Clinical efficacy and toxicity of doxorubicin encapsulated in glutaraldehyde-treated erythrocytes administered to dogs with lymphosarcoma.

Doxorubicin was encapsulated in canine erythrocytes, treated with 0.32% glutaraldehyde, and administered at a dosage equivalent to 30 mg of free doxorubicin/m2 of body surface area to dogs with diagnosis of lymphosarcoma. Compared with administration of free doxorubicin, this method of drug delivery substantially reduced peak plasma concentration and prolonged higher plasma concentration of doxorubicin. As such, this method was comparable to continuous IV infusion. Previous studies have indicated this method's potential for reduction in toxic side effects, particularly cardiotoxicosis, while allowing higher total doses of doxorubicin to be administered. In this study, doxorubicin encapsulated in glutaraldehyde-treated erythrocytes induced a triphasic exponential decay of doxorubicin from plasma, the highest relative contribution to the total area of the curve being the terminal phase. The treatment was effective in inducing complete and partial remissions of lymphosarcoma, with minimal acute toxicosis and no evidence of cardiotoxicosis. However, substantial, unanticipated, chronic, nonregenerative myelosuppression developed, and was mot strikingly expressed as profound thrombocytopenia. Efforts to ameliorate or circumvent this toxic effect will be required prior to further consideration of this doxorubicin delivery system for treatment of systemic neoplasia.

The toxic effects of mature flatpea (Lathyrus sylvestris L cv Lathco) on sheep.

The toxic effects of mature, seed-bearing flatpea (Lathyrus sylvestris L cv Lathco) hay on sheep was studied in a feeding trial with 25 adult ewes. Five ewes were barren; 20 were in the last 10 w of pregnancy. The ewes were blocked by weight and reproductive status for assignment to treatment groups. Four groups of 5 ewes each were allotted to 1 of the following diets: 0% (controls), 35.0%, 52.5% or 70.0% flatpea (FP); and 1 group of 5 ewes was allotted to a diet of increasing levels of 17.5, 35.0, 52.5 and 70.0% FP. Flatpea hay was harvested in the mature, seed-bearing stage, pelleted, reground and incorporated into a basal (control) diet of 30% corn + 70% alfalfa by substitution of an appropriate amount of FP for alfalfa. The resulting diets were fed for up to 42 days. The toxic nature of FP was expressed by the following dose-related responses: Fluctuating reductions in feed intake upon initiation of diets containing 35% FP and above; occurrence of a potentially fatal, acute central nervous system syndrome at FP levels as low as 35%; and reduced weight gain at FP levels of 52.5% and above. A wasting condition was observed in 1 ewe fed 52.5% FP. Four of 5 ewes and 1 lamb fed increasing levels of FP developed acute poisoning. One of these ewes developed acute neurotoxicosis when consuming 52.5% FP; 3 other ewes and 1 40-d-old orphaned lamb developed neurotoxicosis upon raising the FP level to 70.0%.(ABSTRACT TRUNCATED AT 250 WORDS)

Resistance to ivermectin by Haemonchus contortus in goats and calves.

Efficacy of ivermectin on susceptible or resistant populations of the parasitic nematode Haemonchus contortus was determined in cattle and goats held in a barn. Goats were each infected with 3000 infective, ivermectin-susceptible or -resistant H. contortus larvae on day 0 and reinfected with 2000 infective larvae on day 24. Goats were treated orally with 600 micrograms kg-1 ivermectin on day 31. No significant differences were detected in blood packed cell volume (PCV) or total protein (TP), prepatent period, or epg among the four groups of goats that were each infected with one of four parasite strains (one susceptible, three resistant). There were no differences among the four parasite strains in the numbers of infective larvae that developed to the third larval stage from fecal cultures or in the viability of cultured infective larvae when held in the laboratory at 27 +/- 1 degrees C for 14 weeks. After treatment with ivermectin, there were significant differences among the parasite strains in PCV, TP, and epg. Total worm counts were reduced by 94 to 97% with three times the recommended dose. Immature and adult Skrjabinema ovis were also present in two treated goats. In a second test, one goat infected once with 10,000 infective larvae of a resistant strain of H. contortus and then treated with nine doses of ivermectin, increasing from 500 to 2000 micrograms kg-1 over a period of 133 days, had 35 adult worms at necropsy. In a third test, three calves were readily infected with an ivermectin-resistant strain of H. contortus from goats.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of low levels of lice and internal nematodes on weight gain and blood parameters in calves in central Texas.

