伊维菌素原粉急性吸入毒性试验研究

对伊维菌素原粉急性吸入毒性进行研究,采用限量试验,设定2000 mg/m3一个剂量组,动式口鼻式染毒,有效染毒时间2 h。结果显示,伊维菌素原粉对雌雄大鼠的急性吸入半数致死浓度(LC50)均大于2089 mg/m3。伊维菌素原粉急性吸入毒性属低毒,该结论为安全使用提供了依据。     

氟苯尼考混悬型微乳剂的急性毒性试验

为评价氟苯尼考混悬型微乳剂的安全性,按改良寇氏法进行了氟苯尼考混悬型微乳剂的急性毒性试验。根据预实验结果,60只小鼠平均分为6组,雌雄各半,分别按6000、4558.5、3464、2632、2000 mg/kg氟苯尼考混悬型微乳剂和0.5 mL/kg生理盐水注射液给小鼠腹腔一次性注射,同时用氟苯尼考普通注射液做对照,重复上述试验,均连续观察7 d。结果显示：氟苯尼考混悬型微乳剂最大耐受量为6000 mg/kg,其LD50为3658.8 mg/kg,LD5095%可信限为2075.8～5241.8 mg/kg。氟苯尼考注射液的LD50为636.68 mg/kg,LD5095%可信限为538.5～735.1 mg/kg。此剂量氟苯尼考混悬型微乳剂中氟苯尼考的含量相当于临床推荐用量（20 mg/kg）的180倍,表明氟苯尼考混悬型微乳剂毒性显著降低,在治疗剂量范围内使用安全。     

Sodium bicarbonate protects uranium-induced acute nephrotoxicity through uranium-decorporation by urinary alkalinization in rats

To evaluate the effectiveness of sodium bicarbonate (SB) in removing uranium and protecting animals from uranium toxicity, we intramuscularly administered 1 mg/kg of uranyl nitrate to 8-wk-old male SD rats, and 20 min after administration of uranyl nitrate, the animals were given a single oral administration of SB at 0.1, 0.3 or 1 g/kg. The SB treatment at a dose of 0.3 g/kg or more raised the pH of the rats’ urine until 4 h after treatment, and it significantly reduced the uranium amounts in the kidneys at 1 day after treatment. In another experiment, rats were intramuscularly administered 1 mg/kg of uranyl nitrate, and 20 min later, the animals were treated with sodium bicarbonate (0.1 or 1 g/kg). The rats were autopsied at 1, 3 and 7 days after uranium treatment. High-dose SB resulted in a significant increase in urinary uranium excretion in the first 24 h and a reduction of uranium deposition in the kidneys and femurs, and it also significantly suppressed uranium-induced renal toxicity, as shown by both histopathology and clinical chemistry at 3 days after uranium treatment. Low-dose SB did not show such marked effects. Our findings demonstrated that the uranium decorporation effect of sodium bicarbonate was observed at the dosage showing urine alkalinization in rats and that decorporation effect of sodium bicarbonate might be beneficial if it is administered immediately after incorporation of soluble uranium.     

An evaluation of acute toxicity of colloidal silver nanoparticles

Tests for acute oral toxicity, eye irritation, corrosion and dermal toxicity of colloidal silver nanoparticles (AgNPs) were conducted in laboratory animals following OECD guidelines. Oral administration of AgNPs at a limited dose of 5,000 mg/kg produced neither mortality nor acute toxic signs throughout the observation period. Percentage of body weight gain of the mice showed no significant difference between control and treatment groups. In the hematological analysis, there was no significant difference between mice treated with AgNPs and controls. Blood chemistry analysis also showed no differences in any of the parameter examined. There was neither any gross lesion nor histopathological change observed in various organs. The results indicated that the LD(50) of colloidal AgNPs is greater than 5,000 mg/kg body weight. In acute eye irritation and corrosion study, no mortality and toxic signs were observed when various doses of colloidal AgNPs were instilled in guinea pig eyes during 72 hr observation period. However, the instillation of AgNPs at 5,000 ppm produced transient eye irritation during early 24 hr observation time. No any gross abnormality was noted in the skins of the guinea pigs exposed to various doses of colloidal AgNPs. In addition, no significant AgNPs exposure relating to dermal tissue changes was observed microscopically. In summary, these findings of all toxicity tests in this study suggest that colloidal AgNPs could be relatively safe when administered to oral, eye and skin of the animal models for short periods of time.     

