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This article presents the surveillance data from the Feed Contaminants Program (2002-2009) and Salmonella Assignment (2007-2009) of the U.S. Food and Drug Administration (FDA), which monitor the trend of Salmonella contamination in animal feeds. A total of 2,058 samples were collected from complete animal feeds, feed ingredients, pet foods, pet treats, and supplements for pets in 2002-2009. These samples were tested for the presence of Salmonella. Those that were positive for Salmonella underwent serotyping and testing for antimicrobial susceptibility. Of the 2,058 samples, 257 were positive for Salmonella (12.5%). The results indicate a significant overall Salmonella reduction (p≤0.05) in animal feeds from 18.2% (187 samples tested) in 2002 to 8.0% (584 samples tested) in 2009. Among these samples, feed ingredients and pet foods/treats had the most significant reduction (p≤0.05). Of the 45 Salmonella serotypes identified, Salmonella Senftenberg and Salmonella Montevideo were the top two common serotypes (8.9%). Of the 257 Salmonella isolates obtained, 54 isolates (21%) were resistant to at least one antimicrobial. The findings provide the animal feed industries with Salmonella prevalence information that can be used to address Salmonella contamination problems. Our findings can also be used to educate pet owners when handling pet foods and treats at home to prevent salmonellosis.

This article focuses on the regulatory issues to consider when veterinarians are called upon to treat animal toxicoses, in particular those involving food-producing animals. The lack of Food and Drug Administration-approved drugs to treat animal toxicoses has been a long-standing problem. This article reviews extralabel drug use regulations, and the responsibilities of the treating veterinarian. It discusses the legal implications of compounding and the use of unapproved drugs to treat animal toxicoses. Efforts should be made to increase the availability of life-saving antidotal therapies., (Published by Elsevier Inc.)

We conducted a prospective randomised study to compare the efficiency of out-patient progenitor cell mobilisation using either intermediate-dose cyclophosphamide (2 g/m(2)) and lenograstim at 5 micrograms/kg (Cyclo-G-CSF group, n=39) or lenograstim alone at 10 micrograms/kg (G-CSF group, n=40). The end points were to compare the impact of the two regimens on mobilisation efficiency, morbidity, time spent in hospital, the number of apheresis procedures required and engraftment kinetics. Successful mobilisation was achieved in 28/40 (70%) in the G-CSF group vs 22/39 (56.4%) for Cyclo-G-CSF (P=0.21). The median number of CD34+ cells mobilised was 2.3 x 10(6)/kg and 2.2 x 10(6)/kg for G-CSF and cyclo-G-CSF arms following a median of two apheresis procedures. Nausea and vomiting and total time spent in the hospital during mobilisation were significantly greater after Cyclo-G-CSF (P<0.05). Rapid neutrophil and platelet engraftment was achieved in all transplanted patients in both groups. In conclusion, G-CSF at 10 micrograms/kg was as efficient at mobilising progenitor cells as a combination of cyclophosphamide and G-CSF with reduced hospitalisation and side effects and prompt engraftment. When aggressive in-patient cytoreductive regimens are not required to both control disease and generate progenitor cells, the use of G-CSF alone appears preferable to combination with intermediate-dose cyclophosphamide.

Cross-bred, anesthetized female swine were given intravascularly a lethal (72 microg/kg; n = 6) or toxic-sublethal (25 microg/kg; n = 6) dose of microcystin-LR (MCLR), from Microcystis aeruginosa, or the vehicle (n = 4). At the high dose, from 12 to 18 min after administration, central venous pressure and hepatic perfusion were significantly lower, and shortly thereafter, portal venous pressure was significantly higher and aortic mean pressure was significantly lower than controls. By 45 min postdosing, serum bile acids, lactate, potassium, and total bilirubin, as well as blood pO2, were significantly higher, while hematocrit, platelet count, and blood bicarbonate, pCO2, and base excess were significantly lower than controls. By 90 min, serum arginase, urea nitrogen, inorganic phosphorus, and creatinine were significantly higher, while glucose and blood pH were significantly lower than in controls. By 150 min, serum alanine and aspartate aminotransferases, alkaline phosphatase, lactate dehydrogenase, and creatinine phosphokinase activities were significantly higher than controls. At the low dose, significant differences from controls occurred in hemodynamic, organ perfusion, and serum chemistry parameters, but such changes generally took longer to occur and were of a lesser magnitude than at the high dose. Livers of the high-dose swine were swollen and dark red-purple, and exuded excessive blood on the cut surface. Based on increases in liver weight and liver hemoglobin, 38% of the total blood volume was lost into the liver. Terminally, all high-dose swine experienced hyperkalemia, and most had severe hypoglycemia. Death due to acute MCLR toxicosis in intravascularly dosed swine appears to result from severe intrahepatic hemorrhage, partial obstruction of blood flow through the liver, circulatory shock, severe hypoglycemia, and/or terminal hyperkalemia.

