Cannabinoids CB2 Receptors,One New Promising Drug Target for Chronic and Degenerative Pain Conditions in Equine Veterinary Patients

Osteoarticular equine disease is a common cause of malady; in general, its therapy is supported on steroids and nonsteroidal anti-inflammatories. Nevertheless, many side effects may develop when these drugs are administered. Nowadays, the use of new alternatives for this pathology attention is demanded; in that sense, cannabinoid CB2 agonists may represent a novel alternative. Cannabinoid belongs to a group of molecules known by their psychoactive properties; they are synthetized by the Cannabis sativa plant, better known as marijuana. The aim of this study was to contribute to understand the pharmacology of cannabinoid CB2 receptors and its potential utilization on equine veterinary patients with a chronic degenerative painful condition. In animals, two main receptors for cannabinoids are recognized, the cannabinoid receptor type 1 and the cannabinoid receptor type 2. Once they are activated, both receptors exert a wide range of physiological responses, as nociception modulation. Recently, it has been proposed the use of synthetic cannabinoid type 2 receptor agonists; those receptors looks to confer antinociceptive properties but without the undesired psychoactive side effects; for that reason, veterinary patients, whit chronical degenerative diseases as osteoarthritis may alleviate one of the most common symptom, the pain, which in some cases for several reasons, as patient individualities, or side effects produced for more conventional treatments cannot be attended in the best way.     

持续被动运动通过抑制软骨细胞NO合成下调MMP-1和MMP-13表达

目的：观察持续被动运动（CPM）和补充一氧化氮（NO）供体——硝酸甘油（NG）对兔骨关节炎（OA）模型中软骨基质金属蛋白酶-1（MMP-1）和MMP-13表达以及NO含量的影响，探讨CPM下调MMPs的可能机制。方法：30只3~4月龄雄性新西兰大白兔，其中6只进行假手术作为正常对照组（NC组），另外24只建立膝关节OA模型，术后随机分为4组，即OA对照组（OA组）、OA硝酸甘油给药组（NG组）、OA持续被动运动组（CPM组）、OA持续被动运动+硝酸甘油给药组（CPM+NG组），每组各6只。NC组和OA组不作处理，NG组给予NG软膏膝关节局部涂抹，CMP组在CPM训练仪上进行膝关节持续被动运动，CMP+NG组即在运动干预的同时给予NG局部涂抹。4周后取各组软骨组织，硝酸还原酶法测定NO含量，HE染色观察软骨形态学变化并进行Mankin''s评分，实时荧光定量PCR（RQ-PCR）检测MMP-1和MMP-13 mRNA水平，免疫组织化学法测定MMP-1和MMP-13蛋白表达量。结果：NO含量、Mankin''s评分以及MMP-1和MMP-13 mRNA和蛋白水平在OA组明显高于NC组（P<0.01），NG组高于OA组（P<0.01），CPM组低于OA组和NG组（P<0.01），CPM+NG组低于NG组（P<0.01），但高于CPM组（P<0.01）。结论：CPM通过抑制软骨细胞NO合成下调MMP-1和MMP-13表达，进而对软骨细胞起保护作用。     

A prospective,randomized, double-blind,placebo-controlled multisite,parallel-group field study in dogs with osteoarthritis conducted in the United States of America evaluating bedinvetmab,a canine anti-nerve growth factor monoclonal antibody

ObjectiveBedinvetmab, a fully canine anti-nerve growth factor monoclonal antibody, was evaluated in dogs for control of osteoarthritis-related pain in a study conducted to support registration in the USA.Study designRandomized, double-blind, placebo-controlled, multicenter, parallel-group study.AnimalsGeneral practice client-owned dogs with osteoarthritis (n = 272).MethodsDogs were block randomized 1:1 to placebo (saline, n = 137) or bedinvetmab (n = 135; 0.5–1.0 mg kg^–1) administered subcutaneously, once monthly. The primary end point, day 28 Canine Brief Pain Inventory (CBPI) treatment success (TS), required pain severity score (PSS; 0–10) decrease ≥1 and pain interference score (PIS; 0–10) decrease ≥ 2. CBPI TS rates [and number needed to treat (NNT)], change in scores [and standardized effect size (ES)], change in quality of life (QoL) and bedinvetmab half-life were calculated.ResultsSignificant (p < 0.05) improvement with bedinvetmab over placebo occurred (days 28, 42, 56, 84) for CBPI TS. Of cases evaluable for day 28 CBPI TS (placebo, n = 131; bedinvetmab, n = 128), success rates were 36.6% and 47.4%, respectively (p = 0.0410) (NNT, 9.3; PSS and PIS ES, 0.3). CBPI TS increased after the second dose in both groups, plateaued for bedinvetmab at day 42 and decreased for placebo beginning day 84. Day 84 NNT (4.3), PSS (0.4) and PIS (0.5) showed continued improvement with monthly dosing. After the first dose, mean (± standard deviation) bedinvetmab half-life was 19.1 (8.3) days. Adverse events were similar between groups and not considered treatment-related. There was a significant effect of bedinvetmab versus placebo on all CBPI components (PIS, PSS, QoL).Conclusions and clinical relevanceThese results corroborated those previously reported and provide further support of safety and effectiveness of bedinvetmab (0.5–1.0 mg kg^–1) administered subcutaneously at monthly intervals to dogs for control of osteoarthritis-related pain.     

