Differential pharmacokinetics and pharmacokinetic/pharmacodynamic modelling of robenacoxib and ketoprofen in a feline model of inflammation

Robenacoxib and ketoprofen are acidic nonsteroidal anti‐inflammatory drugs (NSAIDs). Both are licensed for once daily administration in the cat, despite having short blood half‐lives. This study reports the pharmacokinetic/pharmacodynamic (PK/PD) modelling of each drug in a feline model of inflammation. Eight cats were enrolled in a randomized, controlled, three‐period cross‐over study. In each period, sterile inflammation was induced by the injection of carrageenan into a subcutaneously implanted tissue cage, immediately before the subcutaneous injection of robenacoxib (2 mg/kg), ketoprofen (2 mg/kg) or placebo. Blood samples were taken for the determination of drug and serum thromboxane (Tx)B2 concentrations (measuring COX‐1 activity). Tissue cage exudate samples were obtained for drug and prostaglandin (PG)E2 concentrations (measuring COX‐2 activity). Individual animal pharmacokinetic and pharmacodynamic parameters for COX‐1 and COX‐2 inhibition were generated by PK/PD modelling. S(+) ketoprofen clearance scaled by bioavailability (CL/F) was 0.114 L/kg/h (elimination half‐life = 1.62 h). For robenacoxib, blood CL/F was 0.684 L/kg/h (elimination half‐life = 1.13 h). Exudate elimination half‐lives were 25.9 and 41.5 h for S(+) ketoprofen and robenacoxib, respectively. Both drugs reduced exudate PGE2 concentration significantly between 6 and 36 h. Ketoprofen significantly suppressed (>97%) serum TxB2 between 4 min and 24 h, whereas suppression was mild and transient with robenacoxib. In vivoIC50COX‐1/IC50COX‐2 ratios were 66.9:1 for robenacoxib and 1:107 for S(+) ketoprofen. The carboxylic acid nature of both drugs may contribute to the prolonged COX‐2 inhibition in exudate, despite short half‐lives in blood

Plant-arthropod interactions: who is the winner?

Herbivorous arthropods have interacted with plants for millions of years. During feeding they release chemical cues that allow plants to detect the attack and mount an efficient defense response. A signaling cascade triggers the expression of hundreds of genes, which encode defensive proteins and enzymes for synthesis of toxic metabolites. This direct defense is often complemented by emission of volatiles that attract beneficial parasitoids. In return, arthropods have evolved strategies to interfere with plant defenses, either by producing effectors to inhibit detection and downstream signaling steps, or by adapting to their detrimental effect. In this review, we address the current knowledge on the molecular and chemical dialog between plants and herbivores, with an emphasis on co-evolutionary aspects

Induced resistance in basket willow against a gall midge

Plants are defended against herbivores and pathogens by means of a vast array of mechanisms such as physical obstacles, chemical defences, phenological escape, and attraction of predators. Plant defence mechanisms may be present independently of the enemy attack, i.e. constitutive, or initiated by the activity of the enemy, thus referred to as induced resistance. This thesis focuses on induced resistance in basket willow (Salix viminalis, Salicaceae) against the leaf roller gall midge Dasineura marginemtorquens (Diptera: Cecidomyiidae). Observations from the field revealed an, for plant/insect systems, unusually great variation among S. viminalis genotypes in resistance to D. marginemtorquens. This great genotypic variation in combination with the fact that D. marginemtorquens is a leaf galler with a relatively sessile life style make this system especially suitable for studies on local resistance reactions in the plant to attack by the insect. We tested the hypothesis that the hypersensitive response (HR), a type of plant- programmed localised cell death, is involved in the resistance. We found support for the hypothesis. Local HR-like necroses were found in resistant but not in susceptible S. viminalis genotypes after larval attempts to initiate galls. The importance of defensive plant signalling transduction pathways was investigated in several experiments. We found that the HR-associated salicylic acid (SA)-dependent pathway mediates the resistance. In contrast, the jasmonic acid (JA)-dependent pathway does not seem to be important in this system either as a mediator of resistance or through suppression of the SA-dependent pathway (negative “cross-talk”). Furthermore, total peroxidase activity was associated with the resistance. As such, the resistance in S. viminalis to D. marginemtorquens seems to be of an HR-type associated with SA-dependent responses including induced peroxidase activity. Thus, great similarity exists between plant resistance in the S. viminalisID. marginemtorquens system and plant/pathogen systems with regards to activation of the HR, the SA-dependent pathway, and peroxidase activity

Macula Densa Derived Nitric Oxide and Kidney Function

The kidney is the major organ regulating the extracellular fluid volume and thereby the arterial blood pressure. The neuronal isoform of nitric oxide synthase (nNOS) in the kidney is predominantly located in the macula densa cells. These cells are sensors for both renin release and the tubuloglomerular feedback mechanism (TGF), which is an important regulator of the glomerular filtration rate and afferent arteriole tone. The aim of this investigation was to elucidate the function of nNOS in the macula densa cells. Acute nNOS inhibition in rats resulted in an increased TGF responsiveness and unchanged blood pressure while, after chronic inhibition, the TGF was normalised and the blood pressure was elevated. The plasma renin concentration was elevated in rats on long-term low salt diet, but was not significantly affected by chronic nNOS inhibition. On the other hand, nNOS inhibition for four days increased plasma renin concentration in rats treated with a low salt diet. The renal vasculature of rats exhibits a diminished renal blood flow and intracellular Ca2+ response to angiotensin II after one week blockade of nNOS while angiotensin II’s effect on the renal blood flow was abolished after four weeks treatment. Acute extracellular volume expansion diminish the TGF sensitivity thus assisting the elimination of excess fluid but after acute addition of nNOS inhibitor to volume expanded rats the TGF sensitivity restored. In conclusion, the results from the present study suggest an important role for nNOS in the macula densa cells in the regulation of the arterial blood pressure and the modulation of the TGF response

Use of Lung Weight as Biomarker for Assessment of Lung Toxicity in Rat Inhalation Studies

Subacute inhalation study (1 week or 2 weeks) is an important process for screening out inhaled compounds causing lung irritation. To investigate whether the lung weight can be used as an indicator for acute lung injury, we have analyzed retrospectively the lung weight data from 30 studies in rats exposed to dry powder inhalation. The lung weight change was correlated with lung histopathology in the majority of studies (25 of 30), showing as either both changed or both unchanged. The sensitivity and specificity of using the weight change in lungs as biomarker for predicting lung histopathology in these studies were over 80%. The pattern of lung weight change was often similar in the 1- to 2- week studies and the 4-week studies. Our analysis of covariance model showed that a study with 40 rats (5 males + 5 females/group and 4 groups) could detect lung weight change greater than 10% to 20% of control value. These results suggested that lung weight is a useful indicator for identifying acute lung toxic effect by inhaled compounds in these subacute inhalation studies