Untitled

Animal Conservation. Print ISSN 1367-9430 Safety of meloxicam to critically endangered Gyps vulturesand other scavenging birds in India D. Swarup1, R. C. Patra2, V. Prakash2, R. Cuthbert3, D. Das2, P. Avari2, D. J. Pain3, R. E. Green3,4,A. K. Sharma1, M. Saini1, D. Das1 & M. Taggart5 1 Indian Veterinary Research Institute, Izatnagar, Uttar Pradesh, India 2 Bombay Natural History Society, Mumbai, India 3 Royal Society for the Protection of Birds, Sandy, Bedfordshire, UK 4 Conservation Biology Group, Department of Zoology, University of Cambridge, Cambridge, UK 5 School of Biological Sciences, Department of Plant and Soil Science, University of Aberdeen, Aberdeen, UK Keywords
NSAID; meloxicam; diclofenac; Gyps vulture; Widespread veterinary use of the non-steroidal anti-inflammatory drug diclofenacis responsible for the population collapse of three species of Gyps vulture in south Correspondence
Asia; these species are now critically endangered. Vultures die when they consume carcasses of livestock that contain lethal residues of diclofenac. National and international conservation organizations have urgently recommended that diclo- fenac be banned and replaced with alternative drugs that are relatively safe to Gyps vultures and other scavenging birds. We tested the safety of the NSAID meloxicamon the oriental white-backed vulture, long-billed vulture and a range of other scavenging birds in India (Egyptian vulture Neophron percnopterus, cattle egret Bubulcus ibis, house crow Corvus splendens, large-billed crow Corvus machror-hynchos and common mynah Acridotheres tristis). Meloxicam was administered by oral intubation [at 0.5 and 2.0 mg kgÀ1 vulture body weight (bw)], or throughfeeding with muscle or liver tissue (at 0.3 to 2.1 mg kgÀ1 vulture bw) frommeloxicam-treated buffalo Bubalus bubalis. We estimate that 2.0 mg kgÀ1 bw isthe maximum likely exposure in the wild. All 31 Gyps vultures and the 20 otherscavenging birds given meloxicam survived. Feeding behaviour remained normaland there were no significant differences between the treated and control groups inbody mass, or the blood haematology and biochemistry parameters monitored,including those known to be affected by diclofenac (uric acid levels and alaninetransferase activity). Meloxicam is used to treat a wide range of livestock ailmentsand is licensed and manufactured in India. We recommend that meloxicam beintroduced as rapidly as possible across the Indian sub-continent as an alternativeto diclofenac.
as in experimentally dosed vultures (Oaks et al., 2004; Shultzet al., 2004; Swan et al., 2006a). Population modelling The major role played by the veterinary drug diclofenac in demonstrates that just 0.1–0.8% of carcasses need to con- the population collapse of Gyps vulture species endemic to tain lethal levels of diclofenac to have caused the observed south Asia is now well supported by several lines of evidence decline in vulture numbers, and that the proportion of dead (Green et al., 2004; Oaks et al., 2004; Shultz et al., 2004).
vultures showing post-mortem evidence of diclofenac poi- soning is consistent with it being the sole or major cause of (NSAID), is routinely used in India, Nepal and Pakistan the observed population declines (Green et al., 2004). In for the management of pain and inflammation in injured 2003, populations of three Gyps vulture species, which used and diseased livestock (Oaks et al., 2004). Vultures are to number tens of millions, had collapsed to less than 5% of exposed to diclofenac when they consume the carcasses of their levels in the early 1990s (Gilbert et al., 2002; Prakash livestock that were dosed with the drug shortly before death.
et al., 2003; Green et al., 2004), and continue to decline at Consumption by vultures of diclofenac-contaminated tis- 22–48% a year (Green et al., 2004). The three affected sues results in renal failure, and they die within days of species [oriental white-backed vulture (OWBV) Gyps benga- exposure with clinical signs of extensive visceral gout. These lensis, long-billed vulure Gyps indicus and slender-billed clinical signs and residues of diclofenac have been found in a vulture Gyps tenuirostris] are all now listed as critically high proportion of vultures found dead in the wild, as well Animal Conservation 10 (2007) 192–198 c
 2007 The Authors. Journal compilation c National and international organizations agree that a information on blood haematology and biochemistry of rapid ban on the veterinary use of diclofenac within the meloxicam-treated birds and also on the safety of melox- Indian sub-continent is essential to prevent the extinction of icam to scavenging species other than Gyps vultures, these species (Anon., 2006). To help facilitate a ban on namely: Egyptian vultures, cattle egrets, large billed crows veterinary diclofenac, it is necessary to identify alternative C. macrorhynchos and house crows and common mynahs.
