Scale-Resolving Simulations of Steady and Pulsatile Flow Through Healthy and Stenotic Heart Valves.

Blood-flow downstream of stenotic and healthy aortic valves exhibits intermittent random fluctuations in the velocity field which are associated with turbulence. Such flows warrant the use of computationally demanding scale-resolving models. The aim of this work was to compute and quantify this turbulent flow in healthy and stenotic heart valves for steady and pulsatile flow conditions. Large eddy simulations (LESs) and Reynolds-averaged Navier-Stokes (RANS) simulations were used to compute the flow field at inlet Reynolds numbers of 2700 and 5400 for valves with an opening area of 70 mm2 and 175 mm2 and their projected orifice-plate type counterparts. Power spectra and turbulent kinetic energy were quantified on the centerline. Projected geometries exhibited an increased pressure-drop (>90%) and elevated turbulent kinetic energy levels (>147%). Turbulence production was an order of magnitude higher in stenotic heart valves compared to healthy valves. Pulsatile flow stabilizes flow in the acceleration phase, whereas onset of deceleration triggered (healthy valve) or amplified (stenotic valve) turbulence. Simplification of the aortic valve by projecting the orifice area should be avoided in computational fluid dynamics (CFD). RANS simulations may be used to predict the transvalvular pressure-drop, but scale-resolving models are recommended when detailed information of the flow field is required.

The impact of shape uncertainty on aortic-valve pressure-drop computations.

Patient-specific image-based computational fluid dynamics (CFD) is widely adopted in the cardiovascular research community to study hemodynamics, and will become increasingly important for personalized medicine. However, segmentation of the flow domain is not exact and geometric uncertainty can be expected which propagates through the computational model, leading to uncertainty in model output. Seventy-four aortic-valves were segmented from computed tomography images at peak systole. Statistical shape modeling was used to obtain an approximate parameterization of the original segmentations. This parameterization was used to train a meta-model that related the first five shape mode coefficients and flowrate to the CFD-computed transvalvular pressure-drop. Consequently, shape uncertainty in the order of 0.5 and 1.0 mm was emulated by introducing uncertainty in the shape mode coefficients. A global variance-based sensitivity analysis was performed to quantify output uncertainty and to determine relative importance of the shape modes. The first shape mode captured the opening/closing behavior of the valve and uncertainty in this mode coefficient accounted for more than 90% of the output variance. However, sensitivity to shape uncertainty is patient-specific, and the relative importance of the fourth shape mode coefficient tended to increase with increases in valvular area. These results show that geometric uncertainty in the order of image voxel size may lead to substantial uncertainty in CFD-computed transvalvular pressure-drops. Moreover, this illustrates that it is essential to assess the impact of geometric uncertainty on model output, and that this should be thoroughly quantified for applications that wish to use image-based CFD models.

Combining statistical shape modeling, CFD, and meta-modeling to approximate the patient-specific pressure-drop across the aortic valve in real-time.

BACKGROUND: Advances in medical imaging, segmentation techniques, and high performance computing have stimulated the use of complex, patient-specific, three-dimensional Computational Fluid Dynamics (CFD) simulations. Patient-specific, CFD-compatible geometries of the aortic valve are readily obtained. CFD can then be used to obtain the patient-specific pressure-flow relationship of the aortic valve. However, such CFD simulations are computationally expensive, and real-time alternatives are desired. AIM: The aim of this work is to evaluate the performance of a meta-model with respect to high-fidelity, three-dimensional CFD simulations of the aortic valve. METHODS: Principal component analysis was used to build a statistical shape model (SSM) from a population of 74 iso-topological meshes of the aortic valve. Synthetic meshes were created with the SSM, and steady-state CFD simulations at flow-rates between 50 and 650 mL/s were performed to build a meta-model. The meta-model related the statistical shape variance, and flow-rate to the pressure-drop. RESULTS: Even though the first three shape modes account for only 46% of shape variance, the features relevant for the pressure-drop seem to be captured. The three-mode shape-model approximates the pressure-drop with an average error of 8.8% to 10.6% for aortic valves with a geometric orifice area below 150 mm2 . The proposed methodology was least accurate for aortic valve areas above 150 mm2 . Further reduction to a meta-model introduces an additional 3% error. CONCLUSIONS: Statistical shape modeling can be used to capture shape variation of the aortic valve. Meta-models trained by SSM-based CFD simulations can provide an estimate of the pressure-flow relationship in real-time.