Polybrominated biphenyls (PBBs), polychlorinated biphenyls (PCBs), and dioxins are shown to have toxic potential in food animals and humans through laboratory research and investigation of accidental exposures. This article discusses the ball clay incident, as well as other examples of known accidental exposures to PBBs and PCBs. Background information regarding the mechanism of toxicity and effects in animals and humans is also included.

During Fiscal Years 1989-1994, the U.S. Food and Drug Administration (FDA) collected and analyzed 545 domestic surveillance samples of mixed feed rations (172 for cattle, 125 for poultry, 83 for swine, 61 for pets, 56 for fish, and 48 miscellaneous). All samples were analyzed by gas-liquid chromatography for organohalogen and organophosphorus pesticides. Of the 545 samples, 88 (16.1%) did not contain detectable pesticide residues. In the 457 samples with detectable pesticide levels, 804 residues (654 quantitable and 150 trace) were found. None of these 804 residues exceeded regulatory guidance. Malathion, chlorpyrifos-methyl, diazinon, chlorpyrifos, and pirimiphos-methyl were the most commonly detected pesticides. These 5 organophosphorus pesticides accounted for 93.4% of all pesticide residues detected (malathion, 52.9%; chlorpyrifos-methyl, 25.2%; diazinon, 7.7%; chlorpyrifos, 4.9%; and pirimiphos-methyl, 2.7%). Their median values in samples containing quantitable levels ranged from 0.014 to 0.098 ppm. The most commonly detected organohalogen compounds were methoxychlor, DDE, PCB, dieldrin, pentachloronitrobenzene, and lindane. These 6 compounds combined accounted for only 4.1% of all residues detected. FDA is continuing its pesticide surveillance of feeds to help ensure animal safety and prevent violative residues in food derived from animals.

The fumonisins are a recently discovered class of mycotoxins produced primarily by Fusarium (F.) moniliforme and F. proliferatum. Fumonisins present in mycotoxin-contaminated feed have been identified as the causative agent of equine leukoencephalomalacia and porcine pulmonary edema. To prevent these diseases, FDA has utilized informal guidance levels for fumonisins in feed and initiated a surveillance program for fumonisins in feed corn and corn by-products during FY 93 and 94. Natural contaminants present in animal feed can enter the human food supply as residues present in animal tissues and other animal derived products. Although fumonisin guidance levels were originally set based on animal safety, FDA also ensures the human food safety of animal products from animals fed mycotoxin-contaminated feed. Recent pharmacokinetic studies in food-producing animals as well as statutory requirements for regulating natural toxins will be discussed in light of FDA's human food safety mandate.

The objectives of this review are to provide 1) information on the FDA Feed Contaminants Program, 2) the legal history of aflatoxins and their current action levels, 3) a report on the levels of aflatoxins, fumonisins, vomitoxin, ochratoxin A, and zearalenone in domestic and import surveillance samples of feed during fiscal years 1989 through 1992, and 4) information on naturally occurring toxins encountered recently by the Center for Veterinary Medicine. Ten of 644 (1.6%) domestic corn samples and 7 of 106 (6.6%) domestic cottonseed samples contained aflatoxins at levels > 300 ppb. The mean fumonisin level in the 1990 survey of 85 corn screening samples was 12.1 ppm, and the values ranged from 2.6 to 32 ppm. The mean vomitoxin levels in the 1991 survey of 207 winter wheat samples and 206 spring wheat samples was 2.4 and .9 ppm, respectively. Ochratoxin A was not detected in 168 samples. Zearalenone was detected at levels > .15 ppm in only 1 of 161 samples. Cottonseed containing 13,000 ppm gossypol was recently implicated in the deaths of dairy cows. Crambe meal and canola meal are sanctioned for use in feed with certain restrictions, including the levels of glucosinolates. The FDA is continuing its surveillance and will strive to provide guidance on the increasing number of naturally occurring toxins.

English Pointer dogs dosed po with encapsulated 2,4-dichlorophenoxyacetic acid (2,4-D) or 2-methoxy-3,6-dichlorobenzoic acid (dicamba) developed varying degrees of myotonia. Dogs given 175 or 220 mg of 2,4-D/kg body weight rapidly developed clinical and electromyographic (EMG) manifestations consistent with a diagnosis of myotonia or pseudomyotonia. Dogs given 2,4-D at 86.7, 43.7 or 8.8 mg/kg body weight developed subclinical manifestations of myotonia detectable only with an electromyograph. The administration of 2,4-D at 1.3 or 1.0 mg/kg body weight failed to produce detectable EMG changes. One dog given dicamba at 86.7 mg/kg body weight developed clinical and EMG manifestations of myotonia similar to those induced by the highest doses of 2,4-D.