NSAIDs that are relatively non-toxic to vultures and can be Lastly, in order to replicate the natural route of exposure used to replace diclofenac for the treatment of livestock. The and to ensure that there are no toxic meloxicam metabolites results of questionnaire surveys of zoo and veterinarians on produced by livestock, we fed G. bengalensis and G. indicus the clinical treatment of vultures identified the NSAID muscle and liver tissues from buffalo Bubalus bubalis that meloxicam as a suitable potential alternative, with 39 birds had been dosed with double the highest normal veterinary from six species of Gyps vulture known to have been treated with this drug (Cuthbert et al., in press). In a phasedprogramme of safety testing on the closely related African white-backed vulture Gyps africanus, meloxicam was admi-nistered to vultures by oral dosing or through the consump- tion of tissues from meloxicam-dosed cattle (Swan et al.,2006b). A total of 43 birds were treated and 40 birds received The trials were held at the Vulture Conservation Breeding meloxicam doses that were higher than the maximum levels Centre (VCBC), Haryana State, India. Meloxicam testing of exposure they would theoretically be exposed to in the was undertaken over three phases between June 2005 and wild. There were no mortalities after dosing with melox- April 2006. Safety testing was undertaken on OWBV and icam, and levels of alanine transferase (ALT) and uric acid long-billed vultures permanently held captive at the VCBC.
in the blood, which increase in diclofenac treated birds Individuals from the five other scavenging species were before death (Swan et al., 2006a), remained constant captured from the wild and held at the centre for the throughout the trials (Swan et al., 2006b). To confirm the duration of the trials. All individuals spent a minimum of safety of meloxicam to Asian vulture species, the final phase of testing treated G. bengalensis and G. indicus within India: Details of the numbers of birds treated and the experi- and again, all birds survived (Swan et al., 2006b).
mental schedule for the three phases of safety testing are With the decline in vulture numbers across Asia, there are presented in Table 1. Birds in phases I and II were adminis- increased feeding opportunities for other scavengers. Live- tered meloxicam 0.5% (Melonex, each millilitre containing stock carcasses in India now attract large numbers of feral Meloxicam BP 5 mg; marketed by Intas Pharmaceuticals dogs, leading to an increase in their population (Anon., Ltd, Ahmedebad, India) as a single dose by oral gavage, 2006), where formerly Gyps vultures would have dominated with the gavage tube flushed with 2 mL of water. In phase I, (Houston, 1983). Excluding Gyps vultures, raptors and doses of meloxicam administered by gavage were 0.5 or other scavenging bird species observed on carcasses include 2 mg kgÀ1. In phase II, all birds were dosed at 2 mg kgÀ1. A cinereous vulture Aegypius monachus, Egyptian vulture dose of 2 mg kgÀ1 meloxicam was selected for safety testing, Neophron percnopterus, red-headed vulture Sarcogyps cal- as this is the estimated maximum likely exposure in the wild vus, steppe eagle Aquila nipalensis, black kite Milvus mi- (see Swan et al., 2006b). To minimize the risk to the birds in grans, cattle egret Bubulcus ibis, house crow Corvus phase I, meloxicam dosing was staggered, with injured non- splendens, jungle crow Corvus machrorhynchos and common releasable birds treated first. The initial two non-releasable mynah Acridotheres tristis. Two of these species (Egyptian birds were first treated at the lowest dose of 0.5 mg kgÀ1, vultures and red-headed vultures) have recently undergone along with one sham-dosed control bird (treated with rapid population declines, possibly as a result of diclofenac distilled water). After 48 h, no apparent ill effects of the poisoning (Cuthbert et al., 2006). Other scavenging species treatment were observed, and hence, a further three birds within the region that may also potentially come into were dosed at 0.5 mg kgÀ1, and two non-releasable birds contact with contaminated carcasses include greater and were given a 2 mg kgÀ1 dose. After another 48 h, the last lesser adjutants Leptoptilos dubius and Leptoptilos javanicus, three birds were also dosed at 2 mg kgÀ1 (along with two which are both