Excess rumen product anions in cattle. I. Blood clearance rates and reduced liver function from sublethal doses of volatile fatty acids, lactate and succinate.

Blood clearance rates of volatile fatty acids, lactate and succinate were estimated in cattle following a single rapid intravenous injection of a Na-anion solution. Bromosulfophthalein was administered immediately before the anion to monitor the effects upon liver function, blood circulation, and dose equilibrium. Acetate, propionate, and valerate at doses up to 5 mmole/kg were cleared quickly from the blood by a first-order process without effects either upon the animal or bromosulfophthalein clearance. Injection of acetic acid solutions produced no effects. Butyrate was toxic at doses above 1 mmole/kg and progressively affected both the rate and progress of bromosulfophthalein clearance as the dose increased. Lactate and succinate were toxic and lethal at doses around 0.25 mmole/kg, and caused both reduced rates and altered progress of bromosulfophthalein clearance. The toxic reactions resulted in total collapse from loss of muscle tone. The butyrate and lactate effects were accentuated when the anion solutions were injected at low pH where a large portion of the anion would be unionized. Levels of butyrate, lactate and succinate in the rumens of feedlot cattle were high enough to provide toxic doses of these anions. The results are discussed in terms of the effects of excess rumen production of these anions upon the liver function and health of feedlot cattle.     

A comparison of the sedative effects of three α2-adrenoceptor agonists (romifidine, detomidine and xylazine) in the horse

The sedative effects of a new alpha 2-adrenoceptor agonist, romifidine, were compared with those of xylazine and detomidine. Five horses were treated with two doses of romifidine (40 micrograms/kg body weight and 80 micrograms/kg body weight), two doses of detomidine (10 micrograms/kg body weight and 20 micrograms/kg body weight) and one dose of xylazine (1 mg/kg body weight) given by intravenous injection using a Latin-square design. The dose of 80 micrograms/kg romifidine appeared equipotent to 1 mg/kg xylazine and 20 micrograms/kg detomidine, although at these doses both xylazine and detomidine had a shorter action. Detomidine 20 micrograms/kg and xylazine both produced greater lowering of the head and a greater degree of ataxia than romifidine at either dose. Romifidine produced sedation similar to that of the other drug regimes. The effect upon imposed stimuli was similar.     

Subacute butyric acid burden in cattle. 1. Clinical results and effects on the carbohydrate-fat metabolism and the liver function of young fattening bulls

Daily butyric acid doses of 0.5 g/kg body weight or 1.0 g/kg were intraruminally applied to 8 young fattening bulls together with regular feed rations, for 19 days, following an initial phase for adaptation. Indigestion phenomena were recordable from 30% of the animals, primarily on the early days of the experiment. Both doses produced sinusoidal beta-OH butyrate curves without major dose-dependent deviations. The concentrations of glucose and free fatty acids were indicative of temporary subclinical ketosis. Neither ASAT, ALAT, and gamma-glutamyltransferase nor bilirubin nor liver glycogen were indicative of liver damage. The lower dose of 0.5 g/kg was widely tolerated, but clearly discernible disorders developed in response to the higher dose of 1.0 g/kg of butyric acid.     

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.     

Pharmacological experiments as a basis for the administration of digoxin in the horse.

It is shown that the concentration of ouabain necessary for 50 per cent inhibition of the Na+K activated membrane ATPase of red cells is similar in man and horse. This is taken to indicate that the two species have similar sensitivity towards cardiac glycosides in general. In five adult healthy horses plasma digoxin concentration was measured with a radioimmunoassay technique after a single intravenous injection of 1 mg/100 kg body weight digoxin. The half time of elimination was 23 h and the apparent volume of distribution 7.3 litres/kg. An approximate estimate of plasma protein binding of digoxin was obtained by measuring digoxin with a fluorimetric assay in the ultrafiltrate from horse plasma containing 2-20 mug/ml. At concentrations below 10(-5)(g/ml 20 to 40 per cent of digoxin present in horse plasma is bound to protein. With this information and by using effective digoxin concentration measured in humans an average daily maintenance dose of 0-5-0-75 mg/100 kg body weight was calculated which may serve as a guideline in the treatment of congestive heart failure with digoxin in the horse.     

