Palmar digital arterial blood flow was measured in 6 conscious, standing horses, using surgically placed perivascular ultrasonic flow probes. The effects of 2 dosages of xylazine (0.55 and 1.1 mg/kg of body weight) and of 3 dosages of acetylpromazine (0.01, 0.02, and 0.04 mg/kg), as well as the effect of vertical load, on digital blood flow were evaluated. Intravenous administration of xylazine induced a significant (P < 0.05), transient decrease in digital blood flow. Intravenous administration of acetylpromazine induced a significant (P < 0.05), prolonged increase in digital blood flow. Correlation between vertical load and digital blood flow was found. The results of this study indicate that use of acetylpromazine may be beneficial in clinical treatment of horses with reduced digital blood flow. Xylazine, on the other hand, may exacerbate ischemic conditions of the digit and should be used with caution.

A bolus dose of methimazole (MMI) was administered IV over 1 minute to 5 healthy adult dogs at a dosage (40 mg/kg of body weight) known to impart protection against cisplatin-induced renal disease. Blood and urine samples for pharmacokinetic analysis were collected over a 24-hour period. Physical examination, CBC, determination of serum thyroid hormone concentrations, and serum biochemistry analysis were performed over a 10-day period to evaluate short-term toxicoses. At this dosage, MMI appears to be safe and well tolerated in dogs; only 1 of the 5 dogs had mild and transient increases in serum activity of hepatic enzymes. In addition, MMI did not alter serum thyroid hormone concentrations. Half-life of 8.82 hours and mean residence time of 12.18 hours were determined for MMI. Renal clearance of native MMI, along with sulfate and glucuronide conjugates, represented only 20% of total systemic clearance. Results of this study provide further information concerning clinical use of MMI in dogs and may contribute to better understanding of the mechanism of MMI protection against chemically induced nephrotoxicosis.

Persistence of the vaccine RH strain of Toxoplasma gondii was studied by bioassay and histologically in 14 pigs. Pigs were euthanatized 2, 4, 7, 8, 14, 15, 21, 29, 36, 42, 52, 57, and 76 days after IM inoculation with 100,000 T gondii tachyzoites. Viable T gondii tachyzoites derived from the RH strain were isolated by bioassay in mice inoculated with tissues of pigs euthanatized up to 14 days after vaccination. Except for fever, pigs vaccinated IM with the RH strain remained clinically normal. Two other pigs inoculated IV with 100,000 T gondii tachyzoites of the RH strain became ill, and 1 pig was comatose by 4 days after inoculation. These findings indicate that route of inoculation may influence the response of pigs to T gondii. To evaluate protective immunity in pigs vaccinated with the RH strain, 16 age-matched pigs were allotted to 4 groups (A-D) of 4 pigs each. Eight pigs (groups A and C) were vaccinated IM with 100,000 RH strain tachyzoites and 8 pigs (groups B and D) were nonvaccinated controls. Pigs of groups A and C were challenge-inoculated orally with a lethal dose of T gondii oocysts (100,000 oocysts) 81 days after vaccination, pigs of groups B and D were inoculated similarly 220 days after vaccination. The concentration of T gondii at 3 days after challenge inoculation of pigs vaccinated 81 days earlier was reduced 100,000-fold in mesenteric lymph nodes, compared with that in a nonvaccinated pig euthanatized at 3 days after challenge inoculation. Another nonvaccinated pig became comatose and had to be euthanatized at 7 days after challenge inoculation, numerous tachyzoites were in its mesenteric lymph nodes, intestines, and liver. The vaccinated pigs generally remained clinically after challenge inoculation with oocysts. Toxoplasma gondii was not isolated by bioassays from tissues of 5 of 8 vaccinated pigs, but was recovered from all nonvaccinated pigs. Results indicate that protective immunity persisted in pigs for at least 7 months after vaccination with the nonpersistent RH strain of T gondii.

