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Journal ArticleDOI

A comparative study on anti-inflammatory drug combinations in domestic pigeons with experimentally induced acute arthritis

Sajedeh Salandari1, Tahoora Shomali1, Najmeh Mosleh1, Saeed Nazifi1 
01 Dec 2019-Acta Veterinaria Hungarica (Akadémiai Kiadó)-Vol. 67, Iss: 4, pp 588-601

TL;DR: One-time combination therapy with anti-inflammatory agents was effective in the acute management of inflammatory pain due to MSU-induced arthritis in pigeons, even by the topical route.

AbstractThe study compares the effect of one-time administration of nonsteroidal and/or steroidal anti-inflammatory combinations by topical or intramuscular (IM) routes to pigeons with monosodium urate (MSU)-induced arthritis. Forty-five adult domestic pigeons were assigned into nine equal groups: NC, negative control; PC, positive control with arthritis; sham, sham control; T1, meloxicam + hydrocortisone; T2, dexamethasone + piroxicam; T3, meloxicam + dexamethasone; T4, hydrocortisone + piroxicam; T5, dexamethasone + hydrocortisone; T6, meloxicam + piroxicam. Arthritis was also induced in T1 to T6 birds. Meloxicam and dexamethasone were administered by IM injection and the other drugs topically right after the induction of arthritis. Different drug combinations significantly decreased one-leg standing time. Induction of arthritis significantly increased TNF-α and IL-6 levels in synovial fluid and serum corticosterone and epinephrine in the PC group. Administration of drugs to birds of Groups T1 and T5 did not significantly change corticosterone concentration, while all different drug combinations decreased epinephrine level. Drug combinations that demonstrated better analgesic effect more strongly reduced serum epinephrine concentration. Meloxicam + hydrocortisone was the most effective combination in reducing inflammatory cytokines. In conclusion, one-time combination therapy with anti-inflammatory agents was effective in the acute management of inflammatory pain due to MSU-induced arthritis in pigeons, even by the topical route.

Topics: Meloxicam (65%), Piroxicam (58%), Arthritis (57%), Dexamethasone (50%)

Summary (2 min read)

WITH EXPERIMENTALLY INDUCED ACUTE ARTHRITIS

  • Moreover, as one of the features in the long and diverse list of their effects on different body functions, glucocorticoids or steroidal anti-inflammatory drugs can reduce pain intensity by inhibiting prostaglandin synthesis and reducing vascular permeability (Leppert and Buss, 2012); for instance, betamethasone has been shown to effectively reduce inflammatory joint pain of chickens (Hocking et al., 2001).
  • This decision can deprive the patient from some of the advantages of the IM route, such as administering a precise amount of drug in a short time to a bird which may not be eager to consume food and/or water due to the nature of the disease or its accompanying factors like pain.
  • The effect of monotherapy with different analgesic agents has been evaluated in avian models with MSU-induced arthritis and has been associated with different outcomes.

Birds and study design

  • Forty-five adult, clinically healthy domestic pigeons (Columba livia domestica) from both sexes with a body weight of 250 ± 50 g that had been raised in the same aviary throughout their life were used in this study.
  • The birds were transferred to isolated rooms with controlled temperature (22 °C) and a 10/14 hours Acta Veterinaria Hungarica 67, 2019 light/dark cycle.
  • All procedures used in this study are in accordance with their institutional ethical guidelines which are based on the EU guidelines for animal experiments.

Recording of standing behaviour

  • After intra-articular injection of MSU or normal saline, each bird was immediately transferred to a transparent glass cage and its behaviour was recorded by a camera fixed in a corner of the cage from 120–180 min post injection.
  • The standing time on the right leg during this period was recorded.
  • The intra-assay and inter-assay coefficients of variation (CVs) were < 8% and < 10%, respectively, for both kits.
  • Levels of TNF-α and IL-6 in the synovial fluid were assayed by sandwich ELISA kits for pigeon TNF-α and IL-6 (MyBioSource Co., USA).

