RESUMO
When conducting toxicology studies, the interpretation of drug-related neurological clinical signs such as convulsions, myoclonus/myoclonic jerks, tremors, ataxia, and salivation requires an understanding of the spontaneous incidence of those observations in commonly used laboratory animal species. The spontaneous incidence of central nervous system clinical signs in control animals from a single facility using cage-side observations or high definition video monitoring was retrospectively analyzed. Spontaneous convulsions were observed at low incidence in Beagle dogs and Sprague-Dawley rats but were not identified in cynomolgus monkeys and Göttingen minipigs. Spontaneous myoclonic jerks and muscle twitches were observed at low incidence in Beagle dogs, cynomolgus monkeys, and Sprague-Dawley rats but were not seen in Göttingen minipigs. Spontaneous ataxia/incoordination was identified in all species and generally with a higher incidence when using video monitoring. Salivation and tremors were the two most frequent spontaneous clinical signs and both were observed in all species. Data from the current study unveil potential limitations when using control data obtained from a single study for toxicology interpretation related to low incidence neurological clinical signs while providing historical control data from Beagle dogs, cynomolgus monkeys, Sprague-Dawley rats, and Göttingen minipigs.
Assuntos
Mioclonia , Ratos , Suínos , Animais , Cães , Ratos Sprague-Dawley , Porco Miniatura , Estudos Retrospectivos , Macaca fascicularis , Tremor/induzido quimicamente , Incidência , Convulsões , AtaxiaRESUMO
In silico modeling offers an opportunity to supplement and accelerate cardiac safety testing. With in silico modeling, computational simulation methods are used to predict electrophysiological interactions and pharmacological effects of novel drugs on critical physiological processes. The O'Hara-Rudy's model was developed to predict the response to different ion channel inhibition levels on cardiac action potential duration (APD) which is known to directly correlate with the QT interval. APD data at 30% 60% and 90% inhibition were derived from the model to delineate possible ventricular arrhythmia scenarios and the marginal contribution of each ion channel to the model. Action potential values were calculated for epicardial, myocardial, and endocardial cells, with action potential curve modeling. This study assessed cardiac ion channel inhibition data combinations to consider when undertaking in silico modeling of proarrhythmic effects as stipulated in the Comprehensive in Vitro Proarrhythmia Assay (CiPA). As expected, our data highlight the importance of the delayed rectifier potassium channel (IKr) as the most impactful channel for APD prolongation. The impact of the transient outward potassium channel (Ito) inhibition on APD was minimal while the inward rectifier (IK1) and slow component of the delayed rectifier potassium channel (IKs) also had limited APD effects. In contrast, the contribution of fast sodium channel (INa) and/or L-type calcium channel (ICa) inhibition resulted in substantial APD alterations supporting the pharmacological relevance of in silico modeling using input from a limited number of cardiac ion channels including IKr, INa, and ICa, at least at an early stage of drug development.
Assuntos
Potenciais de Ação , Simulação por Computador , Canais Iônicos , Miócitos Cardíacos , Potenciais de Ação/efeitos dos fármacos , Humanos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Canais Iônicos/efeitos dos fármacos , Canais Iônicos/metabolismo , Canais Iônicos/fisiologia , Arritmias Cardíacas/induzido quimicamente , Arritmias Cardíacas/fisiopatologiaRESUMO
BACKGROUND: Allergen testing is used to select antigens included in the desensitisation vaccine. Intradermal skin test (IDT) is the gold standard in cats, yet allergen-specific immunoglobulin (Ig)E serological testing (ASIS) is often used. Feline data are lacking regarding the agreement between IDT and ASIS results. HYPOTHESIS/OBJECTIVES: The first objective of the study was to establish a colony of cats with naturally acquired feline atopic syndrome (FAS). Further objectives were to define their hypersensitivity disorder to detail the allergen tests results, and to assess similarity between the allergen tests. ANIMALS: Thirty-five cats with FAS and 10 control cats. MATERIALS AND METHODS: Enrolled cats went through a five phase-screening and quarantine process before joining the colony. An elimination diet trial was performed on all FAS cats. ASIS and IDT were consecutively performed on all cats under sedation. RESULTS: Reactions to 34 allergens were compiled for the 45 cats. Global sensitivity and specificity of ASIS were 34.7% and 78.9%, respectively. Only flea (ICC = 0.26, p = 0.040) and Dermatophagoides pteronyssinus (ICC = 0.48, p < 0.001) allergens had a significant intraclass correlation (weak agreement). Two FAS cats had negative tests including one cat with a concomitant food allergy. CONCLUSIONS AND CLINICAL RELEVANCE: This study depicts the first reported colony of cats with naturally acquired FAS. This is the first feline study to compare and show the poor agreement between allergen tests with a panel of 34 allergens. This colony also harbours two cats with FAS with negative allergen tests. These may represent the first described cats with an intrinsic form of atopic syndrome.