The effects of low levels of both biting and sucking lice, a mixed population of nematodes, and a combination of all these parasites were evaluated in calves held in a barn with no environmental controls in central Texas. Observations at 122 sites on each animal for 16 wk consecutively in 1987 revealed that the largest numbers of all louse species [Haematopinus eurysternus (Nitzsch). Linognathus vituli (L.), and Bovicola bovis (L.)] occurred 3-7 wk after infestation. In 1988 L. vituli populations decreased rapidly after the 3rd wk and B. bovis remained fairly constant for 20 wk consecutively. Average nematode egg counts increased to approximately 300 eggs per gram of feces in 1987 and approximately 600 eggs per gram of feces in 1988. The nematodes Ostertagia ostertagia, Haemonchus placei, Oesophagostomum radiatum, Cooperia spp., and Trichostrongylus spp. were present at the end of the study in both years as determined by necropsy. No significant differences in erythrocyte count, mean cell volume, hematocrit, hemoglobin concentration, leukocyte counts, or serum albumin concentration were detected. However, significant increases in total serum protein concentration and serum globulin levels in calves harboring both groups of parasites were observed. Mean weight gain in calves infested with lice and nematodes was 11.4 and 10 kg less than that of uninfested controls during 16 wk in 1987 and 20 wk in 1988, respectively.

The effects of cadmium on ethanol self-administration using a sucrose-fading procedure.

Rats were exposed for 70 days to either a diet containing 100 ppm cadmium (Group Cadmium) or a control diet with no additives (Group Control). Subsequently, all animals were trained to lever press for a 20% sucrose solution. Across several phases, sucrose was faded out as the reinforcer and gradually replaced with a 10% ethanol solution. A subsequent operant choice (concurrent) test, during which pressing one lever resulted in a dipper presentation of ethanol and the other lever provided water, was followed by a single-lever test where sucrose was reinstated as the reinforcer. The results showed that although cadmium-treated rats lever pressed more than controls during the early phases of the sucrose-fading procedure, animals exposed to cadmium lever pressed at lower rats than controls for ethanol during the concurrent test. There were no group differences on the final sucrose test. The possibility that cadmium may alter sensitivity to ethanol is discussed.

Multiresidue assay for benzimidazole anthelmintics by liquid chromatography and confirmation by gas chromatography/selected-ion monitoring electron impact mass spectrometry.

A multiresidue method utilizing all-disposable labware has been developed for 8 benzimidazole anthelmintics from ovine, bovine, and swine muscle and liver tissues. After an initial extraction with ethyl acetate and subsequent evaporation, a 3-component extraction using hexane, ethanol, and 0.2N HCl was used for final cleanup. Clean extracts were produced for separation and determination by reverse-phase liquid chromatography at 298 nm, using methanol and aqueous buffer as mobile phase. A synthesized internal standard, 2-(n-butylmercapto)benzimidazole, was used for quantitation of all drugs. Results are included along with statistical information verifying the performance of the method. Spiked control tissues and incurred drug tissues were used for an intralaboratory study with a concentration range of 50-1470 ppb. A series of standard curves at 0, 50, 100, and 200 ppb were analyzed. Overall recovery at the 100 ppb level averaged 92% (CV 8%) in liver tissues, across all 3 species and 88% (CV 5%) in muscle tissues across all 3 species. Results were confirmed by gas chromatography/mass spectrometry with acid hydrolysis of the remaining extract in 2N HCl followed by re-extraction of the amine and derivatization to the tert-butyldimethylsilyl derivative. The anthelmintics were identified by gas chromatography/selected ion monitoring electron-impact mass spectrometry. Ion ratio measurements were taken and compared to standard material. CVs averaged 10% or less for all drugs tested.

Alteration of intracellular traffic by monensin; mechanism, specificity and relationship to toxicity.