Evaluation of detomidine as a sedative in goats.

Intramuscular (i.m.) and intravenous (i.v.) administration of detomidine at doses of 10, 20 and 40 micrograms/kg body mass was evaluated for its sedative and analgesic properties in 15 goats (Capra hircus). The drug produced dose- and route-dependent sedation. The 10 micrograms/kg dose was effective only when administered i.v. There was no observable analgesia at this dose. Higher doses produced effective sedation and moderate analgesia of the body with either route of administration. Severe ataxia and sternal recumbency were seen in all the animals after the dose of 40 micrograms/kg. Other effects of detomidine in these goats included mild to moderate salivation, depressed respiratory rate, decreased rectal temperature, bradycardia and hyperglycaemia. Plasma concentrations of total protein, sodium, potassium and chloride were not affected.     

The effect of administration of a single dose of T-2 toxin on blood coagulation in the rabbit.

The single intravenous administration of T-2 toxin to rabbits at a dosage of 0.5 mg per kg body weight produced an alteration in several blood coagulation parameters. The activities of factors VII, VIII, IX, X and XI were decreased by approximately 40% six hours after T-2 toxin administration. Plasma fibrinogen concentration became elevated within 24 hours after T-2 toxin exposure. Circulating platelet numbers were unaffected by T-2 toxin administration. The similarity of coagulation parameter changes induced by T-2 toxin in animals receiving daily subcutaneous injections of vitamin K (0.5 mg per kg body weight) and those in nonvitamin K supplemented animals suggests that T-2 toxin does not function as a vitamin K antagonist.     

Repeated oral administration of coumaphos in sheep: interactions of coumaphos with bishydroxycoumarin, trichlorfon, and phenobarbital sodium.

Interactions between treatments with coumaphos, bishydroxycoumarin (an anticoagulane), trichlorfon (an organophosphorous compound), and phenobarbital sodium (an inducer of microsomal enzymes) were investigated in sheep. A daily dose of 2 mg of coumaphos/kg of body weight for 6 days did not affect the plasma enzymes or the antiprothrombinemic effect of bishydroxy-coumarin in wethers. The treatment of ewes with an intravenous (IV) injection of trichlorfon, insufficient to produce significant inhibition of erythrocyte acetylcholinesterase (AChE) activity, appeared to produce additive effects with those produced by subsequent treatment with 4 mg of coumaphos/kg/day. In ewes given 40 mg of phenobarbital sodium/kg for 5 days intraperitoneally (IP), the anticholinesterase effect of 4 mg of coumaphos/kg was significantly reduced and signs of toxicity were not present. Treatment with daily doses of 2 mg of coumaphos/kg for 6 days did not modify the anticholinesterase effect of a 2nd series of treatments given 6 weeks later.     

Comparative pharmacokinetics of yohimbine in steers, horses and dogs.