Assuntos
Alérgenos , Doenças do Gato , Dermatite Atópica , Imunoglobulina E , Gatos , Animais , Doenças do Gato/imunologia , Doenças do Gato/diagnóstico , Doenças do Gato/sangue , Alérgenos/imunologia , Masculino , Feminino , Dermatite Atópica/veterinária , Dermatite Atópica/imunologia , Dermatite Atópica/sangue , Dermatite Atópica/diagnóstico , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Testes Intradérmicos/veterinária , Sensibilidade e EspecificidadeRESUMO
Validating animal pain models is crucial to enhancing translational research and response to pharmacological treatment. This study investigated the effects of a calibrated slight exercise protocol alone or combined with multimodal analgesia on sensory sensitivity, neuroproteomics, and joint structural components in the MI-RAT model. Joint instability was induced surgically on day (D) 0 in female rats (N = 48) distributed into sedentary-placebo, exercise-placebo, sedentary-positive analgesic (PA), and exercise-PA groups. Daily analgesic treatment (D3-D56) included pregabalin and carprofen. Quantitative sensory testing was achieved temporally (D-1, D7, D21, D56), while cartilage alteration (modified Mankin's score (mMs)) and targeted spinal pain neuropeptide were quantified upon sacrifice. Compared with the sedentary-placebo (presenting allodynia from D7), the exercise-placebo group showed an increase in sensitivity threshold (p < 0.04 on D7, D21, and D56). PA treatment was efficient on D56 (p = 0.001) and presented a synergic anti-allodynic effect with exercise from D21 to D56 (p < 0.0001). Histological assessment demonstrated a detrimental influence of exercise (mMs = 33.3%) compared with sedentary counterparts (mMs = 12.0%; p < 0.001), with more mature transformations. Spinal neuropeptide concentration was correlated with sensory sensitization and modulation sites (inflammation and endogenous inhibitory control) of the forced mobility effect. The surgical MI-RAT OA model coupled with calibrated slight exercise demonstrated face and predictive validity, an assurance of higher clinical translatability.
Assuntos
Neuropeptídeos , Osteoartrite , Animais , Feminino , Roedores , Dor/tratamento farmacológico , Osteoartrite/patologia , Neuropeptídeos/uso terapêutico , Analgésicos/farmacologiaRESUMO
With osteoarthritis being the most common degenerative disease in pet animals, a very broad panel of natural health products is available on the market for its management. The aim of this systematic review and meta-analysis, registered on PROSPERO (CRD42021279368), was to test for the evidence of clinical analgesia efficacy of fortified foods and nutraceuticals administered in dogs and cats affected by osteoarthritis. In four electronic bibliographic databases, 1578 publications were retrieved plus 20 additional publications from internal sources. Fifty-seven articles were included, comprising 72 trials divided into nine different categories of natural health compound. The efficacy assessment, associated to the level of quality of each trial, presented an evident clinical analgesic efficacy for omega-3-enriched diets, omega-3 supplements and cannabidiol (to a lesser degree). Our analyses showed a weak efficacy of collagen and a very marked non-effect of chondroitin-glucosamine nutraceuticals, which leads us to recommend that the latter products should no longer be recommended for pain management in canine and feline osteoarthritis.
Assuntos
Produtos Biológicos , Canabidiol , Doenças do Gato , Doenças do Cão , Osteoartrite , Animais , Produtos Biológicos/uso terapêutico , Canabidiol/uso terapêutico , Gatos , Condroitina/uso terapêutico , Colágeno/uso terapêutico , Suplementos Nutricionais , Doenças do Cão/tratamento farmacológico , Cães , Glucosamina/uso terapêutico , Osteoartrite/tratamento farmacológico , Osteoartrite/veterináriaRESUMO
The metrological properties of two performance-based outcome measures of feline osteoarthritis (OA), namely Effort Path (Path) and Stairs Assay Compliance (Stairs), were tested. Cats naturally affected by OA (n = 32) were randomly distributed into four groups (A: 0.40, B: 0.25, C: 0.15, or D: 0.00 mg firocoxib/kg bodyweight) and assessed during baseline, treatment, and recovery periods. For Path, from an elevated walking platform, the cats landed on a pressure-sensitive mattress and jumped up onto a second elevated platform. Analysis included velocity, time to completion, peak vertical force (PVF), and vertical impulse. For Stairs, the number of steps and time to completion were recorded for 16 steps up and down in a 4 min period. Reliability was moderate to very good for Path and poor to good for Stairs. Different normalization methods are described in the manuscript. The placebo group remained stable within-time in Path, whereas treated cats trotted faster on the ramp (p < 0.0001), improved their PVF (p < 0.018) and completed the task quicker (p = 0.003). The percentage of cats completing the Stairs finish line was higher under treatment (p < 0.036), with huge effect size, the placebo group results being stable within-time. Both are promising performance-based outcome measures to better diagnose and manage feline OA pain.