Eighteen English pointer dogs were randomly assigned to 3 outdoor grass-plot enclosures (6/enclosure) uniformly sprayed once with either the 2,4-dichlorophenoxyacetic acid (2,4-D) dimethylamine formulation (DMA-4) at the maximum recommended application rate, DMA-4 at 4 times the maximum recommended application rate, or the DMA-4 vehicle alone at 4 times the maximum recommended application rate. A heavy rain shower occurred 24 h after application. The dogs were observed for clinical signs and evaluated using an electroencephalograph, electrocardiograph (lead I), and electromyograph prior to exposure, and either 1 or 7 d after continuous exposure. Clinical examination, hematologic and serum biochemical data were obtained, and serum, urine and kidney 2,4-D were quantified. Half of the dogs from each group were killed after 1 d of continuous exposure, while the other half were killed after 7 d. Gross postmortem and histologic examinations were conducted on each dog. No obvious 2,4-D effects were detected in any of the dogs.

Investigation of tricyclic heterocycles related to the 2-arylpyrazolo[4,3-c]quinolin-3(5H)-ones, structures with high affinity for the benzodiazepine (BZ) receptor, led to the synthesis of 2-phenyl-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)-one, a compound with 4 nM binding affinity to the BZ receptor. Analogues were prepared to assess the importance of the 2-substituent and ring substitution in modifying activity. Several novel synthetic routes were designed to prepare the target compounds, including a two-step synthesis beginning with an anthranilonitrile and a hydrazide. Of the 34 compounds screened in this series, three compounds were found to be potent BZ antagonists in rat models. The leading compound, 9-chloro-2-(2-fluorophenyl) [1,2,4]triazolo[1,5- c]quinazolin-5(6H)-one (CGS 16228), showed activity comparable to that of CGS 8216 from the pyrazolo[4,3-c]quinoline series.

Review of all reports involving anthelmintics in dogs and cats to the IAPIC between January 1, 1986 and August 10, 1988, revealed that ivermectin (extra-label use) and piperazine accounted for over 50% of the calls assessed as toxicoses and suspected toxicoses. Both ivermectin and piperazine are gamma-aminobutyric acid (GABA) agonists and their major effects appear to be on the central nervous system. Ivermectin toxicoses at estimated doses of greater than or equal to 100-less than 500 micrograms/kg were reported more than once only in the collies (n = 25) and Australian shepherds (n = 10); these two breeds accounted for 46% (69 of 150) of the toxicoses and suspected toxicoses calls in dogs. Ataxia, behavioral disturbances, tremors, mydriasis, weakness/recumbency, apparent blindness, hypersalivation/drooling (dogs only), and coma were the most commonly reported clinical signs in dogs and cats with suspected ivermectin toxicoses. Shock, dyspnea, vomiting, and ataxia were the most common clinical signs attributed to the microfilaricidal activity of ivermectin. Piperazine was the anthelmintic with the greatest number of reports of toxicoses and suspected toxicoses in cats. Piperazine neurotoxicity in cats and dogs usually was manifested by muscle tremors, ataxia, and/or behavioral disturbances within 24 hours after estimated daily dose(s) between 20 and 110 mg/kg.

CGS 8216 is a novel nonbenzodiazepine that inhibited 3H-flunitrazepam (3H-FLU) binding to rat synaptosomal membranes in vitro at subnanomolar concentrations. It prevented the in vivo labeling of brain benzodiazepine receptors by 3H-FLU with the same potency as diazepam when given orally to mice. Pharmacologic tests showed that it was devoid of benzodiazepine-like activity but it antagonized the actions of diazepam in these tests. It did not interact with alpha- or beta- adrenergic, H1-histaminergic or GABA receptors but it inhibited adenosine-activation of cyclic AMP formation. Studies with 3H-CGS 8216 demonstrated that it bound specifically and with high affinity to rat forebrain membranes and was displaced by drugs with an order of potencies similar to that observed when 3H-diazepam and 3H-FLU were used as radioligands. The regional distribution of 3H-CGS 8216 binding sites in the brain was also similar to that of 3H-FLU. Dissociation of 3H-CGS 8216 binding was slow at 0 degrees C but increased with temperature and was almost complete within 1 min at 37 degrees C. Scatchard analyses were linear, yielding KD values of 0.044, 0.11 and 0.18 nM at 0, 25 and 37 degrees C, respectively; the Bmax value did not change appreciably with temperature and was approximately 1000 fmoles/mg protein. Using 3H-FLU, the value for Bmax as well as for the KD increased with temperature. The total number of binding sites determined for 3H-FLU was greater than that for 3H-CGS 8216 at each temperature. CGS 8216 exhibited mixed-type inhibition of 3H-FLU binding. GABA did not stimulate 3H-CGS 8216 binding whereas it enhanced 3H-FLU binding. CGS 8216 may be a useful ligand for probing the antagonist properties of the benzodiazepine receptor and is likely to exhibit interesting therapeutic effects.

