Jvp_923 128.134

J. vet. Pharmacol. Therap. 31, 128–134, doi: 10.1111/j.1365-2885.2007.00923.x.
The pharmacokinetics of meloxicam in vultures Naidoo, V., Wolter, K., Cromarty, A. D., Bartels, P., Bekker, L., McGaw, L., Taggart, M. A., Cuthbert, R., Swan, G. E. The pharmacokinetics of meloxicam invultures. J. vet. Pharmacol. Therap. 31, 128–134.
Vulture populations across the Asian subcontinent have declined dramaticallyin the last 15 years and are now on the verge of extinction. Although the cause of the population decline was initially unknown, the decrease has recently been conclusively linked to the use of the nonsteroidal anti-inflammatory drug diclofenac in cattle that inadvertently ended up in the vulture food chain. With the vulture numbers continuing to decline by up to 48% a year, the Indian,Nepali and Pakistan governments have recently banned the manufacture and importation of veterinary diclofenac. They have also suggested meloxicam as an alternate anti-inflammatory for use in cattle. This recommendation was based Faculty of Veterinary Science, University of on extensive acute safety studies in the African White-backed vulture (Gyps Pretoria, Pretoria, South Africa;  Vulture africanus), which evaluated worst case scenarios of maximum intake based on a Unit, DeWildt Cheetah and Wildlife Trust, once in three day feeding pattern. However, the possible cumulative pharmacokinetic and pharmacodynamic effects in vultures receiving multiple Pharmacology, Faculty of Health Sciences, daily doses of meloxicam over time were not assessed. At present very little pharmacokinetic or pharmacodynamic information is available to add further Africa; §Wildlife Biodiversity Resources, support for the safety of meloxicam in this animal species. This article discusses National Zoological Gardens of SA, Pretoria, the oral and intramuscular pharmacokinetics of meloxicam in Cape Griffon South Africa; –Department of Plant and Soil vultures (Gyps coprotheres). Therapeutic drug monitoring was also undertaken Science, School of Biological Sciences,University of Aberdeen, Aberdeen, Scotland, in White-backed, Egyptian (Neophron pernopterus) and one Lappet Faced vulture UK; **Royal Society for the Protection of (Torgos tracheliotos). In all these species, meloxicam was characterized by a short half-life of elimination. The rapid metabolism of meloxicam in combina- England, UK;   Instituto de Investigacio´n en tion with a short duration of effect in the studied species Gyps vultures shown in Recursos Cinege´ticos, Ciudad Real, Spain this study makes it unlikely that the drug could accumulate. This confirms thesafety of repeated exposure to meloxicam in vultures of this genus.
(Paper received 16 April 2007; accepted for publication 31 October 2007) V. Naidoo, Private Bag X04, Section of Pharmacology and Toxicology, Faculty ofVeterinary Science, Onderstepoort 0110, South Africa. E-mail: vinny.naidoo@up.ac.za decline rates reported. Diclofenac has also been shown to havean approximate LD50 of 0.098 to 0.225 mg ⁄ kg in vultures Three species of vultures endemic to south Asia are in grave (Swan et al., 2006b), making it more lethal than aldicarb, which danger of extinction across the Indian subcontinent. Populations is regarded as one of the most toxic pharmaceutical compound in of oriental White-backed vultures (Gyps bengalensis), long-billed animals (Pesticide Information Profiles: Aldicarb, 1996).
vultures (G. indicus) and slender-billed vultures (G. tenuirostris) To protect the remaining vulture populations, the govern- have declined by more than 97% in India and Pakistan (Shultz ments of India, Pakistan and Nepal have taken steps to phase et al., 2004) and continue to decline at rates of 22–48% per year out the veterinary use of diclofenac, including bans on the (Green et al., 2004). Oaks et al. (2004) linked the population manufacture and importation of the drug in addition to crash to the veterinary use of diclofenac, a nonsteroidal anti- recommending the use of vulture safe alternatives, such as inflammatory drug (NSAID). In this study, Oaks was able to meloxicam, for livestock treatment (Mo, 2006). The recom- demonstrate that diclofenac residues in the carcasses of dead mendation to use meloxicam was based on an extensive safety- cattle, treated prior to their deaths, were highly toxic to testing study, in which Gyps vultures were exposed to oral scavenging vultures. From subsequent modelling data, Green meloxicam as either pure drug in formulation or residues in et al. (2004) were able to show that residues in few as one in tissues from livestock dosed with meloxicam (Swan et al., approximately 200 carcasses would be sufficient to cause the 2006a; Swarup et al., 2007). While these studies have Ó 2008 The Authors. Journal compilation Ó 2008 Blackwell Publishing Ltd demonstrated the safety of meloxicam (in comparison to from a commercial butchery. The meat was assumed to be free of diclofenac) following single exposure to the drug, the safety of meloxicam and other NSAIDs as South Africa follows the meloxicam following repeated exposure was not documented.