Statistical analysis

  • Data are presented as mean ± standard deviation (SD).
  • Data analysis was performed by one-way analysis of variance method followed by Tukey’s multiple comparison test by using GraphPad Prism Version 6 (GraphPad Software Inc., USA).

One-leg standing time

  • Birds in the PC group showed one-leg standing behaviour for a period of time that was significantly longer than for the NC birds (P < 0.0001) (Fig. 1).
  • Treating birds with all different drug combinations was associated with a significant decrease in one-leg standing time as compared to PC birds (P < 0.0001 for all comparisons).
  • Birds in Group T4 showed the longest one-leg standing time among the treated groups, which was significantly longer than for all other treated groups (P < 0.0001 for all comparisons).

Serum epinephrine concentrations

  • All different drug Acta Veterinaria Hungarica 67, 2019 combinations resulted in a significant decrease in serum epinephrine levels as compared to PC birds (P < 0.0001 for all comparisons); however, only the drug combinations that were administered to T2, T3 and T5 groups could reverse serum epinephrine level to that of the NC group (P > 0.05).
  • Serum epinephrine concentrations were statistically the same among these three (T2, T3 and T5) groups (P > 0.05).

Discussion

  • Anti-inflammatory drugs from both steroidal and nonsteroidal classes are common therapeutic agents that are successfully used to manage inflammatory pain in avian species.
  • Interestingly, when both classes of drugs were administered by injection, the result was not statistically better than when only one drug was used by injection (except for the combination of two NSAIDs).
  • 2005; Kou et al., 2015; Dhanasekar and Rasool, 2016), to the best of their knowledge this is the first time that its involvement in an avian model of this type of arthritis has been demonstrated.
  • On the other hand, topical administration of drugs close to their target site can limit their adverse effects; therefore, it seems that topical hydrocortisone may be a logical choice in inflammatory arthritis in pigeons.
  • Like corticosterone, catecholamines have been used as a humoral index of stress in birds (Le Maho et al., 1992) and it has been shown that pain can stimulate the release of adrenalin and other catecholamines from the adrenal medulla (Tennant, 2013).

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Acta Veterinaria Hungarica 67 (4), pp. 588–601 (2019)
DOI: 10.1556/004.2019.058
0236-6290/$ 20.00 © 2019 Akadémiai Kiadó, Budapest
A COMPARATIVE STUDY ON ANTI-INFLAMMATORY DRUG
COMBINATIONS IN DOMESTIC PIGEONS
WITH EXPERIMENTALLY INDUCED ACUTE ARTHRITIS
Sajedeh SALANDARI
1
, Tahoora SHOMALI
1*
, Najmeh MOSLEH
2
and Saeed NAZIFI
2
1
Division of Pharmacology and Toxicology, Department of Basic Sciences and
2
Department of Clinical Studies, School of Veterinary Medicine, Shiraz University,
P.O. Box 71441-69155, Shiraz, Iran
(Received 7 April 2019; accepted 27 August 2019)
The study compares the effect of one-time administration of nonsteroidal
and/or steroidal anti-inflammatory combinations by topical or intramuscular (IM)
routes to pigeons with monosodium urate (MSU)-induced arthritis. Forty-five
adult domestic pigeons were assigned into nine equal groups: NC, negative con-
trol; PC, positive control with arthritis; sham, sham control; T1, meloxicam + hy-
drocortisone; T2, dexamethasone + piroxicam; T3, meloxicam + dexamethasone;
T4, hydrocortisone + piroxicam; T5, dexamethasone + hydrocortisone; T6, meloxi-
cam + piroxicam. Arthritis was also induced in T1 to T6 birds. Meloxicam and
dexamethasone were administered by IM injection and the other drugs topically
right after the induction of arthritis. Different drug combinations significantly de-
creased one-leg standing time. Induction of arthritis significantly increased TNF-α
and IL-6 levels in synovial fluid and serum corticosterone and epinephrine in the
PC group. Administration of drugs to birds of Groups T1 and T5 did not signifi-
cantly change corticosterone concentration, while all different drug combinations
decreased epinephrine level. Drug combinations that demonstrated better analge-
sic effect more strongly reduced serum epinephrine concentration. Meloxicam +
hydrocortisone was the most effective combination in reducing inflammatory cy-
tokines. In conclusion, one-time combination therapy with anti-inflammatory
agents was effective in the acute management of inflammatory pain due to MSU-
induced arthritis in pigeons, even by the topical route.
Key words: Anti-inflammatory drugs, arthritis, pain, cytokines, pigeon
Diverse groups of pathological conditions, from simple traumatic lesions
to infectious diseases of inflammatory nature, are associated with both acute and
chronic pain in avian species. Birds have developed peripheral and central path-
ways for the detection, transmission, modulation and perception of pain due to
noxious stimuli (Machin, 2014) and therefore can experience the unpleasant feel-
ing of pain that can negatively affect their behaviour, performance and even the
*
Corresponding author; E-mail: tshomali@shirazu.ac.ir; Phone: 0098 (71) 3613-8907

