Insecticide resistance is a major problem for both medicine and agriculture and is frequently associated with overexpression of metabolic enzymes that catalyze the breakdown of pesticides, leading to broad-spectrum resistance. However, the insect tissues within which these metabolic enzymes normally reside remain unclear. Microarray analysis of nine adult tissues from Drosophila melanogaster reveals that cytochrome P-450s and glutathione-S-transferases show highly tissue-specific expression patterns; most were confined to one or more epithelial tissues, and half showed dominant expression in a single tissue. The particular detoxifying enzymes encountered by a xenobiotic thus depend critically on the route of administration. In particular, known insecticide metabolism genes are highly enriched in insect Malpighian (renal) tubules, implicating them in xenobiotic metabolism. The tubules thus display, with the fat body, roles analogous to the vertebrate liver and immune system, as well as its acknowledged renal function. To illustrate this, when levels of a single gene, Cyp6g1, were manipulated in just the Malpighian tubules of adult Drosophila, the survival of the whole insect after 1,1,1-trichloro-2,2-bis(4-chlorophenyl)ethane (DDT) challenge was altered, whereas corresponding manipulations in the nervous system or the fat body were without effect. This shows that, although detoxification enzymes are widely distributed, baseline protection against DDT resides primarily in the insect excretory system, corresponding to less than 0.1% of the mass of the organism.

BackgroundPruritus is a characteristic clinical sign of allergic skin conditions including atopic dermatitis (AD) in the dog. IL‐31 is a cytokine found in the serum of some dogs with AD and can induce pruritic behaviours in laboratory beagle dogs.Hypothesis/ObjectivesThe objectives were to characterize an IL‐31‐induced pruritus model by evaluating the efficacy of prednisolone, dexamethasone and oclacitinib, and to compare the speed of anti‐pruritic effects of oclacitinib against those of prednisolone and dexamethasone.AnimalsPurpose‐bred beagle dogs were used in all studies.MethodsRandomized, blinded, placebo‐controlled studies were designed to evaluate and compare the anti‐pruritic properties of prednisolone, dexamethasone and oclacitinib following a single intravenous injection of recombinant canine IL‐31. Video surveillance was used to monitor and score pruritic behaviours in study animals.ResultsPrednisolone [0.5 mg/kg, per os (p.o.)] reduced IL‐31‐induced pruritus when given 10 h prior to observation. When the time interval between drug treatment and observation was shortened to 1 h, dexamethasone (0.2 mg/kg, intramuscular) but not prednisolone (0.25 or 0.5 mg/kg, p.o.) reduced IL‐31‐induced pruritus. Oclacitinib (0.4 mg/kg, p.o.) reduced pruritus when given 1, 6, 11 and 16 h prior to the observation period, and the anti‐pruritic activity of oclacitinib was greater when compared to prednisolone and dexamethasone at all time points assessed.Conclusion and clinical importanceThe efficacy of prednisolone, dexamethasone and oclacitinib in the IL‐31‐induced pruritus model gives confidence that this may be a relevant model for acute pruritus associated with allergic dermatitis including AD and can be used to evaluate novel compounds or formulations.

This review addresses the potential use of neuropeptide receptors for the discovery of anthelmintic agents, and particularly for the identification of non-peptide ligands. It outlines which nematode neuropeptides are known and have been characterized, the published information on drug discovery around these targets, information about existing high- and low-throughput screening systems and finally the likely safety of neuropeptide mimetics.

A challenge model was used to evaluate a new approach to controlling acute acidosis. Acute acidosis reduces performance in both dairy and beef cattle and most often occurs as a consequence of ingestion of large amounts of readily fermentable starch, resulting in increased production of volatile fatty acids (VFA) and lactic acid and a reduction in ruminal pH. Acarbose is an alpha-amylase and glucosidase inhibitor that slows the rate of degradation of starch to glucose, thereby reducing the rate of VFA production and maintaining rumen pH at a more stable level. It is commercially available (Glucobay, Bayer, Wuppertal, Germany) and indicated for the control of blood glucose in diabetic patients. The ability of acarbose to reduce the incidence of acidosis and the comparative efficacies of acarbose, sodium bicarbonate, and monensin were tested in 3 acute acidosis challenge experiments in cattle. Rumen-cannulated Holstein steers were challenged with a mixture of 48.4% cornstarch, 48.4% ground corn, 2.1% sodium caseinate, and 1.1% urea with or without test substance. The challenge was administered at a rate of 12.5 g/kg of body weight (BW) as a slurry through the cannula directly into the rumen. Ruminal pH was monitored at 10-min intervals throughout the study. Animals were removed from study and rumen contents replaced if they exhibited acute acidosis as defined as pH <4.5. If acidosis was not observed within 24 h, animals were subjected to a second challenge. Ruminal fluid samples were taken for measurement of VFA and lactate concentrations at various intervals after the challenge. In experiment 1, the carbohydrate challenge induced acidosis in 4 of 4 control animals and 0 of 4 animals treated with 2.14 or 21.4 mg of acarbose/kg of BW in the challenge based on the criterion of pH <4.5. In experiment 2, the carbohydrate challenge induced acidosis in 4 of 7 control animals and 1 of 7 animals when 1.07 mg of acarbose/kg of BW was included in the challenge. In experiment 3, acidosis was induced in 7 of 7 animals in the control, 1% sodium bicarbonate, and 12 mg of monensin/kg of dry matter intake groups and in 3 of 8 steers administered 1.07 mg of acarbose/kg of BW in the challenge. Increases in lactate concentrations and decreases in total VFA associated with acute acidosis were mitigated by acarbose. Thus, acarbose, an amylase and glucosidase inhibitor, prevented or reduced the incidence of acidosis in an acute challenge model in steers and was more effective than monensin or sodium bicarbonate.