Effect of tepoxalin on renal function and hepatic enzymes in dogs exposed to hypotension with isoflurane

ObjectiveTo evaluate the possible renal and hepatic toxicity of tepoxalin in dogs exposed to hypotension during isoflurane anesthesia.Study designProspective, randomized experimental study.AnimalsTwenty adult mixed-breed dogs, weighing 18.8 ± 2.8 kg.MethodsThe animals received 10 mg kg^?1 tepoxalin orally 2 hours before the anesthetic procedure (PRE; n = 6), or 30 minutes after anesthesia (POST; n = 6), along with a control group (CON; n = 8), which were only anesthetized. The PRE and POST groups also received the same dose of tepoxalin for 5 days post-procedure. All dogs were anesthetized with propofol and maintained with isoflurane and the end-tidal isoflurane (Fe’Iso) was increased until mean arterial pressure decreased to 50–60 mmHg. These pressures were maintained for 60 minutes. Heart rate, arterial pressures and Fe’Iso were recorded at 0, 10 and every 10 minutes up to 60 minutes of hypotension. Blood gases, pH, electrolytes and bleeding time were analyzed before and at 30 and 60 minutes of hypotension. Renal and hepatic changes were quantified by serum and urinary biochemistry and creatinine clearance.ResultsSerum concentrations of alanine amino transferase (ALT), alkaline phosphatase (ALP) and σ-glutamyl transferase (GGT), blood urea nitrogen (BUN) and creatinine (Cr), and urinary output, urinary Cr, Cr clearance, and GGT:Cr ratio remained stable throughout the evaluations. During the anesthetic procedure there were no important variations in the physiological parameters. No side effects were observed in any of the groups.Conclusions and clinical relevanceTepoxalin did not cause significant effects on renal function or cause hepatic injury in healthy dogs exposed to hypotension with isoflurane, when administered pre- or postanesthetic and continued for five consecutive days.     

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.     

Brunfelsia spp (yesterday, today, tomorrow) toxicity in four dogs

Four dogs were treated for acute toxicity following ingestion of the popular garden shrub 'Yesterday, today, tomorrow' (Brunfelsia spp). Clinical signs included vomiting, diarrhoea, muscle tremors, anxiousness, opisthotonus and seizures. All dogs recovered following treatment with any or all of general anaesthetic, gastric lavage, enema, diazepam, phenobarbitone or propofol sedation. Brunfelsia spp toxicity should be considered in young, previously healthy dogs presenting with gastrointestinal signs that rapidly progress to muscle tremors and seizures. Examination of faeces was required for diagnosis in all cases. Owners should also be questioned thoroughly about their dogs' access to such plants.     

杆菌肽锌在畜禽中的应用及其安全性评价

杆菌肽锌是一种应用广泛的饲料添加剂,可在动物初生至上市各生长阶段使用,没有上市前、产蛋和泌乳期的停药要求,也没有用药的使用期限。1　杆菌肽锌的理化性质杆菌肽锌(ZincBacitracin)由于其高效、无毒副作用、无残留、不产生抗药性及交叉耐药性等优点被广泛应用于畜禽养殖业。1 960年美国批准将杆菌肽锌用作饲料添加剂,使杆菌肽锌得到迅速发展。目前在生产中杆菌肽锌是由地衣芽孢杆菌发酵而制成。杆菌肽锌是一种多肽类畜禽专用抗生素,为淡褐色至褐色粉末,具有特殊气味,易溶于吡啶,难溶于乙醚、甲醇、丙酮和氯仿,不溶于水。杆菌肽锌可在室…     

Prospective clinical evaluation of serum cardiac troponin T in dogs admitted to a veterinary teaching hospital

