Firocoxib efficacy preventing urate-induced synovitis, pain, and inflammation in dogs

This positive-control study evaluated the efficacy of firocoxib versus carprofen, deracoxib, and meloxicam for the prevention of pain and inflammation in a urate crystal synovitis model of lameness. Lameness scoring and force plate gait analysis were used to assess efficacy. The resulting lameness scores and force plate ground reaction forces after urate crystal injection were not significantly different among the groups. Relative to each group's baseline (nonlame) score, only the firocoxib group was not significantly lame, based on lameness score, at the model's peak effect.     

Effects of Flunixin Meglumine,Firocoxib, and Meloxicam in Equines After Castration

This study is “aimed” to evaluate and compare the efficacy of flunixin meglumine (FM), firocoxib (FX), and meloxicam (MX) after castration of horses. Thirty horses were submitted to open castration and divided into three groups (n = 10) depending on the anti-inflammatory drug administered: group I (GI) (FM, 1.1 mg kg¹, IV, once a day [SID], 5 days); group II (GII) (FX, 0.1 mg kg¹, IV, SID, 5 days), and group III (GIII) (MX, 0.6 mg kg¹, IV, SID, 5 days). Clinical, behavioral, and hematological parameters and the peritoneal fluid (PF) were evaluated before (day [D] 0) and 1, 2, 3, 5, and 7 days afterward. In the postoperative, scores of limb rigidity and prepuce edema of animals of GII and GIII were greater than those of GI. Tachycardia was observed in the horses of GII and GIII and hyperthermia in GIII. An increase in the number of leukocytes, neutrophils, and monocytes without exceeding the reference values and hyperfibrinogenemia was observed in the animals of GI (D7), GII (D1-D7), and GIII (D7). There was reduction in serum protein after castration, together with an increase of this in the PF of the animals of the three groups. The PF on D0 was straw yellow and limpid, became reddish and cloudy on D1, and then gradually moved toward its normal color on the ensuing days, but without returning to normal on D7 in any of the groups. The results showed that castration triggers significant clinical and laboratory changes and that FM, FX, and MX are equally effective in controlling pain and inflammation in horses after castration; however, FM was more advantageous.     

Effects of Firocoxib and Tepoxalin on Healing in a Canine Gastric Mucosal Injury Model

Background: Little is known about the effect of dual cyclooxygenase (COX) and lipoxygenase inhibition on canine gastric mucosal healing.
Objective: This study compares the effects of putative dual COX and 5-lipoxygenase inhibition with that of COX-2 selective inhibition on gastric mucosal lesion healing in dogs.
Animals: Six normal adult mixed-breed research dogs.
Methods: Gastric body and pyloric lesions were induced by endoscopic biopsy. Dogs were treated with tepoxalin, firocoxib, or placebo for 7 days in a randomized 3-way crossover study design. Healing was evaluated on days 2, 4, and 7 of treatment by endoscopic lesion scoring. Eicosanoid concentrations in plasma and at the lesion margins were determined on days 2, 4, and 7. Repeated measures analyses were performed. All hypothesis tests were 2-sided with P < .05. Multiple comparisons were adjusted using Tukey's test.
Results: Significant treatment differences were noted in the pyloric lesion area measurements. Overall, the firocoxib group had larger lesions than the placebo ( P = .0469) or tepoxalin ( P = .0089) groups. Despite larger pyloric lesions in the firocoxib group, mucosal prostaglandin production did not differ significantly from placebo. In contrast, the tepoxalin group had significantly lower pyloric mucosal prostaglandin production compared with the firocoxib ( P < .0001) or the placebo ( P < .0001) groups but pyloric lesions were not significantly larger than those of the placebo group ( P = .7829).
Conclusion: COX-2 inhibition by firocoxib slowed wound healing by a mechanism independent of prostaglandin synthesis. Suppression of mucosal prostaglandin production by tepoxalin did not alter mucosal lesion healing compared with placebo.     