ANTI-INFLAMMATORY DRUG COMBINATIONS IN DOMESTIC PIGEONS 589
Acta Veterinaria Hungarica 67, 2019
outcome of the therapeutic approach for the underlying disease. On the other
hand, proper pain management in birds is mandatory for humane and ethical rea-
sons.
Inflammatory pain is a commonly encountered clinical situation in avian
species. Non-steroidal anti-inflammatory drugs (NSAIDs) are well known for
their analgesic effect, which originates not only from their ability to peripherally
reduce inflammation but also from their central anti-nociceptive properties (Rivi-
ere and Papich, 2009). Although the results of pain management with NSAIDs
are not consistent in different avian species, NSAID administration has shown
positive effects in this regard, and drugs like meloxicam and carprofen are com-
monly used for inflammatory pain management in avian species (Malik and Val-
entine, 2018).
Moreover, as one of the features in the long and diverse list of their effects
on different body functions, glucocorticoids or steroidal anti-inflammatory drugs
(SAIDs) can reduce pain intensity by inhibiting prostaglandin synthesis and re-
ducing vascular permeability (Leppert and Buss, 2012); for instance, betame-
thasone has been shown to effectively reduce inflammatory joint pain of chick-
ens (Hocking et al., 2001).
Currently, different agents from the NSAID or SAID classes are commer-
cially available that may be used in avian medicine and are administered by dif-
ferent routes. Unfortunately, the lack of avian species-specific information on ef-
fective drugs and proper protocols for pain management (Mazor-Thomas et al.,
2014), especially for combinatorial drug protocols, complicates the process of
pharmaceutical pain management in clinical settings and makes it a hard task for
the clinician to select the proper approach for pain management in these species.
The situation is worsened further by the high sensitivity of ornamental and wild
birds to stress, e.g. due to the administration of drugs by injection. This reduces
the willingness of clinicians to administer dugs by this route in favour of other
routes like oral administration of drugs usually in the feed or water. However,
this decision can deprive the patient from some of the advantages of the IM
route, such as administering a precise amount of drug in a short time to a bird
which may not be eager to consume food and/or water due to the nature of the
disease or its accompanying factors like pain. On the other hand, administration
of drugs by the topical route, where applicable, is a relatively lower-stress proce-
dure that can also reduce the chance for some of the drug-induced adverse ef-
fects. Therefore, acquiring knowledge about optimised protocols in order to gain
more efficient and/or faster responses is greatly needed.
Since 1962 when Faires and McCarty provoked inflammatory reactions in
the knee joint of dogs and men injected with monosodium urate (MSU) micro-
crystals, the inflammatory nature of this model has been frequently shown in
other animals, especially rodents. For instance, inflammatory cell infiltration and
elevated expressions of nuclear transcription factor-κB p65 (NF-κB p65) in syn-