In steers, horses and dogs, the comparative pharmacokinetics of yohimbine were determined using model-independent analysis. The intravenous dose of yohimbine was 0.25 mg/kg of body weight in steers, 0.075 or 0.15 mg/kg in horses, and 0.4 mg/kg in dogs. The mean residence time (+/- SD) of yohimbine was 86.7 +/- 46.2 min in steers, 106.2 +/- 72.1 to 118.7 +/- 35.0 min in horses, and 163.6 +/- 49.7 min in dogs. The mean apparent volume of distribution of yohimbine at steady state was 4.9 +/- 1.4 L/kg for steers, 2.7 +/- 1.0 to 4.6 +/- 1.9 L/kg for horses, and 4.5 +/- 1.8 L/kg for dogs. The total body clearance of yohimbine was 69.6 +/- 35.1 mL/min/kg for steers, 34.0 +/- 19.4 to 39.6 +/- 16.6 mL/min/kg for horses, and 29.6 +/- 14.7 mL/min/kg for dogs. Between-species comparisons indicated that the mean area under the serum concentration versus time curve was significantly greater (P less than 0.05) in dogs than in horses. There were no significant differences (P greater than 0.05) between the means for the apparent volume of distribution, clearance, mean residence time, terminal rate constant, and area under the curve between horses given the two doses of yohimbine. The harmonic mean effective half-life (+/- pseudo standard deviation) of yohimbine was 46.7 +/- 24.4 min in steers, 52.8 +/- 27.8 to 76.1 +/- 23.1 min in horses, and 104.1 +/- 32.1 min in dogs. The data may explain why steers, horses, and dogs given certain sedatives and anesthetics do not relapse when aroused by an intravenous injection of yohimbine hydrochloride.     

Diphenylamine-induced renal papillary necrosis and necrosis of the pars recta in laboratory rodents

The nephrotoxicity of diphenylamine, the parent compound of the mefenamate family of nonsteroidal anti-inflammatory drugs, was evaluated in male Syrian hamsters, male Sprague-Dawley rats, and male Mongolian gerbils. Total renal papillary necrosis was observed in four of ten, seven of ten, and six of ten male Syrian hamsters orally treated with diphenylamine at respective doses of 400 mg/kg body weight/day, 600 mg/kg body weight/day, and 800 mg/kg body weight/day. Total renal papillary necrosis was also observed in five of ten and four of ten male Syrian hamsters intraperitoneally treated with diphenylamine at respective doses of 600 mg/kg body weight/day and 800 mg/kg body weight/day. Focal intermediate renal papillary necrosis was induced in two hamsters orally given diphenylamine at 600 mg/kg body weight/day and in two of ten hamsters intraperitoneally given diphenylamine at 800 mg/kg body weight/day. Apex-limited necrosis of the medullary interstitial cells and vasa recta and degeneration of the renal interstitial matrix occurred in two Sprague-Dawley rats orally administered diphenylamine at 800 mg/kg body weight/day. Degeneration and necrosis of the pars recta was induced in seven of ten hamsters intraperitoneally given diphenylamine at 400 mg/kg body weight/day. Gross and microscopic renal lesions were not observed in any Mongolian gerbils. It was concluded that the Syrian hamster is more susceptible to the papillotoxic effects of diphenylamine than the Sprague-Dawley rat and the Mongolian gerbil. Renal papillary necrosis in the Syrian hamster treated orally with diphenylamine is reproducible, is of short onset, and is induced in a high proportion of the hamsters (70-90%).(ABSTRACT TRUNCATED AT 250 WORDS)     

A pharmacokinetic study of digoxin in the horse

Digoxin was administered orally and intravenously to seven healthy adult mares and geldings in two separate trials. At a dose of 44 microgram digoxin/kg body weight, the oral study was characterized by an absorption phase with a mean (+/- 1 standard deviation) peak serum digoxin concentration of 2.21 ng/ml (+/- 0.45) at a mean of 2.29 h (+/- 1.52) after administration. A second rise in serum digoxin concentration started about 6-8 h after administration and extended to about 20 h after administration. The mean bioavailability (F) was 23.38% (+/- 5.96). At a dose of 22 microgram digoxin/kg body weight, the intravenous study was characterized by a two-compartment model with the following mean pharmacokinetic measurements: distribution rate constant (alpha), 1.391 h-1 (+/- 0.1909); zero-time serum digoxin concentration determined from the distribution phase (A), 21.247 ng/ml (+/- 5.6614); elimination rate constant (beta), 0.0409 h-1 (+/- 0.0069); zero-time serum digoxin concentration determined from the elimination phase (B), 3.82 ng/ml (+/- 0.433); apparent specific volume of distribution uncorrected for protein binding (Vd beta), 5.003 l/kg (+/- 0.5177). The mean beta corresponded to a biological half-life (T1/2 beta) of 16.9 h. Based upon results of this study, theoretically achievable steady-state serum digoxin concentrations were calculated for maintenance doses given by oral and intravenous routes of administration with appropriate two-compartment, multiple-dose formulae. Loading doses were also calculated for each route. It is the opinion of the authors that the oral route of administration of digoxin is effective in the horse and may preclude the potential risks posed by the high serum digoxin concentrations immediately following intravenous administration.     