Monensin, a monovalent ion-selective ionophore, facilitates the transmembrane exchange of principally sodium ions for protons. The outer surface of the ionophore-ion complex is composed largely of nonpolar hydrocarbon, which imparts a high solubility to the complexes in nonpolar solvents. In biological systems, these complexes are freely soluble in the lipid components of membranes and, presumably, diffuse or shuttle through the membranes from one aqueous membrane interface to the other. The net effect for monensin is a trans-membrane exchange of sodium ions for protons. However, the interaction of an ionophore with biological membranes, and its ionophoric expression, is highly dependent on the biochemical configuration of the membrane itself. One apparent consequence of this exchange is the neutralization of acidic intracellular compartments such as the trans Golgi apparatus cisternae and associated elements, lysosomes, and certain endosomes. This is accompanied by a disruption of trans Golgi apparatus cisternae and of lysosome and acidic endosome function. At the same time, Golgi apparatus cisternae appear to swell, presumably due to osmotic uptake of water resulting from the inward movement of ions. Monensin effects on Golgi apparatus are observed in cells from a wide range of plant and animal species. The action of monensin is most often exerted on the trans half of the stacked cisternae, often near the point of exit of secretory vesicles at the trans face of the stacked cisternae, or, especially at low monensin concentrations or short exposure times, near the middle of the stacked cisternae. The effects of monensin are quite rapid in both animal and plant cells; i.e., changes in Golgi apparatus may be observed after only 2-5 min of exposure. It is implicit in these observations that the uptake of osmotically active cations is accompanied by a concomitant efflux of H+ and that a net influx of protons would be required to sustain the ionic exchange long enough to account for the swelling of cisternae observed in electron micrographs. In the Golgi apparatus, late processing events such as terminal glycosylation and proteolytic cleavages are most susceptible to inhibition by monensin. Yet, many incompletely processed molecules may still be secreted via yet poorly understood mechanisms that appear to bypass the Golgi apparatus. In endocytosis, monensin does not prevent internalization. However, intracellular degradation of internalized ligands may be prevented.(ABSTRACT TRUNCATED AT 400 WORDS)

The effects of naltrexone on cadmium-induced increases in oral ethanol self-administration.

Adult male rats were exposed to a standard laboratory diet (N = 20), or an adulterated diet containing 100 ppm added cadmium (N = 20), for 60 days. On Day 61, half the animals from each dietary condition received subcutaneous implants of two 30 mg naltrexone pellets, and the remaining half the animals received identical implants of 30 mg placebo pellets. One week later, animals from groups created by this interaction (Groups Control-Placebo, Control-Naltrexone, Cadmium-Placebo, Cadmium-Naltrexone) were tested in an ethanol self-administration paradigm that presented a 10% ethanol solution (v/v) in both a choice and nonchoice format. The results indicated that cadmium exposure increased the oral self-administration of ethanol in the choice setting where water was offered as an alternative, and the opiate antagonist naltrexone failed to attenuate this effect.

Photosensitization problems in livestock.

Photosensitization is a sunburn-like condition caused by the presence of certain photoactive compounds in the skin when it is exposed to the appropriate wavelength of light. Most photoactive compounds (phototoxic agents) that cause PS in livestock are of plant origin, others are drugs, chemicals, or endogenous porphyrins. Photosensitization is a disease caused by phototoxic xenobiotics, or by acquired or hereditary dysfunction of (1) heme synthesis or (2) PE excretion by the liver. Hepatotoxins, especially those of plant origin, most frequently are the cause of the condition. Photosensitization primarily is a disorder of sheep and cattle, but all classes of livestock are susceptible. Clinical recognition of the syndrome usually presents no difficulty because of the restriction of lesions to areas of skin unprotected from sunlight. Prognosis generally depends on the extent of hepatic injury. The most important elements of treatment are termination of exposure to the photo- or hepatotoxin, protection from light, treatment and prevention of infection and fly strike, and provision of nutritious feed.

Effects of T-2 toxin on saccharin aversion and food consumption in adult rats.

The present experiment used a saccharin aversion paradigm to evaluate the potential aversive action of T-2 toxin, a trichothecene mycotoxin that induces emesis and weight loss. Adult male rats were fed either a control diet or a diet adulterated with 640 ppm lithium chloride (positive control) or with 2.5, 5.0 or 10.0 ppm T-2 toxin and given access to a 0.1% saccharin solution and to tap water during four training days. The rats were then shifted to the control diet during three extinction days. Moderate saccharin aversion induced by the positive control diet and the 5.0 and 10.0 ppm T-2 diets was apparent on the third day of exposure and the aversion to the saccharin solution abated during the extinction trials. Saccharin aversion was evident at levels of T-2 toxin that did not induce obvious tissue pathology.

Experimentally induced photosensitization in cattle with Cooperia pedunculata.

