Oral and intravenous administration of nimesulide in the horse: rational dosage regimen from pharmacokinetic and pharmacodynamic data

REASONS FOR PERFORMING STUDY: The selective COX-2-inhibitor nimesulide is used extra-label in equine veterinary practice as an anti-inflammatory agent. However, there are no data on which to base the rational use of the drug in this species. OBJECTIVES: To determine the effective COX selectivity of nimesulide in the horse, and suggest a suitable dosing schedule. METHODS: The pharmacokinetics of nimesulide in the horse after oral administration (1 mg/kg bwt), and oral and i.v. administration (1.5 mg/kg bwt) were investigated, effects of feeding status on bioavailability determined, and plasma protein binding of the drug and its principal metabolites measured. Compartmental and noncompartmental pharmacokinetic analyses were performed. The plasma concentration-time profile was used, together with in vitro literature data on nimesulide inhibition of COX isoforms, to determine the effective COX selectivity of nimesulide in the horse, and suggest a suitable dosing schedule. RESULTS AND CONCLUSIONS: The findings suggest that 1.5 mg/kg bwt may produce adequate clinical effects, and the dosing interval should be 12-24 h depending on condition severity. However, at that dose, the concentration in the animal exceeds the in vitro IC50 for both isoforms, so that COX-1/COX-2 selectivity is lost and side-effects due to COX-1 inhibition are a possibility. Nimesulide should therefore be used with caution in equine clinical practice.     

Diversity of Flavobacterium psychrophilum and the potential use of its phages for protection against bacterial cold water disease in salmonids

Flavobacterium psychrophilum causes rainbow trout fry syndrome (RTFS) and cold water disease (CWD) in salmonid aquaculture. We report characterization of F. psychrophilum strains and their bacteriophages isolated in Chilean salmonid aquaculture. Results suggest that under laboratory conditions phages can decrease mortality of salmonids from infection by their F. psychrophilum host strain. Twelve F. psychrophilum isolates were characterized, with DNA restriction patterns showing low diversity between strains despite their being obtained from different salmonid production sites and from different tissues. We isolated 15 bacteriophages able to infect some of the F. psychrophilum isolates and characterized six of them in detail. DNA genome sizes were close to 50 Kbp and corresponded to the Siphoviridae and Podoviridae families. One isolate, 6H, probably contains lipids as an essential virion component, based on its chloroform sensitivity and low buoyant density in CsCl. Each phage isolate rarely infected F. psychrophilum strains other than the strain used for its enrichment and isolation. Some bacteriophages could decrease mortality from intraperitoneal injection of its host strain when added together with the bacteria in a ratio of 10 plaque-forming units per colony-forming unit. While we recognize the artificial laboratory conditions used for these protection assays, this work is the first to demonstrate that phages might be able protect salmonids from RTFS or CWD.     

Pharmacodynamics and pharmacokinetics of cefoperazone and cefamandole in dogs following single dose intravenous and intramuscular administration

The pharmacokinetics and intramuscular (i.m.) bioavailability of cefoperazone and cefamandole (20mg/kg) were investigated in dogs and the findings related to minimal inhibitory concentrations (MICs) for 90 bacterial strains isolated clinically from dogs. The MICs of cefamandole for Staphylococcus intermedius (MIC(90) 0.125 microg/mL) were lower than those of cefoperazone (MIC(90) 0.5 micro/mL) although the latter was more effective against Escherichia coli strains (MIC(90) 2.0 microg/mL vs. 4.0 microg/mL). The pharmacokinetics of the drugs after intravenous administrations were similar: a rapid distribution phase was followed by a slower elimination phase (t((1/2)lambda2) 84.0+/-21.3 min for cefoperazone and 81.4+/-9.7 min for cefamandole). The apparent volume of distribution and body clearance were 0.233 L/kg and 1.96 mL/kg/min for cefoperazone, 0.190 L/kg and 1.76 mL/kg/min for cefamandole. After i.m. administration the bioavailability and peak serum concentration of cefamandole (85.1+/-13.5% and 35.9+/-5.4 microg/mL) were significantly higher than cefoperazone (41.4+/-7.1% and 24.5+/-3.0 micog/mL), but not the serum half-lives (t(1/2el) 134.3+/-12.6 min for cefoperazone and 145.4+/-12.3 min for cefamandole). The time above MIC(90) indicated that cefamandole can be administered once daily to dogs for the treatment of staphylococcal infections (T>MIC for S. intermedius 23.8+/-0.3 and for Staphylococcus aureus 21.6+/-0.6h).     