Cisplatin Toxicity in Cats

Cisplatin (cis-diamminedichloroplatinum; Platinol, Bristol, Syracuse, NY) was administered to 11 cats, divided into three groups of experimental and clinical patients. In group 1, cisplatin was administered at a dose of 60 mg/m2 to four cats. In an attempt to avoid renal toxicity, saline diuresis was induced by administering 0.9% saline solution intravenously at a rate of 20 ml/kg/hr for 4 hours before and 2 hours after cisplatin administration. All four cats became dyspneic and died 48-96 hours after cisplatin administration. Postmortem findings included severe hydrothorax, pulmonary edema, and mediastinal edema. In group 2, four experimental cats entered a trial comparing the effects of saline diuresis and cisplatin (60 mg/m2) with the effects of saline diuresis and placebo (0.9% saline solution). The cats in the saline control group remained completely normal, while the cats that received cisplatin developed clinical signs and gross postmortem pulmonary changes identical to those in the first group of cats. Histopathologic examination showed that the alveolar septa were thickened and congested, and contained macrophages, occasional neutrophils, thrombi, and small foci of necrosis and fibrin. Microangiopathic changes were seen in the alveolar capillaries. In the third group, three additional cats were treated with a lower dose of cisplatin. Two cats that received 40 mg/m2 of cisplatin developed pulmonary changes similar to, but less severe than, those seen in the cats that received the higher dose of cisplatin. One cat treated with 20 mg/m2 of cisplatin showed no pulmonary changes ante mortem or post mortem. This series of 11 clinical and experimental cases identifies an apparent species-specific, dose-related, primary pulmonary toxicity of cisplatin in cats.     

Amputation and Cisplatin for Treatment of Canine Osteosarcoma

Seventy-one dogs with histologically confirmed appendicular osteosarcoma were evaluated. Seventeen dogs were treated with amputation and two postoperative [corrected] doses of IV cisplatin given 21 days apart (group 1). Nineteen dogs were treated with IV cisplatin 21 days before amputation, with a second dose given immediately after amputation (group 2). Thirty-five dogs were treated by amputation of the affected limb with no chemotherapy (group 3). The median disease-free interval for group 1 was 226 days, and 177 days for group 2. This was not significantly different. The median survival time was 262 days for group 1, 282 days for group 2 and 119 days for group 3. Group 1 and 2 dogs had survival times that were significantly longer than for dogs in group 3. Two IV courses of cisplatin given before or after amputation appears to improve the survival of dogs with osteosarcoma.     

Field Trial Validation of the Efficacy and Acceptability of Firocoxib,a Highly Selective Cox-2 Inhibitor,in a Group of 96 Lame Horses

The objective was to generate evidence for clinical efficacy and acceptability of a second generation coxib, firocoxib, administered orally for 14 days to lame horses under field conditions compared with a classic nonsteroidal anti-inflammatory drug, vedaprofen, in a prospective, randomized, controlled, double-blinded, multicenter field trial. Ninety-six client-owned horses with American Association of Equine Practitioners score of at least grade 3 lameness or grade 2 lameness plus at least a score of 2 for either pain on palpation, range of motion, or joint swelling were analyzed. Horses were administered 0.1 mg/kg firocoxib orally at 24 hour intervals (n = 48) or 1.0 mg/kg vedaprofen paste at 12 hour intervals for 14 days (single loading dose of 2.0 mg/kg vedaprofen) (n = 48). Physical examinations and lameness evaluations were conducted on Day 1 (V1, before treatment) and on Days 7 (V2) and 14 (V3). Blood chemistry and hematology profiles were also evaluated. With regard to the primary variable, clinical improvement, 83% of the firocoxib-treated horses improved at V3 compared with 65% of vedaprofen-treated horses improved meeting the criteria defined to demonstrate noninferiority of firocoxib to vedaprofen. Health and behavioral abnormalities for side effect detection occurred at the rate of 2% (1 horse) and 8% (4 horses) for firocoxib- and vedaprofen-treated horses, respectively. Changes in hematology and blood chemistry values from V1 to V3 were not significantly different between treatment groups. Firocoxib, formulated as an oral paste was highly effective, well tolerated, and acceptable for the control of pain and inflammation associated with lameness in horses under field conditions.     