A crude, whole-body extract of female heartworms was administered IV to 10 dogs with and 13 dogs without heartworm (HW) infection. Shock developed in 8 of 10 infected dogs and 11 of 13 non-infected dogs, and blood coagulopathy was observed in 12 of 19 dogs with shock. Prevalence and severity of blood coagulopathy were proportionate to prevalence and severity of shock. Platelet count decreased in all dogs with shock with or without blood coagulopathy; thus, the decrease in platelet count might be related to shock. In 4 dogs, activated partial thromboplastin time (APTT) was prolonged--192.0 seconds at 30 minutes after HW injection--and prothrombin time (PT) was increased--13.8 seconds at initial collapse. In 8 dogs, APTT was increased--200 seconds for 2 hours after HW injection--and PT was increased--200 seconds at 30 minutes after the injection. The APTT prolongation might have been caused mainly by decreases in activities of factors VIII, IX, XI, and XII of the intrinsic blood coagulation pathway. In dogs with severely prolonged PT, plasma fibrinogen concentration and factor II activity decreased slightly. Prolonged PT was corrected in vitro by addition of normal plasma at high concentration (> 80%), but prolonged APTT could not be corrected in vitro by addition of 80% normal plasma. Serum fibrin degradation products concentration was < 10 microgram/ml, and soluble fibrin monomer complex was negative in all dogs. Thrombi were not found in blood vessels of any organ at necropsy and after histologic study. Therefore, it was suggested that blood coagulopathy resulting from inhibition of coagulation factor activities might develop in shock induced by HW extract.

A crude, whole-body extract of female or male heartworms was injected IV into 28 dogs with and 22 dogs without heartworm (HW) infection. The female HW extract caused shock in 22 of 24 dogs with and 12 of 20 dogs without HW infection. The male HW extract induced shock in 4 of 4 dogs with and 1 of 2 dogs without HW infection. Prevalence of shock caused by female HW extract was significantly (P < 0.05) higher in dogs with than without HW infection; shock developed 5 to 30 minutes after HW injection. These signs were observed: marked decrease in blood pressure; collapse (initial collapse); paleness of mucous membranes; weak heart sounds; dyspnea; skin coldness; intestinal hyperperistalsis, and defecation; increases in RBC count, serum total protein concentration, serum osmolality, serum Na and blood glucose concentrations; and decreases in neutrophil, eosinophil, and platelet counts. Alanine transaminase, alkaline phosphatase, and lactate dehydrogenase activities increased substantially from the time of initial collapse to 24 hours after HW injection. Of 39 dogs with shock, 29 recovered from initial collapse, but 5 of the 29 subsequently collapsed again (secondary collapse), with bloody diarrhea followed by death. Of these 39 dogs, 6 died during initial collapse without bloody diarrhea, and 4 were euthanatized during initial collapse. It was confirmed that HW extract had, in fact, induced shock. These clinical, hematologic, and biochemical findings were fundamentally similar to those associated with shock resulting from administration of drugs, such as diethylcarbamazine and milbemycin D, in microfilaremic dogs with HW infection.

