = 8). Pharmacokinetic samples were collected on separate study days in both species. Average plasma concentrations for specific intervals (CAverage0-X) were calculated for moxifloxacin in canines and NHP using times corresponding to super-intervals for the QTc data statistical analysis. The QTc effect was calculated for each super-interval using a linear regression correction incorporating QT and HR data from the whole super-interval. The concentration QTc effects were then modeled. RESULTS: In NHP, a 10.9 ± 0.06 ms (mean ± 95% CI) change in QTc was detected at approximately 1.5× the moxifloxacin plasma concentration that causes a 10 ms QTc change in humans, based on a 0-24 h super-interval. When simulating a drug without QT effects, mock, no effect on QTc was detected at up to 3× the clinical concentration. Similarly, in canines, a 16.6 ± 0.1 ms change was detected at 1.7× critical clinical moxifloxacin concentration, and a 0.04 ± 0.1 ms change was seen for mock. CONCLUSIONS: While simultaneous PK and QTc data points are preferred, practical constraints and the need for QTc averaging did not prevent concentration-QTc analyses. Utilizing a 0-24 h super-interval method illustrates a simple and effective method to address cardiovascular questions when preclinical drug exposures exceed clinical concentrations.


Sujet(s)
Électrocardiographie , Syndrome du QT long , Moxifloxacine , Télémétrie , Animaux , Chiens , Moxifloxacine/pharmacocinétique , Moxifloxacine/administration et posologie , Électrocardiographie/effets des médicaments et des substances chimiques , Électrocardiographie/méthodes , Télémétrie/méthodes , Syndrome du QT long/induit chimiquement , Évaluation préclinique de médicament/méthodes , Fluoroquinolones/pharmacocinétique , Fluoroquinolones/administration et posologie , Rythme cardiaque/effets des médicaments et des substances chimiques , Mâle , Modèles animaux , Relation dose-effet des médicaments , Femelle
2.
Clin Transl Sci ; 16(11): 2253-2264, 2023 11.
Article de Anglais | MEDLINE | ID: mdl-37726963

RÉSUMÉ

Whether a compound prolongs cardiac repolarization independent of changes in beat rate is a critical question in drug research and development. Current practice is to resolve this in two steps. First, the QT interval is corrected for the influence of rate and then statistical significance is tested. There is renewed interest in improving the sensitivity of nonclinical corrected QT interval (QTc) assessment with modern studies having greater data density than previously utilized. The current analyses examine the effects of moxifloxacin or vehicle on the QT interval in nonhuman primates (NHPs) using a previously described one-step method. The primary end point is the statistical sensitivity of the assessment. Publications suggest that for a four animal crossover (4 × 4) in NHPs the minimal detectable difference (MDD) is greater than or equal to 10 ms, whereas in an eight animal crossover the MDD is ~6.5 ms. Using the one-step method, the MDD for the four animal NHP assessments was 3 ms. In addition, the one-step model accounted for day-to-day differences in the heart rate and QT-rate slope as well as drug-induced changes in these parameters. This method provides an increase in the sensitivity and reduces the number of animals necessary for detecting potential QT change and represents "best practice" in nonclinical QTc assessment in safety pharmacology studies.


Sujet(s)
Syndrome du QT long , Animaux , Syndrome du QT long/induit chimiquement , Syndrome du QT long/diagnostic , Moxifloxacine/effets indésirables , Coeur , Électrocardiographie , Rythme cardiaque
3.
Sci Rep ; 13(1): 10043, 2023 06 20.
Article de Anglais | MEDLINE | ID: mdl-37340022

RÉSUMÉ

Avian pathogenic E. coli (APEC) is associated with local and systemic infections in poultry, ducks, turkeys, and many other avian species, leading to heavy economical losses. These APEC strains are presumed to possess zoonotic potential due to common virulence markers that can cause urinary tract infections in humans. The prophylactic use of antibiotics in the poultry sector has led to the rapid emergence of Multiple Drug Resistant (MDR) APEC strains that act as reservoirs and put human populations at risk. This calls for consideration of alternative strategies to decrease the bacterial load. Here, we report isolation, preliminary characterization, and genome analysis of two novel lytic phage species (Escherichia phage SKA49 and Escherichia phage SKA64) against MDR strain of APEC, QZJM25. Both phages were able to keep QZJM25 growth significantly less than the untreated bacterial control for approximately 18 h. The host range was tested against Escherichia coli strains of poultry and human UTI infections. SKA49 had a broader host range in contrast to SKA64. Both phages were stable at 37 °C only. Their genome analysis indicated their safety as no recombination, integration and host virulence genes were identified. Both these phages can be good candidates for control of APEC strains based on their lysis potential.