Mutants of pertussis toxin suitable for vaccine development

Immunization with chemically detoxified pertussis toxin can prevent severe whooping cough with an efficacy similar to that of the cellular pertussis vaccine, which normally gives unwanted side effects. To avoid the reversion to toxicity and the loss of immunogenicity that may follow chemical treatment of pertussis toxin, inactive toxins were constructed by genetic manipulation. A number of genetically engineered alleles of the pertussis toxin genes, constructed by replacing either one or two key amino acids within the enzymatically active S1 subunit, were introduced into the chromosome of strains of Bordetella pertussis, B. parapertussis, and B. bronchiseptica. These strains produce mutant pertussis toxin molecules that are nontoxic and immunogenic and that protect mice from the intracerebral challenge with virulent Bordetella pertussis. Such molecules are ideal for the development of new and safer vaccines against whooping cough.     

Synthesis and antifungal activity of novel bisdithiocarbamate derivatives of carbohydrates against Fusarium oxysporum f. sp. lini

Novel carbamic esters possessing a carbohydrate moiety derived from glycerol or D-glucose with two N,N-diethyldithiocarbamoyl groups and a series of bisdithiocarbamic esters having a ketone or an alkyl ester have been synthesized. The in vitro activity of these new compounds was evaluated against Fusarium oxysporum f. sp. lini. Some of the compounds [bis[1,3-S-(N,N-diethyldithiocarbamoyl)]-1, 3-dideoxyglycerol) and diethyl N,N'-(1,3-dideoxyglycer-1, 3-diyl)bis(dithiocarbamate)] were more active for inhibiting vegetative mycelium growth than, respectively, the commercial N, N-diethyldithiocarbamic acid sodium salt and Maneb. The structure activity of these new compounds is discussed.     

Pharmacokinetics of intravenous ketorolac in cats undergoing gonadectomy

AIM: To determine the pharmacokinetics of ketorolac tromethamine (0.5?mg/kg) when administered I/V to cats undergoing gonadectomy.

METHODS: Ketorolac was administered to nine female and three male shorthair domestic cats as an I/V bolus of 0.5?mg/kg after intubation, and 20 minutes prior to ovariectomy or orchiectomy. Intra-operative cardiorespiratory variables were monitored and blood samples were collected over 24 hours. Concentrations of ketorolac in serum were determined by high-performance liquid chromatography to establish pharmacokinetic parameters.

RESULTS: During surgery, mean end tidal isoflurane concentration was 1.63 (SD 0.24)% and normocapnia and spontaneous ventilation were maintained in all animals. The kinetics of ketorolac was described by a two-compartment model. The distribution and elimination half-lives were 0.09 (SD 0.06) and 4.14 (SD 1.18) hours, respectively. The body clearance was 56.8 (SD 33.1) mL/h/kg. The volume of distribution at steady-state and the mean residence time were 323.9 (SD 115.7) mL/kg and 6.47 (SD 2.86) hours, respectively.

CONCLUSION AND CLINICAL RELEVANCE: On the basis of the results, concentrations of ketorolac in serum in cats were above the human effective concentrations for 5–6 hours postoperatively. However, other studies including a control group are advocated to further investigate the ketorolac kinetics and the analgesic efficacy in this species.     

Impact of fertilization on cover crops and microbial community on a bauxite‐mined soil undergoing reclamation