The ability of IV administered hydroxyethyl-starch-deferoxamine to attenuate radical production in freshly procured cancellous bone specimens was investigated, using spin-trapping and electron spin resonance (ESR) techniques. A core cancellous bone specimen 10 mm long and 5.6 mm in diameter was obtained, using aseptic technique, from the proximal portion of the humerus of 30 adult mixed-breed dogs. After procurement of the initial bone specimen, 10 dogs received a 10% solution of hydroxyethyl-starch-deferoxamine in 0.9% NaCl (50 mg/kg of body weight, IV), 10 dogs received an equivalent volume (5 ml/kg, IV) of a 10% solution of hydroxyethyl-starch in 0.9% NaCl, and 10 dogs received 0.9% saline solution (5 ml/kg, IV). A second core cancellous bone specimen was obtained from the contralateral humerus of each dog 45 minutes after treatment. All specimens were individually incubated in the spin trap alpha-phenyl-N-tert-butylnitrone in Eagle's minimum essential medium, at 26 C for 45 minutes, then were frozen at -20 C until they were prepared for analysis by ESR spectroscopy. Each specimen was thawed, homogenized, and extracted in a low-dielectric organic solvent prior to obtaining an ESR spectrum, which was analyzed for hyperfine splitting constants for radical identification. Each first-derivative spectrum was digitally double-integrated to obtain an area; these areas were used to compare intensities of the spin adducts. Difference in the area obtained before and after treatment for each dog was expressed as a ratio of that dogs pretreatment area ([pretreatment - posttreatment]/pretreatment). The calculated ratios for saline-, hydroxyethyl-starch-, and hydroxyethyl-starch-deferoxamine-treated dogs were compared, using a Kruskal-Wallis (KW) nonparametric test for multiple comparisons of ranked data. Significance was determined at P less than or equal to 0.05. Ad hoc comparisons were performed, using the KW procedure for individual comparisons, with alpha set at 0.05. The mean +/- SD and median ratio for each of the treatment groups were: saline-treated dogs, 0.005 +/- 0.40 and 0.045; hydroxyethyl-starch-treated dogs, -0.063 +/- 0.27 and -0.025; hydroxyethyl-starch-deferoxamine-treated dogs, 0.261 +/- 0.278 and 0.335, respectively. There was a significant (P < 0.01, KW) difference in the ratios between treatment groups. Ratios for hydroxyethyl-starch-deferoxamine-treated dogs were significantly (P < 0.05, KW) higher than that for hydroxyethyl-starch-treated dogs but not for saline-treated dogs. The ratios for saline- and hydroxyethyl-starch-treated dogs were not significantly different. We could not associate significant attenuation of radical generation in freshly harvested core cancellous bone specimens with IV administration of hydroxyethyl-starch-deferoxamine. The potential for unconjugated hydroxyethyl-starch to function as an oxidant must considered.

Diamine oxidase (DAO), an enzyme of small intestinal origin, is released from mucosal storage sites by IV administration of heparin, to yield the plasma postheparin DAO (PHD) curve. The PHD curve is diminished when mucosal surface area is lost, and baseline (without heparin) plasma DAO activity increases when mucosal storage sites are damaged. Plasma DAO activity was measured after 2 doses of heparin were administered Iv in healthy, conscious horses. In anesthetized horses, the PHD curve was studied: during sham small intestinal surgery, and during venous strangulation obstruction (VSO) of the distal 50% of the small intestine. In a third group of anesthetized horses, baseline plasma DAO activity (without heparin) was measured during vso of the distal 50% of the small intestine for 90 minutes, followed by reperfusion for 90 minutes. Postheparin plasma DAO curves in conscious horses were similar to those reported in other species Horses with VSO had a similar PHD curve as did sham-operated controls at all times, except at 15 minutes, when plasma DAO activity was significantly (P < 0.05) greater in the vso group. Horses with VSO and reperfusion had no change in baseline plasma DAO activity throughout the study. Peritoneal fluid DAO activity remained low throughout the study, but increased slightly in horses with VSO that received heparin, possibly because of DAO from extravasated blood in the peritoneal fluid. Results indicated that the plasma DAO response to IV administered heparin in horses is similar to that in other mammals, but, unlike other species, baseline and postheparin DAO activities did not change as expected after small intestinal vascular obstruction and mucosal injury. There may be additional sources of DAO in horses, the type of injury induced was not of sufficient magnitude to affect storage sites of DAO, or the circulatory changes induced by vso might have altered tissue delivery of heparin.