Lipoic acid is 10 times more toxic in cats than reported in humans, dogs or rats

The antioxidant lipoic acid (LA) is administered to humans and pets. We described acute toxicity and maximum tolerated dose (MTD) of LA in cats. In progression, 10 healthy adult male cats received orally 60 (high), 30 (low), or 0 mg LA/kg (control). Serum enzyme activities and concentrations of bile acids, ammonia, amino acids (AA), LA and dihydrolipoic acid (DHLA) were measured, and tissues examined microscopically. Significant clinical toxicity with changes in ammonia and AA concentrations occurred in all high-dose cats. Oral LA produced hepatocellular toxicity and MTD was < 30 mg/kg in cats.     

Successful therapy of balantidiosis of pigs with acetarsol and oxytetracycline

Severe clinical balabtidiosis in 2-month old piglets was treated with acetarsol alone and acetorsol in combination with oxytetracycline. Three groups of 15 animals each were used in this trial. Group 1 received acetarsol at a dose rate of 20 mg/kg body weight orally once daily for 4 days. Group 2 received acetarsol as group 1 plus oxytetracycline at a dose rate of 15 mg/kg body weight orally in feed concentrate twice daily for 4 days. Group 3 animals served as non-treated controls. As judged by clinical and parasitological examinations, acetarsol was found to be 85.7% effective and the combination of acetarsol and oxytetracycline 100% effective. No sign of intolerance or toxicity was observed.     

A 4-week Repeated Dose Toxicity Study of Glycine in Rats by Gavage Administration

In order to examine the toxicity profile of glycine, an authorized food additive, a solution of glycine in water for injection was administered orally (via gavage) to male SD rats (Crl:CD(SD)) once daily for 4 weeks at doses of 500, 1000 and 2000 mg/kg/day in a volume of 10 mL/kg. Control animals received vehicle only. No animals died, and no glycine-related changes were observed in body weight, food consumption, water consumption, hematology, organ weight, gross pathological examination or histopathological examination. In urinalysis, daily urinary volume and urinary Cl excretion were significantly higher in the 2000 mg/kg/day dose group, and urine pH and urinary protein showed lower trends in the glycine-treated groups. However, these changes were considered to be of little toxicological significance, because there were no histopathological changes in the kidneys or urinary bladder and no changes in other urinary parameters. As regards blood chemistry, phospholipids were significantly higher in the 2000 mg/kg/day dose group. However, the increase was small and was not considered to be toxicologically significant. In conclusion, none of the animals in any of the glycine-treated groups showed changes that were considered toxicologically significant. Therefore, the no-observed-adverse-effect level of glycine was estimated to be at least 2000 mg/kg/day under the conditions of this study.     

Acute Phase Pulmonary Responses to a Single Intratracheal Spray Instillation of Magnetite (Fe3O4) Nanoparticles in Fischer 344 Rats