The effect of enterotoxin of Clostridium welchii (perfringens) type A on fowls.

Lethal doses of enterotoxin of Clostridium welchii (perfringens) type A injected intravenously into young fowls caused immediate lassitude, with partial recovery, followed by death seven to 35 h after inoculation. Lesions found were ascites, hydropericardium, oedema of the muscles, hepatic congestion, urate deposits on the peritoneum and the pericardium, and intestinal hyperaemia. Sublethal doses produced no clinical signs or lesion. The LD50 of this enterotoxin was 74-84 mug/kg of body weight.     

Pharmacokinetics and bioavailability of spiramycin in pigs.

The pharmacokinetics of spiramycin in pigs were investigated after intravenous and oral administration. The potential therapeutically effective blood level was established after a single administration and examined in a subsidiary five day study. The rapid intravenous injection of 25 mg spiramycin/kg bodyweight produced marked salivation in all the test animals. The elimination half-life (2.3 +/- 1.2 hours) was relatively short, in accordance with the total body clearance rate (27.3 +/- 10.1 ml/minute/kg). The high volume of distribution (5.2 +/- 2.2 litres/kg) was due to the accumulation of the drug in the body tissues. The maximum plasma concentration (4.1 +/- 1.7 micrograms/ml) after oral administration of 85 to 100 mg spiramycin/kg bodyweight was reached after 3.7 +/- 0.8 hours and the half-life of the elimination phase was 6.0 +/- 2.4 hours. The oral bioavailability was 45.4 +/- 23.4 per cent. Ad libitum feeding of a diet containing 2550 mg spiramycin/kg produced a steady state concentration of 0.96 +/- 0.27 micrograms/ml. This plasma concentration would provide a potentially therapeutically effective blood concentration against Mycoplasma species, Streptococcus species and Staphylococcus species.     

Hemato-clinical changes in phenylhydrazine-induced acute hemolytic anaemia in calves.

Acute anaemia was induced in calves aged 1 week, using the oxidant chemical phenylhydrazine-hydrochloride (PHH). The hematoclinical responses to graded doses were evaluated. Mild anaemia was observed with the 60 mg/kg body weight (B.W.) dose. The 100 mg/kg B.W. dose was too toxic. The sublethal 80 mg/kg B.W. dose produced the desired type of hemolytic anaemia, the peak of which being observed on d 4 post-injection (p.i.). Hemolytic anaemia was evidenced by hemoglobinaemia and hemoglobinuria. The acute toxicity symptoms lasted for about 30 min. Thereafter, the animals appeared to overcome the stress. In general, increases in pulse and respiration coincided with progress of the hemolytic syndrome. Peak response occurred 48 to 60 h p.i.     

Pharmacological and toxicological study of turimycin]

Turimycin is characterised by low acute toxicity. Mean lethal doses for mouse and rat are 750 mg/kg body weight for intraperitoneal application of something in excess of 3,000 mg/kg for oral administration. The blood pressure of anaesthetised cats may be reduced by amounts depending on intravenous Turimycin doses (between 10 and 50 mg/kg). The hypotensive effect of Turimycin is attributable to its negative inotropic effect on the heart and its spasmolytic action on the unstriated muscles. Reversible reduction of urine and ion excretion of rat following intraperitoneal application of 50 mg/kg body weight of Turimycin is interpreted as a consequence of such action upon blood pressure. A preliminary study was conducted into dogs which had orally received daily Turimycin doses of 50 or 125 mg/kg body weight over twelve months. No substance-depending functional or morphological damage was recorded.     