The purpose of this study was to measure serum cardiac troponin T (cTnT) with a commercially available human enzyme-linked immunoassay (ELISA) test in various groups of dogs, including those undergoing doxorubicin chemotherapy. Serum samples were obtained from 6 groups of dogs: (1) normal adult dogs (n = 15); (2) dogs with asymptomatic dilated cardiomyopathy (n = 5); (3) dogs with congestive heart failure (n = 10); (4) dogs with untreated neoplasia (n = 20); (5) dogs with skeletal muscle trauma (n = 10); and (6) dogs with neoplasia receiving doxorubicin chemotherapy (n = 4). One serum sample was obtained from each of the normal dogs, those with asymptomatic cardiomyopathy, those with congestive heart failure, and those with untreated neoplasia. Serum samples were obtained serially from the dogs that were undergoing doxorubicin chemotherapy; samples were collected before doxorubicin (30 mg/m2) administration and then 1, 5, 7, and 14 days after administration throughout 6 cycles for a cumulative total dose of 180 mg/m2. All normal dogs, dogs with untreated neoplasia, and dogs with asymptomatic dilated cardiomyopathy had cTnT concentrations below the lower limits of detection for the assay used (<0.05 ng/mL). Detectable concentrations of cTnT were found in 3 dogs with congestive heart failure and in 2 dogs with skeletal muscle trauma. Detectable concentrations also were found in both dogs that had received 180 mg/m2 of doxorubicin. We conclude that dogs with congestive heart failure and those with skeletal muscle trauma and dogs with neoplasia receiving high-dose doxorubicin chemotherapy may have increased serum cTnT concentration, which may be suggestive of myocardial damage.     

Overdose of D-serine Induces Movement Disorder and Neuromuscular Changes of Zebrafish Larvae

D-serine is a well-known activator of N-methyl-D-aspartate receptors; however, little is known about the teratogenic effects of D-serine overdose during early embryonic development. Here, we used zebrafish as a model to test toxicity and teratogenicity, since they have transparent eggs, making the organogenesis of zebrafish embryos easier to be observed. After D-serine injection (100–1000 ppm), the most evident defective phenotypes were bent trunk phenotypes, including malformed somite boundary, twisted body axis and shorter body length. As the injection dosages increased, the rates of embryos with bent trunk phenotypes decreased (0% for 0 ppm, n=573; 59.9~84.3% for 100–1000 ppm of D-serine, n=383–451). In addition, D-serine-injected embryos exhibited significantly reduced the frequencies of spontaneous in-chorion contraction (21.7 for 0 ppm vs. 18.3–0.9 for 100–1000 ppm D-serine, n=30) in comparison with mock-treated controls (0 ppm). Subtle changes are easily observed by staining with specific monoclonal antibodies F59, Znp1, Zn5 and α-bungarotoxin to detect morphological changes in muscle fibers, primary motor axons, secondary motor axon projections and neuromuscular junctions, respectively. Our data show that overdose of D-serine leads to misalignment of muscle fibers and motor neuron defects, especially secondary motor neuron axonal growth defects.     

天蚕素抗菌肽在饲料应用中的安全性研究

试验通过考察天蚕素抗菌肽急性毒性和亚慢性毒性评价其安全性,为抗菌肽作为饲料添加剂在畜牧行业的应用提供理论依据。急性毒性试验采用昆明种小鼠进行半数致死量（LD50）和最大给药量（MTD）的测定。亚慢性毒性试验选取昆明小鼠50只,分为5组,分别为空白对照组和4个试验组,通过饲喂给药,试验组添加剂量分别为40、400、4000、2万单位/g,连续饲喂4个月,观察饲喂抗菌肽对小鼠的临床表现,进行日增重、日采食量、料肉比、脏器指数、血液常规、血液生化指标检测。急性毒性试验结果显示,在试验期内未发现小鼠死亡,未测得LD50,小鼠最大给药量为1.28万单位/g,灌胃1 mL时未见毒性。亚慢性毒性结果显示,各给药组小鼠的日增重、脏器指数、血液常规、血液生化与对照组均无显著差异（P ＞ 0.05）,未见与抗菌肽作用有关的病理变化。另外结果显示,日粮中添加天蚕素抗菌肽可提高小鼠的生产性能,降低小鼠日采食量和料肉比,对动物机体生长起到了积极作用,可安全应用于畜牧行业。[关键词] 天蚕素抗菌肽|急性毒性|亚慢性毒性|安全性|饲料     