globally threatened. As a consequence, and because there is inter-specific variation in the toxicity of In phase III of safety testing, vultures were given tissues NSAIDs (Anderson, Piper & Swan, 2005), it is vital that any from buffalo treated with a course of meloxicam. To ensure alternative to diclofenac is safe, at the likely exposure levels, that vultures received tissues with high meloxicam levels, to Gyps vultures and also safe, or of low toxicity, to other buffalo were administered a 5-day course of meloxicam with daily subcutaneous injections at a dosage of 1.0 mg kgÀ1 In this study, we present the results of safety testing of body weight (bw), which is twice the highest normal veter- meloxicam on critically endangered Gyps vulture species inary dose. Two animals were slaughtered 8 h after the last and other scavenging birds within India. Data on clinical dose, when meloxicam concentrations in liver and muscle observations and survival of G. bengalensis and G. indicus tissues were likely to be the highest. Two entire livers were after oral treatment with meloxicam have already been collected along with samples of muscle tissue from through- presented in Swan et al. (2006a,b). Here, we present further out the body of both animals. Muscle samples were not Animal Conservation 10 (2007) 192–198 c
 2007 The Authors. Journal compilation c Table 1 Experimental schedule for meloxicam safety testing indicating the phase of study, species, treatment, dose administered, route of
administration and the sample size of birds. Species treated are: Oriental white-backed vulture Gyps bengalensis, long-billed vulture Gyps indicus, Egyptian vulture Neophron percnopterus, cattle egret Bubulcus ibis, crow species (house Corvus splendens and large-billed crow Corvus macrorhynchos) and common myna Acridotheres tristis Data in phase I are also reported in Swan et al. (2006b), bw; body weight.
taken from around the meloxicam injection site. Single istry were measured 48 h after dosing. For birds in phases I samples of muscle, liver and kidney tissue were taken from and II, blood samples were taken before dosing (at 0 h) and at each of the two slaughtered buffalo for meloxicam analysis.
48 h following treatment by oral gavage. In phases I and II, Treated buffalo liver and muscle tissues were fed to seven body mass was recorded at 0 h (to the nearest 0.1 kg), and and 14 vultures, respectively. The seven birds given liver retaken at 7 days and 48 h, respectively. In phase III, blood (which contained meloxicam levels over six times higher than samples and body mass were only taken at 48 h, as it was those found in muscle; see ‘Results’) were all non-releasable highly likely that the disturbance from handling would have individuals, and included the three non-releasable birds used stopped the birds from feeding. No blood samples were taken in phase I of testing. These seven birds were habituated to from common mynahs as their small size did not allow feeding on uncontaminated (NSAID-free) liver for 1 week sufficient blood to be collected for blood haematology and before the experiment, to ensure that they were used to biochemistry analysis. In all three phases, birds were ob- consuming liver tissue. Birds fed buffalo tissues were housed served for a period of 7 days for signs of toxicity and in aviaries holding three and four birds (fed liver), and five abnormal feeding behaviour. Blood samples were collected and nine birds (fed muscle). In order to ensure that all birds by direct veno puncture from the brachial or median meta- had access to food and to quantify the amount taken, muscle tarsal veins. The blood haematology and biochemistry para- and liver tissue was cut into small pieces between 20 and 30 g meters quantified were as follows: total erythrocyte count in mass (mean mass = 26.3 Æ 2.6 g, n= 100). Feeding was (TEC), packed cell volume (PCV), haemoglobin (Hb), mean filmed so that the number of pieces consumed and mass of corpuscular volume (MCV), mean corpuscular haemoglobin liver ingested could be estimated for each bird. Vultures (MCH), mean corpuscular haemoglobin concentration given muscle tissue were observed during feeding and the (MCHC), total leucocyte count (TLC), % heterocytes and crops of all birds (in both treatments) were observed after % lymphocytes as per the standard methods (Jain, 1986).
