@article{singer_cohn_reinero_papich_2011, title={Leflunomide pharmacokinetics after single oral administration to dogs}, volume={34}, ISSN={["0140-7783"]}, DOI={10.1111/j.1365-2885.2011.01275.x}, abstractNote={Dogs are susceptible to a variety of immune-mediated diseases usually treated with corticosteroids, but these drugs cause important morbidity (Elwood & Polton, 2008; Putsche & Kohn, 2008). Alternative and adjunctive immunosuppressive treatments like leflunomide have met anecdotal success. Labeled for treatment of rheumatoid arthritis in humans, it has been used to treat other immune-mediated diseases and to prevent renal transplant rejection (Nguyen et al., 2004; Leca, 2009). After oral administration, leflunomide is rapidly metabolized to the active metabolite A77-1726 (teriflunomide). Two mechanisms of action have been described for the active metabolite. An enzyme involved in pyrimidine synthesis (dihydroorotate dehydrogenase) is inhibited thereby arresting lymphocyte activation and expansion, and tyrosine kinases involved in cellular differentiation and signal transduction are inhibited (Bartlett et al., 1991; Cherwinski et al., 1995; Fox et al., 1999). Leflunomide has been used as an adjunctive therapy for dogs refractory to traditional immunosuppressive drugs and to prevent anti-allograft immune responses (Gregory et al., 1998a,b; Affolter & Moore, 2000; Bianco & Hardy, 2009; Colopy et al., 2010). While doses £ 4 mg ⁄ kg ⁄ day have been used in dogs with no reported adverse effects, anemia and anorexia have been observed at doses >4 mg ⁄ kg ⁄ day (McChesney et al., 1994). Pharmacokinetic studies reported in people show that the active metabolite A77-1726 has a very long half-life (7–10 days) (Li et al., 2002; Rozman, 2002). Little pharmacokinetic data have been published regarding this drug in dogs. (McChesney et al., 1994) Using a small population of animals available for study, our objective was to present additional preliminary data on the pharmacokinetics of leflunomide and its metabolite, teriflunomide, that can potentially serve as a basis for further study. Four female intact mongrel dogs between 6 and 17 months old and weighing between 16.7 and 18 kg (mean, 17.4 kg) were used. All dogs were judged to be in good health based on physical examination, complete blood count, serum biochemistry, and urinalysis. Dogs were cared for in accordance with the NIH Guide for the Care and Use of Laboratory Animals, and all procedures were approved by the Animal Care and Use Committee at the University of Missouri-Columbia. Dogs were monitored daily for appetite and attitude. Four additional untreated young adult healthy pet dogs belonging to the investigators were used to obtain small volumes of blood for use in drug protein binding studies. Each of four study dogs received 4 mg ⁄ kg leflunomide orally once. A combination of 10 mg (Apotex Inc., Toronto, Ontario) and 20 mg (Sandoz Inc., Princeton, New Jersey) tablets were placed in a small volume of canned food; dogs were watched to ensure that the food and tablets were consumed and that there was no regurgitation or vomiting. Jugular venous blood samples (8 mL) were collected at time 0, prior to administration of leflunomide, at 1, 2, 4, 8, 12, 24 h and at 2, 4, 6, 8, 10, 12, 14, 16, 17 days after oral leflunomide administration. Blood samples were immediately placed on ice in plastic tubes containing lithium heparin for a maximum of 15 min before processing. Samples were centrifuged at 1250 g for 10 min at 4 C, and plasma was collected and stored at )80 C until analysis. Canine plasma samples were analyzed for leflunomide and teriflunomide concentrations by HPLC using a modification of previously described methods (Chan et al., 2004; van Roon et al., 2005). The reference standard compounds were purchased from the drug manufacturer (Sanofi Aventis; Deutschland GmbH, Frankfurt, Germany) and were dissolved in methanol to make up a 1 mg ⁄ mL standard solution. Further dilutions were made in distilled water to use as fortifying solutions to generate calibration curves in plasma. The stock solution was kept at 4 C in a tightly sealed dark vial. Reference standard solutions were added to blank (control) plasma, to make up seven calibration standards (range 0.00 lg ⁄ mL to 10 lg ⁄ mL). The mobile phase for HPLC analysis consisted of acetonitrile (52%) and 0.1% trifluoroacetic acid (48%). The HPLC system consisted of a quaternary solvent delivery system at a flow rate of 1 mL ⁄ min, an autosampler, and UV detector set at a wavelength of 295 nm (Agilent Technologies, Wilmington, DE, USA). A C18 reverse-phase column (Agilent Technologies) was used for separation and kept at a constant temperature of 40 C. All incurred plasma samples, calibration samples, and blank (control) plasma samples were prepared identically. Solid phase extraction J. vet. Pharmacol. Therap. 34, 609–611. doi: 10.1111/j.1365-2885.2011.01275.x. SHORT COMMUNICATION}, number={6}, journal={JOURNAL OF VETERINARY PHARMACOLOGY AND THERAPEUTICS}, author={Singer, L. M. and Cohn, L. A. and Reinero, C. R. and Papich, M. G.}, year={2011}, month={Dec}, pages={609–611} }