Assuntos
Osteoartrite , 4-Butirolactona/análogos & derivados , Analgésicos/uso terapêutico , Animais , Gatos , Osteoartrite/tratamento farmacológico , Osteoartrite/veterinária , Reprodutibilidade dos Testes , Sulfonas/uso terapêuticoRESUMO
Respiratory monitoring, using impedance with implanted telemetry in socially housed animals, was not possible until the recent development of digital signal transmission. The objective of this study was to evaluate digital telemetry monitoring of cardiopulmonary parameters (respiratory rate, tidal volume, minute volume, electrocardiography (DII), systemic arterial blood pressure, physical activity, and body temperature) in conscious, single-housed, non-rodent species commonly used in toxicology studies following administration of positive/negative controls (saline, dexmedetomidine, morphine, amphetamine, and doxapram), and also, the effects of various social housing arrangements in untreated female and/or male cynomolgus monkeys, Beagle dogs, and Göttingen minipigs (n = 4 per species). Aggressions were observed in socially housed male minipigs, however, which prevented pair-housed assessments in this species. All tested pharmacological agents significantly altered more than one organ system, highlighting important inter-organ dependencies when analyzing functional endpoints. Stress-related physiological changes were observed with single-housing or pair-housing with a new cage mate in cynomolgus monkeys and Beagle dogs, suggesting that stable social structures are preferable to limit variability, especially around dosing. Concomitant monitoring of cardiovascular and respiratory parameters from the same animals may help reduce the number of animals (3 Rs) needed to fulfill the S7A guidelines and allows for identification of organ system functional correlations. Globally, the data support the use of social housing in non-rodents for safety pharmacology multi-organ system (heart and lungs) monitoring investigations.
Assuntos
Anfetamina/toxicidade , Analgésicos Opioides/toxicidade , Sistema Cardiovascular/efeitos dos fármacos , Dexmedetomidina/toxicidade , Doxapram/toxicidade , Eletrocardiografia/efeitos dos fármacos , Morfina/toxicidade , Animais , Estimulantes do Sistema Nervoso Central/toxicidade , Cães , Impedância Elétrica , Macaca fascicularis , Suínos , Porco MiniaturaRESUMO
INTRODUCTION: Corrected QT (QTc) interval is an essential proarrhythmic risk biomarker, but recent data have identified limitations to its use. The J to T-peak (JTp) interval is an alternative biomarker for evaluating drug-induced proarrhythmic risk. The aim of this study was to evaluate pharmacological effects using spatial magnitude leads and DII electrocardiogram (ECG) leads and common ECG confounders (ie, stress and body temperature changes) on covariate adjusted QT (QTca), covariate adjusted JTp (JTpca), and covariate adjusted T-peak to T-end (Tpeca) intervals. METHODS: Beagle dogs were exposed to body hyper- (42 °C) or hypothermic (33 °C) conditions or were administered epinephrine to assess confounding effects on heart rate corrected QTca, JTpca, and Tpeca intervals. Dofetilide (0.1, 0.3, 1.0 mg/kg), ranolazine (100, 140, 200 mg/kg), and verapamil (7, 15, 30, 43, 62.5 mg/kg) were administered to evaluate pharmacological effects. RESULTS: Covariate adjusted QT (slope -12.57 ms/°C) and JTpca (-14.79 ms/°C) were negatively correlated with body temperature but Tpeca was minimally affected. Epinephrine was associated with QTca and JTpca shortening, which could be related to undercorrection in the presence of tachycardia, while minimal effects were observed for Tpeca. There were no significant ECG change following ranolazine administration. Verapamil decreased QTca and JTpca intervals and increased Tpeca, whereas dofetilide increased QTca and JTpca intervals but had inconsistent effects on Tpeca. CONCLUSION: Results highlight potential confounders on QTc interval, but also on JTpca and Tpeca intervals in nonclinical studies. These potential confounding effects may be relevant to the interpretation of ECG data obtained from nonclinical drug safety studies with Beagle dogs.