feeding to ensure that they had taken a meal. A further five Uric acid (Span Diagnostics, Surat, India), creatinine (Tech- vultures were fed a whole skinned goat Capra hircus to serve opharmachem, M.I.E., Haryana, India), total protein (Quali- as a control group. Goats are kept by VCBC for 7 days gens Diagnostics, Mumbai, India), albumin (Qualigens before slaughter to ensure that they are free from diclofenac Diagnostics), ALT (Span Diagnostics) and aspartate trans- or other NSAIDs (M. Taggart, unpubl. data).
ferase (AST) (Span Diagnostics) were estimated spectropho-tometrially (ECIL Model UV5704SS) using standard kits.
Extraction of meloxicam from tissues/plasma was achieved using 0.5 g of sample extracted using 2 mL of NSAIDs act rapidly and Gyps vultures treated with diclofe- HPLC-grade acetonitrile (MeCN). The sample was weighed nac died within 2 days of treatment (Swan et al., 2006a).
into a new glass test tube, MeCN was added and the mixture Consequently, observations on toxicity and blood biochem- was homogenized for 30 s using an Ultra Turrax IKA T8 Animal Conservation 10 (2007) 192–198 c
 2007 The Authors. Journal compilation c Homogenizer (IKA Labortiehnik, Germany). The mixtures oral gavage at doses of 0.5 mg kgÀ1 (n = 5) and 2.0 mg kgÀ1 were then centrifuged at 1000 Â g for 5 min and the super- (n = 30), or through feeding on muscle tissue (n = 14) or natant was filtered using disposable PTFE/PE syringe filter liver tissue (n = 7) taken from buffalo dosed with meloxi- units of 0.45 mm. The filtered extract was then stored in cam. The two slaughtered buffalo had meloxicam tissue crimp top LC vials at À20 1C until analysis. Meloxicam residues of 12.79 and 6.97 mg kgÀ1 in the liver, 17.09 and levels were determined by LC–ESI/MS (liquid chromato- 12.03 mg kgÀ1 in the kidney and 1.82 and 1.16 mg kgÀ1 in graphy–electrospray ionization mass spectrometry) using an muscle tissue. Vultures given liver consumed an average of Agilent 1100 series instrument 1946D (Agilent, Santa Clara, 0.41 Æ 0.21 kg of liver tissue (range 0.21–0.83 kg), exposing CA, USA). The instrument was calibrated using six stan- birds to an estimated mean meloxicam dose (using the dards ranging from 25 to 1000 mg LÀ1 in meloxicam concen- average of the two liver values) of 1.00 Æ 0.52 mg kgÀ1 bw, tration, generated using meloxicam sodium salt (Sigma- with minimum and maximum doses ranging from 0.5 to Aldrich, St Louis, MO, USA, M3935). The calibration was 2.1 mg kgÀ1 bw for individual birds. The two groups of five linear across this range, with an r2 value of at least 0.99.
and nine vultures given muscle tissue consumed on average Meloxicam was monitored by the MS at the mass/charge 0.76 and 1.49 kg, respectively, and were exposed to an ratio of 352 in the positive ion mode. Chromatographic average meloxicam dose of 0.3 and 0.5 mg kgÀ1 bw.
separation was achieved on the LC using a Waters Xterra No adverse reaction to the drug was observed in any of (Waters Xterra, Milford, MA, USA) MS C18 column the six species treated with meloxicam, and all 51 birds (3.9 mm  150 mm, 5 mm). Samples and standards (20 mL) remained alive and healthy throughout the 7-day-experi- were subjected to a binary gradient elution profile using mental period. For the Gyps vultures treated in phases I and 0.1% acetic acid in water and 100% MeCN. The flow rate III, the survival of all individuals treated with meloxicam is was set at 0.7 mL minÀ1. The limit of quantification (LOQ) a statistically significant difference from the result of treat- for this technique (back calculated to wet tissue/plasma ing G. bengalensis with diclofenac (0 death from 31 expo- concentration) was found to be 7 mg kgÀ1.
