Effects of a novel dual lipid synthesis inhibitor and its potential utility in treating dyslipidemia and metabolic syndrome.

We have identified a novel omega-hydroxy-alkanedicarboxylic acid, ESP 55016, that favorably alters serum lipid variables in obese female Zucker (fa/fa) rats. ESP 55016 reduced serum non-HDL-cholesterol (non-HDL-C), triglyceride, and nonesterified fatty acid levels while increasing serum HDL-C and beta-hydroxybutyrate levels in a dose-dependent manner. ESP 55016 reduced fasting serum insulin and glucose levels while also suppressing weight gain. In primary rat hepatocytes, ESP 55016 increased the oxidation of [(14)C]palmitate in a dose- and carnitine palmitoyl transferase-I (CPT-I)-dependent manner. Furthermore, in primary rat hepatocytes and in vivo, ESP 55016 inhibited fatty acid and sterol synthesis. The "dual inhibitor" activity of ESP 55016 was unlikely attributable to the activation of the AMP-activated protein kinase (AMPK) pathway because AMPK and acetyl-CoA carboxylase (ACC) phosphorylation states as well as ACC activity were not altered by ESP 55016. Further studies indicated the conversion of ESP 55016 to a CoA derivative in vivo. ESP 55016-CoA markedly inhibited the activity of partially purified ACC. The activity of partially purified HMG-CoA reductase was not altered by the xenobiotic-CoA. These data suggest that ESP 55016-CoA favorably alters lipid metabolism in a model of diabetic dyslipidemia in part by initially inhibiting fatty acid and sterol synthesis plus enhancing the oxidation of fatty acids through the ACC/malonyl-CoA/CPT-I regulatory axis.

Pharmacokinetics and intramuscular bioavailability of amikacin in chickens following single and multiple dosing.

The pharmacokinetics of amikacin were studied in healthy mature female chickens (n = 6). Single doses of amikacin were injected as an i.v. bolus (10 mg/kg) and i.m. (20 mg/kg) into the same birds with a 30-day rest period between treatments. Amikacin was determined by the fluorescence polarization immunoassay method. The i.v. pharmacokinetics could be described by a two-compartment model with a t1/2 alpha of 0.150 +/- 0.064 h and a t1/2 beta of 1.44 +/- 0.34 h. The total body clearance was 0.109 +/- 0.017 1/h/kg and the volume of distribution at steady-state was 0.193 +/- 0.060 l/kg. Following a single i.m. injection, the peak plasma concentration (Cmax) was 50.79 +/- 4.05 micrograms/ml and occurred at 0.50 +/- 0.26 h. The i.m. extent of absorption was 91.2 +/- 17.6%. Simultaneous modeling of i.v. and i.m. results provided estimates of an absorption half-life of 0.480 +/- 0.158 h. The i.m. pharmacokinetics after repeated administration were studied following the tenth dose (20 mg/kg, every 8 h). The Cssmax was 38.58 +/- 6.96 micrograms/ml and occurred at 0.79 +/- 0.37 h, and the biological half-life of amikacin was 1.86 +/- 0.47 h. The multiple dosing yielded peak concentrations of 39 micrograms/ml and trough concentrations of 3.26 micrograms/ml. Based on these data, the recommended amikacin dosage in chickens is 20 mg/kg body weight every 8 h.

Pharmacokinetics of phenobarbital in horses after single and repeated oral administration of the drug.

Six healthy mature horses were orally administered a single dose of phenobarbital (26 mg/kg of body weight), then multiple doses (13 mg/kg) orally for 42 consecutive days. Seventeen venous blood samples were collected from each horse after the single dose study and again after the last dose on day 42. Plasma phenobarbital concentration was determined by use of a fluorescence assay validated for horses. Additional blood samples (n = 11) were collected on days 8 and 25 to determine peak and trough concentrations, as well as total body clearance. Phenobarbital disposition followed a one-compartment model. Mean kinetic variables after single and repeated orally administered doses (42 days) were: elimination half-life = 24.2 +/- 4.7 and 11.2 +/- 2.3 hours, volume of distribution = 0.960 +/- 0.060 and 0.914 +/- 0.119 L/kg, and clearance = 28.2 +/- 5.1 and 57.3 +/- 9.6 ml/h/kg, respectively. Results indicated that significant (P less than 0.05) difference in half-life and oral clearance existed between single and repeated dosing. The significant decrease in half-life after repeated dosing with phenobarbital may be indicative of enzyme induction. Significant difference was not observed between baseline serum enzyme concentration and concentration measured on day 42, except for gamma-glutamyltransferase activity, which was significantly increased on day 42 in 3 of the 6 horses. On the basis of increases in oral clearance observed over 42 days, dose adjustments may be required.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of surgical and chemical in ovo bursectomy on lymphocyte density scores and histological evaluations of primary and secondary lymphoid organs in hypertensive and hypotensive turkeys.