Estimation of valvular resistance of segmented aortic valves using computational fluid dynamics.

Aortic valve stenosis is associated with an elevated left ventricular pressure and transaortic pressure drop. Clinicians routinely use Doppler ultrasound to quantify aortic valve stenosis severity by estimating this pressure drop from blood velocity. However, this method approximates the peak pressure drop, and is unable to quantify the partial pressure recovery distal to the valve. As pressure drops are flow dependent, it remains difficult to assess the true significance of a stenosis for low-flow low-gradient patients. Recent advances in segmentation techniques enable patient-specific Computational Fluid Dynamics (CFD) simulations of flow through the aortic valve. In this work a simulation framework is presented and used to analyze data of 18 patients. The ventricle and valve are reconstructed from 4D Computed Tomography imaging data. Ventricular motion is extracted from the medical images and used to model ventricular contraction and corresponding blood flow through the valve. Simplifications of the framework are assessed by introducing two simplified CFD models: a truncated time-dependent and a steady-state model. Model simplifications are justified for cases where the simulated pressure drop is above 10 mmHg. Furthermore, we propose a valve resistance index to quantify stenosis severity from simulation results. This index is compared to established metrics for clinical decision making, i.e. blood velocity and valve area. It is found that velocity measurements alone do not adequately reflect stenosis severity. This work demonstrates that combining 4D imaging data and CFD has the potential to provide a physiologically relevant diagnostic metric to quantify aortic valve stenosis severity.

Efficacy of a novel inactivated Lawsonia intracellularis vaccine in pigs against experimental infection and under field conditions.

The efficacy of a novel inactivated Lawsonia intracellularis vaccine, Porcilis® Lawsonia, was compared to that of a commercially available live attenuated vaccine in three experimental vaccination-challenge studies in pigs. The efficacy of the new vaccine was further tested under field conditions on a farm with a history of acute ileitis. The novel inactivated vaccine consists of a freeze-dried antigen fraction that is dissolved just prior to use in either the adjuvant or in Porcilis® PCV M Hyo; an existing combination vaccine against porcine circovirus type 2 and Mycoplasma hyopneumoniae. The three experimental vaccination-challenge trials had a similar design and for each trial 75 piglets were used, randomly allotted to three groups of 25 piglets. The pigs were vaccinated at 4 or 5 weeks of age with either Porcilis® Lawsonia in adjuvant or in associated mixed use with Porcilis® PCV M Hyo (group 1), with the live vaccine (group 2), or left as unvaccinated controls (group 3). The pigs were challenged with virulent Lawsonia intracellularis 3, 4 or 17 weeks after vaccination. Post-challenge the pigs were evaluated for clinical signs, average daily weight gain, shedding and macroscopic as well as microscopic immuno-histological ileum lesion scores. In the field study, the mortality and key performance parameters were evaluated over a period of 8 months. The results of all three experimental vaccination-challenge trials showed that Porcilis® Lawsonia induced statistically significant protection against experimental Lawsonia intracellularis infection. This was demonstrated by lower clinical scores, improved weight gain, reduction of Lawsonia intracellularis shedding and reduction of macroscopic as well as microscopic ileum lesion scores when compared to the controls. The protection induced was superior to that of the commercially available live vaccine. In the field study, Porcilis® Lawsonia proved to be highly efficacious; reducing Lawsonia associated mortality to zero and improving key production parameters.

Safety and efficacy of a new octavalent combined Erysipelas, Parvo and Leptospira vaccine in gilts against Leptospira interrogans serovar Pomona associated disease and foetal death.