Assuntos
Arritmias Cardíacas/etiologia , Epinefrina/farmacologia , Fenetilaminas/farmacologia , Ranolazina/farmacologia , Sulfonamidas/farmacologia , Verapamil/farmacologia , Animais , Antiarrítmicos/administração & dosagem , Antiarrítmicos/farmacologia , Arritmias Cardíacas/prevenção & controle , Biomarcadores , Temperatura Corporal , Cães , Relação Dose-Resposta a Droga , Eletrocardiografia , Feminino , Frequência Cardíaca , Masculino , Fenetilaminas/administração & dosagem , Ranolazina/administração & dosagem , Estresse Fisiológico/efeitos dos fármacos , Sulfonamidas/administração & dosagem , Verapamil/administração & dosagemRESUMO
BACKGROUND: This study aimed to evaluate the safety and efficacy of reduced-dosage ketoprofen with or without tramadol in dogs. Five healthy dogs receiving standard-dosage ketoprofen (2 mg/kg SC, then 1 mg/kg PO daily) comprised Group A. Twenty dogs with osteoarthritis were randomized to receive reduced-dosage ketoprofen (0.5 mg/kg SC once; 0.25 mg/kg PO daily) alone (Group B) or in combination with tramadol (5 mg/kg/day PO) (Group C). Treatments were administered for 28 days. Platelet aggregation time (PAT), gastrointestinal (GI) endoscopy and glomerular filtration rate (GFR) were performed up to 60 days after treatment initiation. Pain was scored using a validated clinical metrology instrument up to D120. Data were analyzed with general linear mixed model for repeated measures (α = 0.05). RESULTS: PAT was not different between groups but was increased with time for all groups. GI lesion scores were higher in Group A than Groups B and C (day 28; P = 0.005) and were increased with time for Group A (P = 0.005). GFR was lower in Group A than Groups B and C (day 28; P < 0.01) and were decreased with time for group A (P < 0.001). Standard-dosage ketoprofen administration resulted in clinically relevant adverse effects. Pain score decreased in both treated groups (B and C) from D0 to D28. Need of rescue analgesia from D29 to D120 was higher in Group B than in Group C (P = 0.039). CONCLUSIONS: The long-term safety profile of reduced-dosage ketoprofen is similar whether the drug is administered alone or in combination with tramadol to dogs with osteoarthritis. Analgesic efficacy of the combination looks attractive.
Assuntos
Analgésicos Opioides/uso terapêutico , Inibidores de Ciclo-Oxigenase/uso terapêutico , Doenças do Cão/tratamento farmacológico , Cetoprofeno/uso terapêutico , Tramadol/uso terapêutico , Analgésicos Opioides/administração & dosagem , Animais , Doença Crônica/tratamento farmacológico , Doença Crônica/veterinária , Inibidores de Ciclo-Oxigenase/administração & dosagem , Cães , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Cetoprofeno/administração & dosagem , Cetoprofeno/efeitos adversos , Masculino , Osteoartrite/tratamento farmacológico , Agregação Plaquetária/efeitos dos fármacos , Distribuição Aleatória , Tramadol/administração & dosagem , Tramadol/efeitos adversosRESUMO
The monosodium iodoacetate (MIA)-induced joint degeneration in rats is the most used animal model to screen analgesic drugs to alleviate osteoarthritis (OA) pain. This study aimed to evaluate the analgesic efficacy of pregabalin (PGB) in an MIA-induced OA model in rodents by using functional and neuroproteomic pain assessment methods. Treatment group included PGB in curative intent over 9 days compared to gold standard therapy (positive controls) and placebo (negative control). Functional assessments of pain (quantitative sensory testing and operant test) were performed concomitantly with spinal neuropeptides quantification. At day 21 post-OA induction, PGB in MIA rats reduced tactile allodynia (P = 0.028) and improved the place escape/avoidance behaviour (P = 0.04) compared to values recorded at last time-point before initiating analgesic therapy. All spinal neuropeptide concentrations, such as substance P, calcitonin gene-related peptide, bradykinin and somatostatin, came back to normal (non-affected) rat values, compared to their increase observed in MIA rats receiving the placebo (P < 0.0001). Initiated 13 days after chemical OA induction, repeated medication with PGB provided analgesia according to quantitative sensory testing, operant test and targeted neuropeptides pain assessment methods. This report highlights the interest of using reliable and sensitive methods like targeted neuropeptide quantification to detect the analgesic effects of a test article with concomitant functional assessments of pain when studying OA pain components.