Intracavitary Cisplatin Chemotherapy Experience with Six Dogs

Six dogs with a median age of 7 years (range = 5-14 years) were presented for signs referable to thoracic or abdominal effusion associated with neoplasia of the body cavities. Intracavitary cisplatin was administered at 50 mg/m2 every 4 weeks for a median of 2.5 treatments (mean = 3, range = 1-6). Three dogs with pleural mesothelioma had complete resolution of effusion for 289, 129, and greater than 306 days without evidence of tumor growth. Resolution of effusion occurred after one treatment in two dogs and after two treatments in one dog. In three dogs with carcinomatosis of unknown origin, complete responses was seen in two dogs after one treatment for 255 and greater than 807 days, respectively. Intracavitary chemotherapy with cisplatin was associated with palliation and control of malignant pleural and/or abdominal effusion in five of six dogs. Toxicity was minimal, and this method of therapy should be further explored in dogs with similar malignancies.     

Cisplatin: a review of toxicities and therapeutic applications

Cisplatin is a platinum chemotherapeutic used in a variety of malignancies. The antineoplastic activity occurs from DNA cross‐links and adducts, in addition to the generation of superoxide radicals. Nephrotoxicity is the most well‐known and potentially most clinically significant toxicity. Unfortunately, the mechanism for cisplatin nephrotoxicity has not been completely elucidated; however, many theories have been developed. Other toxicities include gastrointestinal, myelosuppression, ototoxicity and neurotoxicity. Saline diuresis is currently the most accepted way to prevent cisplatin nephrotoxicity. Research has focused on pharmaceuticals and enzyme/molecular alterations as alternatives to long‐term diuresis. No agents have currently been identified that can protect from all toxicities. Cisplatin has shown activity against osteosarcoma, transitional cell carcinoma, squamous cell carcinoma (SCC), melanoma, mesothelioma, carcinomatosis and germinal cell tumours in the dog. In the cat, cisplatin cannot be utilized because of fulminant pulmonary oedema that occurs at standard doses. Intralesional cisplatin has been utilized in horses for the treatment of SCC and sarcoids.     

Cisplatin and doxorubicin toxicosis in dogs with osteosarcoma

Toxicosis associated with doxorubicin and cisplatin administration starting either 2 or 10 days after limb amputation for osteosarcoma was examined retrospectively in dogs. The purpose was to determine whether dosage and timing of chemotherapy affected rates of toxicosis after administration of the 1st treatment. Records of 100 dogs with appendicular osteosarcoma without evidence of metastases or concurrent disease were examined. Dogs received chemotherapy with doxorubicin and cisplatin every 3 weeks for 3 treatments starting 2 days (n = 51) or 10 days (n = 49) after amputation. The dosage of cisplatin was 60 mg/m2 and was given with 6-hour saline diuresis and butorphanol. Doxorubicin was given at 12.5-25 mg/ml during fluid administration. Hematologic data were collected before and weekly after treatment. Client interviews were conducted to assess gastrointestinal toxicosis during the interval between treatments. The reported toxicoses were graded on a scale of 0 to 4. Dogs receiving 25 mg/m2 of doxorubicin experienced greater rates of grade 4 toxicity (67%; n = 6) than dogs in groups receiving 12.5-20 mg/m2 of doxorubicin (< or = 25%; n = 94, P = .03). Dogs in the Day 2 group experienced greater rates (35%) of grade 4 toxicity than dogs in the Day 10 group (12%, P = .007). We concluded that chemotherapy administered 2 days after surgery produced an unacceptable level of toxicoses. except at greatly reduced dosages, and that even with a delay of treatment, 25 mg/m2 of doxorubicin, when given in combination with cisplatin at 60 mg/m2, was too toxic for routine use.     

