Pharmacokinetic and Phase I Evaluation of Carboplatin in Dogs

Thirty dogs with spontaneously occurring malignant neoplasms were treated monthly with carboplatin (CBDCA) given as a 30-minute intravenous infusion in a dose escalation study. Twenty-eight dogs were considered evaluable for toxicity. The maximally tolerated dose of CBDCA was conceptually defined as that dose, determined by logistic regression analyses of toxicity data, resulting in a 50% incidence of moderate toxicity (MOD₅₀) or a 5% incidence of severe toxicity (SEV₅). Each designated maximally tolerated dose was calculated for the first course of treatment only and for the first and second courses of treatment combined to estimate cumulative drug toxicity. The MOD₅₀ and SEV₅ for the first treatment course were 340 and 278 mg/M², respectively. MOD₅₀ and SEV₅ values for the first plus second treatment courses were 327 and 231 mg/M², respectively. The nadir of neutrophil and platelet counts occurred approximately 14 days after treatment. The mean neutrophil and platelet values for all dogs experiencing myelosuppression during the first two treatment courses were 1541/μL and 62,600/μL, respectively. Nonparametric pharmacokinetic analysis of plasma CBDCA values suggested that half-life (T_1/2), area-under-the-curve and total body clearance (CL_b) were not dose dependent. Volume of distribution (VD_ss) significantly increased with dose only between 100 and 150 mg/M², not between 150 and 300 mg/M². Dose-independent serum CBDCA pharmacokinetic disposition indicates that detailed investigation of tissue CBDCA distribution would be warranted and may identify novel dosing strategies that could improve the therapeutic index of CBDCA by minimizing toxicity. (Journal of Veterinary Internal Medicine 1993; 7:235–240. Copyright © 1993 by the American College of Veterinary Internal Medicine.)     

Antimicrobial therapy for gastrointestinal diseases.

Antibiotics will always be needed in horses for many types of infections, but the adverse consequences also must be considered. For the conditions described in this article, there is justification for antibiotic therapy. The intestinal problems that antibiotics can induce are among the risks from their administration to horses. Disruption of the endogenous bacterial population, colitis, and diarrhea are the most common complications from antibiotic therapy.     

一种新的赖氨酸源

猪、禽日粮的传统赖氨酸添加源是盐酸Ｌ 赖氨酸。但是 ,如今有了另一种赖氨酸源 ,这种新赖氨酸源在经济上可比传统的盐酸Ｌ 赖氨酸更为合算。这种新赖氨酸源是一种干燥的颗粒状产品 ,其中含硫酸Ｌ 赖氨酸和发酵副产品 ,由谷氨酸棒状杆菌(Ｃｏｒｙｎｅｂａｃｔｅｒｉｕｍｇｌｕｔａｍｉｃｕｍ)发酵产生 ,产地为美国内布拉斯加州。其商品成品提供 60 %盐酸Ｌ 赖氨酸的赖氨酸替代值。此外 ,其发酵副产品还含有盐酸Ｌ 赖氨酸中不含的其它氨基酸、磷和能量 (表 1 )。美国已用猪和肉鸡对其进行了硫酸Ｌ 赖氨酸和盐酸Ｌ 赖氨酸的比较试验。最近在美…     

The nutritional value of low lathyrogenic Lathyrus (Lathyrus sativus) for growing chicks

1. The feeding value of new low β‐N‐oxalyl‐amino‐L‐alanine (BOAA) lines of Lathyrus sativus (lathyrus) and the benefits of dehulling the seed or of pre‐adapting chicks to lathyrus‐based diets were examined in several experiments.

2. Chicks fed on diets containing 400 g/kg of the low (1.3 g BOAA/kg seed) and medium (2.2 g BOAA/kg seed) BOAA lines did not differ (P>0.05) in weight gain (WG) or in apparent fat and protein digestibilities compared to birds fed on a wheat‐based diet.

3. Consumption of 600 g low BOAA lathyrus/kg diet caused a slight, but significant (P< 0.05), decrease in WG. Food efficiency decreased as the amount of dietary lathyrus was increased, suggesting that lathyrus may contain an antinutritive factor(s) other than BOAA.

4. Removal of the hull (70 g hull/kg seed) from the seed did not affect chick performance (P> 0.05).

5. Pre‐adapting chicks for 7 d to diets containing up to 600 g medium line lathyrus/kg diet did not reduce the detrimental effects of the lathyrus.

6. Although dehulling and pre‐adaptation of chicks to lathyrus were not beneficial, the low and medium lines of lathyrus tested show potential for use in chick diets up to at least 400 g lathyrus/kg diet.     