Photosensitization was induced in 2 Charolais heifers following administration of a mixture of air-dried, ground, green (75%) and dead (25%) leaves of the south Texas forb, Cooperia pedunculata, and subsequent exposure to sunlight. Plant material used in this study was collected from a pasture where natural cases of primary bovine photosensitization were occurring. Signs of photosensitization were observed in one heifer after 2 doses of plant material--10 g/kg on day 1 and 5 g/kg on day 2. Continued administration of plant material at 5 g/kg/d on days 3, 4, 7, 8, and 9 resulted in severe signs and lesions of photosensitization and death on day 23. A second heifer developed signs of mild photosensitization following administration of plant material at 1.7 g/kg/d for 4 days. This heifer recovered by day 18. Clinical and pathologic findings of this trial were consistent with the primary form of photosensitization observed in natural cases seen in cattle of south Texas exposed to this plant.

Effect of transport on feeder calves.

One hundred fifty feeder steers (mean body weight, 195 kg) were assigned to 1 of 3 transport groups and were deprived of feed and water (fasted) for 24 hours. Additionally, calves were transported on a commercial livestock trailer for 0 (control-fasted only), 12 (short haul), or 24 (long haul) hours. Blood samples were obtained from the jugular vein before calves were loaded on the transport vehicle and immediately after calves of the long-haul group returned to the research feedlot. Complete blood counts were performed and 32 mineral, enzyme, and biochemical constituents were measured. Calf morbidity, mortality, and average daily weight gain were evaluated during the next 56 days. Duration of transport did not affect average daily gain; however, calves of the short-haul group had significantly (P less than 0.05) higher morbidity and mortality than did those of the control and long-haul groups. In all groups, results of differential leukocyte counts were indicative of stress response. Significant (P less than 0.05) linear contrasts were observed between duration of transport and erythrocyte, leukocyte, segmented neutrophil, lymphocyte, and eosinophil counts and results of serum enzyme (alanine transaminase, hydroxybutyrate dehydrogenase, total lactate dehydrogenase [LD], and LD-1, LD-3, and LD-4 isoenzymes), iron, urea nitrogen, beta-globulin, glucose, and urea nitrogen-to-creatinine ratio determinations. Significant (P less than 0.05) quadratic contrasts were observed between duration of transport and serum unsaturated iron binding capacity, total iron binding capacity, and LD-5 percentage. Calf source had a significant (P less than 0.05) effect on almost all variables tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Photosensitization of cattle in southeast Texas: identification of phototoxic activity associated with Cooperia pedunculata.

A microbiological assay (Candida albicans) was used to screen plants in southeast Texas where bovine photosensitization (PS) of unknown cause was a recurring problem. Phototoxic activity was identified associated with dead leaf tips of Cooperia pedunculata, a native, perennial forb of the Amaryllis family (Amaryllidaceae) from central, southeast, and south Texas and parts of Mexico. A syndrome compatible with naturally occurring PS in cattle was induced in laboratory mice after oral administration of dead leaf material from C pedunculata. Availability and phototoxic activity of dead leaf material of C pedunculata corresponded with occurrence of PS in cattle. Seemingly, C pedunculata was involved in recurring PS.

Experimentally induced Cassia roemeriana poisoning in cattle and goats.

The dried, ground aerial portions of the plant Cassia roemeriana were administered to each of seven calves at a dosage of 10 g/kg of body weight/day for 2 to 10.5 days and to each of six goats at a dosage of 10 g/kg/day for 5 days or 5 or 7 g/kg/day for 23 to 25 days. Experimentally induced C roemeriana poisoning in both species resulted in hepatopathic poisoning characterized by a brief survival period (3.9 to 7.9 days), moderate-to-severe hepatocellular damage, and little or no evidence of injury to skeletal muscle or resulted in myopathic poisoning characterized by a longer period of survival, mild-to-severe skeletal myopathy, and mild hepatocellular injury. The minimal dosage that induced hepatopathic poisoning (also the minimal lethal dosage) was 10 g/kg/day for 3 days in calves and for 5 days in goats. The minimal dosage that induced the myopathic syndrome (as determined by the earliest increase in serum creatine kinase activity) was 10 g/kg/day for 6 days for calves and 5 g/kg/day for 10 to 16 days for goats.

Potassium carbonate as a potassium source and dietary buffer for lactating Holstein cows during hot weather.