Cisplatin Therapy in 41 Dogs With Malignant Tumors

Forty-one dogs with a variety of histopathologically diagnosed, measurable tumors were treated with cisplatin (cis-diamminedichloroplatinum, Platinol, Bristol Laboratories, Syracuse, NY 13221-4755) as a single agent at a dosage of 60 mg/m2 given intravenously at 3-week intervals. In an attempt to avoid renal toxicity of cisplatin, saline diuresis was induced and maintained for 4 hours before and 2 hours following cisplatin administration. The dogs received one to ten doses of cisplatin. To determine response to therapy and to monitor toxicity of the drug, the dogs were evaluated with physical examinations including tumor measurements, radiography, complete blood counts, platelet counts, urinalyses, serum urea nitrogen concentrations, and serum creatinine concentrations. An overall response rate of 19% was observed. Complete remission occurred in one of 11 dogs with squamous cell carcinomas and one of one dog with a mediastinal undifferentiated carcinoma. Partial remissions were documented in one of 11 dogs with squamous cell carcinomas, two of three dogs with metastatic osteosarcomas, one of three dogs with nasal adenocarcinomas, and one of one dog with a thyroid adenocarcinoma. Toxic side effects were primarily gastrointestinal in nature, with vomiting occurring 1-6 hours after cisplatin administration in 27 of 41 dogs. Severe anorexia occurred in three dogs, and hemorrhagic diarrhea was observed in one dog. One dog developed grand mal seizures and died 3 hours following therapy. Granulocytopenia was documented in six dogs, and thrombocytopenia was observed in four dogs. One dog showed an increase in serum urea nitrogen and creatinine concentrations, but this patient had known pre-existing renal disease.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparative nephrotoxicity of Cisplatin and nedaplatin: mechanisms and histopathological characteristics

The antineoplastic platinum complexes cisplatin and its analogues are widely used in the chemotherapy of a variety of human malignancies, and are especially active against several types of cancers. Nedaplatin is a second-generation platinum complex with reduced nephrotoxicity. However, their use commonly causes nephrotoxicity due to a lack of tumor tissue selectivity. Several recent studies have provided significant insights into the molecular and histopathological events associated with nedaplatin nephrotoxicity. In this review, we summarize findings concerning the renal histopathology and molecular pathogenesis induced by antineoplastic platinum complexes, with a particular focus on the comparative nephrotoxicity of cisplatin and nedaplatin in rats.     

Cisplatin chemotherapy for metastatic squamous cell carcinoma in two dogs

Cisplatin was used successfully to treat 2 dogs with metastatic squamous cell carcinoma. One dog was observed to have a complete remission and died of unrelated causes 23 months later. The other dog had a partial remission of the tumor, but relapsed and was euthanatized 4 1/2 months after the beginning of treatment. Both dogs tolerated the treatment well.     