minimum residue limit guidelines proposed by the joint expert Swan et al. (2006a) estimated the maximum levels of exposure committee on food additives of the FAO and WHO (JECFA) in the on the basis of meloxicam residues in livestock liver tissues determination of withdrawal periods (Department of Health, shortly after dosing and for a vulture consuming enough liver 1972). At the end of the study, the birds were returned to tissue at one sitting (1.02 kg) to provide the estimated energetic DeWildt Cheetah and Wildlife Centre from where they were requirements for 3 days: a plausible maximum duration sourced. All captive animals used in this study were in captivity between meals based on observations of wild and captive for at least 1 year prior to inclusion in the study.
vultures (Mundy et al., 1992). This does not, however, consider The birds were given a single dose of meloxicam (Melonex 0.5% the cumulative effect of multiple exposures to meloxicam over a m ⁄ v, Intas Pharmaceuticals, Ahmedabad, India) at 2 mg ⁄ kg by short-time period, which may occur for birds consuming either i.m. injection or oral gavage. Dosage of 2 mg ⁄ kg were selected, as this is the estimated maximum level of exposure to Irrespective of the duration of exposure, when evaluating the meloxicam used in previous safety testing (Swan et al., 2006a).
safety of a NSAID, one other factor which must be considered is For gavage a small diameter tube was passed directly into the crop.
the duration of cyclo-oxygenase (COX) enzyme inhibition i.e.
Once the drug was dosed, the tube was flushed with 2 mL of sterile should COX inhibition be reversible the time required for water. Once the tube was removed, a further 2 mL of water was complete enzyme recovery is important (Boothe, 2001). As an squirted into the mouth of the vulture. Intramuscular injections illustration, carprofen is effective for once a day pain manage- were administered directly into the pectoral muscle.
ment in the dog despite the drug having a half-life of just 8 h Blood samples were collected by means of a 5-mL syringe (Clark, 2006). As such it is plausible that a drug with a short and immediately transferred into 5 mL lithium heparinized pharmacokinetic half-life (noncumulative) could still result in vacutainer. Samples were collected generally from the tarsal toxicity if successive doses lead to prolonged enzyme inhibition vein or when necessary the wing vein, before drug adminis- tration and at 4 and 30 min and at 1, 1.5, 2, 6, 8 and 10 h In this study, we characterize the intramuscular (i.m.) and after treatment. Within 2 h of collection the blood samples oral bioavailability of a single dose of meloxicam in an adult were centrifuged at approximately 3000 g and 4 °C for 15 min G. corportheres vultures to determine the elimination half-life of and the supernatant of each sample transferred to labelled the drug and if possible to extrapolate the plasma profile for multiple exposures over time. The safety of meloxicam was also Plasma concentration data for all animals were analysed evaluated by monitoring birds treated on a daily basis.
using WINNONLIN 4.2 (sponsored by the Pharsight Corporation,Mountain View, CA, USA). The plasma curve for meloxicam forboth i.m. and oral routes were best fitted to a one-compartmentopen model (model 3) and were best described by the Equation 1: The pharmacokinetics (PK) of meloxicam in adult Cape Griffon where C is the plasma concentration at time t, Ka the absorption vultures was evaluated using a single dose, two phase parallel constant, Ke the elimination constant and Vd ⁄ F the apparent study consisting of six birds per treatment group (Table 1).
volume of distribution. The relative bioavailability (Frelative) was The birds were allowed an acclimatization period of 1 week.