The effects of surgical and chemical in ovo bursectomy on the histology of primary and secondary lymphoid organs were studied in hypertensive and hypotensive lines of turkeys. The effects of bursectomy were measured by determining the presence of lymphatic nodules and the presence of lymphocytes in secondary lymphoid organs: spleen, cecal tonsil, Meckel's diverticulum, and Peyer's patches; as well as in the thymus and bursa of Fabricius. No treatment effect on splenic nodule formation occurred, but a significantly lower lymphocyte density score was present in the surgically bursectomized group. Both nodule formation and lymphocyte density scores for the cecal tonsil and Peyer's patches were significantly reduced in the surgically bursectomized and testosterone-treated groups as compared with the control and sham groups. The most consistent depression in lymphatic scores in both the surgically and chemically bursectomized groups occurred in the Peyer's patches followed by cecal tonsils and Meckel's diverticulum. As expected, there were no differences in thymocyte density scores. There was no consistent effect on lymphatic scores due to blood pressure selection; however, the hypertensive line showed significantly lower scores than the hypotensive line in the bursa, cecal tonsils, and Peyer's patches. No differences between the sexes were noted in any organ.

Effect of surgical and chemical in ovo bursectomy on hatchability, mortality rate, and antibody response in hypertensive and hypotensive lines of turkeys.

The effect of in ovo bursectomy on hatchability, mortality rate, and antibody response to keyhole limpet hemocyanin (KLH) was studied in hypertensive and hypotensive lines of turkeys. Experiments were conducted to assess the optimal time to perform surgical in ovo bursectomy in turkey embryos for the lowest mortality rate. Factors such as the ease of operation, hatchability, and least deaths were considered. Surgical bursectomies at 25, 24, 23, and 22 day embryonation resulted in 75, 20, 0, and 10% hatchability, respectively. The surgical procedure performed at 25-day embryonation resulted in superior hatchability and ease of operation, and it was less traumatic as evidenced by fewer deaths. The hatchability of embryos injected with testosterone (TE) at 15 days incubation was 55%. Birds subjected to surgery or chemical treatment had increased mortality rates. Cyclophosphamide (CY) treatment at 1 and 2 days posthatch caused a significant increase in deaths over groups not treated with CY. Both primary and secondary KLH responses were significantly lower in bursectomized and TE-injected groups, than in shamoperated or nonoperated control groups.

Pharmacokinetics of single doses of digoxin administered intravenously to ducks, roosters, and turkeys.

A single dose of digoxin was injected, IV, into 5 mature male turkeys (0.066 mg/kg of body weight), 8 male ducks (0.066 mg/kg), and 6 roosters (0.33 mg/kg). Twenty-three serial venous blood samples were collected before (baseline) and after the administration of digoxin to turkeys, ducks, and roosters. Plasma concentrations of digoxin were determined in duplicate by a radioimmunoassay that was validated for avian species. The plasma concentrations were best fitted by a 3 (turkeys, ducks)- and 2 (roosters)-compartment open model, with first-order elimination from the central compartment. Significant (P less than 0.05) kinetic differences were determined among species. Mean half-life (t1/2) for ducks, roosters, and turkeys were 8.30 +/- 2.70 (mean +/- SD), 6.67 +/- 3.50, and 23.7 +/- 4.8 hours, respectively. The volume of distribution at steady state (Vss) was 14.7 +/- 2.9, 3.13 +/- 0.49, and 2.27 +/- 0.36 L/kg, and total body clearance (CL) of drug was 1.54 +/- 0.43, 0.461 +/- 0.187, and 0.136 +/- 0.022 L/h/kg for ducks, roosters, and turkeys, respectively. The mean residence time was 10.3 +/- 3.9, 8.37 +/- 4.97, and 16.8 +/- 2.2 hours, respectively. Volume of distribution at steady state and CL in ducks were several fold higher than that in turkeys. The terminal half-life of digoxin determined for ducks and roosters in this study was considerably shorter than those previously reported for several mammalian species.