sures for meloxicam versus 16 deaths from 24 exposures fordiclofenac; the two-tailed Fisher exact test, Po0.0001). Thedifference in survival is significant regardless of the route of administration (feeding tissues from treated livestock, 0/21 In phases I and II, the effect of meloxicam dosing on each deaths for meloxicam vs. 13/20 deaths for diclofenac, the blood haematology and biochemistry parameter was ana- two-tailed Fisher exact test Po0.001; by gavage, 0 deaths lysed by two-way ANOVA, with Treatment (meloxicam or from 10 exposures for meloxicam vs. three deaths for four control) and Period (pre- and post-dosing) as the main exposures for diclofenac; the two-tailed Fisher exact test, effects and Treatment  Period as an interaction effect. In P = 0.051). The ten meloxicam-dosed vultures from phase I phase III, where blood parameters for the three groups (liver, (6  G. bengalensis and 4  G. indicus) were still alive muscle, control) were only measured at 48 h, the results were 11 months after dosing, suggesting no long-term deleterious analysed by one-way ANOVA. Because of the large number effect of a single meloxicam dose on survival. All 20 of variables measured, we used a Bonferroni correction to set experimental and 18 control birds of the four other scaven- an appropriate P value for exploratory data analysis. In ging species (phase II) were successfully released into the total, 15 haematological and blood biochemistry variables wild 21 days after the end of the trial, providing a total were analysed for OWBV, Egyptian vultures and cattle period of 4 weeks of observation following dosing with egrets. Values for PCV, MCV and MCHC could not be meloxicam. Feeding behaviour of all meloxicam-dosed birds obtained for crows at 48 h because of the small blood volume remained normal throughout the 7 days of post-dose ob- available for analysis, and 12 variables were analysed for servation for all three phases of the study. There was no crows. We had an a priori expectation that uric acid and significant change in body mass for any meloxicam-dosed ALT levels would increase and body mass would decline if birds in phases I and II (ANOVA for Treatment  Period; meloxicam had toxic effects similar to diclofenac (Swan phase I, Gyps vultures, F2,29=0.00, P=0.998; phase II, et al., 2006a), and as a result we did not apply the Bonferroni Egyptian vulture, F1,17=0.00, P=0.978; cattle egret, correction and used P = 0.05 as the significance level for F1,17 =0.19, P=0.670; crows, F1,19 =0.02, P=0.897; com- these parameters. For the remaining variables, P was set at 0.00384 (0.05/13) for OWBV, Egyptian vultures and cattle There was no significant effect of meloxicam on uric acid egrets and 0.005 (0.05/10) for crows. We compared the levels (Figs 1 and 2) during any phase of the study (ANOVA survival of Gyps vultures in these experiments with for Treatment  Period, uric acid F2,20=0.13, P =0.879, G. bengalensis dosed with diclofenac administered either by for Gyps vultures in phase I; and P40.334 for Egyptian oral gavage or through feeding on tissues of livestock treated vultures, cattle egrets and crows in phase II). There was no with a veterinary course of the drug (Oaks et al., 2004).
significant difference in serum uric acid and ALT activity at48 h following feeding with meloxicam-dosed liver, melox- icam-dosed muscle or untreated goat tissues (phase III; One-way ANOVA; uric acid, F2,12=0.24, P=0.791; ALT, Over the course of all three phases of the study, a total of F2,9 =1.50, P=0.274). Nor was there any significant differ- 51 birds were dosed with meloxicam, administered either by ence between the route of meloxicam administration Animal Conservation 10 (2007) 192–198 c
 2007 The Authors. Journal compilation c Figure 1 Effect of administration of meloxi-
cam on serum uric acid levels and alanine transferase (ALT) activity in Gyps bengalensis for birds dosed with meloxicam by oral gavage at 0.5 and 2.0 mg kgÀ1 (phase I), given muscle and liver tissues from meloxicam-dosed buffa- lo Bubalus bubalis (phase III) with vultures receiving estimated doses of 0.3–0.5 mg kgÀ1 (muscle) and 0.5–2.1 mg kgÀ1 (liver), and for control birds (phase I). Values are arithmetic means Æ one standard error for uric acid and ALT measured before dosing (unshaded) and at 48 h after dosing (shaded). Values before dosing are unavailable for birds receiving mus- cle and liver tissues, and only values at 48 h ison, data are presented for G. bengalensis 0.25–2.5 mg kgÀ1 (Oaks et al., 2004), with uric acid levels measured, before death, at 1 h (unshaded) and 24 h (shaded) after dosing.
