Pharmacokinetics, pharmacodynamics, toxicology and therapeutics of mavacoxib in the dog: a review.

Mavacoxib is a novel nonsteroidal anti-inflammatory drug (NSAID), with a preferential action on the cyclooxygenase (COX)-2 isoform of COX and a long duration of action. It is classified chemically as a member of the sulphonamide subgroup of coxibs. Mavacoxib is highly lipid but very poorly water soluble. In the dog, the pharmacokinetic (PK) profile comprises very slow body clearance, long elimination half-life and a relatively large distribution volume. Biotransformation and renal excretion are very limited, and elimination occurs primarily by biliary secretion and excretion of unchanged drug in faeces. The PK profile of mavacoxib differs quantitatively between young healthy dogs (Beagles and mongrels) and clinical cases with osteoarthritis (OA). In OA dogs, mavacoxib exhibits a much longer terminal half-life, associated principally with their greater median body weight compared with dogs used in preclinical studies. There is also some evidence of breed differences and a small effect of age on mavacoxib PK in the OA canine population. The pharmacodynamics (PD) of mavacoxib has been established: (i) in whole blood assays at the molecular level (inhibition of COX-1 and COX-2 isoforms); (ii) in preclinical models of inflammation and pain; and (iii) in clinical OA subjects treated with mavacoxib. The dosage schedule of mavacoxib for clinical use has been determined by owner and veterinary clinical assessments and is supported by integration of PK and PD preclinical data with clinical responses in canine disease models and in dogs with naturally occurring OA. The dosage regimen has been further confirmed by correlating levels of inhibition of COX isoforms in in vitro whole blood assays with plasma concentrations of mavacoxib achieved in OA dogs. In addition to the specific properties of mavacoxib, some general aspects of the PK and PD of other agents of the NSAID group, together with pathophysiological and clinical aspects of OA, are reviewed, as a basis for correlating with the safety and efficacy of mavacoxib in therapeutic use. Integration of PK and PD data suggests that the recommended dosage regimen of 2 mg/kg bw once for 14 days, followed by administration at monthly intervals, is optimal from both efficacy and safety perspectives and is further confirmed by clinical field studies.

Comparative efficacy and safety of mavacoxib and carprofen in the treatment of canine osteoarthritis.

A multi-site, masked, randomised parallel group study employing a double dummy treatment design was performed in canine veterinary patients to determine the comparative efficacy and safety of mavacoxib and carprofen in the treatment of pain and inflammation associated with osteoarthritis for a period of 134 days. Treatments were administered according to their respective summaries of product characteristics. Of 139 dogs screened, 124 were suitable for study participation: 62 of which were dosed with mavacoxib and 62 with carprofen. Both treatments resulted in a very similar pattern of considerable improvement as indicated in all parameters assessed by both owner and veterinarian. The primary efficacy endpoint 'overall improvement' was a composite score of owner assessments after approximately six weeks of treatment. Both drugs were remarkably effective, with 57/61 (93.4 per cent) of mavacoxib-treated dogs and 49/55 (89.1 per cent) of carprofen-treated dogs demonstrating overall improvement and with mavacoxib's efficacy being non-inferior to carprofen. The treatments had a similar safety profile as evidenced by documented adverse events and summaries of clinical pathology parameters. The positive clinical response to treatment along with the safety and dosing regimen of mavacoxib makes it an attractive therapy for canine osteoarthritis.

The pharmacokinetics of oclacitinib maleate, a Janus kinase inhibitor, in the dog.