The safety and protective efficacy of a new octavalent combination vaccine containing inactivated Erysipelothrix rhusiopathiae, Parvovirus, and Leptospira interrogans (sensu lato) serogroups Canicola, Icterohaemorrhagiae, Australis (Bratislava), Grippotyphosa, Pomona and Tarassovi - Porcilis(®) Ery+Parvo+Lepto - was evaluated in laboratory studies and under field conditions. The safety (2× overdose and repeated dose) was tested in 26 gilts. In this study, neither vaccine related temperature increase nor other systemic reactions were observed after intramuscular vaccination. No local reactions were observed except for one animal that had a small local reaction (2cm diameter) that lasted for 5 days after the third vaccination. Efficacy was tested in 40 gilts. A group of 20 gilts was vaccinated at 20 and 24 weeks of age with Porcilis(®) Ery+Parvo+Lepto and a group of 20 age- and source-matched animals served as the control group. The gilts were inseminated at 41 weeks or 66 weeks of age and were challenged with serovar Pomona 10 weeks after insemination, corresponding to 6 months (n=2×10) and 12 months (n=2×10) after the last vaccination. After both the 6- and 12-month challenges the control animals developed clinical signs (fever, lethargy and anorexia) and leptospiraemia as determined by positive blood culture. In addition, both the 6- and 12-month challenges resulted in death of 21% and 27% of the total number of foetuses in the control groups, respectively. Clinical signs and leptospiraemia were statistically significantly lower in vaccinated gilts after both the 6- and 12-month challenges. In addition, foetal death was statistically significantly lower (3% and 2%, respectively) in vaccinated gilts after both the 6- and 12 month challenges. The vaccine was tested further under field conditions on a Portuguese farm with a history of an increasing abortion rate associated with a Leptospira serovar Pomona infection (confirmed by PCR and serology). This study was designed as an observational-longitudinal field study. At the start of the study, all breeding sows and replacement gilts on the farm were vaccinated twice with Porcilis(®) Ery+Parvo+Lepto at an interval of 4 weeks. Starting six months after the primary vaccination schedule, the animals were re-vaccinated during the second week of every subsequent lactation. New replacement gilts were vaccinated using the same schedule. After vaccination, the abortion rate reduced rapidly from 12.6% in winter months of 2012 (December 2011 to March 2012) to 0.5% in winter months of 2013, a statistical significant decrease of 96%. The total number of abortions on the farm decreased from 55 in 2012 to 6 in 2013. Thereafter, the abortion rate remained stable and in the period December 2013 to April 2014 was still low (0.6%). In conclusion, the present studies demonstrate that the octavalent Porcilis(®) Ery+Parvo+Lepto vaccine can be safely used in gilts and sows and induces significant protection, for the duration of at least one year, against serovar Pomona induced clinical signs, leptospiraemia and foetal death. Protection against Pomona associated reproductive failure was confirmed under field conditions where a significant reduction in abortion rate was observed.

A novel octavalent combined Erysipelas, Parvo and Leptospira vaccine provides (cross) protection against infection following challenge of pigs with 9 different Leptospira interrogans serovars.

BACKGROUND: In the present study the efficacy and cross protection of a novel ready-to-use combination vaccine, Porcilis® Ery + Parvo + Lepto, against swine leptospirosis, was investigated. The octavalent vaccine contains inactivated antigens of Erysipelothrix rhusiopathiae, Parvovirus and 6 Leptospira interrogans sensu lato strains of serogroups Canicola, Icterohaemorrhagiae, Grippotyphosa, Australis (Bratislava), Pomona and Tarassovi. In this study ninety pigs were vaccinated twice with Porcilis® Ery + Parvo + Lepto at six and ten weeks of age and ninety age and source-matched animals served as unvaccinated control. Two weeks after booster vaccination, groups of vaccinated and control pigs (ten pigs per group) were challenged with fresh virulent cultures of either of the nine different challenge strains. Compared to the vaccine strains the challenge strains were heterologous strains of the same serovar or of a different serovar within the same serogroup. The challenge strains tested were of serovar Canicola, Icterohaemorrhagiae, Copenhageni (serogroup Icterohaemorrhagiae), Grippotyphosa, Bananal/Liangguan (serogroup Grippotyphosa), Pomona, Tarassovi and Vughia (serogroup Tarassovi). RESULTS: After the different challenges most control animals became leptospiraemic for 2-7 days. The vaccinated pigs remained blood culture negative except for two animals after serovar Icterohaemorrhagiae and two animals after serovar Tarassovi challenge which became leptospiraemic for only 1 day. The incidence of Leptospiraemia (as determined by blood culture) was significantly less in vaccinates compared to the controls after all challenges. The vaccine also prevented renal infection and urinary shedding after serovar Canicola challenge. The other serovars did not induce detectable renal infection or urinary shedding. CONCLUSION: The present study demonstrates that the new combination vaccine Porcilis® Ery + Parvo + Lepto induces significant (cross) protection against nine different serovars within the serogroups Canicola, Icterohaemorrhagiae, Grippotyphosa, Australis (Bratislava), Pomona and Tarassovi.