Iron nanomaterials are of considerable interest for application to nanotechnology-related fields including environmental catalysis, biomedical imaging, drug delivery and hyperthermia, because of their superparamagnetic characteristics and high catalytic abilities. However, information about potential risks of iron nanomaterials is limited. The present study assessed pulmonary responses to a single intratracheal spray instillation of triiron tetraoxide nanoparticles (magnetite) in rats. Ten-week-old male and female Fischer 344 rats (n=5/group) were exposed to a single intratracheal spray instillation of 0 (vehicle), 5.0, 15.0 or 45.0 mg/kg body weight (BW) of magnetite. After 14 days, the rats were sacrificed, and biological consequences were investigated. The lung weights of the 15.0 and 45.0 mg/kg BW male and female groups were significantly higher than those of the control groups. The lungs of treated rats showed enlargement and black patches originating from the color of magnetite. The typical histopathological changes in the lungs of the treated rats included infiltration of macrophages phagocytosing magnetite, inflammatory cell infiltration, granuloma formation and an increase of goblet cells in the bronchial epithelium. The results clearly show that instilled magnetite causes foreign body inflammatory and granulating lesions in the lung. These pulmonary responses occur in a dose-dependent manner in association with the increase in lung weight.     

Observations of Cattle, Goats and Pigs After Administration of Synthetic Interferon Inducers and Subsequent Exposure to Foot and Mouth Disease Virus

Polyriboinosinic-polyribocytidylic acid (poly [rI.rC]) was administered intravenously to 11 cattle and 13 goats in doses of 0.25 to 4.0, and 1.0 to 5.0 mg/kg, respectively. Subsequent exposure of these and untreated control animals to foot and mouth disease virus (FMDV) failed to demonstrate any differences in either the course or severity of the disease. Serum interferon was detected in cattle one hour after the intravenous administration of poly (rI.rC).

Six pigs given 4, 20, or 100 mg/kg of itaconic-acrylic acid copolymer (IAA, HMW) intraperitoneally reacted clinically the same as six untreated control pigs after contact exposure to FMDV.

Three pigs given 50, 100, or 200 mg/kg of divinyl ether-maleic anhydride copolymer (DVE/MA, pyran) intraperitoneally similarly failed to show any difference in clinical reaction from three untreated control pigs after intranasal instillation of FMDV. Three pigs given 100, 200 or 400 mg/kg of DVE/MA intraperitoneally developed rapid diffuse peritonitis causing the death of one in 48 hours.

     

An evaluation of the efficacy of netobimin against Dicrocoelium dendriticum in sheep

A trial was carried out to assess the efficacy of a nitrophenylguanidine compound, netobimin against Dicrocoelium dendriticum in naturally infected sheep. At a dose rate of 20 mg/kg bodyweight administered orally the drug was highly effective, producing a mean reduction of 98.9 per cent in the fluke burdens of treated animals compared with untreated controls. No side effects were observed in the treated sheep.     

Acute, subchronic, and chronic toxicity of ecadotril in dogs

OBJECTIVE: To determine the toxicity of ecadotril in dogs. ANIMALS: 74 healthy 4- to 11-month-old Beagles. PROCEDURE: To determine acute toxicity, ecadotril (2,000 mg/kg of body weight, PO) in a gelatin capsule was administered once to 2 dogs, and dogs were observed for 2 weeks. To determine subchronic and chronic toxicity, ecadotril was administered every day for 3 months (50 mg/kg [n = 8], 100 mg/kg [8], 300 mg/kg [12]) and 12 months (25 mg/kg [n = 8], 50 mg/kg [8], 100 mg/kg [8]), respectively. Dogs in control groups (n = 12 or 8) received an empty gelatin capsule. Physical examinations, CBC, plasma biochemical analyses, and urinalyses were performed before and at various times during each experiment. Dogs were euthanatized at the end of each experiment, and necropsies were performed. RESULTS: Dogs that received 1 dose of 2,000 mg of ecadotril/kg developed nonspecific clinical signs of toxicosis. Dogs that received 300 mg of ecadotril/kg/d for 3 months developed pronounced anemia, bone marrow suppression, and some evidence of liver impairment. There was no evidence of an effect accumulated over time, and reversibility of toxic effects was evident. Dogs that received < or =100 mg of ecadotril/kg/d for 3 or 12 months tolerated treatment without apparent effect. CONCLUSIONS AND CLINICAL RELEVANCE: Degree of acute toxicity of a single high dose of ecadotril in dogs was low. The no-observable adverse effect level of ecadotril following daily oral administration was 100 mg/kg/d; repeated administration of 300 mg/kg/d revealed the hematopoietic system as the primary toxicologic target.     