A survey of the selenium status of beef cows in Alberta.

An epidemiological survey was conducted in Alberta to measure the selenium status in blood of beef cows during the fall and to determine the risk of selenium deficiency among specific geographic regions of Alberta. Three census divisions of Alberta based on the Statistics Canada Census of Agriculture were chosen as the study areas for the project. Soils and plants in area A (Edmonton area) and area B (Calgary area) were known to be deficient in selenium, while soils and plants in area C (southeast corner of Alberta) were known to have adequate levels of selenium. Blood samples were collected from 335 cows on 29 farms from the 3 study areas. These samples were collected from cows that had recently been removed from pasture in October and November 1992. Answers to a short questionnaire pertaining to various herd characteristics and management practices were also obtained for each herd. The average value of selenium for all cows sampled was 2.20 mumol/L. The average value of selenium of cows in areas A and B was 1.93 mumol/L. The average value of selenium of cows in area C was significantly (P < 0.05) higher at 2.70 mumol/L. Nine percent of the cows in the study were considered marginal or deficient in selenium (< 1.27 mumol/L selenium). Herds located in area C, herds that were provided with supplemental feed on pasture, and herds that were pregnancy checked had higher average herd selenium values than did other herds. Cow-calf producers located in areas with selenium-deficient soils should pay particular attention to selenium supplementation for their cows. Some of the negative "geographic" effects on selenium values can be overcome by more progressive management practices.     

‘Plantibodies’: a flexible approach to design resistance against pathogens

Engineering resistance against various diseases and pests is hampered by the lack of suitable genes. To overcome this problem we started a research program aimed at obtaining resistance by transfecting plants with genes encoding monoclonal antibodies against pathogen specific proteins. The idea is that monoclonal antibodies will inhibit the biological activity of molecules that are essential for the pathogenesis. Potato cyst nematodes are chosen as a model and it is thought that monoclonal antibodies are able to block the function of the saliva proteins of this parasite. These proteins are, among others, responsible for the induction of multinucleate transfer cells upon which the nematode feeds. It is well documented that the ability of antibodies to bind molecules is sufficient to inactivate the function of an antigen and in view of the potential of animals to synthesize antibodies to almost any molecular structure, this strategy should be feasible for a wide range of diseases and pests.Antibodies have several desirable features with regard to protein engineering. The antibody (IgG) is a Y-shaped molecule, in which the domains forming the tips of the arms bind to antigen and those forming the stem are responsible for triggering effector functions (Fc fragments) that eliminate the antigen from the animal. Domains carrying the antigen-binding loops (Fv and Fab fragments) can be used separately from the Fc fragments without loss of affinity. The antigen-binding domains can also be endowed with new properties by fusing them to toxins or enzymes. Antibody engineering is also facilitated by the Polymerase Chain Reaction (PCR). A systematic comparison of the nucleotide sequence of more than 100 antibodies revealed that not only the 3′-ends, but also the 5′-ends of the antibody genes are relatively conserved. We were able to design a small set of primers with restriction sites for forced cloning, which allowed the amplification of genes encoding antibodies specific for the saliva proteins ofGlobodera rostochiensis. Complete heavy and light chain genes as well as single chain Fv fragments (scFv), in which the variable parts of the light (V_L) and heavy chain (V_H) are linked by a peptide, will be transferred to potato plants. A major challenge will be to establish a correct expression of the antibody genes with regard to three dimensional folding, assembly and intracellular location.     

Effects of sub-minimum inhibitory concentration antibiotic levels and temperature on growth kinetics and outer membrane protein expression in Mannheimia haemolytica and Haemophilus somnus

The objective of this study was to determine the effects of sub-minimum inhibitory concentrations (sub-MICs) of 2 veterinary antibiotic preparations, chlortetracycline (CTC) and chlortetracycline-sulfamethazine (CTC + SMZ), on growth kinetics and outer membrane protein expression in Mannheimia haemolytica and Haemophilus somnus at normal and febrile body temperatures. Sub-minimum inhibitory concentrations of both antibiotics reduced the growth rates of M. haemolytica and H. somnus. Growth of both species was not inhibited when grown at 41 degrees C compared to 37 degrees C. There was no detectable consistent effect of antibiotic or temperature on outer membrane protein expression for either species. Our study indicates that sub-MIC levels of CTC and CTC + SMZ markedly impair growth of clinical M. haemolytica and H. somnus isolates, potentially allowing more effective host clearance during infection.