Assuntos
Analgésicos/farmacologia , Neuropeptídeos/metabolismo , Osteoartrite/complicações , Osteoartrite/tratamento farmacológico , Dor/complicações , Pregabalina/farmacologia , Animais , Feminino , Osteoartrite/metabolismo , Medição da Dor , Ratos , Ratos Sprague-DawleyRESUMO
INTRODUCTION: Based on the ICH S7B and E14 guidance documents, QT interval (QTc) is used as the primary in vivo biomarker to assess the risk of drug-induced torsades de pointes (TdP). Clinical and nonclinical data suggest that drugs that prolong the corrected QTc with balanced multiple ion channel inhibition (most importantly the l-type calcium, Cav1.2, and persistent or late inward sodium current, Nav1.5, in addition to human Ether-à-go-go-Related Gene [hERG] IKr or Kv11.1) may have limited proarrhythmic liability. The heart rate-corrected J to T-peak (JTpc) measurement in particular may be considered to discriminate selective hERG blockers from multi-ion channel blockers. METHODS: Telemetry data from Beagle dogs given dofetilide (0.3 mg/kg), sotalol (32 mg/kg), and verapamil (30 mg/kg) orally and Cynomolgus monkeys given medetomidine (0.4 mg/kg) orally were retrospectively analyzed for effects on QTca, JTpca, and T-peak to T-end covariate adjusted (Tpeca) interval using individual rate correction and super intervals (calculated from 0-6, 6-12, 12-18, and 18-24 hours postdose). RESULTS: Dofetilide and cisapride (IKr or Kv11.1 blockers) were associated with significant increases in QTca and JTpca, while sotalol was associated with significant increases in QTca, JTpca, and Tpeca. Verapamil (a Kv11.1 and Cav1.2 blocker) resulted in a reduction in QTca and JTpca, however, and increased Tpeca. Medetomidine was associated with a reduction in Tpeca and increase in JTpca. DISCUSSION: Results from this limited retrospective electrocardiogram analysis suggest that JTpca and Tpeca may discriminate selective IKr blockers and multichannel blockers and could be considered in the context of an integrated comprehensive proarrhythmic risk assessment.
Assuntos
Bloqueadores dos Canais de Cálcio/farmacologia , Eletrocardiografia/efeitos dos fármacos , Frequência Cardíaca/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Bloqueadores dos Canais de Sódio/farmacologia , Animais , Biomarcadores , Cisaprida/farmacologia , Cães , Avaliação Pré-Clínica de Medicamentos , Síndrome do QT Longo/induzido quimicamente , Macaca fascicularis , Masculino , Medetomidina/farmacologia , Fenetilaminas/farmacologia , Sotalol/farmacologia , Sulfonamidas/farmacologia , Telemetria , Verapamil/farmacologiaRESUMO
OBJECTIVES: To validate a thermal threshold (TT) nociceptive model in bearded dragons (Pogona vitticeps) and to document TT changes after administration of morphine. STUDY DESIGN: A two-part randomized, blinded, controlled, experimental study. ANIMALS: Five adult bearded dragons (242-396 g). METHODS: A TT device delivered a ramped nociceptive stimulus (0.6 °C second-1) to the medial thigh until a response (leg kick/escape behavior) was observed or maximum (cut-off) temperature of 62 °C was reached. In phase I, period 1, six TT readings were determined at 20 minute intervals for evaluation of repeatability. Two of these readings were randomly assigned to be sham to assess specificity of the behavioral response. The same experiment was repeated 2 weeks later (period 2) to test reproducibility. In phase II, animals were administered either intramuscular morphine (10 mg kg-1) or saline 0.9%. TTs (maximum 68 °C) were determined before and 2, 4, 8, 12 and 24 hours after treatment administration. Data were analyzed using one-way anova (temporal changes and repeatability) and paired t tests (reproducibility and treatment comparisons) using Bonferroni correction (p < 0.05). RESULTS: Mean TT values were 57.4 ± 3.8 °C and 57.3 ± 4.3 °C for periods 1 and 2, respectively. Data were repeatable within each period (p = 0.83 and p = 0.07, respectively). Reproducibility between periods was remarkable (p = 0.86). False-positive responses during sham testing were 10%. TTs were significantly increased after morphine administration at 2, 4 and 8 hours compared with baseline, and at 2 and 4 hours compared with saline 0.9%. The highest TT was 67.7 ± 0.7 °C at 4 hours after morphine administration. CONCLUSIONS AND CLINICAL RELEVANCE: Testing was repeatable, reproducible and well tolerated in bearded dragons. TT nociceptive testing detected morphine administration and may be suitable for studying opioid regimens in bearded dragons.