Sujet(s)
Bactériophages , Infections à Escherichia coli , Maladies de la volaille , Animaux , Humains , Escherichia coli/génétique , Infections à Escherichia coli/prévention et contrôle , Infections à Escherichia coli/médecine vétérinaire , Infections à Escherichia coli/microbiologie , Bactériophages/génétique , Oiseaux/microbiologie , Volaille , Maladies de la volaille/prévention et contrôle , Maladies de la volaille/microbiologie , Poulets
4.
J Pharmacol Toxicol Methods ; 117: 107211, 2022.
Article de Anglais | MEDLINE | ID: mdl-36007862

RÉSUMÉ

Preclinical risk assessment of drug-induced arrhythmias is critical for drug development and relies on heart rate corrected QT interval (QT) prolongation as a biomarker for arrhythmia risk. However, the methods used to correct QT vary in complexity and don't account for all changes in the QT-rate relationship. Thus, we developed the novel Ratio QT correction method which characterizes that relationship at each timepoint using the ratio between QT, adjusted for a species-specific constant, and rate (RR interval). This ratio represents the slope between the intercept and the datapoint being corrected, which is then used in a linear equation like individual methods. A unique correction coefficient for each datapoint avoids assuming static relationships. We hypothesize that the simple and dynamic nature of the Ratio method will provide more consistent rate correction and error reduction compared to Bazett's and individual regression methods. Comparisons were made using ECG data from non-human primates (NHPs) treated with dofetilide or moxifloxacin, separated into small groups (n = 4). The methods were compared based on corrected QT vs RR slopes, standard error, and minimal detectable difference (MDD) for each method. The Ratio method resulted in smaller corrected QT-rate relationship slopes than Bazett's, more closely matching those of individual methods. It produced similar or lower MDDs compared to individual and Bazett's correction, respectively, with more consistent reduction in standard error. This simple and effective method has the potential for easy translatability across species.


Sujet(s)
Électrocardiographie , Syndrome du QT long , Animaux , Troubles du rythme cardiaque/induit chimiquement , Troubles du rythme cardiaque/traitement médicamenteux , Électrocardiographie/méthodes , Rythme cardiaque , Syndrome du QT long/induit chimiquement , Moxifloxacine/pharmacologie
5.
Biomedicines ; 10(5)2022 Apr 19.
Article de Anglais | MEDLINE | ID: mdl-35625675

RÉSUMÉ

Despite the addition of several new agents to the armamentarium for the treatment of multiple myeloma (MM) in the last decade and improvements in outcomes, the refractory and relapsing disease continues to take a great toll, limiting overall survival. Therefore, additional novel approaches are needed to improve outcomes for MM patients. The oncogenic transcription factor MYC drives cell growth, differentiation and tumor development in many cancers. MYC protein levels are tightly regulated by the proteasome and an increase in MYC protein expression is found in more than 70% of all human cancers, including MM. In addition to the ubiquitin-dependent degradation of MYC by the 26S proteasome, MYC levels are also regulated in a ubiquitin-independent manner through the REGγ activation of the 20S proteasome. Here, we demonstrate that a small molecule activator of the 20S proteasome, TCH-165, decreases MYC protein levels, in a manner that parallels REGγ protein-mediated MYC degradation. TCH-165 enhances MYC degradation and reduces cancer cell growth in vitro and in vivo models of multiple myeloma by enhancing apoptotic signaling, as assessed by targeted gene expression analysis of cancer pathways. Furthermore, 20S proteasome enhancement is well tolerated in mice and dogs. These data support the therapeutic potential of small molecule-driven 20S proteasome activation for the treatments of MYC-driven cancers, especially MM.

6.
Sci Rep ; 12(1): 5732, 2022 04 06.
Article de Anglais | MEDLINE | ID: mdl-35388062

RÉSUMÉ

Salmonella enterica serovar Typhimurium is a foodborne pathogen causing occasional outbreaks of enteric infections in humans. Salmonella has one of the largest pools of temperate phages in its genome that possess evolutionary significance for pathogen. In this study, we characterized a novel temperate phage Salmonella phage BIS20 (BIS20) with unique tail fiber genes. It belongs to the subfamily Peduovirinae genus Eganvirus and infects Salmonella Typhimurium strain (SE-BS17; Acc. NO MZ503545) of poultry origin. Phage BIS20 was viable only at biological pH and temperature ranges (pH7 and 37 °C). Despite being temperate BIS20 significantly slowed down the growth of host strain for 24 h as compared to control (P < 0.009). Phage BIS20 features 29,477-base pair (bp) linear DNA genome with 53% GC content and encodes for 37 putative ORFs. These ORFs have mosaic arrangement as indicated by its ORF similarity to various phages and prophages in NCBI. Genome analysis indicates its similarity to Salmonella enterica serovar Senftenberg prophage (SEStP) sequence (Nucleotide similarity 87.7%) and Escherichia virus 186 (~ 82.4% nucleotide similarity). Capsid genes were conserved however those associated with tail fiber formation and assembly were unique to all members of genus Eganvirus. We found strong evidence of recombination hotspot in tail fiber gene. Our study identifies BIS20 as a new species of genus Eganvirus temperate phages as its maximum nucleotide similarity is 82.4% with any phage in NCBI. Our findings may contribute to understanding of origin of new temperate phages.