The pharmacokinetics of oclacitinib maleate was evaluated in four separate studies. The absolute bioavailability study used a crossover design with 10 dogs. The effect of food on bioavailability was investigated in a crossover study with 18 dogs. The breed effect on pharmacokinetics was assessed in a crossover study in beagles and mongrels dogs. Dose proportionality and multiple dose pharmacokinetics were evaluated in a parallel design study with eight dogs per group. In all four studies, serial blood samples for plasma were collected. Oclacitinib maleate was rapidly and well absorbed following oral administration, with a time to peak plasma concentration of <1 h and an absolute bioavailability of 89%. The prandial state of dogs did not significantly affect the rate or extent of absorption of oclacitinib maleate when dosed orally, as demonstrated by the lack of significant differences in pharmacokinetic parameters between the oral fasted and oral fed treatment groups. The pharmacokinetics of oclacitinib in laboratory populations of beagles and mixed breed dogs also appeared similar. Following oral administration, the exposure of oclacitinib maleate increased dose proportionally from 0.6 to 3.0 mg/kg. Additionally, across the pharmacokinetic studies, there were no apparent differences in oclacitinib pharmacokinetics attributable to sex.

Population pharmacokinetics of mavacoxib in osteoarthritic dogs.

Mavacoxib (Trocoxil™) is an oral long-acting COX-2 inhibitor approved for the treatment of osteoarthritis in dogs. Two field trials were conducted in client-owned dogs suffering from osteoarthritis, with dosages of 4 mg/kg body weight (BW) (Study 1) or 2 mg/kg BW (Study 2). Mavacoxib plasma concentrations were determined from trough blood samples and from blood samples collected at 4-10 months after the last dose. A one-compartment linear model was fitted to the concentration data (1317 concentration records from 286 patients), and parameters for oral clearance (Cl/F), apparent volume of distribution (V(d) /F) and their between-subject variabilities (BSV) were estimated. Covariates were included in the model based on the outcomes of stepwise regression procedures. In the final model, the typical value of Cl/F was a function of BW, age and breed. German shepherds and Labrador retrievers were found to have 31% higher values of Cl/F than patients from different breeds with similar ages and BWs. The typical value of V(d) /F was found to be dependent only on BW. The two field studies appeared to differ similarly with respect to Cl/F and V(d) /F. The explanation for this difference is not known, but the difference was accounted for in the final model as a 23.9% lower bioavailability in Study 2. Mavacoxib exhibited relatively broad BSV in Cl/F and V(d) /F, with coefficients of variation of 47% and 19%, respectively. The typical value for mavacoxib's terminal elimination plasma half-life (t(1/2) ) was 44 days, but a minority of patients (approximately 5%) had empirical Bayes estimates of t(1/2) exceeding 80 days. Simulations with the model indicated that the majority of patients treated with mavacoxib 2 mg/kg will maintain trough plasma mavacoxib concentrations associated with efficacy. Results of the population pharmacokinetic analysis helped to reduce the dose from 4 to 2 mg/kg and thus increased the therapeutic index for this molecule.

Development of an evaluation function for eye-hand coordination robotic therapy.

This paper is the continuation of a work presented at ICORR 07, in which we discussed the possibility of improving eye-hand coordination in children diagnosed with this problem, using a robotic mapping from a haptic user interface to a virtual environment. Our goal is to develop, implement and refine a system that will assess and improve the eye-hand coordination and grip strength in children diagnosed with poor graphomotor skills. A detailed analysis of patters (e.g., labyrinths, letters and angles) was conducted in order to select three very distinguishable levels of difficulty that could be included in the system, and which would yield the greatest benefit in terms of assessment of coordination and strength issues as well as in training. Support algorithms (position, force, velocity, inertia and viscosity) were also developed and incorporated into the tasks in order to introduce general computer assistance to the mapping of the user's movements to the computer screen without overriding the user's commands to the robotic device. In order to evaluate performance (given by %accuracy and time) of the executed tasks, a sophisticated evaluation function was designed based on image analysis and edge detection algorithms. This paper presents the development of the haptic tasks, the various assistance algorithms, the description of the evaluation function and the results of a study implemented at the Motor Development Clinic at Cal Poly Pomona. The results (Accuracy and Time) of this function are currently being used as inputs to an Intelligent Decision Support System (described in), which in turn, suggests the next task to be executed by the subject based on his/her performance.

The pharmacokinetics of mavacoxib, a long-acting COX-2 inhibitor, in young adult laboratory dogs.