薯蓣皂苷元对顺铂诱导大鼠肾损伤的缓解作用

【目的】 探究薯蓣皂苷元（diosgenin,Dio）对顺铂（cisplatin,CP）诱导大鼠肾损伤的缓解作用。【方法】 选取24只健康的雄性Wistar大鼠,随机分为对照组（C）、Dio组（Dio）、模型组（CP）和Dio干预组（Dio+CP）。C和CP组每天灌胃6 mL 0.5% CMC-Na,Dio和Dio+CP组每天灌胃Dio （60 mg/kg）,连续灌胃10 d。在试验第7天,CP和Dio+CP组大鼠经尾静脉注射CP （6 mg/kg）,然后每天继续灌胃Dio,CP给药72 h后处死各组大鼠,无菌分离肾脏组织,用HE染色观察肾脏病理变化;用试剂盒检测总抗氧化能力（T-AOC）、过氧化氢酶（CAT）活性及丙二醛（MDA）含量;用实时荧光定量PCR和Western blotting分别检测肾脏肿瘤坏死因子-α（TNF-α）、核因子κB p65（NFκB p65）、环氧合酶-2（COX-2）、白细胞介素-1β（IL-1β）和IL-10 mRNA和蛋白的表达;用免疫化学法检测肾脏受体相互作用蛋白激酶-1（RIPK1）和RIPK3蛋白的表达。【结果】 HE染色结果显示,对照组和Dio组肾脏结构正常;CP组大鼠肾小管上皮细胞发生脱落以及空泡变性,肾脏结构被破坏,Dio+CP组肾小管的损伤明显减轻。与对照组相比,CP和Dio+CP组肾脏中MDA含量极显著升高（P<0.01）,T-AOC和CAT活性均极显著降低（P<0.01）;与CP组相比,Dio+CP组肾脏中MDA含量极显著降低（P<0.01）,T-AOC和CAT活性均极显著增加（P<0.01）。实时荧光定量PCR和Western blotting结果表明,与对照组相比,CP组大鼠肾脏中TNF-α、COX-2、NFκB p65和IL-1β mRNA和蛋白的表达量均极显著升高（P<0.01）,IL-10 mRNA和蛋白的表达量均极显著降低（P<0.01）;与CP组相比,Dio+CP组TNF-α、COX-2、NFκB p65和IL-1β mRNA和蛋白的表达量均显著或极显著降低（P<0.05;P<0.01）,IL-10 mRNA和蛋白的表达量均极显著升高（P<0.01）。免疫组化结果表明,与对照组相比,CP组大鼠肾脏中RIPK1和RIPK3蛋白的表达量均极显著升高（P<0.01）;与CP组相比,Dio+CP组大鼠肾脏中RIPK1和RIPK3蛋白的表达量分别极显著（P<0.01）和显著（P<0.05）降低。【结论】 Dio通过抑制肾脏氧化应激、炎症反应和细胞程序性坏死缓解CP诱导的大鼠肾损伤。     

Cisplatin for treatment of transitional cell and squamous cell carcinomas in dogs

Thirteen dogs with tumors were treated with monthly infusions of cisplatin. Complete responses were not observed. Of 8 dogs with urinary tract transitional cell carcinomas, 1 (12.5%) had a partial response of 31 weeks' duration, and 4 (50%) had stable disease for 12, 30, 32, and 34 weeks. Three (60%) of 5 dogs with head and neck squamous cell carcinomas had partial responses for 2, 10, and 15 weeks. All 13 dogs were evaluated for signs of toxicosis. Transient episodes of vomiting were recorded for 7 dogs (54%), and 2 dogs (15%) had mild thrombocytopenia. Although renal function gradually decreased in 2 dogs (15%), none of the dogs had an episode of acute renal failure attributable to cisplatin. These findings suggest that cisplatin may be a safe and potentially effective agent for treatment of transitional cell and squamous cell carcinomas in dogs.     

Treatment of Canine Appendicular Osteosarcoma Using Cobalt 60 Radiation and Intraarterial Cisplatin

Twelve dogs with appendicular osteosarcoma were treated with 24–40 Gy of cobalt 60 radiation and two doses of intraarterial cisplatin. Improvement in limb function occurred in four dogs, and three dogs, which had only mild initial lameness, had no worsening of their lameness post-treatment. In nine dogs in which local control was evaluable, eight had local failure, with the median (95% CI) duration of local control being 5.9 (4.6, 6.7) months. Two dogs had metastatic disease before therapy, and an additional nine dogs had metastatic disease at a median time of 6.4 months. Pathologic fracture was present in four dogs; two fractures occurred before treatment and two were documented at the time of tumor recurrence. Median (95% CI) survival time for all 12 dogs was 4.9 (3.4, 6.8) months. Excluding the two dogs with preexisting metastatic disease, median survival time was 6.7 months. Three dogs survived longer than 1 year. This mode of therapy was well tolerated and may be considered an alternative to amputation or limb-sparing surgical procedures in selected dogs with appendicular osteosarcoma.     