 @inbook{cohn_fischer_adler_1997, title={Airway epithelial cells in asthma.}, booktitle={Allergy and allergic diseases.}, author={Cohn, L. A. and Fischer, B. M. and Adler, K. B.}, year={1997}, pages={263–283} }
 @article{fischer_wright_li_li_cohn_akley_adler_1995, title={Endogenously-generated nitric oxide (NO) may be a key signaling molecule in hypersecretion of mucin by guinea pig tracheal epithelial (GPTE) cells in vitro.}, volume={151}, journal={American Journal of Respiratory and Critical Care Medicine}, author={Fischer, B. M. and Wright, D. T. and Li, H. and Li, C. M. and Cohn, L. A. and Akley, N. J. and Adler, K. B.}, year={1995}, pages={A337} }
 @inbook{cohn_adler_1994, title={Alternatives to in vivo toxicological testing of rodent airway epithelia.}, booktitle={Animal test alternatives: refinement-reduction-replacement.}, author={Cohn, L. A. and Adler, K. B.}, year={1994}, pages={233–239} }
 @article{cohn_adler_1994, title={Antioxidant scavenging by guinea pig and human airway epithelial cells in vitro: mechanisms of H2O2 clearance.}, volume={265}, number={10}, journal={American Journal of Physiology. Lung Cellular and Molecular Physiology}, author={Cohn, L. A. and Adler, K. B.}, year={1994}, pages={397–404} }
 @article{adler_wright_fischer_cohn_li_li_choe_akley_1994, title={Effects of oxidant stress on airway epithelial cells in vitro.}, volume={8}, journal={FASEB Journal}, author={Adler, K. B. and Wright, D. T. and Fischer, B. M. and Cohn, L. A. and Li, C. and Li, H. and Choe, N. H. and Akley, N. J.}, year={1994}, pages={A896} }
 @article{adler_fischer_wright_cohn_becker_1994, title={INTERACTIONS BETWEEN RESPIRATORY EPITHELIAL-CELLS AND CYTOKINES - RELATIONSHIPS TO LUNG INFLAMMATION}, volume={725}, ISBN={["0-89766-856-1"]}, ISSN={["0077-8923"]}, DOI={10.1111/j.1749-6632.1994.tb00275.x}, abstractNote={Epithelial cells lining respiratory airways can participate in inflammation in a number of ways. They can act as target cells, responding to exposure to a variety of inflammatory mediators and cytokines by altering one or several of their functions, such as mucin secretion, ion transport, or ciliary beating. Aberrations in any of these functions can affect local inflammatory responses and compromise pulmonary defense. For example, oxidant stress can increase secretion of mucin and depress ciliary beating efficiency, thereby affecting the ability of the mucociliary system to clear potentially pathogenic microbial agents. Recent studies have indicated that airway epithelial cells also can act as "effector" cells, synthesizing and releasing cytokines, lipid mediators, and reactive oxygen species in response to a number of pathologically relevant stimuli, thereby contributing to inflammation. Many of these epithelial-derived substances can act locally, affecting both neighboring cells and tissues, or, via autocrine or paracrine mechanisms, affect structure and function of the epithelial cells themselves. Studies in our laboratories utilized cell cultures of both human and guinea pig tracheobronchial and nasal epithelial cells, and isolated human nasal epithelial cells, to investigate activity of respiratory epithelial cells in vitro as sources of cytokines and inflammatory mediators. Primary cultures of guinea pig and human tracheobronchial and nasal epithelial cells synthesize and secrete low levels of IL-6 and IL-8 constitutively. Production and release of these cytokines increases substantially after exposure to specific inflammatory stimuli, such as TNF or IL-1, and after viral infection.}, journal={CELLS AND CYTOKINES IN LUNG INFLAMMATION}, author={ADLER, KB and FISCHER, BM and WRIGHT, DT and COHN, LA and BECKER, S}, year={1994}, pages={128–145} }