Blue-green algae toxins include (1) hepatotoxic peptides that are known to be toxic to cattle, dogs, swine, waterfowl, and sometimes other species; (2) a nicotinic agonist neurotoxin that appears to be toxic to a wide range of animal species; (3) a peripheral-acting cholinesterase inhibitor that is very toxic to swine, birds, and dogs; (4) toxins that impair nervous transmission by blocking sodium channels in nerve cells; and (5) lipopolysaccharide endotoxins. This article provides current information on the mechanisms of action of the primary toxins recognized to date as well as on procedures important in the diagnosis and management of some of the more common cyanobacterial toxicoses in livestock and waterfowl.

CGS 7525A, a new tetracyclic compound, was evaluated for alpha 2 adrenoceptor antagonism in receptor binding assays and in behavioral and electrophysiological tests. 3H-Clonidine, but not 3H-prazosin, binding was potently inhibited in vitro by CGS 7525A. In vivo, CGS 7525A attenuated the suppressant action of clonidine on phenylquinone-induced writhing and on locus coeruleus neuronal firing rate. Mianserin was nearly equipotent with CGS 7525A in the 3H-clonidine binding assay, but considerably less potent in the measures of alpha 2 adrenoceptor antagonism in vivo. Both CGS 7525A and mianserin displaced 3H-spiroperidol binding from frontal cortex 5-HT2 binding sites. Although yohimbine resembled CGS 7525A in most respects, its activity at 5-HT2 binding sites was relatively low, CGS 7525A was not associated with any appreciable blockade of norepinephrine or serotonin uptake in vitro. Thus, CGS 7525A appears to be a promising new pharmacological tool for investigating the behavioral function of brain alpha 2 adrenoceptors.

Male Balb/C and Swiss Webster (SW) mice were administered various i.p. doses of microcystin-LR (MCLR) to establish dose-response curves and to determine if a sublethal dose of MCLR would protect against an approximate LD100 min given 2 or 3 days later. Micocystin-LR has an extremely steep dose-lethal response curve in BC mice--LD50 = 32.5 micrograms (micrograms)/kg, approximate LD0 max = 25 micrograms/kg and approximate LD100 min = 40 micrograms/kg. Liver weights increased 64% (BC) and 51% (SW) and kidney weights increased 32% (BC) and 20% (SW) within 200 minutes following administration of an approximate LD100 min of MCLR in naive mice. Grossly and histologically the marked increase in liver weight appeared to be caused primarily from intrahepatic hemorrhage and death is probably a result of hemorrhagic shock. Twenty-four hours following administration of a sublethal dose of MCLR to naive BC mice, liver weights were increased significantly (8.7%), but no clinical signs or histologic lesions were observed. In SW mice, administration of a LD23 of MCLR resulted in significantly increased survivability and survival times when an approximate LD100 min of MCLR was given 3 days later. Survivors of the LD23/LD100 min regimen had 96 hour postdosing liver weights not significantly different from those of mice which died acutely after the same hepatotoxin treatments. These survivors showed weakness, recumbency, anorexia, and icterus, and had marked gross liver lesions. Histologically these lesions were undergoing rapid reparative processes.

The effects of the tetracyclic antidepressant oxaprotiline and its two optically active enantiomers on the norepinephrine (NE) receptor coupled adenylate cyclase system were determined in slices of the rat cerebral cortex. While oxaprotiline does not change the response of the cyclic AMP generating system to NE after a single dose, chronic administration of the drug for 3 to 14 days down-regulates the receptor system. The noradrenergic subsensitivity is linked to a reduction in the Bmax value of beta-adrenergic receptors as assessed by (3H)-dihydroalprenolol binding without changes in the Kd value. The action of oxaprotiline on the NE receptor coupled adenylate cyclase system resides entirely in the (+)-enantiomer which is a potent inhibitor of the neuronal uptake of NE. The (-)-enantiomer of oxaprotiline which is a weak inhibitor of NE reuptake, failed, even in high doses, to modify the noradrenergic receptor system. Though not excluding co-regulatory factors in addition to NE, the studies support the view that an enhanced and persistent NE receptor interaction is one of the prerequisites for the in vivo down-regulation of central noradrenergic receptor function. The results also suggest that the therapeutic activity of oxaprotiline may reside in its (+)-enantiomer.