Sujet(s)
Bactériophages , Phages de Salmonella , Bactériophages/génétique , Génome viral , Humains , Myoviridae/génétique , Nucléotides , Prophages/génétique , Salmonella , Phages de Salmonella/génétique , Salmonella typhimurium/génétique
7.
Viruses ; 14(2)2022 01 25.
Article de Anglais | MEDLINE | ID: mdl-35215834

RÉSUMÉ

Salmonella Typhimurium, a foodborne pathogen, is a major concern for food safety. Its MDR serovars of animal origin pose a serious threat to the human population. Phage therapy can be an alternative for the treatment of such MDR Salmonella serovars. In this study, we report on detailed genome analyses of a novel Salmonella phage (Salmonella-Phage-SSBI34) and evaluate its therapeutic potential. The phage was evaluated for latent time, burst size, host range, and bacterial growth reduction in liquid cultures. The phage stability was examined at various pH levels and temperatures. The genome analysis (141.095 Kb) indicated that its nucleotide sequence is novel, as it exhibited only 1-7% DNA coverage. The phage genome features 44% GC content, and 234 putative open reading frames were predicted. The genome was predicted to encode for 28 structural proteins and 40 enzymes related to nucleotide metabolism, DNA modification, and protein synthesis. Further, the genome features 11 tRNA genes for 10 different amino acids, indicating alternate codon usage, and hosts a unique hydrolase for bacterial lysis. This study provides new insights into the subfamily Vequintavirinae, of which SSBI34 may represent a new genus.


Sujet(s)
Myoviridae/génétique , Phages de Salmonella/génétique , Salmonella typhimurium/virologie , Animaux , Bactériolyse , Agents de lutte biologique , Génome viral , Spécificité d'hôte , Myoviridae/classification , Myoviridae/isolement et purification , Myoviridae/physiologie , Cadres ouverts de lecture , Phagothérapie , Phylogenèse , Volaille/microbiologie , Salmonelloses/thérapie , Phages de Salmonella/classification , Phages de Salmonella/isolement et purification , Phages de Salmonella/physiologie , Salmonella typhimurium/isolement et purification
8.
J Pharmacol Toxicol Methods ; 113: 107126, 2022.
Article de Anglais | MEDLINE | ID: mdl-34655760

RÉSUMÉ

The use of QT-prolongation as a biomarker for arrhythmia risk requires that researchers correct the QT-interval (QT) to control for the influence of heart rate (HR). QT correction methods can vary but most used are the universal correction methods, such as Bazett's or Van de Water's, which use a single correction formula to correct QT-intervals in all the subjects of a study. Such methods fail to account for differences in the QT/HR relationship between subjects or over time, instead relying on the assumption that this relationship is consistent. To address these changes in rate relationships, we test the effectiveness of linear and non-linear individual correction methods. We hypothesize that individual correction methods that account for additional influences on the rate relationship will result in more effective and consistent correction. To increase the scope of this study we use bootstrap sampling on ECG recordings from non-human primates and beagle canines dosed with vehicle control. We then compare linear and non-linear individual correction methods through their ability to reduce HR correlation and standard deviation of corrected QT values. From these results, we conclude that individual correction methods based on post-treatment data are most effective with the linear methods being the best option for most cases in both primates and canines. We also conclude that the non-linear methods are more effective in canines than primates and that accounting for light status can improve correction while examining the data from the light periods separately. Individual correction requires careful consideration of inter-subject and intra-subject variabilities.


Sujet(s)
Électrocardiographie , Syndrome du QT long , Animaux , Troubles du rythme cardiaque , Chiens , Rythme cardiaque
9.
Microbiol Resour Announc ; 10(1)2021 Jan 07.
Article de Anglais | MEDLINE | ID: mdl-33414290

RÉSUMÉ

Limosilactobacillus fermentum is a probiotic species; however, L. fermentum AGR1487 increases colon inflammation in germfree mice and decreases barrier integrity in Caco-2 cells. The AGR1487 genome was sequenced to explore these phenotypes. The genome is a single, circular, 1,939,032-bp chromosome with a G+C content of 52.17% and no plasmids.