Determination of macrophage chemotaxis to atherosclerotic plaque extract in domestic turkeys with hypertension.

The chemotactic activity of turkey peritoneal macrophages in response to an atherosclerotic plaque extract from a hypertensive strain of turkeys was determined. Atherosclerotic plaque extract stimulated macrophage chemotaxis, whereas normal aortic extract did not stimulate macrophage chemotaxis. However, differences were not revealed by sodium dodecyl sulfate-polyacrylamide gel electrophoretic analysis of extracts of atherosclerotic plaque and normal aorta. Chemotactic activity was diminished with pronase treatment, suggesting the chemo-attractant is a protein. Seemingly, atherosclerotic plaque of turkeys contains a macrophage chemotaxin.

Pharmacokinetics of single-dose intravenous or intramuscular administration of gentamicin in roosters.

Healthy mature roosters (n = 10) were given gentamicin (5 mg/kg of body weight, IV) and, 30 days later, another dose IM. Serum concentrations of gentamicin were determined over 60 hours after each drug dosing, using a radioimmunoassay. Using nonlinear least-square regression methods, the combined data of IV and IM treatments were best fitted by a 2-compartment open model. The mean distribution phase half-life was 0.203 +/- 0.075 hours (mean +/- SD) and the terminal half-life was 3.38 +/- 0.62 hours. The volume of the central compartment was 0.0993 +/- 0.0097 L/kg, volume of distribution at steady state was 0.209 +/- 0.013 L/kg, and the total body clearance was 46.5 +/- 7.9 ml/h/kg. Intramuscular absorption was rapid, with a half-life for absorption of 0.281 +/- 0.081 hours. The extent of IM absorption was 95 +/- 18%. Maximal serum concentration of 20.68 +/- 2.10 micrograms/ml was detected at 0.62 +/- 0.18 hours after the dose. Kinetic calculations predicted that IM injection of gentamicin at a dosage of 4 mg/kg, q 12 h, and 1.5 mg/kg, q 8 h, would provide average steady-state serum concentrations of 6.82 and 3.83 micrograms/ml, with minimal steady-state serum concentrations of 1.54 and 1.50 micrograms/ml and maximal steady-state serum concentrations of 18.34 and 7.70 micrograms/ml, respectively.

Pharmacokinetics of single doses of gentamicin given intravenously and intramuscularly to turkeys.

The disposition and absorption kinetics of gentamicin were studied in healthy, mature male and female turkeys (n = 10). Single doses of gentamicin (5 mg/kg) were injected either i.v. or i.m. with a 30-day rest period between each treatment. Baseline and serial venous blood samples (n = 17) were collected from each turkey. Serum concentrations of gentamicin were determined in duplicate for 24 h after each treatment, using radio-immunoassay. Using nonlinear least-square regression methods, the combined data of the i.v. and i.m. treatments were best described by a two-compartment open model. Kinetic analysis of the data after a single i.v. dose provided the following mean values: t1/2 alpha = 0.170 +/- 0.093 h, t1/2 beta = 2.57 +/- 0.79 h, MRT = 3.62 +/- 0.96 h, Vc = 0.090 +/- 0.017 l/kg, Vd(ss) = 0.172 +/- 0.024 l/kg, Vd(area) = 0.190 +/- 0.030 l/kg, and Clt = 49.8 +/- 9.8 ml/h/kg. After a single i.m. dose, the following mean values were determined: MRT = 5.10 +/- 1.73 h, t1/2abs = 0.74 +/- 0.66 h, tlag = 0.07 +/- 0.19 h, Clt/F = 50.7 +/- 12.5 ml/h/kg, Vd(area)/F = 0.193 +/- 0.044 l/kg, and F = 102 +/- 21%. Kinetic calculations made with the single i.m. data predicted that an i.m. injection of gentamicin at the dosage rate of 3 mg/kg q. every 12 h would provide average steady state serum concentrations of 4.93 micrograms/ml.

Effects of fenbendazole administration on hematology, clinical chemistries and selected hormones in the white Pekin duck.