Polymyxin B and an antiserum against an Re mutant Salmonella typhimurium were evaluated for protective effect in an equine model of endotoxemia. Six 3- to 5-month-old foals were given endotoxin (0.25 micrograms/kg of body weight) IV after no pretreatment, or pretreatment with polymyxin B (6,000 U/kg, IV) or S typhimurium antiserum (1.5 ml/kg, IV). When given without pretreatment, endotoxin caused transient recumbency and increases in rectal temperature, and heart and respiratory rates. In addition, leukopenia and increases in circulating tumor necrosis factor (TNF) and interleukin 6 (IL-6) activities were detected. Compared with results obtained when endotoxin was given alone, pretreatment with polymyxin B resulted in significantly (P < 0.05) lower maximal plasma TNF and IL-6 activities, and significantly lower rectal temperature and respiratory rate. In contrast, compared with effects of endotoxin given without pretreatment, use of antiserum was associated with significantly (P < 0.05) higher respiratory rate, maximal plasma IL-6 activity, and total TNF response (as determined by areas under curves of plasma TNF vs time). These results indicate that polymyxin B may have potential as a treatment for equine endotoxemia. Salmonella typhimurium antiserum had no positive effect in this model, and, under certain conditions, may exacerbate the actions of endotoxin.

In a crossover trial, 7 healthy, 7- to 29-day-old, unweaned Finnish Ayrshire calves were given a single dose of 20 mg of tinidazole/kg of body weight, IV, and a single dose of 25 mg of tinidazole/kg orally. Blood samples were collected serially, and serum concentration of tinidazole was measured by use of high-performance liquid chromatography. Serum concentration vs time data were analyzed by use of the statistical moment theory. Terminal half-life was 394 minutes after IV administration and 524 minutes (harmonic mean) after oral administration. The corresponding system moment mean residence times were 542 +/- 61.8 minutes and 812 +/- 117 minutes (arithmetic mean +/- SD), respectively. Estimated volume of distribution at steady state and total body clearance were 0.74 +/- 0.05 L/kg and 1.37 +/- 0.13 ml/min/kg, respectively. Tinidazole was rapidly and totally absorbed from the gastrointestinal tract. Mean absorption time was 270 +/- 160 minutes, and the observed peak serum concentration was detected at 240 minutes. Bioavailability was 99.5 +/- 3.9%.

A commercially available automated enzyme-multiplied immunoassay technique (EMIT) was used to determine serum caffeine concentration after oral and IV administrations of caffeine at dosage of 5 mg/ kg of body weight to 12 clinically normal dogs. Dogs were allotted to 2 groups of 6 dogs each; 1 group initially received caffeine orally and the other received caffeine IV. After 72 hours, caffeine administration was repeated in all dogs in the alternate manner. Serum samples were obtained at multiple intervals over 24 hours to determine distribution and elimination kinetics. Analysis of the drug concentration-time data indicated IV elimination half-life (t1/2) of 6.39 +/- 1.87 hours, volume of distribution at steady state of 685.3 +/- 132.2 ml/kg, total body clearance of 1.31 +/- 0.38 ml/min/kg, absorption t1/2 of 1.02 +/- 0.68 hour, oral elimination t1/2 of 6.53 +/ - 2.72 hours, lag time after oral administration of 0.0614 +/- 0.0661 hour, highest measured concentration of 5.29 +/- 1.17 micrograms/ml, time to peak concentration of 2.74 +/- 1.30 hours, and bioavailability of 99.4 +/- 19.4%. Data from 6 dogs best fit a 1-compartment open model and those from 6 other dogs best fit a 2-compartment open model. On the basis of data from the 6 dogs that best fit a 2-compartment model, t1/2 of distribution was 0.58 +/- 0.72 hour. Data for oral administration best fit a single absorption phase and a single elimination phase. The increased availability and simplicity of the EMIT offers an opportunity to study the application of caffeine elimination for clinical evaluation of dogs with liver disease. Data obtained from this study allow determination of t1/2 and clearance to be simplified by obtaining samples 4 and 8 hours after oral or IV administrations and establishes canine reference values for elimination kinetics of caffeine administered at dosage of 5 mg/kg and assayed by use of the EMIT.