X-ray crystallographic data for 2,9-dimethyl-3'-hydroxy-5-phenyl-6,7-benzomorphan (I) as its p-bromobenzoyl ester are presented. The structure of I is compared with that of morphine, meperidine, alpha-allylprodine, methadone, and moramide as well as with a proposed structure of the enkephalins. A quantitative relationship is found between in vitro opiate receptor binding potency and in vivo analgesia for analgesics of diverse structure, including I. A new view of the analgetic pharmacophore is presented. Programs for the TI Programmable 59 calculator are described for conversion of X-ray crystallographic data to rectangular coordinates with reorientation of the molecule and for the calculation of torsion angles.

Rats (Sprague-Dawley) and mice (Balb/c) were given microcystin LR intraperitoneally and were killed at intervals up to 24 hr (rats) or 90 min (mice) and necropsied. The lowest consistently lethal dose was 160 micrograms/kg in rats and 100 micrograms/kg in mice. Rats that were clinically unaffected had no lesion. All clinically affected rats in all dose groups died (from 20 to 32 hr after toxin) and had similar hepatic lesions. Livers were enlarged and dark red beginning 40 to 60 min after toxin. Mild disassociation and rounding of centrilobular hepatocytes developed within 20 min. By 60 min after toxin, degeneration and necrosis of hepatocytes involved most of the lobules except for small periportal zones. Weights of livers and kidneys were significantly increased. Eosinophilic fibrillar material filled renal glomerular capillaries as early as 9 hr after toxin. At 18 to 24 hr there was moderate vacuolation of proximal tubular epithelium with mild tubular dilatation. Beginning at 1 hr, intact hepatocytes and hepatic debris were present in pulmonary vessels. Analysis of serum revealed an increase in alanine aminotransferase 40 min after toxin; at 6 to 12 hr there were significant increases in alkaline phosphatase, total bilirubin, blood urea nitrogen, and creatinine. Mice survived only 60 to 90 min after toxin. Hepatic lesions were similar to those in rats, but renal and pulmonary lesions were not seen.

Two male English Setters were noticed to be breathing rapidly, hyperexcitable, and atactic after roaming a rural area for 2 hours. Both dogs' cost were stained with yellow liquid. One dog died while en route to the veterinarian. Treatment was begun for the surviving dog for what was initially diagnosed to be organophosphorus or carbamate insecticide toxicosis. Before the diagnosis could be confirmed, the second dog died. The yellow liquid on the dogs' skin was identified as dinoseb in high concentrations. Dinoseb is an acutely toxic, substituted dinitrophenolic herbicide believed to act as an uncoupler of electron transport from oxidative phosphorylation.

Kinetic studies showed that under appropriate conditions, [3H]clonidine binds to two distinct receptor sites in calf cortex membranes. At 23 degrees C, binding was obtained at a low-affinity site (dissociation constant, KD = 5.4 nM) and a high-affinity site (KD = 1.1 nM). In contrast, at 0 degree C, selective binding occurred to the low-affinity site only. Consequently, at 0 degree C, it was possible to evaluate the interaction of drugs with the low-affinity receptor directly. On the other hand, competition with the high-affinity receptor could be ascertained by generating displacement curves representing the differential between specific binding values obtained at 23 and 0 degree C. Guanine nucleotides selectively decreased binding to the high-affinity site without apparent influence on the low-affinity [3H]clonidine binding. The activities of various pharmacological agents at the low- and high-affinity clonidine receptors are discussed and compared with WB-4101 binding data.

Administration of pure 1-delta(9)-tetrahydrocannabinol to mice had the following dose-dependent nzeurochemical and behavioral effects: a slight but significant increase in concentrations of 5-hydroxytryptamine in whole brain; a decrease in concentration of norepinephrine in brain after administration of low doses and an increase after high doses; diminished spontaneous activity, mloderate hypothermnia, hypersetisitivity to tactile and auditory stimiuli, and ataxia after low doses; and sedation, pronounced hypothermia, and markedly diminished spon taneous activity and reactivity after high doses. The duration of the effects on body temperature and spontaneous activity correlated generally with the changes in brain amines. The characteristic changes in brain amines do not correspond exactly to those observed with other psychotropic drugs.