Assuntos
Lagartos , Medição da Dor/veterinária , Limiar da Dor/fisiologia , Analgésicos Opioides , Animais , Morfina , Medição da Dor/métodos , Distribuição Aleatória , Reprodutibilidade dos TestesRESUMO
OBJECTIVE: Reporting the rate of positive (+) and negative (-) responders based on an objective outcome measure of pain-related functional disability/lameness in dogs with naturally occurring osteoarthritis (OA), and the relationship between initial lameness severity and the odds of being a (+) responder. STUDY DESIGN: Retrospective analysis of published peer-reviewed clinical trials in dogs with naturally occurring OA. ANIMALS: Dogs (n = 213) with hip and/or stifle afflicted-joints. METHODS: A responder analysis was undertaken using a previously determined cut-off value of ±2.0% of body weight using the peak of vertical force (PVF). Among the selected trials, PVF was acquired under similar conditions. Therapeutic approaches were therapeutic diets, natural health products and nonsteroidal anti-inflammatory drugs. RESULTS: Among dogs receiving a therapeutic approach as described above (n = 121), 62.8% [95% confidence interval, 53.9-70.9] were defined as (+) responders, whereas 11.6% [7.0-18.5] were (-) responders, accounting for a net (+) response rate by 51.2% [42.0-60.4]. In dogs receiving a negative control (n = 92), the net (+) response rate was 1.1% [0.0-5.9]. The number needed to treat was 4, and the effect size 0.7 [0.4-1.0]. The odds ratio of being a (+) responder under the therapeutic approaches was 2.85 [1.57-5.17] (p < 0.001). For every less severe lameness manifested with an increment in PVF by 1% body weight, the chance of being a (+) responder following treatment decreased by 9% (odds ratio 0.91 [0.86-0.97], p = 0.006). CONCLUSION AND CLINICAL RELEVANCE: The rate of (+) responder optimizes decision making for the management of pain-related clinical signs of OA. Evidence-based medicine was further supported by clinical metrics based on an objective outcome measure of pain-related functional disability/lameness. This study also revealed that dogs with a mild lameness are less prone to be improved, emphasizing the need to carefully manage OA dogs in spite of a more subtle affliction.
Assuntos
Analgésicos/uso terapêutico , Doenças do Cão/terapia , Osteoartrite/veterinária , Animais , Anti-Inflamatórios não Esteroides/uso terapêutico , Doenças do Cão/dietoterapia , Doenças do Cão/tratamento farmacológico , Cães , Osteoartrite/dietoterapia , Osteoartrite/tratamento farmacológico , Osteoartrite/terapia , Manejo da Dor/métodos , Manejo da Dor/veterinária , Estudos Retrospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: To compare the motor and sensory block efficacy and duration of a modified paravertebral brachial plexus block (PBPB) after administration of lidocaine alone (LI) or combined with epinephrine (LE). STUDY DESIGN: Prospective, randomized, blinded, crossover study. ANIMALS: A total of eight healthy female Beagle dogs. METHODS: Under general anesthesia, modified PBPB was performed on the left thoracic limb using neurostimulation and/or ultrasound guidance to administer lidocaine (2 mg kg-1; 0.2 mL kg-1) either alone (treatment LI, n = 10) or with epinephrine (1:100,000; treatment LE, n = 9). Sensory block was evaluated through reaction to a painful mechanical stimulus applied at five sites on the limb. Motor block effect was evaluated according to visual gait assessments and thoracic limb vertical force measurements under dynamic and static conditions. Data were analyzed using repeated-measures generalized estimating equations. All statistical tests were performed two-sided at the α = 0.05 significance threshold. RESULTS: The duration of sensory block did not differ significantly between treatments. Visible gait impairment was more persistent in LE than in LI (118 ± 63 minutes for LI and 163 ± 23 minutes for LE; mean ± standard deviation) (p = 0.027). At nadir value, dynamic peak vertical force was lower in LE than in LI (p = 0.007). For both dynamic and static evaluations, the nadir and the return to baseline force were delayed in LE (return to normal at 180-200 minutes) when compared with LI (130-140 minutes) (p < 0.005). CONCLUSIONS AND CLINICAL RELEVANCE: The addition of epinephrine to lidocaine prolonged the duration and increased the intensity of the regional block, as verified by visual gait assessment and kinetic analysis. No significant difference was noted between treatments regarding sensory blockade. Kinetic analysis could be useful to evaluate regional anesthetic effect in dogs.
Assuntos
Anestésicos Combinados/administração & dosagem , Anestésicos Locais/administração & dosagem , Bloqueio do Plexo Braquial/veterinária , Plexo Braquial/efeitos dos fármacos , Epinefrina/administração & dosagem , Lidocaína/administração & dosagem , Anestesia Geral/veterinária , Animais , Bloqueio do Plexo Braquial/métodos , Estudos Cross-Over , Cães , Feminino , Cinética , Estudos ProspectivosRESUMO
Validation of the French version of the UNESP-Botucatu multidimensional composite pain scale for assessing postoperative pain in cats. The aim of this study was to validate the French version of the UNESP-Botucatu multidimensional composite pain scale (MCPS-Fr) to assess postoperative pain in cats. Two veterinarians and one DVM student identified three domains of behavior based on video analyses: "psychomotor change", "protection of the painful area" and "physiological variables". Internal consistency was excellent (Cronbach's alpha coefficient of 0.94, 0.90 and 0.61, respectively). Criterion validity was good to very good when evaluations from the three observers were compared with a "gold standard". Inter- and intra-rater reliability for each scale item were good to very good. The optimal cut-off point identified with a ROC curve was > 7 (scale range 0-30 points), with a sensitivity of 97.8% and specificity of 99.1%. The MCPS-Fr is a valid, reliable and responsive instrument for assessing acute pain in cats undergoing ovariohysterectomy.(Translated by Dr. Beatriz Monteiro).