ALT levels are shown for African white-backed vultures Gyps africanus administered diclofe- nac by gavage at 0.8 mg kgÀ1 (Swan et al., 2006a,b), measured at 4 h (unshaded) and 24 h Figure 2 Effect of administration of melox-
icam on serum uric acid levels and alanine transferase (ALT) activity in Egyptian vultures Neophron percnopterus, cattle egrets Bubul- cus ibis and crow species (house crow Cor- vus splendens and large-billed crow Corvus machrorhynchos) for birds dosed with melox- icam by oral gavage at 2.0 mg kgÀ1 and sham- dosed control birds. Values are arithmetic means Æ one standard error for uric acid and ALT measured before dosing (unshaded) and at 48 h after dosing (shaded). There were no significant (Po0.05) Treatment  Period in- teractions in uric acid and ALT for any spe- increase in ALT activity in Egyptian vultures (P = 0.033) in both control and meloxicam- Animal Conservation 10 (2007) 192–198 c
 2007 The Authors. Journal compilation c (muscle, liver or gavage) and uric acid levels at 48 h (phase I six bird species, including Cape griffon vultures Gyps and III; One-way ANOVA, F2,18=0.13, P=0.879). There coprotheres, indicates that meloxicam is very rapidly meta- was a significant increase in ALT activity in Egyptian bolized in birds with a half-life of less than one hour and will vultures following dosing (F1,16=5.72, P=0.033); how- be completely eliminated within one day (Baert & De Backer ever, this was found in both the meloxicam-dosed and 2003; V. Naidoo, pers. comm.). The clinical treatment of control groups, and there was no significant interaction vultures and scavenging birds with meloxicam further sup- between Treatment  Period (F1,16=1.00, P=0.334). Ana- ports the safety following long-term exposure, with drug lysis of all other haematological and blood biochemistry treatments lasting between 1 and 120 days and no reported parameters (with significance levels set at P/k; where k adverse effects (Cuthbert et al., in press).
represents number of variables i.e. 13 or 10) found no To be a suitable alternative to diclofenac, it is essential significant effect of meloxicam treatment for Gyps vultures that meloxicam is effective for the treatment of livestock.
in phases I and III, or for Egyptian vultures, cattle egrets Meloxicam is a second-generation NSAID with preferential and crows in phase II. Unadjusted P values suggest that for COX-2 inhibition, conferring analgesic, antipyretic and Egyptian vultures, the total leucocyte count increased and anti-inflammatory properties and a reduced risk of adverse the % lymphocytes decreased over the course of the experi- effect on renal functioning (Engelhard et al., 1995; Brater, ment (F1,17=8.95, P=0.010 and F1,17=10.76, P =0.005, 2002). Meloxicam is used to treat a variety of veterinary respectively), possibly due to the stress (as a result of capture ailments and for cattle, horses and pigs, its use is recom- and handling) observed for this species. However, there was mended for the treatment of acute respiratory infection, no significant interaction between meloxicam treatment and diarrhoea, lameness, inflammation of acute and chronic period for these two parameters (F1,17 =3.03, P=0.104 and musculo-skeletal disorders, and for the treatment of mastitis in combination with antibiotic therapy (EMEA, 2006).