The disposition of theophylline in camels after intravenous administration

The pharmacokinetics of theophylline were determined after an intravenous (i.v.) dose of 2.36 mg/kg in six camels and 4.72 mg/kg body weight in three camels. The data obtained (median and range) for the low and high dose, respectively, were as follows: the distribution half-lives (t1/2 alpha) were 1.37 (0.64-3.25) and 2.66 (0.83-3.5) h, the elimination half-lives (t1/2 beta) were 11.8 (8.25-14.9) and 10.4 (10.0-13.5) h, the steady state volumes of distribution (Vss) were 0.88 (0.62-1.54) and 0.76 (0.63-0.76) L/kg, volumes of the central compartment (Vc) were 0.41 (0.35-0.63) and 0.51 (0.36-0.52) L/kg, total body clearances (Clt) were 62.3 (39.4-97.0) and 50.2 (47.7-67.4) mL/h.kg body weight and renal clearance (Vr) for the low dose was 0.6 (0.42-0.96) mL/h.kg body weight. There was no significant difference in the pharmacokinetic parameters between the two doses. Theophylline protein binding at a concentration of 5 micrograms/mL was 32.2 +/- 3.3%. Caffeine was identified as a theophylline metabolite but its concentration in serum and urine was small. Based on the pharmacokinetic values obtained in this study, a dosage of 7.5 mg/kg body weight administered by i.v. injection at 12 h intervals can be recommended. This dosing regimen should achieve an average steady state serum concentration of 10 micrograms/mL with peak serum concentration not exceeding 15 micrograms/mL.     

Pharmacokinetic interactions between flunixin and sulphadimidine in horses.

The pharmacokinetic aspects of sulphadimidine were studied in clinically healthy (control) and Flunixin-medicated horses after a single intravenous and oral administration of 100 mg/kg body weight. Plasma sulphadimidine concentration were determined by high-performance liquid chromatography (HPLC). Following the intravenous injection, all plasma sulphadimidine data were best approximated by a two-compartment open model using sequential, weight non-linear regression. Flunixin induced a 67% increase in the rate of sulphadimidine return to the central compartment from peripheral tissues (K21) and there were a trend to a 30% increase in K12. The sulphadimidine elimination half-life was decreased 21%, the Vdss was reduced by 18% and MRT was decreased by 20%. Following the oral administration, sulphadimidine was rapidly absorbed in control and Flunixin-medicated horses with absorption half-lives (t1/2 ab) of 0.5 and 0.43 hours respectively. The peak plasma concentration (Cmax) were 93.7 and 109 micrograms/ml attained at (tmax) 2.36 and 1.9 hours respectively. The elimination half-life after oral administration (t1/2 ab) was shorter in flunixin pre-medicated horses than in control ones. The systemic bioavalability percentages (F%) of sulphadimidine after oral administration of 100 mg/kg body weight was 79.3 and 71.2% in control and flunixin medicated horses, respectively. Therefore care should be exercised in the use of sulphadimidine in equine patients concurrently treated with flunixin.     

Corticosterone plasma concentration in male mule ducks: effects of sampling sites, repeated samplings and ACTH injections.

1. Changes in plasma corticosterone concentrations according to puncture sites and various challenges including injections of an ACTH agonist (Immediate Synacthen) were investigated in male mule ducks. 2. Lower concentrations were measured in samples drawn by puncture from the occipital sinus than at a wing vein site. 3. Immobilisation and a single intramuscular injection of saline solution (1 ml, 0.9%) had no effect on plasma corticosterone after 15 min. 4. A single intramuscular injection of ACTH (5 microg/kg body weight) produced a rise (P<0.05) in corticosterone. Maximum concentrations were measured after 10 min and, in the absence of further sampling, a return to initial levels was observed by 1 h. 5. On the other hand, repeated bleedings following ACTH challenge maintained higher corticosterone concentrations. 6. A single intramuscular injection of ACTH at doses ranging between 0.625 to 20 microg/kg body weight increased corticosterone concentrations (P<0.05) in a dose-dependent manner, with the responses plateauing at doses of 1.25 microg/kg and higher.     