Temporal pattern of locomotor activity recuperation after administration of propofol in Japanese quail (Coturnix coturnix japonica)

The present study evaluates the organization and complexity of the temporal pattern of locomotion after an acute administration of propofol in Japanese quail by using traditional and fractal analysis. Birds were administered with propofol 0, 10, 20, 40 or 80 mg/kg. Ten min after administration, they were placed in an open-field apparatus and their locomotor activity was recorded during 45 min at a resolution of 0.5 s. A significant dose dependant increase in the latency to initiate ambulation was observed for doses of 20, 40 and 80 mg/kg when compared to the control group. A rapid recuperation of normal locomotor activity was observed after sedation with 20 mg/kg. Birds administered with propofol 40 mg/kg showed signs of recuperation of normal locomotion after 30 and 40 min (males and females, respectively) of propofol administration, that was not observed in quail treated with propofol 80 mg/kg. Our results suggest that depending on the dose, propofol administration in quail may allow full locomotor recovery of a sedative/anesthetic dose as early as 30 min post-administration.     

Dose determination and confirmation for ceftiofur crystalline-free acid administered in the posterior aspect of the ear for control and treatment of bovine respiratory disease

Three studies were conducted to determine and confirm the effective dosage rate of ceftiofur crystalline-free acid sterile suspension (CCFA-SS, 200 mg ceftiofur equivalents [CE]/ml), a long-acting ceftiofur formulation, for control and treatment of bovine respiratory disease (BRD). In each study, CCFA-SS was administered once by subcutaneous (SC) injection in the middle third of the posterior aspect of the ear. Study 1 was conducted using an intratracheal challenge with Mannheimia (formerly Pasteurella) haemolytica and dosages ranging from 0 to 8.8 mg CE/kg to select a dosage for further field testing. In Study 2, a single dose of CCFA-SS at 0.0, 4.4, or 6.6 mg CE/kg was administered when uniform clinical signs of BRD were present in feedlot cattle. Study 3 was conducted in several feedlots to evaluate the efficacy, practicality, and safety of CCFA-SS at 4.4 or 6.6 mg CE/kg compared with a placebo control or tilmicosin for preemptive control of BRD. In Study 1, the effective dose was determined to be 5.35 mg CE/kg; therefore, 4.4 and 6.6 mg CE/kg were selected as the dosages for further field testing. Administration of CCFA-SS at 4.4 or 6.6 mg CE/kg improved treatment success compared with negative controls (P < or =.05 for both doses) in Study 2. In Study 3, a single administration of 4.4 or 6.6 mg CE/kg was comparable to tilmicosin (P <.001) and was significantly better than placebo (P <.001) for the control of BRD. Using the ear as an administration site was acceptable under field conditions and was well tolerated by all animals. These studies demonstrated that a single administration of CCFA-SS by SC injection in the middle third of the posterior aspect of the ear at 4.4 or 6.6 mg CE/kg is effective, safe, and practical for preemptive control and treatment of the bacterial component of BRD in feedlot cattle. Administration in an inedible tissue results in a short withdrawal time and no injection-site trimming at slaughter.     