10.
Microbiol Resour Announc ; 9(36)2020 Sep 03.
Article de Anglais | MEDLINE | ID: mdl-32883793

RÉSUMÉ

Lactobacillus fermentum is found in food products and is generally considered safe. L. fermentum AGR1485 promotes barrier integrity in Caco-2 cells and has genetic similarities to other known probiotic L. fermentum strains. L. fermentum AGR1485 has potential as a probiotic and was sequenced to explore these probiotic properties. The genome is a 2.2-Mbp circular chromosome with no plasmids and a GC content of 51.15%.

11.
J Pharmacol Toxicol Methods ; 100: 106622, 2019.
Article de Anglais | MEDLINE | ID: mdl-31398384

RÉSUMÉ

A vital aspect of the drug discovery and development process is the identification and filtering of drugs with high risk of dangerous adverse events. Torsade de Pointes (TdP) is one example of an adverse event that requires thorough in vitro and in vivo drug screening. This is because TdP, a tachycardic ventricular arrhythmia, can develop into fatal cardiac events if left unresolved and has been missed during drug development with profound consequences. These factors led to the development of pre-clinical screening guidelines based on the presence of drug induced QT prolongation (QTp), which has been linked to TdP. These guidelines have high sensitivity, but low specificity, as they tend to predict QTp, which precedes TdP events but does not always lead to TdP. Computational models have the potential to improve these prediction methods by bridging the gaps between preclinical and clinical data. This study proposes the use of adverse event reports obtained from the FDA Adverse Event Reporting System as a representation of clinical TdP risk. By incorporating these reports into computational models, a more accurate risk prediction may be developed.


Sujet(s)
Troubles du rythme cardiaque/induit chimiquement , Développement de médicament/méthodes , Effets secondaires indésirables des médicaments/prévention et contrôle , Animaux , Troubles du rythme cardiaque/prévention et contrôle , Simulation numérique , Découverte de médicament/méthodes , Évaluation préclinique de médicament/méthodes , Humains , Syndrome du QT long/induit chimiquement , Syndrome du QT long/prévention et contrôle , Torsades de pointes/induit chimiquement , Torsades de pointes/prévention et contrôle
12.
J Med Chem ; 62(9): 4350-4369, 2019 05 09.
Article de Anglais | MEDLINE | ID: mdl-30951312

RÉSUMÉ

Through a phenotypic high-throughput screen using a serum response element luciferase promoter, we identified a novel 5-aryl-1,3,4-oxadiazol-2-ylthiopropionic acid lead inhibitor of Rho/myocardin-related transcription factor (MRTF)/serum response factor (SRF)-mediated gene transcription with good potency (IC50 = 180 nM). We were able to rapidly improve the cellular potency by 5 orders of magnitude guided by sharply defined and synergistic SAR. The remarkable potency and depth of the SAR, as well as the relatively low molecular weight of the series, suggests, but does not prove, that binding to the unknown molecular target may be occurring through a covalent mechanism. The series nevertheless has no observable cytotoxicity up to 100 µM. Ensuing pharmacokinetic optimization resulted in the development of two potent and orally bioavailable anti-fibrotic agents that were capable of dose-dependently reducing connective tissue growth factor gene expression in vitro as well as significantly reducing the development of bleomycin-induced dermal fibrosis in mice in vivo.


Sujet(s)
Acides carboxyliques/usage thérapeutique , Antienzymes/usage thérapeutique , Fibrose/traitement médicamenteux , Oxadiazoles/usage thérapeutique , Facteur de réponse au sérum/antagonistes et inhibiteurs , Transactivateurs/antagonistes et inhibiteurs , Animaux , Acides carboxyliques/synthèse chimique , Acides carboxyliques/pharmacocinétique , Facteur de croissance du tissu conjonctif/métabolisme , Antienzymes/synthèse chimique , Antienzymes/pharmacocinétique , Femelle , Fibrose/anatomopathologie , Souris de lignée C57BL , Microsomes du foie/effets des médicaments et des substances chimiques , Structure moléculaire , Oxadiazoles/synthèse chimique , Oxadiazoles/pharmacocinétique , Sclérodermie systémique/traitement médicamenteux , Sclérodermie systémique/anatomopathologie , Transduction du signal/effets des médicaments et des substances chimiques , Peau/anatomopathologie , Relation structure-activité , Transcription génétique/effets des médicaments et des substances chimiques , Protéines G rho/antagonistes et inhibiteurs
13.
J Med Chem ; 62(10): 4884-4901, 2019 05 23.
Article de Anglais | MEDLINE | ID: mdl-31013090

RÉSUMÉ

Novel pyridine- and pyrimidine-based allosteric inhibitors are reported that achieve PDE4D subtype selectivity through recognition of a single amino acid difference on a key regulatory domain, known as UCR2, that opens and closes over the catalytic site for cAMP hydrolysis. The design and optimization of lead compounds was based on iterative analysis of X-ray crystal structures combined with metabolite identification. Selectivity for the activated, dimeric form of PDE4D provided potent memory enhancing effects in a mouse model of novel object recognition with improved tolerability and reduced vascular toxicity over earlier PDE4 inhibitors that lack subtype selectivity. The lead compound, 28 (BPN14770), has entered midstage, human phase 2 clinical trials for the treatment of Fragile X Syndrome.