Clinical trials demonstrate the efficacy of meloxicam to be similar to or better than other NSAIDs tested (Noble &Balfour, 1996; del Tacca et al., 2002; Deneuche et al., 2004; The results of this study demonstrate the safety of the Friton et al., 2004). Meloxicam is already licensed and NSAID meloxicam to India’s critically endangered Gyps manufactured as a veterinary drug in India and Nepal, and vultures and to several other scavenging bird species. All of is available at an affordable price. Given these factors, we the birds dosed with meloxicam survived the trials, and the recommend that meloxicam be introduced as rapidly as vultures tested in the first stage of the trials remain alive and possible across the Indian sub-continent as an alternative healthy nearly one year after treatment. No sub-lethal to diclofenac to reduce the risk to Gyps vultures and other effects of meloxicam could be detected, with no change observed in feeding behaviour or body mass, or any increasein uric acid and ALT levels related to treatment, as occurredin vultures dosed with diclofenac (Swan et al., 2006a). There was an increase in ALT activity in Egyptian vultures for We would like to thank the Additional Director General of both meloxicam-dosed and control groups, although the Forests (Wildlife), Ministry of Environment and Forests, observed increase is markedly different from the six-fold and the Chief Wildlife Warden, Haryana State, for granting increase in ALT following dosing with diclofenac (Figs 1 permission to undertake safety testing on vultures, and to and 2). While ALT levels do increase following diclofenac the Director, and Joint Director (Research), Indian Veter- dosing causing renal damage (Swan et al., 2006a), ALT is inary Research Institute, Izatnagar, Assistant Director Gen- generally not considered to be organ specific in birds (Camp- eral (Animal Health) Indian Council of Agricultural bell, 2004) and the increase in Egyptian vultures may have Research, New Delhi, for granting permission for carrying resulted through muscular damage, possibly as a result of out this study. This work was funded by the UK Govern- handling. No detectable differences were found for a wide ment’s Darwin Initiative for the Survival of Species, with range of other blood variables that would indicate ill health additional financial support from the Royal Society for the or damage to liver and/or kidney function. The five species Protection of Birds, Bombay Natural History Society and tested in this study are from the orders Falconiformes, The Indian Council of Agricultural Research. We acknowl- Ciconiiformes and Passeriformes, indicating that meloxicam edge technical assistance extended by Mr Brijesh Tyagi T-3 appears to be safe to a taxonomically diverse group of birds.
Division of Medicine, IVRI, Izatnagar, and advice from Information from a survey of veterinarians and zoological Prof. Gerry Swan, and Dr Vinny Naidoo University of institutions on the clinical treatment of vultures, raptors and other scavenging birds confirms that meloxicam is of lowtoxicity to a wide range of birds: over 700 birds from60 species are known to have been treated with meloxicam and yet there have been no reported instances of mortality(Cuthbert et al., in press). Repeated long-term exposure to Anderson, M.D., Piper, S.E. & Swan, G.E. (2005). Non- meloxicam, as may occur among scavenging birds in the steroidal anti-inflammatory drug use in South Africa and wild, is unlikely to alter these conclusions, as research on possible effects on vultures. S. Afr. J. Sci. 101, 112–114.
Animal Conservation 10 (2007) 192–198 c
 2007 The Authors. Journal compilation c Anon. (2006). Recommendations from the International con- Gilbert, M., Virani, M.Z., Watson, R.T., Oaks, J.L., Benson, ference on vulture conservation, 31 January – 1 February P.C., Kahn, A.A., Ahmed, S., Chaudhry, J., Arshad, M., 2006. Ministry of Environment and Forests, New Delhi, Mahmood, S. & Shah, Q.A. (2002). Breeding and mortality of Oriental white-backed vulture Gyps bengalensis in Baert, K. & De Backer, P. (2003). Comparative pharmacoki- Punjab Province, Pakistan. Bird Conserv. Int. 12, netics of three non-steroidal anti-inflammatory drugs in five bird species. Comp. Biochem. Physiol. C 134, 25–33.
Green, R.E., Newton, I., Shultz, S., Cunningham, A.A., Brater, D.C. (2002). Renal effects of cyclooxygyenase-2- Gilbert, M., Pain, D.J. & Prakash, V. (2004). Diclofenac selective inhibitors. J. Pain Symp. Mgmt. 23, S15–S20.
poisoning as a cause of vulture population declines across Campbell, T.W. (2004). Blood biochemistry of lower verte- the Indian subcontinent. J. Appl. Ecol. 41, 793–800.
brates. ACVP & ASVCP Proceedings, http://www.
Houston, D.C. (1983). The adaptive radiation of the griffon ivis.org.proceedings/ACVP/2004/Campbell2/chapter_frm vultures. In Vulture biology and management: 360–363.
Cuthbert, R., Green, R.E., Ranade, S., Saravanan, S.S., Pain, Wilbur, S.R. & Jackson, J.A. (Eds). Berkeley: University D.J., Prakash, V. & Cunningham, A.A. (2006). Rapid population declines of Egyptian vulture Neophron perc- nopterus and red-headed vulture Sarcogyps calvus in India.