Acute insulin response to intravenous arginine in nonobese healthy cats

The purpose of this study was to document and characterize insulin response to intravenous administration of arginine, a nonglucose secretagogue, and compare it to insulin response during intravenous glucose tolerance tests (IVGTTs) in clinically healthy nonobese cats. In addition, we examined the influence of plasma glucose level on insulin response to arginine in cats. Five dosages of 10% L-arginine hydrochloride (0.015, 0.025, 0.05, 0.1, and 0.2 g/kg of body weight) were administered to 5 cats. All doses of arginine elicited an abrupt insulin response that peaked at 2-4 minutes and returned to basal concentrations within 30 minutes. Mean insulin peak response (IPR) and mean area under the curve of plasma insulin concentration evaluated for the initial 10 minutes after administration (AUC10) increased with each progressive increase in arginine dosage. An asymptotic maximal response estimated by mean insulin AUC10 reached plateau at 0.1-0.2 g arginine/kg. Arginine at 0.2 g/kg induced hypersalivation in 2 of 4 cats. No adverse effects were evident at lower doses. Mean insulin AUC10 produced by equimolar amount of glucose (0.086 g/kg) was only 42% of that seen in response to 0.1 g arginine/kg, and mean IPR was much lower (18 +/- 7 versus 61 +/- 17 microU/mL). Mild hyperglycemia (211 +/- 6 mg/dL) induced by variable infusion rate of glucose resulted in a significant (P < .05) potentiation of insulin response to arginine; mean insulin AUC10 increased 287 +/- 26 to 551 +/- 167 microU/mL/10 minutes. These findings indicate that the arginine challenge is a more meaningful tool than is the IVGTT for evaluating the insulin secretory capacity in cats.     

烟酰胺与丁酸钠对高密度笼养肉鸡肝脏和肠道氧化应激与炎症反应的影响

为探究烟酰胺和丁酸钠对高密度笼养肉鸡抗氧化和缓解炎症的作用效果,试验采用342只26日龄AA+雄性肉鸡,随机分为5组,每组6个重复。对照组为正常密度组(12.9只/m²)和高密度组(17.1只/m²),试验组为高密度分别饲喂烟酰胺组(50 mg/kg)、丁酸钠(500 mg/kg)、复合添加组(50 mg/kg烟酰胺+500 mg/kg丁酸钠),饲养至46日龄,测定生产性能、血清抗氧化指标、肝脏抗氧化基因mRNA表达和盲肠炎性因子mRNA表达。结果表明:高饲养密度较正常密度组显著降低了肉鸡采食量和体增重,烟酰胺组和复合添加组可缓解高饲养密度造成的生产性能下降的趋势;与正常密度组相比,高密度组显著上调了肝脏中血红素加氧酶(HO-1)、核因子E2相关因子2(Nrf2)、盲肠扁桃体白介素6(IL6)、白介素10(IL10)mRNA的表达;与高密度组相比,复合添加烟酰胺和丁酸钠显著上调了肝脏谷胱甘肽过氧化物酶(GSH-Px)、HO-1、肿瘤坏死因子α(TNF-α)和Nrf2的mRNA表达量,显著下调盲肠扁桃体IL6、IL10基因mRNA的表达量。综上可知,在高密度笼养条件下,家禽饲粮中复合添加烟酰胺和丁酸钠可以提高肉鸡的生产性能,缓解高密度氧化应激导致的肉鸡炎症基因表达,Keap1-Nrf2-ARE信号通路可能参与了烟酰胺和丁酸钠对肉鸡抗氧化能力的调控。