Assuntos
Doenças do Gato/diagnóstico , Medição da Dor/veterinária , Dor/veterinária , Animais , Gatos , Variações Dependentes do Observador , Dor/diagnóstico , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
To evaluate the toxicity of short-term high doses of meloxicam in American kestrels ( Falco sparverius ), 32 male captive-born, 1- to 4-year-old American kestrels were randomly assigned to 4 groups: 3 groups treated with meloxicam (n = 9 per group) and a control group (n = 5). Meloxicam was administered orally via feeding tube in the proventriculus at 2, 10, and 20 mg/kg every 12 hours for 7 days for the treatment groups, while the control group received saline solution. The birds were evaluated for the presence of clinical signs, abnormalities in the complete blood cell count and in the plasma biochemical panel for the 20-mg/kg group, and gross and histopathologic lesions. No clinical signs or mortality were observed in any group. No significant differences of clinical relevance were found in results of the packed cell volume, total solids, and biochemical panel, and no evidence of renal toxicity was found in the treatment or control groups. A significant correlation was found between hepatic lipidosis and meloxicam dose (P = .02). Two of 9 birds in the 20-mg/kg group developed gastric ulcers, although this result was not significant. None of the birds in the 2- and 10-mg/kg groups had similar lesions. Finally, meloxicam dosages up to 20 mg/kg did not result in nephrotoxicity in American kestrels. Further toxicologic studies to evaluate hepatotoxicity and gastrotoxicity of meloxicam in avian species are needed.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Doenças das Aves/induzido quimicamente , Falconiformes , Tiazinas/administração & dosagem , Tiazóis/administração & dosagem , Administração Oral , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Relação Dose-Resposta a Droga , Fígado/efeitos dos fármacos , Meloxicam , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/veterinária , Úlcera Gástrica/veterinária , Tiazinas/efeitos adversos , Tiazóis/efeitos adversosRESUMO
OBJECTIVE: To evaluate the analgesic efficacy of meloxicam oral transmucosal spray (OTMS) alone and with tramadol in cats with osteoarthritis (OA). STUDY DESIGN: Randomized, blinded study. ANIMALS: Fifteen geriatric cats weighing 4.5 ± 1.0 kg. METHODS: Healthy cats with OA were randomly administered a placebo (every 12 hours orally) and meloxicam OTMS (approximately 0.05 mg kg-1 every 24 hours) (group M, n = 7), or tramadol (3 mg kg-1 every 12 hours orally) and meloxicam OTMS (group TM, n = 8) for 25 days. Evaluations performed before treatment (D0) and at week 3 (W3) consisted of peak vertical force, motor activity and response to mechanical temporal summation of pain (RMTS). Data were analyzed with mixed models and Fisher's exact test. RESULTS: Mean ± standard deviation peak vertical force (percentage of body weight) increased significantly in both groups (p = 0.02), from 47.7 ± 6.5% to 60.5 ± 9.4% in group M, and from 51.8 ± 5.0% to 64.1 ± 6.5% in group TM, with no difference between groups. Motor activity increased in M (from 43 ± 12 to 56 ± 13; p = 0.02), but not in TM. The number of stimulations from RMTS increased in TM only. Cut-off values were reached in a larger number of cats (n = 5) in TM than M (n = 1) (p < 0.05). Gastrointestinal adverse effects were self-limiting in six cats, including five in TM. CONCLUSIONS AND CLINICAL RELEVANCE: Meloxicam OTMS had similar effects on peak vertical force, motor activity and pain sensitization as previously reported for oral meloxicam in OA cats. The tramadol-meloxicam combination provided no evident benefit over meloxicam alone, except for central hypersensitivity (assessed with RMTS). Further assessment of the potential toxicity of the combination is required prior to clinical use. Gingival administration was well accepted overall.
Assuntos
Analgésicos Opioides/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Doenças do Gato/tratamento farmacológico , Osteoartrite/tratamento farmacológico , Osteoartrite/veterinária , Tiazinas/uso terapêutico , Tiazóis/uso terapêutico , Tramadol/uso terapêutico , Administração através da Mucosa , Analgésicos Opioides/administração & dosagem , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Gatos , Quimioterapia Combinada/veterinária , Feminino , Masculino , Meloxicam , Sprays Orais , Projetos Piloto , Método Simples-Cego , Tiazinas/administração & dosagem , Tiazóis/administração & dosagem , Tramadol/administração & dosagemRESUMO
Over the past 2 decades the measurement of ground reaction forces (GRF) has been extensively used in dogs and cats to gain insights on normal locomotion, discrepancies under pathologic conditions, and biomechanical changes following surgical procedures. Ground reaction forces have become a well-established outcome measure of pain-related functional impairment in animals affected by experimental and naturally occurring osteoarthritis. This paper comprehensively reviews the nature of GRF and presents arguments regarding its measurement in osteoarthritis research.