590 SALANDARI et al.
Acta Veterinaria Hungarica 67, 2019
ovial tissues accompanied by increased levels of tumour necrosis factor-α (TNF-
α) and different interleukins (ILs) in the synovial fluid or serum of rats and mice
have been reported (Liu-Bryan et al., 2005; Kou et al., 2015; Dhanasekar and
Rasool, 2016). Although MSU-induced arthritis in birds is also an inflammatory
process, knowledge on the possible changes in inflammatory cytokines is scarce
in avian species.
The microcrystal arthritis model for acute inflammatory pain is among the
few pain models that have been successfully evaluated in pigeons. This model
has the ability to reflect both nociception and inflammation, and can be properly
used for the evaluation of pharmaceutical agents for pain control (Brune et al.,
1974). In chickens, it has been shown that the pain due to microcrystalline MSU
injection is associated with increased sensitivity of the joint capsule C-fibre re-
ceptors as the peripheral neural component for the pain (Gentle et al., 1999).
Moreover, it has been clarified that pain due to acute inflammatory joint condi-
tions is processed in specific areas of the parrot cerebrum, including the nidopal-
lium (Paul-Murphy et al., 2005).
The effect of monotherapy with different analgesic agents has been evalu-
ated in avian models with MSU-induced arthritis and has been associated with
different outcomes. Some examples include subcutaneous colchicine in pigeons
(Floersheim et al., 1973), bupivacaine (Hocking et al., 1997), morphine sulphate
and fentanyl citrate (Gentle et al., 1999), betamethasone, dexamethasone (sodium
phosphate) and methylprednisolone (Hocking et al., 2001) as well as NSAIDs
(carprofen, flunixin, ketoprofen and sodium salicylate, intramuscularly) in fowls
(Hocking et al., 2005) and meloxicam administered by IM injection in Hispanio-
lan parrots (Cole et al., 2009). As far as we know, there is no information on the
possible outcome of one-time combination therapy with anti-inflammatory
agents for the acute management of pain in this model.
This study compares the therapeutic outcome (pain-relieving effect deter-
mined by the time that the birds stand on the contralateral leg) of NSAID and/or
SAID combinations that are administered by topical or IM routes to pigeons with
experimentally induced arthritis. Selected biochemical parameters related to
stress/pain (serum epinephrine and corticosterone levels) or inflammation (IL-6
and TNF-α levels in the synovial fluid) were also assayed.
Materials and methods
Birds and study design
Forty-five adult, clinically healthy domestic pigeons (Columba livia do-
mestica) from both sexes with a body weight of 250 ± 50 g that had been raised in
the same aviary throughout their life were used in this study. The birds were trans-
ferred to isolated rooms with controlled temperature (22 °C) and a 10/14 hours

ANTI-INFLAMMATORY DRUG COMBINATIONS IN DOMESTIC PIGEONS 591
Acta Veterinaria Hungarica 67, 2019
light/dark cycle. They had free access to a commercial pellets for pigeons (Tiba
Bird
®
, Iran) and tap water and were kept in metal cages (five birds randomly al-
located to each cage with at least 3,600 cm
2
area considered for each bird) that
were equipped with perches.
Table 1
Experimental design
Group
Treatments
Arthritis
Pectoral muscle injection Topical tarsus
Saline
Dexa-
methasone
Meloxicam Petrolatum
Hydro-
cortisone
Piroxicam
N
C – – – – – – –
SHAM – + – – + –
PC + + – + –
T1 + + – + – + –
T2 + + + – – – +
T3 + – + + – – –
T4 + + + +
T5 + + + – – + –
T6 + + – + – – +
NC: negative control; PC: positive control with arthritis; sham: sham control; T1: birds with arthri-
tis that received injectable meloxicam + topical hydrocortisone; T2: birds with arthritis that re-
ceived injectable dexamethasone + topical piroxicam; T3: birds with arthritis that received injecta-
ble meloxicam + injectable dexamethasone; T4: birds with arthritis that received topical hydrocor-
tisone + topical piroxicam; T5: birds with arthritis that received injectable dexamethasone + topical
hydrocortisone; T6: birds with arthritis that received injectable meloxicam + topical piroxicam
The acclimatisation period for birds was one week; each cage containing
five birds was randomly assigned to treatment groups as follows (Table 1): (1)
Negative control (NC) group: the birds did not receive any special treatment dur-
ing the experiment; (2) Sham control (sham) group: the birds received 0.05 mL
of normal saline by intra-articular injection into the left intertarsal joint, accom-
panied by two-sided IM injection of normal saline in the pectoral muscles and
topical administration of petrolatum (Vaseline
®
, USA) circumferentially on the
left intertarsal joint; (3) Positive control (PC) group: acute inflammatory arthritis
was induced by aseptically injecting 0.05 mL of autoclaved microcrystalline so-
dium urate (Sigma, USA) in normal saline (8% suspension) into the left inter-
tarsal joint. The method for induction of arthritis in pigeons was adopted from
Brune et al. (1974). These pigeons also received IM injections of normal saline
and topically administered petrolatum as previously described for the sham
group. Arthritis was also induced in the left intertarsal joint of all birds in Groups
T1–T6 as stated above and then different therapeutic approaches were used in
these groups as follows: (4) Group T1: meloxicam (IM) + topical hydrocortisone