 @article{wright_cohn_li_fischer_li_adler_1994, title={Interactions of oxygen radicals with airway epithelium.}, volume={102}, DOI={10.1289/ehp.94102s1085}, abstractNote={Reactive oxygen species (ROS) have been implicated in the pathogenesis of numerous disease processes. Epithelial cells lining the respiratory airways are uniquely vulnerable regarding potential for oxidative damage due to their potential for exposure to both endogenous (e.g., mitochondrial respiration, phagocytic respiratory burst, cellular oxidases) and exogenous (e.g., air pollutants, xenobiotics, catalase negative organisms) oxidants. Airway epithelial cells use several nonenzymatic and enzymatic antioxidant mechanisms to protect against oxidative insult. Nonenzymatic defenses include certain vitamins and low molecular weight compounds such as thiols. The enzymes superoxide dismutase, catalase, and glutatione peroxidase are major sources of antioxidant protection. Other materials associated with airway epithelium such as mucus, epithelial lining fluid, and even the basement membrane/extracellular matrix may have protective actions as well. When the normal balance between oxidants and antioxidants is upset, oxidant stress ensues and subsequent epithelial cell alterations or damage may be a critical component in the pathogenesis of several respiratory diseases. Oxidant stress may profoundly alter lung physiology including pulmonary function (e.g., forced expiratory volumes, flow rates, and maximal inspiratory capacity), mucociliary activity, and airway reactivity. ROS may induce airway inflammation; the inflammatory process may serve as an additional source of ROS in airways and provoke the pathophysiologic responses described. On a more fundamental level, cellular mechanisms in the pathogenesis of ROS may involve activation of intracellular signaling enzymes including phospholipases and protein kinases stimulating the release of inflammatory lipids and cytokines. Respiratory epithelium may be intimately involved in defense against, and pathophysiologic changes invoked by, ROS.}, number={11}, journal={Environmental Health Perspectives. Supplements}, author={Wright, D. T. and Cohn, L. A. and Li, H. and Fischer, B. M. and Li, C. M. and Adler, K. B.}, year={1994}, pages={85–90} }
 @article{cohn_adler_1993, title={Antioxidant scavenging by guinea pig and human airway epithelial cells in vitro: mechanisms of H2O2 clearance.}, volume={147}, journal={American Review of Respiratory Disease}, author={Cohn, L. A. and Adler, K. B.}, year={1993}, pages={A440} }
 @inbook{cohn_akley_adler_1993, title={Study of xenobiotics and airway epithelium in vitro.}, booktitle={Fiber toxicology.}, author={Cohn, L. A. and Akley, N. J. and Adler, K. B.}, year={1993}, pages={171–194} }
 @article{adler_cohn_1993, title={Use of air/liquid interface cultures to assess polarized responses of airway epithelium to toxicants.}, volume={29A}, journal={In Vitro Cellular & Developmental Biology. Animal}, author={Adler, K. B. and Cohn, L. A.}, year={1993}, pages={46A} }
 @article{adler_cohn_1993, title={Use of air/liquid interface guinea pig tracheal epithelial cell culture systems for assessment of interactions between inhaled substances and airways.}, volume={1993}, journal={Proceedings of the Toxicology Forum 1993.}, author={Adler, K. B. and Cohn, L. A.}, year={1993} }
 @article{adler_cohn_1992, title={Guinea pig tracheal epithelial cells in primary air/liquid interface culture scavenge H2O2 via a mechanism only partially dependent on catalase and the glutathione system.}, volume={6}, journal={FASEB Journal}, author={Adler, K. B. and Cohn, L. A.}, year={1992}, pages={A939} }
 @article{adler_kinnula_akley_lee_cohn_crapo_1992, title={INFLAMMATORY MEDIATORS AND THE GENERATION AND RELEASE OF REACTIVE OXYGEN SPECIES BY AIRWAY EPITHELIUM INVITRO}, volume={101}, ISSN={["0012-3692"]}, DOI={10.1378/chest.101.3_supplement.53s}, abstractNote={Epithelial cells lining the respiratory airways represent the first cells with which inhaled inorganic particulates and microbes come into contact upon inhalation, yet surprisingly, little is known about interactions between these substances and epithelial cells. Most studies of such interactions relate to airway epithelial response as a classical “target” type of cell, responding to exogenous stimuli or related local inflammatory reactions by altering one or more facets of epithelial function, such as mucin secretion, ion transport, and ciliary beating. 1 Phipps RJ Denas SM Sielczak MW Wanner A. Effects of 0.5 ppm ozone on glycoprotein secretion, ion, and water fluxes in sheep trachea. J Appl Physiol. 1986; 60: 918-927 PubMed Google Scholar}, number={3}, journal={CHEST}, author={ADLER, KB and KINNULA, VL and AKLEY, N and LEE, JW and COHN, LA and CRAPO, JD}, year={1992}, month={Mar}, pages={S53–S54} }