The pharmacokinetics of mavacoxib were evaluated in an absolute bioavailability study, a dose-proportionality study and a multi-dose study in young healthy adult laboratory Beagle dogs and in a multi-dose safety study in Beagle-sized laboratory Mongrel dogs. When administered as the commercial tablet formulation at 4 mg/kg body weight (bw) to fasted dogs, the absolute bioavailability (F) of mavacoxib was 46.1%; F increased to 87.4% when mavacoxib was administered with food. Following intravenous administration, the total body plasma clearance of mavacoxib was 2.7 mL·h/kg, and the apparent volume of distribution at steady-state was 1.6 L/kg. The plasma protein binding of mavacoxib was approximately 98% in various in vitro and ex vivo studies. The dose-normalized area under the plasma concentration-time curve was similar in Beagle and Beagle-sized Mongrel dogs when mavacoxib was administered with food. Mavacoxib exhibited dose-proportional pharmacokinetics for single oral doses of 2-12 mg/kg in Beagle dogs and for multiple oral doses of 5-25 mg/kg in Beagle-sized Mongrel dogs. Only minor accumulation occurred when mavacoxib was administered at doses of 2-25 mg/kg bw orally to laboratory dogs with a 2-week interval between the 1st two doses but with a monthly interval thereafter. Across all three Beagle studies (n = 63) the median terminal elimination half-life (t(½) ) was 16.6 days, with individual values ranging 7.9-38.8 days. The prolonged t(½) for mavacoxib supports the approved regimen in which doses are separated by 2-4 weeks.

Efficacy and safety of cefovecin for the treatment of urinary tract infections in cats.

OBJECTIVES: To determine the efficacy and safety of cefovecin (Convenia); Pfizer Animal Health) in the treatment of urinary tract infections in cats. METHOD: A multi-centre, masked, randomised study was conducted in cats presenting with clinical signs indicative of urinary tract infections. Cephalexin (Rilexine); Virbac) administered orally twice daily at 15 mg/kg bodyweight for 14 days was compared with a single subcutaneous injection of cefovecin in cats. The primary efficacy parameter assessed was bacterial elimination of the pretreatment uropathogen. RESULTS: Four hundred and thirty-four cats were screened for urinary tract infections. One hundred and eighty-five cats were treated with either cefovecin (n=124) or cephalexin (n=61). Ninety-seven cats (22.2 per cent) had confirmed bacteriuria and 82 cats were included in efficacy analysis. Escherichia coli was eliminated in 76.7 per cent (23 of 30) of cefovecin-treated cats compared with 62.5 per cent (10 of 16) of cephalexin-treated cats. Cefovecin demonstrated statistical non-inferiority compared with cephalexin for bacterial elimination. There were no suspected adverse drug reactions attributable to treatment with cefovecin or cephalexin. CLINICAL SIGNIFICANCE: Cefovecin was demonstrated to be an effective and safe treatment for urinary tract infections.

The efficacy and safety of cefovecin in the treatment of feline abscesses and infected wounds.

OBJECTIVES: To determine the efficacy and safety of cefovecin for the treatment of bacterial abscesses and wounds in cats at clinics in Germany, France, Spain and the UK. METHOD: Cats with abscesses or wounds were enrolled. Cats (217) were randomised to treatment with either cefovecin administered by subcutaneous injection at 14 day intervals or amoxicillin/clavulanic acid as twice-daily oral tablets for 14 days. Treatment courses were repeated at 14 day intervals, when deemed necessary. Clinicians assessing lesions were masked to treatment allocation. Only animals with a confirmed pretreatment bacterial pathogen were included in the efficacy analysis. Cases were evaluated 28 days after initiation of the final course of treatment. RESULTS: Cefovecin was as efficacious as amoxicillin/clavulanic acid, and efficacy was 100 per cent for both treatments. CLINICAL SIGNIFICANCE: Cefovecin, administered as a single subcutaneous injection repeated at 14 day intervals as required, was shown to be as efficacious as oral amoxicillin/clavulanic acid in the treatment of abscesses/wounds in cats.