Field safety evaluation of cambendazole in horses

Cambendazole paste 31% w/w, at 20 and 40 mg/kg, was tested in a series of field trials involving 237 horses of various ages, sex and pregnancy status. No drug-related sequelae were observed except for a mild anorexia in 10 thoroughbreds in training and on concentrate feed. Forty-nine thoroughbred mares, more than three months pregnant, showed no drug-related sequelae to themselves or their foals. Of 10 dosed at 80 or 160 mg/kg, one (80 mg/kg) showed elevated temperature at % hours after dosing.

Faecal egg counts were reduced 99% when conducted on 86 cambendazole treated animals seven to eight days after dosing at 20 or 40 mg/kg.     

Deep learning-based image-analysis algorithm for classification and quantification of multiple histopathological lesions in rat liver

Artificial intelligence (AI)-based image analysis is increasingly being used for preclinical safety-assessment studies in the pharmaceutical industry. In this paper, we present an AI-based solution for preclinical toxicology studies. We trained a set of algorithms to learn and quantify multiple typical histopathological findings in whole slide images (WSIs) of the livers of young Sprague Dawley rats by using a U-Net-based deep learning network. The trained algorithms were validated using 255 liver WSIs to detect, classify, and quantify seven types of histopathological findings (including vacuolation, bile duct hyperplasia, and single-cell necrosis) in the liver. The algorithms showed consistently good performance in detecting abnormal areas. Approximately 75% of all specimens could be classified as true positive or true negative. In general, findings with clear boundaries with the surrounding normal structures, such as vacuolation and single-cell necrosis, were accurately detected with high statistical scores. The results of quantitative analyses and classification of the diagnosis based on the threshold values between “no findings” and “abnormal findings” correlated well with diagnoses made by professional pathologists. However, the scores for findings ambiguous boundaries, such as hepatocellular hypertrophy, were poor. These results suggest that deep learning-based algorithms can detect, classify, and quantify multiple findings simultaneously on rat liver WSIs. Thus, it can be a useful supportive tool for a histopathological evaluation, especially for primary screening in rat toxicity studies.     

A complication probability planning study to predict the safety of a new protocol for intracranial tumour radiotherapy in dogs

Technical advances make it possible to deliver radiation therapy for canine intracranial tumours in fewer fractions, under the assumption of equivalent tumour control. With the aim of estimating the late toxicity risk profile for various tumour sizes and locations, the present paper evaluates the normal tissue complication probability (NTCP) values for the intracranial organs at risk. By making isoeffect calculations, a new 10‐fraction radiation protocol was developed with the same tumour control probability (TCP) as a currently used 20‐fraction standard protocol, and complication risk profiles for brain, brainstem and optic chiasm were modelled using a representative population of 64 dogs with brain tumours. For >59% of cases, the new 10‐fraction protocol yielded an acceptable, low risk estimate of late toxicity (<10%). Our calculations suggest that it may be safe to treat small to intermediate‐sized tumours that are neither located near the optic chiasm nor at the brainstem with 10 daily fractions of 4.35 Gy.     

Luteal toxicity evaluation in rats

The corpora lutea (CL) are endocrine glands that form in the ovary after ovulation and secrete the steroid hormone, progesterone (P4). P4 plays a critical role in estrous and menstrual cycles, implantation, and pregnancy. The incomplete rodent estrous cycle stably lasts 4–5 days and its morphological features can be distinguished during each estrous cycle stage. In rat ovaries, there are two main types of CL: newly formed ones due to the current ovulation (new CL), and CL remaining from prior estrous cycles (old CL). In the luteal regression process, CL were almost fully regressed after four estrous cycles in Sprague-Dawley rats. P4 secretion from CL in rodents is regulated by the balance between synthesis and catabolism. In general, luteal toxicity should be evaluated by considering antemortem and postmortem data. Daily vaginal smear observations provided useful information on luteal toxicity. In histopathological examinations, not only the ovaries and CL but also other related tissues and organs including the uterus, vagina, mammary gland, and adrenal glands, must be carefully examined for exploring luteal changes. In this review, histological and functional characteristics of CL in rats are summarized, and representative luteal toxicity changes are presented for improved luteal toxicity evaluation in preclinical toxicity research.     