To facilitate the management of the study, the i.m. and oral dosing was separated by 1 week. The vultures were housed within the University of Pretoria’s Biomedical Research Centre (UPBRC) in single aviaries of 1 · 1 · 2.5 m. During the study where AUC represents the area under curve to the last time- the birds were fed twice weekly with 1 kg of beef each, bought point for the oral and i.m. routes of administration.
Table 1. A list of the different birds included in this study. All the listed birds were incaptivity following attempted rehabilitation Ó 2008 The Authors. Journal compilation Ó 2008 Blackwell Publishing Ltd Studies on metabolite ion fragmentation were conducted by Liquid chromatography tandem mass spectrometry direct infusion of plasma extracts, known to contain the Sample extraction and preparation was done using a method metabolites, dissolved in 30% acetonitrile and 0.1% formic acid, developed in our laboratory and reported previously (Swan et al., into the ESI source. To elucidate the origin of the fragment ions 2006a). Briefly, 2 mL acetonitrile was added to 200 lL of and potential dissociation pathways, MS3 experiments were plasma, mixed for 4 min on a Lab-tek multitube vortexer and performed on samples containing the metabolites (Table 2).
subsequently centrifuged at 1200 g. The supernatants weretransferred to clean glass tubes and evaporated to dryness at Meloxicam clinical and therapeutic monitoring 60 °C under a stream of nitrogen gas in a Zymak TurboVapÒ LVEvaporator (Hopkinton, MA, USA). Reconstitution was per- Some of the birds included in this study were injured (soft tissue formed with 50 lL 100% methanol, followed by addition of injuries) and showed signs of pain, such as drooping heads, 100 lL 0.4% acetic acid in methanol ⁄ dH2O (60:40).
decreased feed intake and reluctance to place weight on their The sample extracts were analysed by LC ⁄ MS ⁄ MS using an injured limb or fly (Table 1). In total 11 vultures from four Agilent 1100 series high pressure liquid chromatograph with different species were monitored for signs of toxicity following temperature controlled autosampler and diode-array detector treatment with meloxicam at the dose of 2 mg ⁄ kg, by i.m.
(collecting the cumulative absorbance from 210 to 400 nm) administration into the pectoral muscle. With the exception of coupled to an Applied Biosystems API4000 QTrap mass spec- the White-backed vultures, which received only one dose of trometer (Foster city, CA, USA) fitted with a ‘Turbo V’ electrospray meloxicam, all the birds received multiple treatments at 24 h ionization (ESI) source. The HPLC column used was a Phenome- nex Prodigy ODS(3) C18 column (4.6 · 100 mm, 3 lm particle Of the treated vultures one Cape vulture (Gyps coprotheres) and size) and the mobile phase a 20:80 mixture of A: 0.1% formic acid White-backed vulture (Gyps africanus) were monitored for and B: 60% acetonitrile in 0.1% formic acid at a flow rate of clinical signs of toxicity for their 14 and 5 days of treatment, 1000 lL ⁄ min for 6.5 min (Wiesner et al., 2003). The sample respectively, without quantifying plasma concentrations. For the injection volume used was 2 lL. The ion source was operated in other birds, prior to each 24 h treatment, plasma samples were the positive mode at 450 °C with the source-specific nebuliser and source gasses set at the optimal pressures as determined during described above. This included one Lappet Faced vulture (Torgos FIA optimization. Analytes were detected and quantitated by tracheliotos) from which samples were collected at 0, 24, 48, 72, means of characteristic ion transitions from protonated parent 96 and 120 h; one Egyptian vulture (Neophron pernopterus) from ions to fragment ions generated by collisionally activated disso- which samples were collected at 0, 4, 18 and 24 h and five ciation (CAD) utilizing the multiple reaction monitoring mode African White-backed vultures (G. africanus) from which samples (MRM). The collision gas was nitrogen at the high setting (using a were collected at 0, 4, 12 and 24 h.
CMC nitrogen generator), and collision energies were optimizedfor each analyte as listed in Table 2. Additionally the extractedwavelength diode array chromatograms (350 ± 20 nm) were used to confirm the retention times of the meloxicam metabolites.