Clinical efficacy and safety of cefovecin in the treatment of canine pyoderma and wound infections.

OBJECTIVES: To determine the efficacy and safety of cefovecin in the treatment of bacterial skin infections in dogs. METHOD: Dogs with superficial or deep pyoderma or wounds/abscesses were enrolled in three separate studies. Dogs (354) were randomised to treatment and received either cefovecin administered by subcutaneous injection at 14 day intervals, as clinically necessary, or amoxicillin/clavulanic acid as oral tablets twice daily for 14 days. Courses of treatment were repeated at 14 day intervals up to a total of four courses. Clinicians responsible for assessing lesions were masked to treatment allocation. Only animals where the presence of a pretreatment bacterial pathogen was confirmed were included in the analysis of efficacy. Cases were evaluated for clinical efficacy at 28 days after initiation of the final course of treatment. Clinical efficacy was assessed by scoring the clinical signs typical of skin infections. RESULTS: Cefovecin demonstrated statistical non-inferiority compared with amoxicillin/clavulanic acid for all three clinical diagnoses; for cefovecin, up to 96.9 per cent efficacy was observed versus 92.5 per cent for amoxicillin/clavulanic acid. CLINICAL SIGNIFICANCE: Cefovecin was shown to be as effective as amoxicillin/clavulanic acid administered orally in the treatment of bacterial skin infections in dogs. Cefovecin offers the additional benefit of eliminating owner non-compliance.

Efficacy and safety of cefovecin (Convenia) for the treatment of urinary tract infections in dogs.

OBJECTIVES: To determine the efficacy and safety of cefovecin (Convenia); Pfizer Animal Health) in the treatment of urinary tract infections in dogs. METHODS: A multi-centre, blinded, randomised study was conducted in 129 dogs with urinary tract infections. Cephalexin (Rilexine) administered twice daily at 15 mg/kg bodyweight orally for 14 days was compared with a single, subcutaneous injection of cefovecin (Convenia) in dogs. The primary efficacy parameter assessed was bacterial elimination of the pretreatment uropathogen. RESULTS: One hundred and twenty-nine dogs were included in efficacy assessments. Escherichia coli was eliminated in 90.5 per cent of cefovecin-treated dogs compared with 52.9 per cent of cephalexin-treated dogs (P=0.0004). Overall cure rates for dogs with Escherichia coli infections were 79.1 per cent for cefovecin and 36.4 per cent for cephalexin-treated dogs (P=0.0003). There were no suspected adverse drug reactions attributed to treatment with cefovecin or cephalexin. CLINICAL SIGNIFICANCE: Cefovecin was shown to be an effective and safe treatment for urinary tract infections.

Pharmacokinetics and pharmacodynamics of cefovecin in dogs.

A series of in vivo, ex vivo and in vitro studies were conducted to determine the pharmacokinetic and pharmacodynamic properties of cefovecin, a new injectable cephalosporin, in dogs. Absolute bioavailability was determined in a two-phase cross-over study in dogs receiving 8 mg/kg bodyweight (b.w.) of cefovecin by either subcutaneous (s.c.) or intravenous (i.v.) route. After s.c. administration, cefovecin was fully bioavailable (100%), the mean maximum plasma concentration (Cmax) was 121 microg/mL and the mean apparent elimination half-life (t1/2) was 133 h. Clearance was measured to be 0.76 mL/h/kg after i.v. dosing. The concentration of cefovecin in urine measured 14 days after s.c. administration was 2.9 microg/mL. Plasma protein binding was determined by equilibrium dialysis; over concentrations ranging from 10 to 100 microg/mL (i.e. up to the approximate Cmax following an 8 mg/kg dose), protein binding of 98.7% to 96.0% was observed, however, binding was lower at higher concentrations. Total and free concentrations of cefovecin were determined in plasma, transudate and exudate collected from dogs previously implanted subcutaneously with tissue cages. Mean peak concentrations of free cefovecin were almost three times higher in transudate than in plasma and remained above 0.25 microg/mL for 19 days. The ex vivo antibacterial killing activity (vs. Staphylococcus intermedius, MIC 0.25 microg/mL) was measured in serum, transudate and exudate collected from dogs which had received 8 mg/kg b.w. of cefovecin subcutaneously. Transudate exhibited higher antimicrobial killing activity than serum. Activity in serum and exudate exhibited a mean reduction in bacterial counts of S. intermedius of at least three log units up to 72 h postadministration. Bactericidal activity (>3 log10 reduction of bacterial counts) was observed in transudate up to 12 days postadministration. The slow elimination and long lasting ex vivo antibacterial killing activity following administration of cefovecin are desirable pharmacokinetic and pharmacodynamic attributes for an antimicrobial drug with 14-day dosing intervals.