592 SALANDARI et al.
Acta Veterinaria Hungarica 67, 2019
cream; (5) Group T2: dexamethasone (IM) + topical piroxicam; (6) Group T3:
dexamethasone (IM) + meloxicam (IM); (7) Group T4: topical hydrocortisone +
piroxicam; (8) Group T5: dexamethasone (IM) + topical hydrocortisone; (9)
Group T6: meloxicam (IM) + topical piroxicam.
Injectable solutions (NSAID or SAID) were administered in the left pectoral
muscle and normal saline in the right pectoral muscle of the birds. The volume of
normal saline for IM injection was calculated as the volume of its counterpart drug
in a pigeon with similar body weight. In Group T3 NSAID was injected in the left
pectoral muscle and SAID in the right pectoral muscle. The birds received meloxi-
cam (Meloxivet
®
2% injectable solution in 50 mL vial, Razak Pharmaceutical Lab.,
Iran) at 0.5 mg kg
–1
(Cole et al., 2009) and/or dexamethasone (Dexacoid
®
0.4% in-
jectable solution in 20-mL vial, Nasr Pharmaceutical Co., Iran) at 2 mg kg
–1
(Plumb, 2008). Piroxicam (Piroxicam-Najo
®
0.5% gel, Iran Najo Pharmaceutical
Co., Iran) or hydrocortisone cream (Cortinil
®
1%, Sina Darou, Iran) was used topi-
cally on the left intertarsal joint as petrolatum administration.
Each pigeon was weighed on the day before starting the experiment and
administration of drugs was performed immediately after injecting MSU for the
induction of arthritis.
All procedures used in this study are in accordance with our institutional
ethical guidelines which are based on the EU guidelines for animal experiments.
The study design and procedures were approved by our institutional ethical
committee before commencing the experiment.
Recording of standing behaviour
After intra-articular injection of MSU or normal saline, each bird was im-
mediately transferred to a transparent glass cage and its behaviour was recorded
by a camera fixed in a corner of the cage from 120–180 min post injection. The
standing time on the right leg during this period was recorded. Each footage was
checked twice by an observer unaware of the grouping system and the sum of the
‘one-leg-only standing time’ was determined for each bird. Choosing the time
period was based on the study by Brune et al. (1974) demonstrating that pigeons
show the most prominent one-leg standing behaviour during this period of time
in an MSU-induced arthritis model.
Blood sampling, epinephrine and corticosterone assays
At the end of the recording time, blood samples (maximum 2.5 mL) were
obtained by venipuncture of the wing vein using a 2.5-mL sterile syringe with
23 G needle size and transferred to plain glass tubes without anticoagulant. Sam-
pling of all birds was performed from 10 to 11 a.m. Blood samples were centri-
fuged at 2800 g for 5 min and sera were harvested and stored at –20 °C until analy-
sis.