The method was shown to have no interference when plasma from untreated birds were injected and demonstrated a limit ofdetection (LOD), defined at a signal-to-noise ratio 3:1, was The pharmacokinetic parameters obtained are listed in Table 3 <30 ng ⁄ mL for meloxicam while the limit of quantification for both routes and illustrated in Fig. 1. Oral absorption of (LOQ) was <125 ng ⁄ mL in spiked plasma. Calibration curves for meloxicam in the vultures was characterized by a relative meloxicam were linear over a range of 125–12 500 ng ⁄ mL with regression coefficients of at least 0.99. Average accuracy over the Meloxicam was also rapidly absorbed with Cmax being achieved concentration range analysed was 96% and precision varied from within approximately 0.5 h of administration for both routes of 13% to 0.5% depending on the concentration with the highest administration. The absorption half-life (t1 ⁄ 2a) of 0.41 ± 0.33 h variation observed at the lowest concentrations.
and 0.33 ± 0.17 h for the i.m. and oral routes, respectively, Table 2. The analytical and mass spectrome- metabolites of meloxicam in Gyps coprotheresplasma samples 352 > 115 (100)* 352 > 141 (40) 352 > 153 (5) *MRM transition signal used for quantification of the compound; n.d., not detected.
Ó 2008 The Authors. Journal compilation Ó 2008 Blackwell Publishing Ltd Table 3. Pharmacokinetics parameters for meloxicam following intra- backed vultures in which a 4-h sample was collected. None of muscular and oral administration in Gyps coprotheres using a one- the other time-points, had detectable drug concentrations.
The Cape Griffon vulture that was treated with meloxicam for 14 days was eventually terminated due to nonrecovery for an injured leg. From the full postmortem of this bird, no gross pathological lesions were evident, except muscle atrophy for the Although the reason for the higher oral bioavailability (107%) is unknown it may be an artefact as absorption was more rapidfollowing oral administration resulting in the increased oral Cmax. In our opinion this is the reason for the higher AUCoral and is areflection of the sampling intervals rather than drug effect. This supported by Toutain and Bousquet-Melou (2004), who stated that small differences of this nature are usually nonsignificant and may result from the predetermined sampling interval.
However, to determine the actual significance of the higher oral bioavailability the absolute bioavailability for both routes will Conc (ug/ml) 1.5
With the absorption and elimination half-lives being almost identical for each route, this tends to suggest that absorption is the limiting factor in the rate of elimination of the drug. It is, therefore, possible that a degree of flip-flop kinetics is being seen and requires further investigation following intravenous admin-istration. A Vd ⁄ F was observed following both oral and i.m.
Fig. 1. Mean plasma concentration vs. time curve following oral and administration. The result was similar to results previously intramuscular meloxicam administration in adult G. corprotheres vul- reported for the pigeon and a consistent finding for most NSAIDs (Boothe, 2001; Baert & De Backer, 2003). With the NSAIDsbeing highly plasma protein bound in birds, the low Vd ⁄ F likely was very similar to their elimination half-life (t1 ⁄ 2b) of results from extensive macro-molecular binding and possibly 0.42 ± 0.1 and 0.32 ± 0.17 h respectively. A small apparent rapid metabolism (Boothe, 2001; Baert & De Backer, 2002; Baert volume of distribution (Vd ⁄ F) was observed following both oral & De Backer, 2003; Lees et al., 2004).
This rapid half-life of elimination is extremely important as it can prevent drug accumulation and delayed toxicity. With theassumption that 99% of all drug is eliminated in 10 elimination half-lives, these birds will be virtually free of the drug 5–7 h We identified three peaks as potential metabolites due to their postexposure (Brown, 2001). The main objective of this study was time-dependent increase in concentration in conjunction with to assess the potential for meloxicam’s accumulation following meloxicam’s decline (Figs 2 & 3). Based on molecular mass they multiple feedings: given the observed time to elimination a vulture correspond to two hydroxymethyl metabolites together with one will have to consume numerous meals in 1 day for accumulation to occur. Ecological studies of vultures in the wild indicate that it isnormal for birds to engorge themselves at one session if sufficientfood is available, making it unlikely that a bird will be able to Meloxicam clinical and therapeutic monitoring consume more than one meal a day (Mundy et al., 1992).