Pharmacokinetics of cefovecin in cats.

The pharmacokinetics of the novel cephalosporin cefovecin were investigated in a series of in vivo, ex vivo and in vitro studies following administration to adult cats at 8 mg/kg bodyweight. Bioavailability and pharmacokinetic parameters were determined in a cross-over study after intravenous (i.v.) and subcutaneous (s.c.) injections. [14C]cefovecin was used to evaluate excretion for 21 days after s.c. administration. Protein binding was determined in vitro in feline plasma and ex vivo in transudate from cats surgically implanted with tissue chambers. After s.c. administration, cefovecin was characterized by rapid absorption with mean peak plasma concentrations of 141+/-12 microg/mL being achieved within 2 h of s.c. injection with full bioavailability (99%). The mean elimination half-life was 166+/-18 h. After i.v. administration, volume of distribution was 0.09+/-0.01 L/kg and mean plasma clearance was 0.35+/-0.04 mL/h/kg. Approximately 50% of the administered radiolabelled dose was eliminated over the 21-day postdose period via urinary excretion and up to approximately 25% in faeces. In vitro and ex vivo plasma protein binding ranged from 99.8% to 99.5% over the plasma concentration range 10-100 microg/mL. Ex vivo protein binding in transudate was as low as 90.7%. From 8 h postdose, concentrations of unbound (free) cefovecin in transudate were consistently higher than in plasma, with mean unbound cefovecin concentrations being maintained above 0.06 microg/mL (MIC90 of Pasteurella multocida) in transudate for at least 14 days postdose. The slow elimination and long-lasting free concentrations in extracellular fluid are desirable pharmacokinetic attributes for an antimicrobial with a 14-day dosing interval.

Antimicrobial activity and spectrum of cefovecin, a new extended- spectrum cephalosporin, against pathogens collected from dogs and cats in Europe and North America.

Cefovecin is a new extended-spectrum semisynthetic cephalosporin indicated for the treatment of bacterial infections in dogs and cats. This study evaluated the in vitro activity and spectrum of cefovecin against 2,641 recent clinical isolates (1,660 canine and 981 feline isolates) from Europe and the United States. MIC determinations against cefovecin and other reference antimicrobials were performed by broth microdilution methods recommended by the Clinical and Laboratory Standards Institute (CLSI, formerly NCCLS). Cefovecin demonstrated bactericidal activity against both gram-positive and gram-negative pathogens. Cefovecin exhibited in vitro activity against all major aerobic and anaerobic bacterial pathogens associated with skin, urinary tract, and periodontal infections in dogs and cats. The MIC90 values of cefovecin against Staphylococcus intermedius, Escherichia coli, and Pasteurella multocida were 0.25 microg/ml, 1.0 microg/ml, and 0.06 microg/ml, respectively. No significant differences were observed in terms of the activities of cefovecin against pathogens from different European countries and against pathogens of European and U.S. origin.

Toll-like receptor (TLR) polymorphisms in African children: common TLR-4 variants predispose to severe malaria.