Twenty-four lactating Holstein cows were offered diets containing .93, 1.29, and 1.53% potassium during hot weather. Cows fed 1.53% potassium consumed more dry matter than cows fed either .93 or 1.29% potassium. Milk production and composition were not different. Potassium intake and fractional excretion increased, and fecal output as a percentage of intake declined with diets containing 1.29 and 1.53% potassium. Magnesium fractional excretion was least and fecal output greatest in cows fed 1.29% potassium. Fecal sodium output and fecal output as a percentage of intake was reduced by 1.53% dietary potassium. During comparison period 2, potassium carbonate at 0, .5, or 1.0% had no effect on feed consumption or milk yield, but buffered diets increased milk fat percentage and depressed milk protein percentage. No effects of buffers on ruminal pH, volatile fatty acids, or digestibility of dry matter or fiber were noted. Cows responded favorably during hot weather to potassium supplementation at 1.53% of the diet, but with high dietary potassium, effects on other minerals must be considered. Chloride, although present above requirements in all diets, was greater in the highest potassium diet.

Delta-aminolevulinic acid dehydratase (EC4.3.1.24) activity in erythrocytes from cattle administered low concentrations of lead acetate.

Four different age groups of cattle, which had never been exposed to Pb, were used to determine normal age-related values for erythrocyte delta-aminolevulinic acid dehydratase (ALAD) activity. Acute or chronic Pb intoxication was experimentally induced in young calves, and their ALAD values were compared with the normal values. Results indicated that ALAD of normal bovine erythrocytes increased 2- to 3-fold from 1 week to 9 weeks of age and then slowly returned to the initial (1 week old) value by 9 months of age. Erythrocyte ALAD from cattle greater than or equal to 9 months old was uniform. Because of the age-related changes in normal ALAD of cattle less than 9 months old, the age of an animal should be carefully established and age-matched controls evaluated simultaneously when ALAD is used to assess calves suspected of having Pb poisoning. A significant negative correlation was found between blood Pb concentration and ALAD during the first 24 hours after the initial administration of Pb, indicating a high sensitivity of erythrocyte ALAD to Pb. However, when blood Pb concentrations reached 50 micrograms/dl, ALAD did not change further. Because single ingestions of Pb can raise blood Pb concentrations greater than 50 micrograms/dl, ALAD appears to have little value in differentiating acute from chronic Pb intoxication. Within 7 days after Pb administration ceased, ALAD did not increase significantly, even when calves were given calcium ethylenediaminetetraacetic acid (CaNa2EDTA); however, blood Pb concentration decreased by 50%. The rapid change in blood Pb concentration gave a false indication of a positive treatment effect when no real effect was detected by ALAD.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation and treatment of frontal sinus fractures.

We treated twenty-three patients with blunt or penetrating wounds of the frontal sinus from 1978 through 1983. Nondisplaced anterior wall fractures were observed or explored. Posterior table fractures--with displacement confirmed by computed tomography or polycycloidal tomography--were explored. Either obliteration of the sinus or nasofrontal duct reconstruction with a Sewall-Boyden-McKnaught flap was selected, depending on the magnitude of duct injury. In all cases, the anterior wall was primarily reconstructed. All penetrating wounds with posterior table involvement were treated by cranialization of the frontal sinus and temporalis muscle obliteration of the nasofrontal ducts. Only one case of meningitis occurred, resulting in prolonged hospitalization.

Tolerance and effect of chronic dietary cobalt on sheep.

Degeneration and necrosis of the testes and reduced spermatogenesis were recently observed in rats after prolonged intake of dietary cobalt (Co). The objective of the present study was to evaluate the effect of chronic Co intake on testicular and other tissues in sheep. Adult cross-bred rams were dosed daily for 70 days with gelatin capsules containing either 0, 3.0, or 4.5 mg Co/kg body weight. The Co dosages were increased on days 71 to 109 to 0, 10.0 and 15.0 mg Co/kg. Blood and serum samples were collected weekly and the rams were submitted to necropsy on day 109. Tissues were evaluated for histopathological changes and tissue Co residues and testicular spermatid reserves were determined. Highly significant (P less than 0.005) increases in Co levels were present in the blood, liver, kidney and testes of the treated rams. Neither gross nor microscopic lesions were observed in the testes or other tissues. Spermatid reserves remained unchanged. The absence of lesions and nonsignificant alterations in hematological and biochemical determinations indicated that prolonged exposure to Co at the dosages administered did not induce testicular degeneration in sheep and was tolerated without apparent pathological manifestations.