No signs of toxicity were seen in the Egyptian (N. pernopterus), Moreover, the dose of 2.0 mg ⁄ kg administered in this study, is the Lappet Faced (T. tracheliotos), African White-backed (G. africanus) likely maximum level of exposure based upon a bird consuming or Cape Griffon (G. corprotheres) vultures following repeated 3 days of food (1.02 kg) at just one sitting, and consuming only treatment with parenteral meloxicam. While no drug was liver tissues from an animal dosed with meloxicam in the hours detectable for the Lappet Faced vulture, the plasma concentra- immediately prior to death. Given this scenario, it is very unlikely tions in the Egyptian vulture was 5 lg ⁄ mL at 4 h. Meloxicam that birds can take in larger concentrations of meloxicam at levels (0.22 ± 0.20 lg ⁄ mL) was detectable for all the dosed White- Ó 2008 The Authors. Journal compilation Ó 2008 Blackwell Publishing Ltd Fig. 2. Identified meloxicam metabolites as determined by LCMS ⁄ MS. (a) Glucuronide metabolite, (b) hydroxyl metabolite 1, (c) hydroxyl metabolite 2and (d) meloxicam.
1992). This is believed to have two important effects, first toscare off the threatening animal and second to make the bodylighter and quicken escape times. As a result it is impossible to get close to these birds soon after feeding for blood collection, as they immediately regurgitate the ingested meal. Realistically we do not believe that will have a major influence on the safetyof the product as slower absorption should promote lower plasma concentrations and lower the drug’s toxic potential.
In mammals, meloxicam is metabolized by CYP2C9 during the Fig. 3. Change in the average area under curve over time for each phase I reactions and by glucuronide transferase in phase II.
metabolite following the oral administration of meloxicam, using diode- The predominant phase I metabolites in laboratory animals and array detection. The initial increase over time corresponded to a decreasein plasma meloxicam concentrations (M, meloxicam parent; M-OH1, man are the 5-hydroxymethyl derivative and a 5-carboxy hydroxy metabolite 1; G, glucuronide metabolite; M-OH2, hydroxy metabolite (Busch et al., 1998; Chesne et al., 1998). With two hydroxymethyl metabolites together with one glucuronideconjugate being tentatively identified, it is likely that vultures With this study making use of the drug in formulation instead make use of the cytochrome P450 enzyme system, perhaps even of residues in meat, it may be possible that the presence of meat CYP2C9 as in man, for initial metabolic transformation and could adversely influence the process of absorption, i.e. food glucuronidation for the synthetic reaction (Chesne et al., 1998).
decreasing the rate of absorption. Although this has never been The presence of a glucuronide conjugate also indicates that this specifically found with meloxicam, the consumption of food in species appears to use the standard metabolic pathways for people is known to slow the rate of absorption of ketoprofen NSAID metabolism as described in other animals (Busch et al., (Busch et al., 1990; Bannwarth et al., 2004). Unfortunately we 1998; Kumar et al., 2002; Baert & De Backer, 2003). Unlike in are doubtful that the influence of a meal on meloxicam’s mammals the carboxy metabolite (m ⁄ z = 391) was absent.
absorption can ever be properly determined in the vulture as As the hydroxyl metabolite is converted to a carboxy metabolite unlike mammals, one of the defence mechanisms of the vulture by a noncytochrome-dependant pathway, the absence of the is to regurgitate its meal at the first sign of a threat (Mundy et al., peak suggests the absence of these pathways in the vulture Ó 2008 The Authors. Journal compilation Ó 2008 Blackwell Publishing Ltd (Chesne et al., 1998). More work is, however, required to Comparative Biochemistry and Physiology. Toxicology & Pharmacology, Bannwarth, A., Lapicque, F., Netter, P., Monot, C., Tamisier, J.N., Tho- mas, P. & Royer, R.J. (2004) The effect of food on the systemic avail- Meloxicam clinical and therapeutic monitoring ability of ketoprofen. European Journal of Clinical Pharmacology, 33,643–645.