 @misc{cohn_adler_1992, title={INTERACTIONS BETWEEN AIRWAY EPITHELIUM AND MEDIATORS OF INFLAMMATION}, volume={18}, ISSN={["0190-2148"]}, DOI={10.3109/01902149209031687}, abstractNote={Epithelial cells lining the respiratory airways classically are considered to be "target" cells, responding to exposure to a variety of inflammatory mediators by altering one or several of their functions, such as mucin secretion, ion transport, or ciliary beating. Specific responses of epithelial cells in vivo or in vitro to many of these inflammatory mediators are discussed. Recent studies have indicated that airway epithelial cells also can act as "effector" cells, responding to a variety of exogenous and/or endogenous stimuli by generating and releasing additional mediators of inflammation, such as eicosanoids, reactive oxygen species, and cytokines. Many of these epithelial-derived substances can diffuse away and affect neighboring cells and tissues, or can act, via autocrine or paracrine mechanisms, to affect structure and function of epithelial cells themselves. Studies dealing with airway epithelium as a source of inflammatory mediators and related compounds also are discussed.}, number={3}, journal={EXPERIMENTAL LUNG RESEARCH}, author={COHN, LA and ADLER, KB}, year={1992}, pages={299–322} }
 @article{cohn_adler_1991, title={INVITRO STUDIES OF MECHANISMS OF LUNG INJURY IN THE RODENT}, volume={19}, ISSN={["0192-6233"]}, DOI={10.1177/0192623391019004-111}, abstractNote={ In order to better define the responses of lung cells to potentially pathogenic insults, primary cell cultures of dissociated respiratory epithelial cells have been established. These epithelial cells have been obtained from various areas of the respiratory tract ranging from the trachea to the alveolus and the cultures have been demonstrated to mimic the differentiated state of these cell types as observed in situ. Several procedures which enhance the differentiated state have been evaluated, which include maintenance on more physiologically-relevant substrata, such as collagen gels, use of defined serum-free medium and use of air/liquid interface systems. These approaches have allowed intracellular responses of respiratory epithelium to toxic insult to be better defined. }, number={4}, journal={TOXICOLOGIC PATHOLOGY}, author={COHN, LA and ADLER, KB}, year={1991}, pages={419–427} }
 @article{adler_cohn_1991, title={In vitro studies on mechanisms of lung injury in the rodent.}, volume={10}, journal={Proceedings of the 10th International Symposium of Society of Toxicological Pathologists}, author={Adler, K. B. and Cohn, L. A.}, year={1991} }
 @article{cohn_spaulding_cullen_bunch_metcalf_hardie_maclachlan_breitschwerdt_1991, title={Intrahepatic Postsinusoidal Venous Obstruction in a Dog}, volume={5}, ISSN={0891-6640 1939-1676}, url={http://dx.doi.org/10.1111/j.1939-1676.1991.tb03144.x}, DOI={10.1111/j.1939-1676.1991.tb03144.x}, abstractNote={Intrahepatic postsinusoidal obstruction, similar to congenital Budd‐Chiari syndrome in human patients, was diagnosed in a young Basenji dog. Sonographic, radiographic, and manometric studies were used in antemortem localization of this unusual functional lesion, that was believed to be congenital.}, number={6}, journal={Journal of Veterinary Internal Medicine}, publisher={Wiley}, author={Cohn, Leah A. and Spaulding, Kathy A. and Cullen, John M. and Bunch, Susan E. and Metcalf, Michael R. and Hardie, Elizabeth M. and MacLachlan, N. James and Breitschwerdt, Edward B.}, year={1991}, month={Nov}, pages={317–321} }
 @article{cohn_1991, title={THE INFLUENCE OF CORTICOSTEROIDS ON HOST DEFENSE-MECHANISMS}, volume={5}, ISSN={["0891-6640"]}, DOI={10.1111/j.1939-1676.1991.tb00939.x}, abstractNote={Glucocorticosteroid hormones affect virtually every tissue type in the body, including tissues of host‐defense systems. There is an enormous body of literature concerning specific effects of corticosteroids on host defenses. This literature review examines the affects of corticosteroids on leukocyte kinetics, phagocytic immunity, cell‐mediated immunity, and humoral immunity in steroid‐resistant species.}, number={2}, journal={JOURNAL OF VETERINARY INTERNAL MEDICINE}, author={COHN, LA}, year={1991}, pages={95–104} }
 @article{cohn_meuten_1990, title={Bone fragility in a kitten: An osteogenesis imperfecta-like syndrome}, volume={197}, number={1}, journal={Journal of the American Veterinary Medical Association}, author={Cohn, L. A. and Meuten, D. J.}, year={1990}, pages={98} }