Mesure cinétique de la démarche du chien et du chat en contexte de recherche sur l'arthrose. Au cours des deux dernières décennies, la mesure des forces de réaction au sol (FRS) a été largement utilisée chez les chiens et les chats afin de mieux comprendre la locomotion normale, les anomalies en conditions pathologiques et les changements biomécaniques suivant une procédure chirurgicale. Les FRS au sol sont devenues un critère d'évaluation bien connu de la limitation fonctionnelle liée à la douleur chez l'animal atteint d'arthrose expérimentale et naturelle. Le présent manuscrit dresse un aperçu de la nature des FRS et présente les arguments qui supportent son usage dans un contexte de recherche sur l'arthrose.(Traduit par les auteurs).
Assuntos
Doenças do Gato/fisiopatologia , Doenças do Cão/fisiopatologia , Marcha/fisiologia , Osteoartrite/veterinária , Animais , Fenômenos Biomecânicos , Gatos , Cães , Coxeadura Animal/fisiopatologia , Osteoartrite/fisiopatologiaRESUMO
Background: Micro-RNAs could provide great insights about the neuropathological mechanisms associated with osteoarthritis (OA) pain processing. Using the validated Montreal Induction of Rat Arthritis Testing (MI-RAT) model, this study aimed to characterize neuroepigenetic markers susceptible to correlate with innovative pain functional phenotype and targeted neuropeptide alterations. Methods: Functional biomechanical, somatosensory sensitization (peripheral-via tactile paw withdrawal threshold; central-via response to mechanical temporal summation), and diffuse noxious inhibitory control (via conditioned pain modulation) alterations were assessed sequentially in OA (n = 12) and Naïve (n = 12) rats. Joint structural, targeted spinal neuropeptides and differential expression of spinal cord micro-RNAs analyses were conducted at the sacrifice (day (D) 56). Results: The MI-RAT model caused important structural damages (reaching 35.77% of cartilage surface) compared to the Naïve group (P < 0.001). This was concomitantly associated with nociceptive sensitization: ipsilateral weight shift to the contralateral hind limb (asymmetry index) from -55.61% ± 8.50% (D7) to -26.29% ± 8.50% (D35) (P < 0.0001); mechanical pain hypersensitivity was present as soon as D7 and persisting until D56 (P < 0.008); central sensitization was evident at D21 (P = 0.038); pain endogenous inhibitory control was distinguished with higher conditioned pain modulation rate (P < 0.05) at D7, D21, and D35 as a reflect of filtrated pain perception. Somatosensory profile alterations of OA rats were translated in a persistent elevation of pro-nociceptive neuropeptides substance P and bradykinin, along with an increased expression of spinal miR-181b (P = 0.029) at D56. Conclusion: The MI-RAT OA model is associated, not only with structural lesions and static weight-bearing alterations, but also with a somatosensory profile that encompasses pain centralized sensitization, associated to active endogenous inhibitory/facilitatory controls, and corresponding neuropeptidomic and neuroepigenetic alterations. This preliminary neuroepigenetic research confirms the crucial role of pain endogenous inhibitory control in the development of OA chronic pain (not only hypersensitivity) and validates the MI-RAT model for its study.
RESUMO
Veterinarians face the lack of a rapid, reliable, inexpensive, and treatment-sensitive metrological instrument reflecting feline osteoarthritis (OA) pain. The Montreal Instrument for Cat Arthritis Testing, for Use by Veterinarians (MI-CAT(V)) has been refined in 4 sub-sections, and we proposed its concurrent validation. Cats naturally affected by OA (n = 32) were randomly distributed into 4 groups of firocoxib analgesic (Gr. A: 0.40; B: 0.25; C: 0.15, and P: 0.00 mg/kg bodyweight). They were assessed during Baseline, Treatment, and Recovery periods using MI-CAT(V) and objective outcomes (effort path, stairs assay compliance, and actimetry). The MI-CAT(V) total score correlated to the effort path and actimetry (RhoS = -0.501 to -0.453; p < 0.001), also being sensitive to treatment responsiveness. The pooled treatment group improved its total, gait, and body posture scores during Treatment compared to the Baseline, Recovery, and placebo group (p < 0.05). The MI-CAT(V) suggested a dose-(especially for Gr. B) and cluster-response. Cats in the moderate and severe MI-CAT(V) clusters responded to firocoxib with a remaining analgesic effect, while the mild cluster seemed less responsive and experienced a negative rebound effect. The MI-CAT(V) was validated for its OA pain severity discriminatory abilities and sensitivity to firocoxib treatment, providing a new perspective for individualized care.