Sujet(s)
Encéphalopathies/traitement médicamenteux , Cyclic Nucleotide Phosphodiesterases, Type 4/métabolisme , Conception de médicament , Syndrome du chromosome X fragile/traitement médicamenteux , Inhibiteurs de la phosphodiestérase-4/synthèse chimique , Régulation allostérique/effets des médicaments et des substances chimiques , Animaux , Comportement animal/effets des médicaments et des substances chimiques , Encéphalopathies/enzymologie , Cyclic Nucleotide Phosphodiesterases, Type 4/génétique , Syndrome du chromosome X fragile/enzymologie , Humains , Concentration inhibitrice 50 , Mâle , Souris de lignée ICR , Structure moléculaire , Inhibiteurs de la phosphodiestérase-4/composition chimique , Inhibiteurs de la phosphodiestérase-4/pharmacologie , Relation structure-activité
14.
Physiol Rep ; 6(12): e13753, 2018 06.
Article de Anglais | MEDLINE | ID: mdl-29952109

RÉSUMÉ

Fibrosis of the lung constitutes a major clinical challenge and novel therapies are required to alleviate the associated morbidity and mortality. Investigating the antifibrotic efficacy of drugs that are already in clinical practice offers an efficient strategy to identify new therapies. The phosphodiesterase 4 (PDE4) inhibitors, approved for the treatment of chronic obstructive pulmonary disease, harbor therapeutic potential for pulmonary fibrosis by augmenting the activity of endogenous antifibrotic mediators that signal through cyclic AMP. In this study, we tested the efficacy of several PDE4 inhibitors including a novel compound (Compound 1) in a murine model of lung fibrosis that results from a targeted type II alveolar epithelial cell injury. We also compared the antifibrotic activity of PDE4 inhibition to the two therapies that are FDA-approved for idiopathic pulmonary fibrosis (pirfenidone and nintedanib). We found that both preventative (day 0-21) and therapeutic (day 11-21) dosing regimens of the PDE4 inhibitors significantly ameliorated the weight loss and lung collagen accumulation that are the sequelae of targeted epithelial cell damage. In a therapeutic protocol, the reduction in lung fibrosis with PDE4 inhibitor administration was equivalent to pirfenidone and nintedanib. Treatment with this class of drugs also resulted in a decrease in plasma surfactant protein D concentration, a reduction in the plasma levels of several chemokines implicated in lung fibrosis, and an in vitro inhibition of fibroblast profibrotic gene expression. These results motivate further investigation of PDE4 inhibition as a treatment for patients with fibrotic lung disease.


Sujet(s)
Pneumocytes/anatomopathologie , Benzamides/usage thérapeutique , Isoquinoléines/usage thérapeutique , Inhibiteurs de la phosphodiestérase-4/usage thérapeutique , Fibrose pulmonaire/traitement médicamenteux , Aminopyridines/usage thérapeutique , Animaux , Benzamides/administration et posologie , Benzamides/sang , Cellules cultivées , Chimiokines/sang , AMP cyclique/métabolisme , Cyclopropanes/usage thérapeutique , Relation dose-effet des médicaments , Évaluation préclinique de médicament/méthodes , Fibroblastes/métabolisme , Humains , Isoquinoléines/administration et posologie , Isoquinoléines/sang , Souris de lignée C57BL , Souris transgéniques , Inhibiteurs de la phosphodiestérase-4/administration et posologie , Inhibiteurs de la phosphodiestérase-4/sang , Fibrose pulmonaire/sang , Fibrose pulmonaire/prévention et contrôle , Protéine D associée au surfactant pulmonaire/sang , Pyridines/usage thérapeutique , Facteur de nécrose tumorale alpha/métabolisme
15.
BMC Endocr Disord ; 18(1): 24, 2018 May 02.
Article de Anglais | MEDLINE | ID: mdl-29720169