饲用五环三萜提取物的急性毒性和亚慢性毒性评价

为初步评价五环三萜提取物的饲用安全性,选用大、小鼠进行急性毒性试验,以每千克体重5.0g五环三萜提取物灌胃ICR小鼠和Wistar大鼠,观察大、小鼠存活情况;同时选用大鼠进行亚慢性毒性试验,分别以每千克体重0、1.25、2.5和5.0g五环三萜提取物饲喂Wistar大鼠,每周称量大鼠体重并计算耗料量,饲喂90 d后进行...     

酶联免疫吸附技术在安全检测中的应用

酶联免疫吸附技术(Enzyme Linked Imm—unosorbent Assay,ELISA)简称酶标法,是由瑞典和荷兰的生物科学家提出并建立的,它是利用抗原一抗体的免疫学反应和酶的高效催化底物反应特点的检测技术,测定灵敏度可高达纳克(10-9g),甚至皮克(10-12g)水平。经过30多年的探索和完善,已成为一种普遍应用的分析方法。     

Practical approaches for evaluating adrenal toxicity in nonclinical safety assessment

The adrenal gland has characteristic morphological and biochemical features that render it particularly susceptible to the actions of xenobiotics. As is the case with other endocrine organs, the adrenal gland is under the control of upstream organs (hypothalamic-pituitary system) in vivo, often making it difficult to elucidate the mode of toxicity of a test article. It is very important, especially for pharmaceuticals, to determine whether a test article-related change is caused by a direct effect or other associated factors. In addition, antemortem data, including clinical signs, body weight, food consumption and clinical pathology, and postmortem data, including gross pathology, organ weight and histopathologic examination of the adrenal glands and other related organs, should be carefully monitored and evaluated. During evaluation, the following should also be taken into account: (1) species, sex and age of animals used, (2) metabolic activation by a cytochrome P450 enzyme(s) and (3) physicochemical properties and the metabolic pathway of the test article. In this review, we describe the following crucial points for toxicologic pathologists to consider when evaluating adrenal toxicity: functional anatomy, blood supply, hormone production in each compartment, steroid biosynthesis, potential medulla-cortex interaction, and species and gender differences in anatomical features and other features of the adrenal gland which could affect vulnerability to toxic effects. Finally practical approaches for evaluating adrenal toxicity in nonclinical safety studies are discussed.     

Retrospective evaluation of toceranib phosphate (Palladia®) toxicity in cats

The purpose of this study was to describe the toxicity profile of toceranib phosphate in tumour bearing cats. Medical records were reviewed from seven institutions. Patients with incomplete medical records and those receiving concurrent chemotherapy or NSAIDs (non‐steroidal anti‐inflammatory) were excluded. Fifty‐five cats met the inclusion criteria. Carcinoma was diagnosed in 55% of cases. Median oral toceranib dose was 2.7 mg kg^?1 and was most commonly administered on Monday, Wednesday and Friday. Thrombocytopenia (16.3%) and neutropenia (9.1%) were the most common haematologic toxicities. Azotemia (14.5%) and alanine aminotransferase (ALT) elevations (7.2%) were the most frequently encountered biochemical alterations. Gastrointestinal (GI) toxicity was seen in 21.8% of cats, and was lower than previously reported in dogs. The results of this study showed that treatment of cats with toceranib is well‐tolerated and toxicity is uncommon. Additional studies to define a more structured dosing schedule and to evaluate the efficacy of toceranib in the treatment of feline cancers are needed.