Calponin Expression in Renal Tubulointerstitial Fibrosis Induced in Rats by Cisplatin

Renal tubulointerstitial fibrosis is the common feature of chronic renal failure, regardless of its etiology. Myofibroblasts play important roles in progression of the fibrosis and are characterized by expressions of various cytoskeletons such as vimentin, desmin and α-smooth muscle actin (α-SMA). To pursue the characteristics of the cells, we immunohistochemically investigated the relationship between calponin (a marker of terminal smooth muscles) expression and myofibroblasts in cisplatin-induced rat renal tubulointerstitial fibrosis. Calponin-expressing interstitial cells increased with fibrosis and reacted simultaneously to vimentin or α-SMA (a marker of well-differentiated myofibroblasts) but not desmin or Thy-1 (a marker of myofibroblasts at the early stage). The present study shows that calponin may be expressed transiently in relatively well-developed myofibroblasts in rat renal fibrosis. Calponin could become a marker for myofibroblast development in chronic renal toxicity in rats.     

Cobalt Radiation with or without Low-Dose Cisplatin for Treatment of Canine Naso-Sinus Carcinomas

The objective of this study was to determine if low-dose cisplatin could be added safely to radiation therapy for the treatment of naso-sinus carcinomas in dogs. Thirty-one dogs were evaluated; 18 of these dogs received cobalt radiation in combination with low-dose cisplatin while 13 dogs received radiation alone. No difference was observed for acute or late radiation effects. Cisplatin was administered at a dosage of 7.5 mg/m2 20 min prior to every other radiation treatment. An initial dose of 10 mg/m2 was intended but toxicity (primarily azotemia) was unacceptable. Cisplatin was administered as prescribed in 12 of 18 dogs. Cisplatin was discontinued in 2 dogs because of azotemia. In the other 4 dogs cisplatin was not administered as prescribed because the dogs were withdrawn from treatment due to disease progression or radiation effects. There was no long-term renal disease in patients who developed azotemia. The overall median survival was 433 days with 4 (12.9%) dogs still alive at the completion of the study.     

Biochemical and Histological Study of Rat Liver and Kidney Injury Induced by Cisplatin

Cisplatin is a chemotherapeutic agent widely used in treatment of several cancers. It is documented as a major cause of clinical nephrotoxicity and hepatotoxicity. The purpose of this study was to investigate the involvement of oxidative stress in the pathogenesis of cisplatin-induced liver and kidney injury. Wistar rats were divided into four groups. Group 1 (control) was intraperitoneally (IP) injected with a single dose of 0.85% normal saline. Groups 2, 3 and 4 were IP injected with single doses of cisplatin at 10, 25 and 50 mg/kg body weight (BW), respectively. At 24, 48, 72, 96 and 120 h after injection, BW, levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), creatinine, malondialdehyde (MDA), and activity of superoxide dismutase (SOD) and histology of the liver and kidney were evaluated. Cisplatin caused a reduction in BW of rats in groups 2, 3 and 4 at all post injection intervals. The levels of serum ALT, AST, BUN and creatinine and MDA of the kidney and liver were markedly increased especially at 48 and 72 h, whereas the activity of SOD was decreased after cisplatin injection. Liver sections revealed moderate to severe congestion with dilation of the hepatic artery, portal vein and bile duct and disorganization of hepatic cords at 50 mg/kg of cisplatin. Kidney sections illustrated mild to moderate tubular necrosis at 25 and 50 mg/kg of cisplatin. Therefore, oxidative stress was implicated in the pathogenesis of liver and kidney injury causing biochemical and histological alterations.