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TL;DR: Progress in the characterization of intercellular mediators — proteins that are now known as cytokines — has led to the realization that one cytokine, tumour-necrosis factor (TNF; previously known as TNF-α), has an important role in the pathogenesis of rheumatoid arthritis.
Abstract: The aetiology of systemic, autoimmune, chronic inflammatory diseases--such as rheumatoid arthritis--is not known, and their pathogenesis is complex and multifactorial. However, progress in the characterization of intercellular mediators--proteins that are now known as cytokines--has led to the realization that one cytokine, tumour-necrosis factor (TNF; previously known as TNF-alpha), has an important role in the pathogenesis of rheumatoid arthritis. This discovery heralded a new era of targeted and highly effective therapeutics for rheumatoid arthritis and, subsequently, other chronic inflammatory diseases.

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Abstract: Objective In gout, incompletely defined molecular factors alter recognition of dormant articular and bursal monosodium urate monohydrate (MSU) crystal deposits, thereby inducing self-limiting bouts of characteristically severe neutrophilic inflammation. To define primary determinants of cellular recognition, uptake, and inflammatory responses to MSU crystals, we conducted a study to test the role of Toll-like receptor 2 (TLR-2), TLR-4, and the cytosolic TLR adapter protein myeloid differentiation factor 88 (MyD88), which are centrally involved in innate immune recognition of microbial pathogens. Methods We isolated bone marrow–derived macrophages (BMDMs) in TLR-2−/−, TLR-4−/−, MyD88−/−, and congenic wild-type mice, and assessed phagocytosis and cytokine expression in response to endotoxin-free MSU crystals under serum-free conditions. MSU crystals also were injected into mouse synovium-like subcutaneous air pouches. Results TLR-2−/−, TLR-4−/−, and MyD88−/− BMDMs demonstrated impaired uptake of MSU crystals in vitro. MSU crystal–induced production of interleukin-1β (IL-1β), tumor necrosis factor α, keratinocyte-derived cytokine/growth-related oncogene α, and transforming growth factor β1 also were significantly suppressed in TLR-2−/− and TLR-4−/− BMDMs and were blunted in MyD88−/− BMDMs in vitro. Neutrophil influx and local induction of IL-1β in subcutaneous air pouches were suppressed 6 hours after injection of MSU crystals in TLR-2−/− and TLR-4−/− mice and were attenuated in MyD88−/− mice. Conclusion The murine host requires TLR-2, TLR-4, and MyD88 for macrophage activation and development of full-blown neutrophilic, air pouch inflammation in response to MSU crystals. Our findings implicate innate immune cellular recognition of naked MSU crystals by specific TLRs as a major factor in determining the inflammatory potential of MSU crystal deposits and the course of gouty arthritis.

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Abstract: Crystal-related joint diseases are often associated with systemic inflammatory manifestations, including increased levels of acute-phase proteins, leukocytosis, and fever. Recently, interleukin-6 (IL-6) has been identified as a pluripotent mediator of inflammatory and immunologic responses and the major hepatocyte-stimulating factor. In this study, we demonstrated that monosodium urate (MSU) and calcium pyrophosphate dihydrate (CPPD) crystals, and to a lesser extent, hydroxyapatite crystals, increased IL-6 production by synoviocytes and monocytes in vitro. Immunoprecipitation experiments showed that MSU and CPPD crystals, but not hydroxyapatite crystals, were able to increase the release of newly synthesized IL-6. Crystal-induced IL-6 stimulated acute-phase protein synthesis, immunoglobulin production, and hybridoma cell proliferation, which was neutralized by a specific antibody to IL-6. High levels of IL-6 were found in synovial fluid from patients with gout and pseudogout. These results demonstrate that MSU and CPPD crystals can induce IL-6 production in synoviocytes and monocytes, and that synovial fluid from patients with gout and pseudogout contains high levels of IL-6. Crystal-induced IL-6 is likely to be an important mediator of inflammatory responses in acute gout and pseudogout.

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Frequently Asked Questions (1)
Q1. What are the contributions mentioned in the paper "A comparative study on anti-inflammatory drug combinations in domestic pigeons with experimentally induced acute arthritis" ?

The study compares the effect of one-time administration of nonsteroidal and/or steroidal anti-inflammatory combinations by topical or intramuscular ( IM ) routes to pigeons with monosodium urate ( MSU ) -induced arthritis.