Pharmacodynamics and pharmacokinetics of nonsteroidal anti-inflammatory drugs in species of veterinary interest

This review summarises selected aspects of the pharmacokinetics (PK) and pharmacodynamics (PD) of nonsteroidal anti-inflammatory drugs (NSAIDs). It is not intended to be comprehensive, in that it covers neither minor species nor several important aspects of NSAID PD. The limited objective of the review is to summarise those aspects of NSAID PK and PD, which are important to an understanding of PK-PD integration and PK-PD modelling (the subject of the next review in this issue). The general features of NSAID PK are: usually good bioavailability from oral, intramuscular and subcutaneous administration routes (but with delayed absorption in horses and ruminants after oral dosing), a high degree of binding to plasma protein, low volumes of distribution, limited excretion of administered dose as parent drug in urine, marked inter-species differences in clearance and elimination half-life and ready penetration into and slow clearance from acute inflammatory exudate. The therapeutic effects of NSAIDs are exerted both locally (at peripheral inflammatory sites) and centrally. There is widespread acceptance that the principal mechanism of action (both PD and toxicodynamics) of NSAIDs at the molecular level comprises inhibition of cyclooxygenase (COX), an enzyme in the arachidonic acid cascade, which generates inflammatory mediators of the prostaglandin group. However, NSAIDs possess also many other actions at the molecular level. Two isoforms of COX have been identified. Inhibition of COX-1 is likely to account for most of the side-effects of NSAIDs (gastrointestinal irritation, renotoxicity and inhibition of blood clotting) but a minor contribution also to some of the therapeutic effects (analgesic and anti-inflammatory actions) cannot be excluded. Inhibition of COX-2 accounts for most and possibly all of the therapeutic effects of NSAIDs. Consequently, there has been an intensive search to identify and develop drugs with selectivity for inhibition of COX-2. Whole blood in vitro assays are used to investigate quantitatively the three key PD parameters (efficacy, potency and sensitivity) for NSAID inhibition of COX isoforms, providing data on COX-1:COX-2 inhibition ratios. Limited published data point to species differences in NSAID-induced COX inhibition, for both potency and potency ratios. Members of the 2-arylpropionate sub-groups of NSAIDs exist in two enantiomeric forms [R-(-) and S-(+)] and are licensed as racemic mixtures. For these drugs there are marked enantiomeric differences in PK and PD properties of individual drugs in a given species, as well as important species differences in both PK and PD properties.     

Insulin resistance and abomasal motility disorders in cows detected by use of abomasoduodenal electromyography after surgical correction of left displaced abomasum

OBJECTIVE: To determine the correlation between insulin concentrations and myoelectrical activity of the abomasum in cows with a left displaced abomasum (LDA). ANIMALS: 14 dairy cows with an LDA at the onset of lactation. PROCEDURE: During surgical correction of an LDA, 3 pairs of electrodes were placed in the smooth muscle of the gastrointestinal tract (abomasal body, pars pylorica, and duodenum) of each cow. Electromyographic recordings were obtained once per day for 7 days. Samples were collected and tested to determine concentrations of insulin, glucagon, cortisol, glucose, beta-hydroxybutyrate, and nonesterified fatty acids. RESULTS: All 14 cattle had high glucose and insulin concentrations at the time of admission, independent of ketosis. Concentrations of glucose and insulin decreased slowly after surgical treatment and were associated with a progressive increase in abomasoduodenal myoelectric activity. The 14 cows were allocated into 2 groups (suspected insulin-resistant cattle, n = 7; suspected non-insulin-resistant cattle, 7) on the basis of persistent hyperinsulinemia during the postoperative period. Seven days after surgery, the abomasoduodenal myoelectric patterns were still significantly lower for the insulin-resistant cows, compared with patterns for the non-insulin-resistant cows. CONCLUSIONS AND CLINICAL RELEVANCE: Insulin resistance appears to be common in cows with an LDA. Analysis of results of this study reveals that abomasal atony in cows with an LDA depends on persistence of high serum concentrations of insulin. Results of this study could provide an explanation for a pathogenetic factor of LDAs and the frequent relapses of cattle affected by this condition.     