LOW-FIELD MAGNETIC RESONANCE IMAGING OF EARLY SUBCHONDRAL CYST-LIKE LESIONS IN INDUCED CRANIAL CRUCIATE LIGAMENT DEFICIENT DOGS

Six healthy adult male mongrel dogs underwent cranial cruciate ligament transection in the left stifle. Survey radiography of both stifles and low-field (0.064 T) MRI of the left stifle were performed preoperatively and at 2, 6, and 12 weeks postoperatively. Focal changes in signal intensity were seen with MRI in the subchondral bone of the medial tibial condyle at 2 and 6 weeks postoperatively. At 12 weeks postoperative, a cyst-like lesion was detected using MRI in the subchondral bone of the medial tibial condyle in 4 of 6 dogs and a less defined lesion at this site in the remaining 2 dogs. The cyst-like lesion was spherical in shape and showed typical characteristics of fluid with low signal intensity on T1-weighted images, high signal intensity on T2-weighted images and high signal intensity on inversion recovery images. The lesion was seen in the subchondral bone of the caudal medial and/or middle region of the tibial plateau slightly cranial to the insertion of the caudal cruciate ligament. No subchondral cysts were seen in the tibia on radiographs. Histopathologically, the tibia was characterized by a loose myxomatous phase of early subchondral cyst formation.     

Developmental orthopaedic disease and early osteoarthritis of the temporomandibular joint in a 15-month-old Quarter Horse filly

A 15-month-old Quarter Horse filly presented for evaluation of hard swellings over the left temporomandibular joint (TMJ) and the right metatarsophalangeal joint (MTPJ). The TMJ swelling had been noted since she was weaned at 4 months of age and had slowly enlarged since then. Radiographs of both TMJs and the right MTPJ were performed, which revealed severe osteoarthrosis associated with osteochondrosis-like lesions. The filly was subjected to euthanasia due to the poor prognosis for performance. Computed tomography and post-mortem examination, including histopathology of the left TMJ, revealed early osteoarthritis (OA) associated with osteochondrosis-like lesions of the left TMJ and the right MTPJ, while the right hind proximal interphalangeal joint (PIPJ) was diagnosed with early OA.     

EX VIVO MAGNETIC RESONANCE IMAGING OF THE DISTAL ROW OF EQUINE CARPAL BONES: ASSESSMENT OF BONE SCLEROSIS AND CARTILAGE DAMAGE

The distal row of carpal bones (C2, C3, and C4) from eight left intercarpal joints--four from Standardbred Trotters and four from Swedish Warmblood horses--were used to assess the potential of magnetic resonance (MR) imaging to detect cartilage and bone lesions. The joints used in the study were classified by macroscopic and radiographic examinations as having normal, mild, moderate, or severe articular cartilage lesions and bone sclerosis. Those classifications correlated well with the appearance of the MR images. Bone sclerosis in the MR images was observed as regions of decreased signal intensity. Upon quantitative analysis of the MR images there was a significant difference (p < 0.0001) in the MR signal intensity from areas where radiographic bone sclerosis was observed compared to areas of radiographic nonsclerotic bone. In addition, the MR images were used to pilot the location of histology slices through areas of interest that were then examined microscopically; hence, the lesions found from the MR imaging examination were verified microscopically. It was concluded that cartilage lesions and cartilage loss are related to the sclerotic state of the underlying bone. The MR protocols developed in this study were applied on five intact cadaveric carpal joints, and it was concluded that MR imaging could successfully be used in the intact joint to detect minor cartilage and bone lesions not visualized by either radiography or macroscopic examination. Hence, MR imaging can be used to delineate interactions between articular cartilage and subchondral bone over time and in vivo.     

Dose range finding study for the efficacy of meloxicam administered prior to sodium urate-induced synovitis in cats

ObjectiveTo determine the lowest efficacious dose of oral meloxicam for relieving pain in cats with a sodium urate (SU)-induced acute inflammatory synovitis.Study designRandomized, blinded, controlled, and four-way crossover study.AnimalsEight surgically neutered cats (four males, four females) paired according to sex.MethodsEach pair of cats was treated with 0 (placebo), 0.025, 0.05, or 0.075 mg kg^?1 oral meloxicam once daily for 4 days prior to injection, into alternating stifles, of 1 mL of 20 mg mL^?1 SU crystals, beginning with the right stifle. Each cat received each of the four treatments, separated by at least 21 days. Analgesic efficacy was evaluated based on objective (e.g., pressure mat data total force, contact pressure, and contact area) and subjective (e.g., scores for Analgesia Scale [AS], Lameness Scale [LS], and Visual Analog Scale [VAS]) outcome measures for pain assessment. All outcome measures were recorded before and during 30 hours after SU injection. The pre-defined primary outcome measure was the area under the response–time curve (AUC_0–30 hours) of the total force of the injected limb. Data were analyzed by analysis of variance. A sequential test procedure was applied and the test sequence stopped in case of a nonsignificant result.ResultsMeloxicam at doses of 0.05 and 0.075 mg kg^?1 day^?1 PO was significantly different from placebo for the pre-defined primary outcome measure (i.e., AUC_0–30 hours of total force). All tested meloxicam doses were lower than placebo for the subjective outcome measures (i.e., AUC_0–30 hours of AS, LS, and VAS).Conclusions and clinical relevanceThe lowest efficacious dose of meloxicam for relieving pain in cats with an SU-induced synovitis was 0.05 mg kg^?1 day^?1 PO according to the pre-defined primary outcome measure. However, lower doses may also be effective as seen in the subjective outcome measures.