Pharmacokinetics and pharmacodynamics of antiulcer agents in llama

Plasma concentration time curves following intravenous (i.v.) administration of 1.5 mg/kg of ranitidine, 0.2 mg/kg, 0.4 mg/kg and 0.8 mg/kg of omeprazole, respectively, were analysed in six llamas. Plasma profiles after i.v. administration of both drugs showed plasma concentrations declining in a biexponential manner with a rapid distribution phase. Pharmacokinetics parameters after ranitidine administration to six llamas showed a mean elimination half-life of 1.53 +/- 0.26 h. The mean volume of distribution (Vdss) in llamas was 1.77 +/- 0.31 L/kg, and mean body clearance in llamas was 0.778 +/- 0.109 L/kg/h. Ranitidine produced only a small transitory (<1 h) decline in acid production when administered i.v. at a dose of 1.5 mg/kg. Omeprazole showed dose-dependent nonlinear pharmacokinetics. The mean half-life of 0.2 mg/kg i.v. omeprazole was shorter than that of 0.4 and 0.8 mg/kg i.v. omeprazole, i.e. 0.61, 0.72 and 1.07 h, respectively. The area under the curve (AUC) and mean residence time (MRT) increased with increasing dose, while clearance decreased as dose increased. The decline in acid production following 0.2 mg/kg i.v. omeprazole was highly variable and did not produce a clinically useful suppression of third compartment acid production. In contrast, both 0.4 mg/kg and 0.8 mg/kg omeprazole i.v. administration significantly reduced third compartment acid production. The reduction in acid production following 0.8 mg/kg omeprazole was not significantly greater than the reduction observed following 0.4 mg/kg dosage. Misoprostol (10 microg/kg) was administered i.v. in an absolute alcohol solution. Two animals collapsed following drug administration. While the side-effects could have been produced by either misoprostol or the alcohol vehicle, the clinical changes were more consistent with an adverse drug reaction. Unfortunately, the limitation of UV detection did not provide the sensitivity needed to quantify the amount of misoprostol in llama plasma, and the pharmacokinetics could not be evaluated.     

Experimental evidence that tryptamine alkaloids do not cause Phalaris aquatica sudden death syndrome in sheep

The acute toxicity for sheep of 3 alkaloids that occur in Phalaris acquatica was examined by intravenous and oral administration. The lowest tested dose rates that produced clinically observed signs were, for 5-methoxy dimethyltryptamine, 0.1 mg/kg body weight intravenously and 40 mg/kg orally; for gramine, 10 mg/kg intravenously and 500 mg/kg orally; and for hordenine, 20 mg/kg intravenously and 800 mg/kg orally. All induced the clinical signs observed in the nervous form of phalaris toxicity, but none induced the cardiac, sudden death, syndrome.     

Effects of a histamine type 2 receptor antagonist, BMY-26539-01, on equine gastric acid secretion.

A dose-response study was undertaken of the effects of a newly developed histamine type 2 receptor antagonist, BMY-26539-01, on gastric acid secretion in 4 fasted horses. Doses of 0.1 mg/kg, 0.3 mg/kg, 0.5 mg/kg, or placebo were administered in a randomly assigned treatment sequence. Hydrogen ion concentration and pH were variable during baseline measurements in all 4 animals; however, following BMY-26539-01 administration, mean pH increased and hydrogen ion concentration decreased in a dose-related pattern. At the 0.3 mg/kg and 0.5 mg/kg dose levels, pH remained elevated for > 4 h and > 8 h, respectively. No adverse effects were observed. A significant level of 0.01 was used for all statistical methods.     

Assessment of the potential toxicity of a poison for rabbits, pindone (2-pivalyl 1, 3 indandione), to domestic animals

The toxicity of pindone, a rabbit poison, to horses, cattle, goats, chickens, dogs and cats was investigated, using extension of prothrombin time (PT) as an index of poisoning. The daily dose of pindone, administered for 5 days, ranged from 0.3 mg/kg for dogs to 2.5 mg/kg for chickens. This range of dose rates was considered to be indicative of the worst possible case that could arise following a campaign of baiting for rabbits. Although significant elevations in PT (more than double baseline values) were noted in all species other than horses, clinical signs of anticoagulant poisoning were not observed in any of the species tested. From the observed PT, cattle and cats appeared to be the most susceptible, and horses the least susceptible, to pindone toxicity. The half-lives of the elevated PT were calculated as 3.1 days for cattle, 2.8 days for goats and chickens, 1.9 days for horses and dogs and less than one day for cats. It is proposed that these half-lives can be used as a guide for determining the duration of treatment of pindone-affected animals.     