Erratum to: A novel octavalent combined Erysipelas, Parvo and Leptospira vaccine provides (cross) protection against infection following challenge of pigs with 9 different Leptospira interrogans serovars.

[This corrects the article DOI: 10.1186/s40813-015-0011-0.].

Efficacy of a non-updated, Matrix-C-based equine influenza subunit-tetanus vaccine following Florida sublineage clade 2 challenge.

Assessing the ability of current equine influenza vaccines to provide cross-protection against emerging strains is important. Horses not vaccinated previously and seronegative for equine influenza based on haemagglutination inhibition (HI) assay were assigned at random to vaccinated (n=7) or non-vaccinated (control, n=5) groups. Vaccination was performed twice four weeks apart with a 1 ml influenza subunit (A/eq/Prague/1/56, A/eq/Newmarket/1/93, A/eq/Newmarket/2/93), tetanus toxoid vaccine with Matrix-C adjuvant (EquilisPrequenza Te). All the horses were challenged individually by aerosol with A/eq/Richmond/1/07 three weeks after the second vaccination. Rectal temperature, clinical signs, serology and virus excretion were monitored for 14 days after challenge. There was no pain at the injection site or increases in rectal temperature following vaccination. Increases in rectal temperature and characteristic clinical signs were recorded in the control horses. Clinical signs were minimal in vaccinated horses. Clinical (P=0.0345) and total clinical scores (P=0.0180) were significantly lower in the vaccinated than in the control horses. Vaccination had a significant effect on indicators of viraemia - the extent (P=0.0006) and duration (P=<0.0001) of virus excretion and the total amount of virus excreted (AUC, P=0.0006). Vaccination also had a significant effect (P=0.0017) on whether a horse was positive or negative for virus excretion during the study. Further research is needed to fully understand the specific properties of this vaccine that may contribute to its cross-protective capacity.

Tunable resistivity of individual magnetic domain walls.

Despite the relevance of current-induced magnetic domain wall (DW) motion for new spintronics applications, the exact details of the current-domain wall interaction are not yet understood. A property intimately related to this interaction is the intrinsic DW resistivity. Here, we investigate experimentally how the resistivity inside a DW depends on the wall width Δ, which is tuned using focused ion beam irradiation of Pt/Co/Pt strips. We observe the nucleation of individual DWs with Kerr microscopy, and measure resistance changes in real time. A 1/Δ(2) dependence of DW resistivity is found, compatible with Levy-Zhang theory. Also quantitative agreement with theory is found by taking full account of the current flowing through each individual layer inside the multilayer stack.

Domain-wall pinning by local control of anisotropy in Pt/Co/Pt strips.

We theoretically and experimentally analyze the pinning of a magnetic domain wall (DW) at engineered anisotropy variations in Pt/Co/Pt strips with perpendicular magnetic anisotropy. An analytical model is derived showing that a step in the anisotropy acts as an energy barrier for the DW. Quantitative measurements are performed showing that the anisotropy can be controlled by focused ion beam irradiation with Ga ions. This tool is used to experimentally study the field-induced switching of nanostrips which are locally irradiated. The boundary of the irradiated area indeed acts as a pinning barrier for the domain wall and the pinning strength increases with the anisotropy difference. Varying the thickness of the Co layer provides an additional way to tune the anisotropy, and it is shown that a thinner Co layer gives a higher starting anisotropy thereby allowing tunable DW pinning in a wider range of fields. Finally, we demonstrate that not only the anisotropy itself, but also the width of the anisotropy barrier can be tuned on the length scale of the domain wall.

Duration of immunity induced by an equine influenza and tetanus combination vaccine formulation adjuvanted with ISCOM-Matrix.