The effects of single i.v. and p.o. doses (5 mg/kg) of fenbendazole, were evaluated on thyroxine, tri-iodothyronine, corticosterone, hematology, clinical chemistries, and serum proteins in 10 white Pekin ducks. Fenbendazole was administered i.v. (n = 5) as a 3% dimethyl sulfoxide solution and p.o. (n = 5) as a 10% commercial suspension. Serum enzyme concentrations, total protein and protein fractions, glucose, cholesterol, uric acid, sodium, and potassium were unchanged from baseline values. Serum triglycerides decreased consistently in the i.v.-treated group but remained unchanged in the p.o.-treated group. Serum chloride was consistently elevated above baseline values for both i.v.- and p.o.-treated ducks, while inorganic phosphate was consistently decreased only in the i.v.-treated group. Hemoglobin and hematocrit values generally were below baseline values. Leukocyte values varied considerably and were not significantly different from baseline values. Serum thyroxine and tri-iodothyronine values in both the i.v.- and p.o.-treated groups were not changed significantly from baseline values. Serum corticosterone values were not changed in the i.v.-treated groups but they were decreased at various times in the p.o.-treated group. Although there were some sporadic significant changes in the parameters measured versus baseline values all values remained within the physiologic limits for ducks. The safety of fenbendazole has been previously demonstrated for several species.

Erythrocyte distribution in ducks.

A study on erythrocyte distribution was performed on 10 healthy, nonstressed adult white Pekin ducks. Results indicated 2 populations of erythrocytes, with average mean corpuscular volumes of 128.37 fl/cell and 308.50 fl/cell. Variations in erythrogram patterns were evident over time, when comparing specimens from different ducks or the same duck. There were 5 patterns of cell number/volume distribution observed between the 2 cell populations when all ducks were studied. Females had a greater change than did males when population density and volume percentage comparisons were made on erythrocyte compartments.

Atherosclerosis in coronary, aortic, and sciatic arteries from wild male turkeys (Meleagris gallopavo silvestris).

Heart, aorta, and sciatic arteries were collected from 157 wild male turkeys (Meleagris gallopavo silvestris) by hunters in 9 states during the spring 1983 and 1984 hunting seasons. In descending order of extent and severity, intimal vascular changes were observed in the left sciatic artery, aorta at the celiac region, cranial abdominal portion of the aorta, sciatic bifurcation, caudal abdominal portion of the aorta, coronary arteries, and thoracic portion of the aorta. Only the aorta from the celiac region and right sciatic artery had significant differences (P less than 0.05) among turkeys from various locations. Turkeys from Indiana had significantly (P less than 0.05) larger plaque scores in the celiac region than did those from Alabama, Missouri, and South Carolina. Turkeys from Indiana also had significantly (P less than 0.05) greater plaque scores in the right sciatic artery than did turkeys from Arkansas. When all tissues were considered, tissues from turkeys from Michigan had the highest plaque scores and those from Iowa had the lowest. Plaque scores for turkeys from Michigan were significantly (P less than 0.05) higher overall (including all blood vessels) than were plaque scores for turkeys from Alabama, Arkansas, Iowa, and South Carolina. Few significant (P less than 0.05) correlations were detected among plaque scores in turkeys from within states of origin (geographic location). Also, only a few significant (P less than 0.05) correlations were determined between age or body weight and atherosclerosis for blood vessels from turkeys within various states.

Effect of age and physiological status on sperm storage 24 hours after artificial insemination in broiler breeder hens.

1. Uterovaginal junction (UVJ) tissues were collected 24 h after artificial insemination (AI) from 85- and 125-week-old broiler breeder hens in three physiological states: laying hard shell eggs (HS), laying shell-less eggs (SL) and non-laying (NL). This was confirmed by egg production records and visual appraisal of the oviduct at the time of necropsy. 2. Three longitudinal sections of each UVJ were evaluated microscopically and sperm host glands (SHG) were scored in 5 categories: glandular morphology evident but not lumen present, basophilic stained epithelium and no spermatoza present, glands that contained one to five spermatozoa; glands that contained 6 to 20 spermatozoa and glands that contained more than 20 spermatozoa. 3. Laying hens (HS and SL) at 85 weeks of age had significantly more sperm host glands (SHG) containing spermatozoa than NL hens. At 125 weeks of age HS and SL hens had significantly more unscorable glands. 4. The only category that showed no difference between age and physiological status group was the empty category. No significant differences were observed for any gland category in 82- and 125-week-old NL hens. 5. A greater proportion of the 85-week-old group of HS and SL hens had more SHG containing spermatozoa and fewer unscorable glands that the 125-week-old birds. The only category that showed any difference within the SL group was the low category.