Jain, N.C. (1986). Schalm’s veterinary hematology. 4th edn.
Philadelphia: K.M. Vurghese Company.
Cuthbert, R., Parry-Jones, J., Green, R.E. & Pain, D.J. (in Noble, S. & Balfour, J.A. (1996). Meloxicam. Drugs 51, press). NSAIDs and scavenging birds: potential impacts beyond Asia’s critically endangered vultures. Biol. Lett.
Oaks, J.L., Gilbert, M., Virani, M.Z., Watson, R.T., Meteyer, C.U., Rideout, B., Shivaprasad, H.L., Ahmed, S., Chaudhry, Del Tacca, M., Colucci, R., Fornai, M. & Blandizzi, C.
M.J.I., Arshad, M., Mahmood, S., Ali, A. & Khan, A.A.
(2002). Efficacy and tolerability of Meloxicam a COX-2 (2004). Diclofenac residues as the cause of vulture population preferential nonsteroidal anti-inflammatory drug. Clin.
declines in Pakistan. Nature 427, 630–633.
Prakash, V., Pain, D.J., Cunningham, A.A., Donald, P.F., Deneuche, A.J., Dufayet, C., Goby, L., Fayolle, P. & Desbois, Prakash, N., Verma, A., Gargi, R., Sivakumar, S. & C. (2004). Analgesic comparison of meloxicam or ketopro- Rahmani, A.R. (2003). Catastrophic collapse of Indian fen for orthopaedic surgery in dogs. Vet. Surgery 33, white-backed Gyps bengalensis and long-billed Gyps indicus vulture populations. Biol. Conserv. 109, 381–390.
EMEA (1997). The European agency for the evaluation of Shultz, S., Baral, H.S., Charman, S., Cunningham, A.A., Das, medicinal products. Committee for veterinary medicinal D., Ghalsasi, G.R., Goudar, M.S., Green, R.E., Jones, A., products, Meloxicam summary report (1) EMEA/MRL/ Nighot, P., Pain, D.J. & Prakash, V. (2004). Diclofenac poisoning is widespread in declining vulture populations EMEA (2006). The European agency for the evaluation of across the Indian subcontinent. Proc. Royal Soc. Lond. Ser.
medicinal products. Scientific discussion: Metacam.
B 271 (Suppl.): S458–S460, (DOI: 10.1098/rsbl.2004.0223).
www.emea.eu.int/vetdocs/PDFs/EPAR/metacam/ Swan, G.E., Cuthbert, R., Quevdeo, M., Green, R.E., Pain, D.J., Bartels, P., Cunningham, A., Duncan, N., Oaks, J.L., Engelhard, G., Homma, D., Schlegel, K., Utzmann, R. & Parry-Jones, J., Taggart, M., Verdoorn, G. & Wolter, K.
Schnitzler, C. (1995). Anti-inflammatory, analgesic, anti- (2006a). Toxicity of diclofenac to Gyps vultures. Biol. Lett.
pyretic and related properties of meloxicam, a new non- steroidal anti-inflammatory agent with favourable gastro- Swan, G.E., Naidoo, V., Cuthbert, R., Green, R.E., Pain, intestinal tolerance. Inflam. Res. 44, 422–433.
D.J., Swarup, D., Prakash, V., Taggart, M., Bekker, L., Friton, G.M., Cajal, C., Romero, R.R. & Kleeman, R. (2004).
Das, D., Diekmann, J., Diekmann, M., Killian, E., Clinical efficacy of Meloxicam (Metacams) and Flunixin Meharg, A., Patra, R.C., Saini, M. & Wolter, K. (2006b).
(Finadynes) as adjuncts to antibacterial treatment of Removing the threat of diclofenac to critically endangered respiratory disease in fattening cattle. Berl. Muench.
Asian vultures. PLoS Biology 4, 1–8, (DOI: 10.1371/ Tierarztl. Wochenschr. 117, 304–309.
Animal Conservation 10 (2007) 192–198 c
 2007 The Authors. Journal compilation c

Source: http://save-vultures.org/Documents/Swarup%20et%20al%202007%20Meloxicam%20safety%20testing%20in%20India.pdf