A scoring system for risk assessment of the introduction and spread of bovine viral diarrhoea virus in dairy herds in Northern Italy

To support a voluntary disease control program, this study aimed to develop an integrated scoring system for the risk assessment of bovine viral diarrhoea virus (BVDV) infection in dairy herds in Northern Italy. Sixty-two dairy herds were classified according to their BVDV serological status. Farmers were interviewed using a questionnaire on potential BVDV risk factors. Scores were used to define risk levels for factors related to (1) BVDV introduction (through livestock trade, attendance of animals at shows/exhibitions and grazing common pasture), (2) within-herd spread of BVDV and (3) the results of initial serological testing. The calculated odds ratios were significant for all categories, except for livestock trade. The application of the screening test, the questionnaire and the related risk assessment showed this to be a practical approach to predicting BVDV herd status.     

Pharmacokinetics of cefuroxime after intravenous,intramuscular, and subcutaneous administration to dogs

Cefuroxime pharmacokinetic profile was investigated in 6 Beagle dogs after single intravenous, intramuscular, and subcutaneous administration at a dosage of 20 mg/kg. Blood samples were withdrawn at predetermined times over a 12‐h period. Cefuroxime plasma concentrations were determined by HPLC. Data were analyzed by compartmental analysis. Peak plasma concentration (C_max), time‐to‐peak plasma concentration (T_max), and bioavailability for the intramuscular and subcutaneous administration were (mean ± SD) 22.99 ± 7.87 μg/mL, 0.43 ± 0.20 h, and 79.70 ± 14.43% and 15.37 ± 3.07 μg/mL, 0.99 ± 0.10 h, and 77.22 ± 21.41%, respectively. Elimination half‐lives and mean residence time for the intravenous, intramuscular, and subcutaneous administration were 1.12 ± 0.19 h and 1.49 ± 0.21 h; 1.13 ± 0.13 and 1.79 ± 0.24 h; and 1.04 ± 0.23 h and 2.21 ± 0.23 h, respectively. Significant differences were found between routes for K_a, MAT, C_max, T_max, t_½(a), and MRT. T > MIC = 50%, considering a MIC of 1 μg/mL, was 11 h for intravenous and intramuscular administration and 12 h for the subcutaneous route. When a MIC of 4 μg/mL is considered, T > MIC = 50% for intramuscular and subcutaneous administration was estimated in 8 h.     

Thin film deposition by PECVD using HMDSO-O<Subscript>2</Subscript>-Ar gas mixture on knitted wool fabrics in order to improve pilling resistance

In this work knitted wool fabrics were coated by a Si:O_x:C_y:H_z thin film with the aim to promote pilling resistance. The wool samples were plasma coated in a radio frequency (RF) glow discharge using hexamethyldisiloxane (HMDSO) as the precursor, in mixture with argon and oxygen gases, for different deposition times and reaction pressures, at constant discharge power. Deposited films were characterized by means of Fourier transform infrared (FTIR) spectroscopy and surface morphology by means of scanning electron microscopy; moreover, propensity to pilling of treated samples was investigated, showing that treated fabrics had a better pilling performance respect to untreated ones.     

An Evaluation of Trace Metals in High-Altitude Lakes of the Central Alps

Alpine areas in north-western Italy are subject to high deposition of atmospheric pollutants. Chemical investigations on high-altitude lakes indicate that most of them are recovering from acidification; however, they are still affected by the deposition of pollutants from the atmosphere, especially of heavy metals. This study compares the concentrations of heavy metals in alpine lake waters with those found in atmospheric depositions, to identify the possible contribution of deposition inputs to surface water ecosystems. The results were analysed by multivariate statistical techniques to identify the main emission sources of the various metals. Levels of trace metals in alpine lakes are generally low, and bedrock and surficial geology proved to be a major factor controlling metal concentrations in lake water. In fact, terrigenous elements show a wide range of concentrations while metals of anthropogenic origin, such as lead and cadmium, are often below the detection limits of the method; chrome and nickel are also present in very low concentrations. The median values of heavy metals in Italian alpine lakes are similar to those found in other lake surveys performed in remote areas, especially as regards metals of anthropogenic origin. The Visual MINTEQ model was applied to long-term chemical data of selected alpine lakes, to calculate aluminium speciation and to simulate its change in response to gradual modifications in a unit of pH. The ultimate aim of the modelling was to evaluate the possible threat to aquatic organisms of these highly toxic compounds.