Equine influenza is a contagious disease caused by equine influenza virus which belongs to the orthomyxovirus family. Outbreaks of equine influenza cause severe economic loses to the horse industry and consequently horses in competition are required to be regularly vaccinated against equine influenza. Unlike the existing inactivated vaccines, Equilis Prequenza Te is the only one able to induce protection against clinical disease and virus excretion after a primary vaccination course consisting of two vaccine applications 4-6 weeks apart until the recommended time of the third vaccination. In this paper we describe the duration of immunity profile, tested in an experimental setting according to European legislation, of this inactivated equine influenza and tetanus combination vaccine. In addition to influenza antigen, the formulation contains a second generation ISCOM (the so called ISCOMatrix) as an adjuvant. The vaccine aims at the induction of protection from the primary vaccination course until the time of annual revaccination 12 months later, against challenge with a virulent equine influenza strain. The protection against A/equine/Kentucky/95 (H3N8) at the time of annual revaccination was evidenced by a significant reduction of clinical signs of influenza, a significant reduction of virus excretion and a significant reduction of fever. The effect of the annual revaccination on the duration of immunity against influenza and tetanus was also studied by serology. For tetanus, as a consequence of the 24 months duration of immunity, an alternating annual vaccination schedule consisting of Prequenza and Prequenza Te is proposed after the first three doses of Prequenza Te.

The first safe inactivated equine influenza vaccine formulation adjuvanted with ISCOM-Matrix that closes the immunity gap.

Equine influenza is a contagious diseases caused by equine influenza viruses which belong to the orthomyxovirus family. Outbreaks of equine influenza cause severe economic loses to the horse industry and consequently competition horses are required to be regularly vaccinated against equine influenza. Currently available inactivated vaccines are only able to induce protection against clinical disease and virus excretion after a primary vaccination course consisting of three vaccine applications at 4-6 and 22-26 weeks apart, respectively. It has been suggested that these vaccines induce no adequate protection in horses at 22-26 weeks (5 months) in the primary vaccination course (immediately prior to the last booster), despite various alternative vaccination regimens proposed. In this paper we describe the efficacy and safety profile, tested in an experimental setting according to European legislation of a novel inactivated equine influenza vaccine formulation (Prequenza). This formulation consists besides influenza antigen, of second generation ISCOM-Matrix as an adjuvant. The vaccine aims at the induction of protection from the onset of immunity, i.e. after the first two vaccine applications, until the first booster given 5 months later, against challenge with a virulent equine influenza strain. The protection against A/equine/Kentucky/95 (H3N8) was evidenced by a reduction of clinical signs of influenza, a reduction of virus excretion and a reduction of fever. The vaccine was shown to be safe in pregnant mares, foals and is used safely since 2 years as a commercial vaccine in Europe.

Local health policy development processes in the Netherlands: an expanded toolbox for health promotion

Although much research has been done on the existence and formation of risk and issue based health policies, there is only little insight in health policy development processes in a broader context. This hampers intervention in these policy processes to adequately develop integrated and effective health policies. Legislation in the Netherlands requires municipalities to develop and implement local health policies. These policies are supposed to aim at the promotion of health across sectors and with a strong community involvement. Health policy development processes have been studied in four Dutch municipalities. For each case, we identified a range of stakeholders and monitored the change or stability of their characteristics over 3 years. In addition, for each case, three overlaying maps of networks were made addressing communication and collaboration actions within the defined set of stakeholders. We point out a number of barriers which impede integrated policy development at the local level: the importance given to local health policy, the medical approach to health development, the organizational self-interest rather than public health concern, the absence of policy entrepreneurial activity. Furthermore, this article advocates the use of complementary theoretical frameworks and the expansion of the methodological toolbox for health promotion. The value of stakeholder and network analysis in the health promotion domain, at this stage, is two-fold. First, mapping relevant actors, their positions and connections in networks provides us with insight into their capacity to participate and contribute to health policy development. Second, these new tools contribute to a further understanding of policy entrepreneurial roles to be taken up by health promotion professionals and health authorities in favour of the socio-environmental approach to health. Notwithstanding the value of this first step, more research is required into both the practical application as well as in the theoretical connections with, for example, Multiple Streams theory. (AU)

Local health policy development processes in the Netherlands: an expanded toolbox for health promotion