RÉSUMÉ

BACKGROUND: Cushing's syndrome in humans shares many similarities with its counterpart in dogs in terms of etiology (pituitary versus adrenal causes), clinical signs, and pathophysiologic sequelae. In both species, treatment of pituitary- and adrenal-dependent disease is met with limitations. ATR-101, a selective inhibitor of ACAT1 (acyl coenzyme A:cholesterol acyltransferase 1), is a novel small molecule therapeutic currently in clinical development for the treatment of adrenocortical carcinoma, congenital adrenal hyperplasia, and Cushing's syndrome in humans. Previous studies in healthy dogs have shown that ATR-101 treatment led to rapid, dose-dependent decreases in adrenocorticotropic hormone (ACTH) stimulated cortisol levels. The purpose of this clinical study was to investigate the effects of ATR-101 in dogs with Cushing's syndrome. METHODS: ATR-101 pharmacokinetics and activity were assessed in 10 dogs with naturally-occurring Cushing's syndrome, including 7 dogs with pituitary-dependent disease and 3 dogs with adrenal-dependent disease. ATR-101 was administered at 3 mg/kg PO once daily for one week, followed by 30 mg/kg PO once daily for one (n = 4) or three (n = 6) weeks. Clinical, biochemical, adrenal hormonal, and pharmacokinetic data were obtained weekly for study duration. RESULTS: ATR-101 exposure increased with increasing dose. ACTH-stimulated cortisol concentrations, the primary endpoint for the study, were significantly decreased with responders (9 of 10 dogs) experiencing a mean ± standard deviation reduction in cortisol levels of 50 ± 17% at study completion. Decreases in pre-ACTH-stimulated cortisol concentrations were observed in some dogs although overall changes in pre-ACTH cortisol concentrations were not significant. The compound was well-tolerated and no serious drug-related adverse effects were reported. CONCLUSIONS: This study highlights the potential utility of naturally occurring canine Cushing's syndrome as a model for human disease and provides proof of concept for ATR-101 as a novel agent for the treatment of endocrine disorders like Cushing's syndrome in humans.


Sujet(s)
Acetyl-coA C-acetyltransferase/antagonistes et inhibiteurs , Hormone corticotrope/métabolisme , Syndrome de Cushing/médecine vétérinaire , Maladies des chiens/métabolisme , Hydrocortisone/métabolisme , Phénylurées/pharmacologie , Animaux , Syndrome de Cushing/traitement médicamenteux , Syndrome de Cushing/métabolisme , Syndrome de Cushing/anatomopathologie , Chiens , Femelle , Mâle , Phénylurées/pharmacocinétique , Distribution tissulaire
16.
Am J Vet Res ; 76(5): 445-53, 2015 May.
Article de Anglais | MEDLINE | ID: mdl-25909377

RÉSUMÉ

OBJECTIVE: To evaluate pharmacokinetics of ammonium tetrathiomolybdate (TTM) after IV and oral administration to dogs and effects of TTM administration on trace mineral concentrations. ANIMALS: 8 adult Beagles and Beagle crossbreds (4 sexually intact males and 4 sexually intact females). PROCEDURES: Dogs received TTM (1 mg/kg) IV and orally in a randomized crossover study. Serum molybdenum and copper concentrations were measured via inductively coupled plasma mass spectrometry in samples obtained 0 to 72 hours after administration. Pharmacokinetics was determined via noncompartmental analysis. RESULTS: For IV administration, mean ± SD terminal elimination rate constant, maximum concentration, area under the curve, and half-life were 0.03 ± 0.01 hours(-1), 4.9 ± 0.6 µg/mL, 30.7 ± 5.4 µg/mL•h, and 27.7 ± 6.8 hours, respectively. For oral administration, mean ± SD terminal elimination rate constant, time to maximum concentration, maximum concentration, area under the curve, and half-life were 0.03 ± 0.01 hours(-1), 3.0 ± 3.5 hours, 0.2 ± 0.4 µg/mL, 6.5 ± 8.0 µg/mL•h, and 26.8 ± 8.0 hours, respectively. Oral bioavailability was 21 ± 22%. Serum copper concentrations increased significantly after IV and oral administration. Emesis occurred after IV (2 dogs) and oral administration (3 dogs). CONCLUSIONS AND CLINICAL RELEVANCE: Pharmacokinetics for TTM after a single IV and oral administration was determined for clinically normal dogs. Absorption of TTM after oral administration was variable. Increased serum copper concentrations suggested that TTM mobilized tissue copper. Further studies will be needed to evaluate the potential therapeutic use of TTM in copper-associated chronic hepatitis of dogs.


Sujet(s)
Chélateurs/pharmacocinétique , Chiens/métabolisme , Molybdène/pharmacocinétique , Oligoéléments/métabolisme , Administration par voie intraveineuse/médecine vétérinaire , Administration par voie orale , Animaux , Biodisponibilité , Chélateurs/administration et posologie , Études croisées , Femelle , Période , Mâle , Molybdène/administration et posologie
17.
J Pharmacol Toxicol Methods ; 67(3): 148-61, 2013.
Article de Anglais | MEDLINE | ID: mdl-23438450