     

Production,Characterization and Biocompatibility of Marine Collagen Matrices from an Alternative and Sustainable Source: The Sea Urchin Paracentrotus lividus

Collagen has become a key-molecule in cell culture studies and in the tissue engineering field. Industrially, the principal sources of collagen are calf skin and bones which, however, could be associated to risks of serious disease transmission. In fact, collagen derived from alternative and riskless sources is required, and marine organisms are among the safest and recently exploited ones. Sea urchins possess a circular area of soft tissue surrounding the mouth, the peristomial membrane (PM), mainly composed by mammalian-like collagen. The PM of the edible sea urchin Paracentrotus lividus therefore represents a potential unexploited collagen source, easily obtainable as a food industry waste product. Our results demonstrate that it is possible to extract native collagen fibrils from the PM and produce suitable substrates for in vitro system. The obtained matrices appear as a homogeneous fibrillar network (mean fibril diameter 30–400 nm and mesh < 2 μm) and display remarkable mechanical properties in term of stiffness (146 ± 48 MPa) and viscosity (60.98 ± 52.07 GPa·s). In vitro tests with horse pbMSC show a good biocompatibility in terms of overall cell growth. The obtained results indicate that the sea urchin P. lividus can be a valuable low-cost collagen source for mechanically resistant biomedical devices.     

Carotenoid composition and heterotic effect in selected Italian maize germplasm

Maize (Zea mays L.) is a promising crop for improving the nutritional quality of foods, because of the presence of broad natural variability for the content of carotenoids. One hundred Italian and nine public lines were screened by PCR to identify the alleles of Hydroxylase3 (HYD3) and Lycopene epsilon cyclase (LCYE) genes, codifying for key enzymes of the carotenoid pathway and associated with high or low β-carotene contents. Nineteen selected genotypes carrying different alleles were grown in 2011 and/or 2012, and used to obtain F1 seeds. HPLC analysis highlighted the richness in zeaxanthin and β-cryptoxanthin of Italian germplasm (mean values 12.63 and 2.88 mg/kg d.m., respectively). The percentage of positive and significant mid parent heterosis (MPH) and best parent heterosis (BPH) values (51% and 29%) indicated the presence of a high heterotic response for carotenoids. The compounds on the same branch of the pathway were found to be positively correlated; on the contrary, no consistent correlation was observed between the different HYD3 alleles and β-carotene content. Finally, total antioxidant capacity (TAC) was also measured. These lines resulted therefore as interesting raw materials for the market of maize-based foods.     

Acute Toxicity by Oral Co-Exposure to Palytoxin and Okadaic Acid in Mice

The frequent occurrence of marine dinoflagellates producing palytoxin (PLTX) or okadaic acid (OA) raises concern for the possible co-presence of these toxins in seafood, leading to additive or synergistic adverse effects in consumers. Thus, the acute oral toxicity of PLTX and OA association was evaluated in mice: groups of eight female CD-1 mice were administered by gavage with combined doses of PLTX (30, 90 or 270 μg/kg) and OA (370 μg/kg), or with each individual toxin, recording signs up to 24 h (five mice) and 14 days (three mice). Lethal effects occurred only after PLTX (90 or 270 μg/kg) exposure, alone or combined with OA, also during the 14-day recovery. PLTX induced scratching, piloerection, abdominal swelling, muscle spasms, paralysis and dyspnea, which increased in frequency or duration when co-administered with OA. The latter induced only diarrhea. At 24 h, PLTX (90 or 270 μg/kg) and OA caused wall redness in the small intestine or pale fluid accumulation in its lumen, respectively. These effects co-occurred in mice co-exposed to PLTX (90 or 270 μg/kg) and OA, and were associated with slight ulcers and inflammation at forestomach. PLTX (270 μg/kg alone or 90 μg/kg associated with OA) also decreased the liver/body weight ratio, reducing hepatocyte glycogen (270 μg/kg, alone or combined with OA). No alterations were recorded in surviving mice after 14 days. Overall, the study suggests additive effects of PLTX and OA that should be considered for their risk assessment as seafood contaminants.