米尔贝肟大鼠急性中毒的病理学研究

以SD大鼠为研究对象,采用一次性灌胃给药法进行米尔贝肟的急性毒性试验,研究了试验大鼠对米尔贝肟的毒性反应和病理变化.结果显示,米尔贝肟对SD大鼠具有雄雌差异性,半数致死量(LD50)分别为2002、1131 mg/kg·BW.大鼠急性中毒4h后,出现明显的临床症状,主要表现为共济失调、立毛、精神委靡、呼吸困难、食欲减退,且呈明显的量效关系.组织病理学变化主要为肝脏中央静脉淤血,肝索排列紊乱,肝细胞颗粒变性;肺淤血;肾小管上皮细胞和消化道黏膜上皮颗粒变性、坏死;脾脏淤血;大脑皮层血管炎症细胞浸润,边缘空泡化.根据WHO外源性急性毒性分级标准,米尔贝肟属低毒化学物.米尔贝肟急性中毒后会广泛损害大鼠肝、肺、肾和肠等多种组织器官,甚至引起这些组织器官的变性坏死,并可对神经组织造成一定的损伤.     

Phase I and pharmacokinetic evaluation of the combination of orally administered docetaxel and cyclosporin A in tumor-bearing cats

Intravenously administered docetaxel (DT) is problematic in cats because of the requirement for premedication to ameliorate acute vehicle-induced hypersensitivity reactions. Previously we have revealed that therapeutic plasma concentrations of DT can be achieved in normal and tumor-bearing dogs when DT is administered PO in combination with oral cyclosporin A (CSA). The purpose of this study was to identify the maximally tolerated dosage and characterize the pharmacokinetic disposition of oral DT combined with CSA in cats with tumors. Eighteen tumor-bearing cats were enrolled in this phase I dose escalation and pharmacokinetic study. DT was administered by gavage with CSA (5 mg/kg) twice over a 3-week period. The starting dose of DT was 1.0 mg/kg. Based on the clinical toxicity profile, with gastrointestinal adverse effects and hematologic toxicity the maximal tolerated dose of oral DT was 1.75 mg/kg in combination with 5 mg/kg CSA. Additional studies are necessary to determine the efficacy of DT/CSA in cats with epithelial tumors.     

Fetal and neonatal goiter in cynomolgus monkeys following administration of the antithyroid drug thiamazole at high doses to dams during pregnancy

To evaluate morphologic alterations in the thyroid gland in the second generation in cynomolgus monkeys, pregnant dams were exposed to high doses of thiamazole. In Experiment A, dams received thiamazole intragastrically via a nasogastric catheter from gestation day (GD) 50 to GD 150 or on the day before delivery. Initially, the dose level was 20 mg/kg/day (10 mg/kg twice daily); however, the dose level was subsequently decreased to 5 mg/kg/day (2.5 mg/kg twice daily), since deteriorated general conditions were observed in two dams. Six out of seven neonates died on the day of birth. The cause of neonatal death was tracheal compression and suffocation from goiter. The transplacental exposure to thiamazole affected the fetal thyroid glands and induced goiter in all neonates. The surviving neonate was necropsied 767 days after discontinuation of thiamazole exposure and showed reversibility of the induced changes. In Experiment B, dams were intragastrically administered thiamazole at 5 mg/kg/day (2.5 mg/kg twice daily) for treatment periods from GDs 51 to 70, 71 to 90, 91 to 110, 111 to 130 and 131 to 150. All fetuses showed enlarged thyroid glands but were viable. Histopathologically, hypertrophy and/or hyperplastic appearance of the follicular epithelium of the thyroid gland was observed at the end of each treatment period. The most active appearance of the follicular epithelium, consisting of crowded pedunculated structure, was demonstrated at end of the treatment period from GD 131 to 150. This is the first report on the morphology of fetal and neonatal goiter in the cynomolgus monkey.