RÉSUMÉ

INTRODUCTION: Understanding the appropriate application of telemetry and other technologies for nonclinical investigation of functional safety issues in the context of ongoing toxicology evaluations is a current industry challenge. One major issue is related to the potential impact of surgical implantation of a telemetry device on contemporarily established measures of drug toxicity, and potential for confounding pathological issues related to the systemic and local response of the experimental animal to the presence of a foreign body. This study was designed to evaluate the potential local and systemic impact of different implanted telemetry devices with varying requisite degrees of surgical complexity on general toxicology study endpoints. METHODS: Sixteen male beagle dogs 1) no surgical instrumentation [n=4], 2) Jacketed External Telemetry (JET) with femoral artery blood pressure implant (PA-C10 LA) [n=4], or 3) fully implantable (DSI-D70-CCTP) devices [n=8], were assigned to experimental groups and evaluated within the context of a standard repeat-dose toxicology design to determine the potential impact of these treatments on routine in-life and post-mortem toxicological endpoints. RESULTS: Device implantation, regardless of the level of invasiveness/complexity was without effect on any in-life safety parameter, including clinical chemistry and hematology, assessed in the experimental design. Histopathological findings were limited to the expected, primarily minimal to mild localized effects characteristic of a foreign body reaction (fibrosis, inflammation) in the area immediately in contact with the body of the transmitter device and associated sites of ECG lead and pressure catheter interface with local tissues. DISCUSSION: This study represents the first definitive evaluation of the influence of variably invasive telemetry device implantation on standardized, essential toxicology endpoints in the context of a simulated repeated dose experimental design. The data suggest that, when carefully evaluated, the local effects of implanted telemetry devices can be managed in the context of a standard Investigational New Drug (IND)-enabling toxicology study. This study provides support for the potential incorporation of unrestrained cardiovascular assessments via implanted or external telemetry into standard multi-dose toxicology studies.


Sujet(s)
Télémétrie/effets indésirables , Télémétrie/instrumentation , Animaux , Pression sanguine/effets des médicaments et des substances chimiques , Poids/effets des médicaments et des substances chimiques , Chiens , Contamination des aliments , Mâle , Répartition aléatoire , Solutions/administration et posologie , Solutions/effets indésirables
18.
Toxicol Sci ; 128(1): 22-41, 2012 Jul.
Article de Anglais | MEDLINE | ID: mdl-22539625

RÉSUMÉ

In carcinogenicity studies, pregabalin increased hemangiosarcoma incidence in mice but not in rats. Investigative studies, ranging in length from 24 h to 12 months, were conducted in mice (1000 or 5000 mg/kg) and rats (900 mg/kg) to evaluate a potential mode-of-action scheme for tumor formation. Three areas were evaluated: (1) hematopoiesis (because endothelial and hematopoietic cells arise from the same precursor and hemangiosarcomas are primarily located in mouse hematopoietic tissues), (2) angiogenic growth factors (because increased angiogenic growth factors may stimulate vascular tumors), and (3) pulmonary/blood gas parameters (because hypoxia is a known driver for endothelial cell proliferation). In mice, pregabalin rapidly increased platelet and megakaryocyte counts, activated platelets and bone marrow erythrophages, decreased the myeloid-to-erythroid (M:E) ratio (49%), and produced bone marrow and splenic congestion and extramedullary hematopoiesis (EMH). Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor immunohistochemical staining were also increased in mouse bone marrow and spleen and vascular endothelial growth factor receptor 2 immunolabeling was increased in liver. Serum bicarbonate was increased within 24 h of pregabalin administration, persisted over time, and was accompanied by decreased respiratory rate (up to 34%) and increased partial pressure of carbon dioxide (pCO(2)), resulting in sustained metabolic alkalosis and elevated blood pH in mice. In contrast, in rats, pregabalin decreased overall bone marrow cellularity, including decreased number of megakaryocytes (24%) with no evidence of erythrophages, no change in M:E ratio, no EMH, and no increase in angiogenic growth factors or blood pH. Persistent alterations in serum bicarbonate, respiratory function, and blood gas parameters in mice, without adequate compensatory mechanisms, has the potential to create chronic tissue hypoxia, an accepted driver of endothelial cell proliferation.


Sujet(s)
Hydrogénocarbonates/métabolisme , Érythropoïèse , Facteur de croissance fibroblastique de type 2/métabolisme , Hémangiosarcome/induit chimiquement , Activation des macrophages/effets des médicaments et des substances chimiques , Facteur de croissance endothéliale vasculaire de type A/métabolisme , Acide gamma-amino-butyrique/analogues et dérivés , Animaux , Gazométrie sanguine , Femelle , Hémangiosarcome/métabolisme , Souris , Prégabaline , Rats , Rat Wistar , Tests de la fonction respiratoire , Études rétrospectives , Acide gamma-amino-butyrique/toxicité
19.
Auton Neurosci ; 140(1-2): 66-71, 2008 Jun.
Article de Anglais | MEDLINE | ID: mdl-18499531