Although much research has been done on the existence and formation of risk and issue based health policies, there is only little insight in health policy development processes in a broader context. This hampers intervention in these policy processes to adequately develop integrated and effective health policies. Legislation in the Netherlands requires municipalities to develop and implement local health policies. These policies are supposed to aim at the promotion of health across sectors and with a strong community involvement. Health policy development processes have been studied in four Dutch municipalities. For each case, we identified a range of stakeholders and monitored the change or stability of their characteristics over 3 years. In addition, for each case, three overlaying maps of networks were made addressing communication and collaboration actions within the defined set of stakeholders. We point out a number of barriers which impede integrated policy development at the local level: the importance given to local health policy, the medical approach to health development, the organizational self-interest rather than public health concern, the absence of policy entrepreneurial activity. Furthermore, this article advocates the use of complementary theoretical frameworks and the expansion of the methodological toolbox for health promotion. The value of stakeholder and network analysis in the health promotion domain, at this stage, is two-fold. First, mapping relevant actors, their positions and connections in networks provides us with insight into their capacity to participate and contribute to health policy development. Second, these new tools contribute to a further understanding of policy entrepreneurial roles to be taken up by health promotion professionals and health authorities in favour of the socio-environmental approach to health. Notwithstanding the value of this first step, more research is required into both the practical application as well as in the theoretical connections with, for example, Multiple Streams theory. (AU)

Local health policy development processes in the Netherlands: an expanded toolbox for health promotion.

Although much research has been done on the existence and formation of risk and issue based health policies, there is only little insight in health policy development processes in a broader context. This hampers intervention in these policy processes to adequately develop integrated and effective health policies. Legislation in the Netherlands requires municipalities to develop and implement local health policies. These policies are supposed to aim at the promotion of health across sectors and with a strong community involvement. Health policy development processes have been studied in four Dutch municipalities. For each case, we identified a range of stakeholders and monitored the change or stability of their characteristics over 3 years. In addition, for each case, three overlaying maps of networks were made addressing communication and collaboration actions within the defined set of stakeholders. We point out a number of barriers which impede integrated policy development at the local level: the importance given to local health policy, the medical approach to health development, the organizational self-interest rather than public health concern, the absence of policy entrepreneurial activity. Furthermore, this article advocates the use of complementary theoretical frameworks and the expansion of the methodological toolbox for health promotion. The value of stakeholder and network analysis in the health promotion domain, at this stage, is two-fold. First, mapping relevant actors, their positions and connections in networks provides us with insight into their capacity to participate and contribute to health policy development. Second, these new tools contribute to a further understanding of policy entrepreneurial roles to be taken up by health promotion professionals and health authorities in favour of the socio-environmental approach to health. Notwithstanding the value of this first step, more research is required into both the practical application as well as in the theoretical connections with, for example, Multiple Streams theory.

The pharmacokinetics of vedaprofen and its enantiomers in dogs after single and multiple dosing.

Vedaprofen is a chiral nonsteroidal anti-inflammatory drug that has been developed as a gel formulation for oral administration to dogs and horses. The pharmacokinetics of vedaprofen and its enantiomers were studied in beagle dogs after single (intravenous solution and oral gel) and multiple (oral gel) dosing at a dosage of 0.5 mg/kg body weight. Plasma concentrations of vedaprofen and its enantiomers were analysed by HPLC. The plasma protein binding of vedaprofen was studied by ultrafiltration. The absorption of vedaprofen was rapid (tmax 0.63 +/- 0.14 h) and almost complete after oral administration (bioavailability 86 +/- 7%). The terminal half-lives after intravenous and oral administration, 16.8 +/- 2.2 and 12.7 +/- 1.7 h respectively, were of the same order of magnitude. Enantioselective analysis showed that the R(-) enantiomer predominated in plasma. The change in the plasma time course of the plasma R(-)/S(+) enantiomer concentration ratio over time was similar after single intravenous and oral dosing, with R(-)/S(+) ratios in the AUC of 1.7 +/- 0.5 and 1.9 +/- 0.2 respectively. Plasma protein binding of vedaprofen and its enantiomers was high (> 99.5%). Vedaprofen is absorbed rapidly from the gastrointestinal tract, has a high bioavailability and does not accumulate in plasma in dogs following repeated oral administration.

Pharmacokinetics of oestriol after repeated oral administration to dogs.