Relationship between fertility duration and in vivo sperm storage in broiler breeder hens.

1. Seventy Hubbard hens, 75 weeks of age, were divided into groups containing equal numbers of hens on the basis of duration of fertility. Average fertile periods were 14.5 d (long, L) and 6.9 d (short, S). Each hen was artificially inseminated (AI) on three consecutive days with an average of 1.61 X 10(9)/0.05 ml spermatozoa per insemination. Seven hens from each group were killed 1, 3, 6, 9, and 13 d after insemination. 2. Three longitudinal sections of uterovaginal junction were evaluated microscopically for spermatozoal storage capacity by assigning each sperm host gland (SHG) to one of 5 categories: unscorable, empty, one to 5 spermatozoa, 6 to 20 spermatozoa and greater than 20 spermatozoa. 3. The only significant difference in sperm storage at any time between the L and S duration groups occurred at day 1 after AI, when L duration hens possessed significantly more glands with more than 20 spermatozoa. 4. One day after AI the proportion of SHG containing sperm were 28.8% (L group) and 18.6% (S group). There was a significant decrease in the number of glands containing 1 to 5, 6 to 20 and greater than 20 spermatozoa between days 1 to 3 in both groups. 5. Numbers of glands in all categories containing sperm decreased throughout the 13-d period. The L duration group possessed 18.5% more glands with 1 to 5, 6 to 20 and greater than 20 spermatozoa than the S duration group. 6. There were no significant differences between groups in the proportion of unscorable or empty glands throughout, which ranged from 35.9 to 56.8% and 36.3 to 47.1%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Correlation of broiler breeder male semen production and testes morphology.

Broiler breeder males were fed either a 9, 12, or 15% protein diet (2,819 kcal/kg metabolizable energy) from 6 to 50 wk of age. From 48 through 49 wk of age semen volume (VOL) and concentration (CONC) and number of spermatozoa per ejaculate (NSE) were determined, and at 50 wk of age body weight (BWT) and testes weight (TWT) were measured. Spermatogenic activity was evaluated histologically by a) a computer-aided assessment of seminiferous epithelial area (SEA), tubular diameter (TD), and epithelial height (EH); and b) visual appraisal of seminiferous tubular size and maturity of cell types (testes score-TS). Relationships among NSE, TS, SEA, TD, EH, BWT, and TWT were determined. Dietary protein had no significant effect on VOL, CONC, NSE, BWT, TWT, TS, SEA, EH, or TD. Significant positive correlation coefficients were observed among NSE, TS, SEA, TD, and EH, indicating moderate effectiveness of these methods in evaluating reproductive state. Low correlations between NSE and other variables may have resulted from 25% of the males having high TS but failing to ejaculate semen. Body weight and TWT, as well as BWT and NSE, were positively correlated. The SEA and TD had higher correlations with TWT than with BWT.

Comparative albumin determinations in ducks, chickens, and turkeys by electrophoretic and dye-binding methods.

Serum total protein, albumin, and globulin concentrations in male ducks, turkeys, and chickens were compared, using electrophoretic and dye-binding methods, as well as using a bovine and chicken albumin standard. When a chicken standard was used for determination of albumin and globulin concentrations by automated methods, results were more comparable with results of electrophoresis than were those when a bovine standard was used.

Techniques for blood sampling in avian species.

In avian species' common sites for blood sampling include the basilic, jugular, and superficial plantar metatarsal veins, heart and occipital sinus. The lateral thoracic vein is also used in the turkey. The sites with the least trauma to the animal are the basilic, superficial plantar metatarsal, and lateral thoracic veins from which adequate volumes of blood can be obtained. Heart puncture and occipital sinus sampling procedures are expedient and large volumes of blood can be obtained however these sites are the most traumatic. The superficial plantar metatarsal vein was the site for best repeat sampling in the duck and the chicken and the basilic in the turkey.

Baseline hematologic, endocrine, and clinical chemistry values in ducks and roosters.

Venous blood samples were collected at 3-day intervals for a total of six samples from each of five adult male pekin ducks and five adult Ross roosters. Twenty biochemical, six hematologic, and three endocrine determinations were performed on each blood or serum sample collected. The data obtained provide reference values for future studies of avian species and illustrate the utility of an automated clinical chemistry analyzer in assessing multiple serum biochemistry values in small sample volumes obtained from birds.