The reclamation of bauxite‐mined areas can be favored by the application of organic and/or chemical fertilization to restore the vegetation. Otherwise, the impact of fertilizations on soil microbiota or plant–microbe interactions as land reclamation progresses is less understood. To address this issue, we evaluated the impact of organic and chemical fertilization on plants and soil microbial community within the first 36 months of land reclamation in a bauxite‐mined site. The experiment was set up according to a split‐plot design in which the main plots received fertilizations [non‐fertilized control (NF), chemical fertilization (CF; NPK and rock phosphate), organic fertilization (OF; poultry litter), and CF+OF combined], and the subplots received cover crops [no cover crops (NC), grass (B; Brachiaria), legume (S, Stylosanthes), and B+S combined]. Cover crops biomass yield was assessed annually with five field campaigns per year. We used phospholipid fatty acids (PLFAs) to infer the impacts of mining and restoration practices on actinobacteria, Gram‐negative and Gram‐positive bacteria, arbuscular mycorrhizal fungi, and fungi. Accordingly, PLFAs were determined before bauxite mining (pre‐mining), six months after topsoil reconfiguration (post‐mining), and after 14 and 36 months following the application of the fertilizations and cover crops. PLFAs results indicated that in post‐mining, the living microbiota was significantly lower than in pre‐mining. Cover crops biomass yield was highest for B and B+S fertilized with CF+OF at 14 and 36 months. Both parametric and non‐parametric statistics showed a temporal variation in the response of living microbes to the treatments applied. After 14 months, living microbes showed greatest response to OF, while at 36 months their response was strongest in the treatments with highest plant biomass production (B and B+S). These results suggest that in the early stages of land reclamation, living microbial biomass benefit the most from organic fertilizers. As this initial boost decline, living microbes are more likely to thrive in areas undergoing reclamation where they can develop synergistic interactions with plants.     

School food in Mexican children

OBJECTIVE: To establish the school eating habits of Mexican children, who are prone to obesity and later to high rates of adult chronic diseases. DESIGN: Questionnaires for students and parents with staff questionnaires and interviews. SETTING: Randomly sampled schools in a socio-economically representative district of Mexico City. SUBJECTS: Subjects were 1504 adolescents aged 10-19 years attending schools in Mexico City, 27 teachers and seven headmasters, sampled from both public and private schools and from the full range of socio-economic groups. RESULTS: Foods brought from home were of a higher nutritional quality than those purchased at school, where purchases were dominated by crisps, soft drinks and other items with high energy density. Girls were more inclined to purchase inappropriately; those from poorer homes purchased less. Private-school students irrespective of socio-economic grade brought more food from home and purchased more expensive food at school. School policies allowed food and drink vendors to market any products within the schools, which benefited financially from these activities. CONCLUSIONS: Current school food policies are conducive to amplifying the current epidemic of obesity and related adult chronic diseases, and need to change.     

Cat and dog ownership and management patterns in central Italy

Three hundred and ninety-seven randomly selected households were interviewed by telephone to determine the numbers and management of owned cats and dogs in the Teramo Province of Italy. The households were selected using stratified random sampling for each municipality; municipalities were combined into coastal, central hills and mountain regions for analysis. The interviews were completed during May and June of 2004 with a response rate of 74% (397/536). Forty-six percent of households (n=181) owned pets; 15% of all households (n=60) owned cats and 33% (n=130) owned dogs. Twenty-seven of these households (7%) owned both cats and dogs. Data were provided on 91 cats evenly divided between males and females. The median age was 3 years (range 0.2-10 years). Forty-one percent of cats (36/87) entered the household as strays. Nearly half lived entirely outside. Seventy percent (62/88) had visited a veterinarian at least once; 43% (39/91) were sterilized. About 1/3 had had a litter and all litters were considered accidental rather than planned. Age, indoor/outdoor status, veterinarian visit and region were all associated with sterilization. Age, confined to a yard, veterinary visit and region were associated with allowing the cat to roam freely. Data were provided on 182 dogs. Sixty-two percent (113/181) were male, with a median age of 4 years (range newborn to 17 years) and 40% (72/181) were purebred. Almost half were acquired as a gift. Sixty-two percent (112/180) were kept entirely outside despite the fact that 82% (147/180) were considered companions rather than working dogs. Almost all of the dogs had been to a veterinarian at least once; only 20% (n=29) were sterilized. Male dogs were significantly less likely to be sterilized than females. Almost half the dogs had had at least one litter. Seventy-six percent (137/180) of dogs knew some basic commands. Sex, source and training to sit/stay/come were significantly associated with whether the dog was sterilized. Dog size, confinement to a yard, trained to leash walk, veterinary visit and region were predictors of roaming freely. Source and trained to leash walk were associated with dog registration. For cats and dogs, education about sterilization seemed to be critically important. For dogs, factors relating to training, which may reflect the strength of the human-animal bond, were also important.