For the Egyptian vulture in which drug was detectable at only Boothe, D.M. (2001) The analgesic, antipyretic and anti-inflammatory 4 h, we estimate a t1 ⁄ 2b of below 2 h. More birds will have to be drugs. In Veterinary Pharmacology and Therapeutics, 8th edn. Eds evaluated to confirm the half-life of the drug in the Egyptian Adams, H.R., pp. 433–451. Iowa State University Press, Ames, IA.
vulture. As for the Egyptian vulture, the terminal half-life could Brown, S.A. (2001) Pharmacokinetics: disposition and fate of drugs in be established for the White-backed vulture as only one time- the body. In Veterinary Pharmacology and Therapeutics, 8th edn. EdsAdams, H.R., pp. 15–56. Iowa State University Press, Ames, IA.
point had detectable drug concentrations. None the less the Busch, U., Heinzel, G. & Narjes, H. (1990) Effect of food on pharmaco- plasma concentration for this species fits the equation described kinetics of meloxicam, a new non steroidal anti-inflammatory drug for meloxicam disposition in the G. corprotheres where the (NSAID). Inflammation Research, 32, 52–53.
concentration is 0.29 ± 0.27 lg ⁄ mL at 4 h. This tends to Busch, U., Schmid, J., Heinzel, G., Schmaus, H., Baierl, J., Huber, C. & suggest that the half-life and absorption of meloxicam is likely Roth, W. (1998) Pharmacokinetics of meloxicam in animals and rel- evance to humans. Drug Metabolism & Disposition, 23, 1206–1213.
The lack of notable pathology in the Cape vulture treated for Chesne, C., Guyomard, C., Guillouzo, A., Schmid, J., Ludwig, E. & Sauter, T. (1998) Metabolism of meloxicam in human liver involves cyto- 2 weeks in addition to the absence of clinical signs of toxicity in chrome P4502C9 and 3A4. Xenobiotica, 28, 1–13.
any of the birds receiving repeated therapy was considered a Clark, T.P. (2006) The clinical pharmacology of cyclooxygenase-2- significant finding as this clearly shows that toxicity will not selective and dual inhibitors. The Veterinary Clinics of North America.
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Lees, P., Landoni, M.F., Giraudel, J. & Toutain, P.L. (2004) Pharmaco- birds feeding once a day. For vultures being treated therapeuti- dynamics and pharmacokinetics of non-steroidal anti-inflammatory cally it is possible that with a rapid half-life birds may require more drugs in species of veterinary interest. Journal of Veterinary Pharma- frequent therapy than the daily regime used at present. Although cology and Therapeutics, 27, 479–490.
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Oaks, J.L., Gilbert, M., Virani, M.Z., Watson, R.T., Meteyer, C.U., Rideout, B.A., Shivaprasad, H.L., Ahmed, S., Chaudhry, M.J., Arshad, M., This research project was approved by the Animal Use and Care Mahmood, S., Ali, A. & Khan, A.A. (2004) Diclofenac residues as the Committee of the University of Pretoria and the Vulture Unit of cause of vulture population decline in Pakistan. Nature, 427, 630– the DeWildt Cheetah and Wildlife Trust. The importation of the unregistered drug Melonex was approved by the Medicines Pesticide Information Profiles: Aldicarb (1996) Extoxnet. Available at: Control Council of South Africa. The necessary permits to use http://extoxnet.orst.edu/pips/aldicarb.htm.
Shultz, S., Baral, H.S., Charman, S., Cunningham, A.A., Das, D., Ghals- and move the birds across provincial boundaries were obtained asi, G.R., Goudar, M.S., Green, R.E., Jones, A., Nighot, P., Pain, D.J. & Prakash, V. (2004) Diclofenac poisoning is widespread in decliningvulture populations across the Indian subcontinent. Proceedings. Bio-logical Sciences ⁄ The Royal Society, 271, S458–S460.
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K.J., Hundt, A.F. & Els, J. (2003) Sensitive and rapid liquid chroma- (2007) The safety of meloxicam to critically endangered Gyps vultures tography-tandem mass spectrometry method for the determination of and other scavenging birds in India. Animal Conservation, 10, meloxicam in human plasma. Journal of Chromatography, 785, Ó 2008 The Authors. Journal compilation Ó 2008 Blackwell Publishing Ltd

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