The aim of the present study was to investigate the pharmacokinetics of oestriol in plasma in the dog after repeated oral administration of oestriol tablets, a preparation intended for the treatment of urinary incontinence in the bitch. The study was performed in six healthy, entire, adult female beagle dogs. The bitches were treated once daily with two tablets, containing 1 mg oestriol per tablet, for seven consecutive days (days 1-7). Blood samples were taken from the jugular vein before treatment, frequently on days 1, 3 and 7 of the treatment period and daily just before (C(trough)) and 1 h after dosing (C(t=1h)). During the washout period samples were taken at a 24 h interval up to four days post-treatment. Oestriol concentrations were determined in plasma by radioimmunoassay. Pharmacokinetic parameters, AUC, C(max) and t(max), were determined from the plasma concentration-time curves using non-compartmental methods. The between animal variation in C(max) and the AUC was high. Individual values of the C(max) varied from 206 pg/ml (day 1) to 1128 pg/ml (day 7) and the AUC(0-24h) from 789 pg x h/ml (day 1) to 5718 pg x h/ml (day 7). t(max) occurred within 1 h. The mean C(trough) value was slightly above the pre-treatment level ( 38+/-2 pg/ml vs. 18+/-5 pg/ml). Within 48 h after the last treatment the concentrations had returned to the pre-treatment values. C(max) and C(trough) did not increase during the treatment period, indicating that no accumulation occurred. A shoulder in the concentration-time curve around 8-12 h after treatment strongly suggested the existence of enterohepatic recirculation (EHR). The average relative contribution of the EHR to the AUC(0-24h) was estimated to be 22%, 38% and 44% on days 1, 3 and 7, respectively. These mean values were calculated from five animals per time point, because one dog failed to show EHR on days 1 and 3 and was therefore excluded from the calculations.

Comparison of vedaprofen and meloxicam in dogs with musculoskeletal pain and inflammation.

In this randomised, multicentre clinical study, dogs with musculoskeletal pain and inflammation were treated with either vedaprofen or meloxicam administered orally at the recommended dose rates. Clinical examinations were carried out regularly and clinical severity scores assigned. In total, 214 cases (73 acute, 141 chronic) were evaluated. Treatment with vedaprofen and meloxicam was continued for 14 and 17 days, respectively, in the acute cases, and 38 and 39 days in the chronic cases. NSAID treatment resulted in a significant improvement in clinical scores. The overall response to treatment ('responders') at the final clinical examination was 89 per cent and 87 per cent in the acute cases and 72 per cent and 65 per cent in the chronic cases in the vedaprofen and meloxicam groups, respectively. Mild transient gastrointestinal signs were observed in both groups (11 per cent vedaprofen, 12 per cent meloxicam). Adverse effects related to NSAIDs resulted in treatment cessation in 5 per cent of the dogs in each group. Vedaprofen and meloxicam were efficacious in, and well tolerated by, most of the dogs in the study.

A pharmacodynamic and pharmacokinetic study with vedaprofen in an equine model of acute nonimmune inflammation.

The pharmacodynamics and enantioselective pharmacokinetics of vedaprofen were studied in six ponies in a two period cross-over study, in which a mild acute inflammatory reaction was induced by carrageenan soaked sponges implanted subcutaneously in the neck. Vedaprofen, administered intravenously at a dosage of 1 mg/kg, produced significant and prolonged inhibition of ex vivo serum thromboxane B2 (TXB2) synthesis and short-lived inhibition of exudate prostaglandin E2 (PGE2) and TXB2 synthesis. Vedaprofen also partially inhibited oedematous swelling and leucocyte infiltration into exudate. Vedaprofen displayed enantioselective pharmacokinetics, plasma concentrations of the R(-) enantiomer exceeding those of S(+) vedaprofen. The plasma concentration ratio, R:S, increased from 69:31 at 5 min to 96:4 at 3 h and plasma mean AUC values were 7524 and 1639 ng x h/mL, respectively. Volume of distribution was greater for S(+) vedaprofen, whilst elimination half-life (t(1/2beta)) and mean residence time were greater for R(-) vedaprofen. The penetration of vedaprofen into inflammatory exudate was also enantioselective. For R(-) and S(+) vedaprofen maximum concentration (Cmax) values were 2950 and 1534 ng/mL, respectively, and corresponding AUC values were 9755 and 4400 ng x h/mL. Vedaprofen was highly protein bound (greater than 99%) in both plasma and exudate. The significance of these data for the therapeutic use of vedaprofen is discussed.