Genetic host factors play a substantial role in susceptibility to and severity of malaria, which continues to cause at least one million deaths per year. Recently, members of the toll-like receptor (TLR) family have been shown to be involved in recognition of the etiologic organism Plasmodium falciparum: The glycosylphosphatidylinisitol anchor induces signaling in host cells via TLR-2 and -4, while hemozoin-induced immune activation involves TLR-9. Binding of microbial ligands to the respective TLRs triggers the release of pro-inflammatory cytokines via the TLR/IL-1 receptor (TIR) domain and may contribute to the host response, including pro-inflammatory cytokine induction and malarial fever. In a case-control study among 870 Ghanaian children, we examined the influence of TLR-2, -4, and -9 polymorphisms in susceptibility to severe malaria. TLR-2 variants common in Caucasians and Asians were completely absent. However, we found a new, rare mutation (Leu658Pro), which impairs signaling via TLR-2. We failed to detect any polymorphisms within the TLR-9/interleukin-1 receptor domain. Two frequent TLR-9 promoter polymorphisms did not show a clear association with malaria severity. In contrast, the TLR-4-Asp299Gly variant occurred at a high rate of 17.6% in healthy controls, and was even more frequent in severe malaria patients (24.1%, p<0.05). Likewise, TLR-4-Thr399Ile was seen in 2.4% of healthy children and in 6.2% of patients (p=0.02). TLR-4-Asp299Gly and TLR-4-Thr399Ile conferred an 1.5- and 2.6-fold increased risk of severe malaria, respectively. These findings suggest TLR4-mediated responses to malaria in vivo and TLR-4 polymorphisms to be associated with disease manifestation. However some gray areas also suggest the scope for further improvements.

Comparative susceptibilities of various animal-pathogenic mycoplasmas to fluoroquinolones.

The in vitro activities of six antimicrobial agents were tested against 162 mycoplasma strains of eight species isolated from poultry and livestock at different geographic sites. Tiamulin was most active (MICs at which 90% of the isolates were inhibited [MIC90s], 0.025 to 0.25 microg/ml); enrofloxacin and danofloxacin had near equivalent activities (MIC90s, 0.05 to 1.0 microg/ml), but were much more active than flumequine (MIC90s, 1 to 50 microg/ml). The MIC90s of tylosin and oxytetracycline were 0.25 to > 100 microg/ml and 0.25 to 100 microg/ml, respectively.

The cell surface of isolated cardiac myocytes--a light microscope study with use of fluorochrome-coupled lectins.

In cells isolated from guinea-pig or rat ventricular muscle occurrence and distribution of carbohydrate components of the surface coat were monitored using fluorochrome-coupled lectins. Fluorescence of membrane-bound lectins was assayed by an image analysis system. The lectins ConA, WGA, sWGA, LFA and RCA-I showed specific binding to the whole myocyte surface, indicating a homogeneous distribution of alpha-mannosyl, alpha-glycosyl, N-acetylglucosaminyl, N-acetylneuraminate and beta-galactosyl residues. Binding of DBA and SBA, with specific affinity for N-acetylgalactosaminyl residues, to guinea-pig cardiac myocytes was mainly at the cell poles corresponding to intercalated discs in intact tissue. Both lectins failed to interact with rat myocytes. UEA-I, specific for alpha-L-fucose, bound slightly to rat and not to guinea-pig myocytes. Binding of PNA to guinea-pig myocytes was observed only after cleaving off sialic acids from cell surface, suggesting that sialic acids mask galactosyl-beta(1,3)-N-acetylgalactosamine residues. Specificity of lectin-cell interaction was tested by an inhibition assay where free sugars were tested for their capacity to inhibit lectin binding to the myocytes. When comparing different isolation procedures based on different proteolytic enzymes, the myocytes' affinity to any lectin was found to be qualitatively unchanged. Investigation of lectin-decorated myocytes by means of confocal laser scan microscopy showed that lectin binding sites are not confined to the cell surface but are also present in sarcolemmal invaginations, i.e. transverse tubules. This suggests that the tubular system is lined with a carbohydrate layer similar to, and continuous with, that of the peripheral cell surface.