RÉSUMÉ

Autonomic tone has been suggested to be a significant determinant of ventricular repolarization duration with both rate dependent and independent effects. Using the His bundle-paced dog, a model that eliminates the need for QT correction factors, we explored the rate-independent effects of sympathetic and parasympathetic blockade on ventricular repolarization shortening following an excitatory stimulus. Six male His bundle-paced beagle dogs were paced at 80 bpm and fitted with jackets, surface ECG electrodes, and radiotelemeters. Dogs were given propranolol, atropine methyl nitrate, or the appropriate control in a four-period crossover design. Doses were based on literature reviews and unpublished pharmacokinetic/pharmacodynamic modeling to provide efficacious beta- and parasympathetic blockade throughout the data collection period. Data collection began at 11 am and concluded at 11 am the following day, with event stimuli provided by investigators entering the room at 5 pm and at 7 am the following morning. One minute of ECG data were sampled every 15 min and these means were averaged to generate hourly means for the 24 hour data collection period. Treatment with atropine attenuated RT interval shortening when compared with the vehicle group at both the 5 pm and 7 am stimulus. In contrast, propranolol was not associated with significant effects on RT interval duration at either time point. These results suggest that parasympathetic withdrawal is the primary factor responsible during both awake hours (5 pm) and in the transition from deep sleep to the awake state (7 am) in the facilitation of RT interval shortening following an excitatory stimulus. The attenuation of RT interval shortening following atropine treatment may be a direct effect, or an indirect effect requiring an excited state to become evident. The use of a model that eliminates the need to apply correction factors to repolarization indices helps to clarify the role of the autonomic nervous system on ventricular repolarization.


Sujet(s)
Système nerveux autonome/physiologie , Rythme cardiaque/physiologie , Ventricules cardiaques/innervation , Coeur/innervation , Coeur/physiologie , Fonction ventriculaire , Antagonistes bêta-adrénergiques/pharmacologie , Animaux , Atropine/pharmacologie , Système nerveux autonome/effets des médicaments et des substances chimiques , Horloges biologiques/effets des médicaments et des substances chimiques , Horloges biologiques/physiologie , Faisceau de His/effets des médicaments et des substances chimiques , Faisceau de His/physiologie , Rythme circadien/physiologie , Chiens , Stimulation électrique , Électrocardiographie/effets des médicaments et des substances chimiques , Rythme cardiaque/effets des médicaments et des substances chimiques , Mâle , Potentiels de membrane/effets des médicaments et des substances chimiques , Potentiels de membrane/physiologie , Modèles animaux , Antagonistes muscariniques/pharmacologie , Pacemaker , Système nerveux parasympathique/effets des médicaments et des substances chimiques , Système nerveux parasympathique/physiologie , Propranolol/pharmacologie , Système nerveux sympathique/effets des médicaments et des substances chimiques , Système nerveux sympathique/physiologie , Facteurs temps
20.
Ann Noninvasive Electrocardiol ; 11(4): 289-98, 2006 Oct.
Article de Anglais | MEDLINE | ID: mdl-17040276

RÉSUMÉ

BACKGROUND: Accurate detection of drug-induced QT interval changes is often confounded by concurrent heart rate changes. Application of heart rate correction formulas has been the traditional approach to account for heart rate-induced QT interval changes, and thereby identify the direct effect of the test article on cardiac repolarization. Despite numerous recent studies identifying the imprecision of these formulas they continue to be applied. METHODS: Using a chronic atrioventricular dissociated His-paced canine model, heart rate correction methods were evaluated for their ability to generate a corrected QT interval independent of original heart rate. Additionally, His bundle pacing at a heart rate of 60 beats/min allowed calculation of the magnitude of error introduced by application of heart rate correction formulas. RESULTS: Of the fixed parameter heart rate correction formulas, only Van de Water was able to predict corrected QT values independent of the original heart rate. The magnitude of error discovered by application of heart rate correction formulas varied, but in many cases was very large. Bazett's formula was associated with a mean overcorrection of 67.9 ms; Fridericia's 28.7 ms. Van de Water was the best fixed parameter formula with a mean error of 10.8 ms. As expected, group and individual corrections derived from linear regression of the HR-QT data offered improvement over the traditional formulas. Both were able to predict QTc values independent of the heart rate. However, errors of the magnitude of 10 and 6 ms, respectively, were still introduced. CONCLUSION: Van de Water and linear regression correction methods were superior to others in this study, but all methods generated QTc errors equal to or much greater than the magnitude of interest for drug safety evaluation.


Sujet(s)
Électrocardiographie , Rythme cardiaque/effets des médicaments et des substances chimiques , Syndrome du QT long/physiopathologie , Modèles cardiovasculaires , Animaux , Chiens , Syndrome du QT long/induit chimiquement , Analyse de régression
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