Detection,quantifications, and pharmacokinetics of ponazuril in healthy swine

A study on pharmacokinetics of ponazuril in piglets was conducted after a single oral dose of 5.0 mg/kg b.w. Plasma concentrations were measured by high‐performance liquid chromatography assay with UV detector at 255‐nm wavelength. Pharmacokinetic parameters were derived by use of a standard noncompartmental pharmacokinetic analysis. Samples from six piglets showed good plasma concentrations of ponazuril, which peaked at 5.83 ± 0.94 μg/mL. Mean ± SD area under the plasma concentration–time curve was 1383.42 ± 363.26 h/μg/mL, and the elimination half‐life was 135.28 ± 19.03 h. Plasma concentration of ponazuril peaked at 42 h (range, 36–48 h) after administration and gradually decreased but remained detectable for up to 33 days. No adverse effects were observed during the study period. The results indicate that ponazuril was relatively well absorbed following a single dose, which makes ponazuril likely to be effective in swine.     

Synthesis and detection of toltrazuril sulfone and its pharmacokinetics in horses following administration in dimethylsulfoxide

Triazine-based antiprotozoal agents are known for their lipophylic characteristics and may therefore be expected to be well absorbed following oral administration. However, although an increase in lipid solubility generally increases the absorption of chemicals, extremely lipid-soluble chemicals may dissolve poorly in gastrointestinal (GI) fluids, and their corresponding absorption and bioavailability would be low. Also, if the compound is administered in solid form and is relatively insoluble in GI fluids, it is likely to have limited contact with the GI mucosa, and therefore, its rate of absorption will be low. Based on the above considerations, we sought a solvent with low or no toxicity that would maintain triazine agents in solution. As the oral route is most preferred for daily drug therapy, such a solvent would allow an increased rate of absorption following oral administration. In present study, it was demonstrated that dimethylsulfoxide (DMSO) increased the oral bioavailability of toltrazuril sulfone (Ponazuril) threefold, relative to oral administrations of toltrazuril sulfone suspended in water. The cross-over study of toltrazuril sulfone formulated in DMSO indicated that the absolute oral bioavailability of toltrazuril sulfone in DMSO is 71%. The high bioavailability of the DMSO-preparation suggests that its daily oral administration will routinely yield effective plasma and cerebral spinal fluid (CSF) concentrations in all horses treated. Also, this improved formulation would allow clinicians to administer loading doses of toltrazuril sulfone in acute cases of Equine Protozoal Myeloencephalitis. Another option would involve administration of toltrazuril sulfone in DMSO mixed with feed (1.23 kg daily dose) meeting the US Food and Drug Administration (FDA) recommendations for the levels of DMSO permissible in pharmaceutical preparations.     

Evaluation of a rebound tonometer (Tonovet®) in clinically normal cat eyes

Objective  To determine the accuracy of and to establish reference values for a rebound tonometer (Tonovet^®) in normal feline eyes, to compare it with an applanation tonometer (Tonopen Vet^®) and to evaluate the effect of topical anesthesia on rebound tonometry.
Procedures  Six enucleated eyes were used to compare both tonometers with direct manometry. Intraocular pressure (IOP) was measured in 100 cats to establish reference values for rebound tonometry. Of these, 22 cats were used to compare rebound tonometry with and without topical anesthesia and 33 cats to compare the rebound and applanation tonometers. All evaluated eyes were free of ocular disease.
Results  Both tonometers correlated well with direct manometry. The best agreement with the rebound tonometer was achieved between 25–50 mmHg. The applanation tonometer was accurate at pressures between 0 and 30 mmHg. The mean IOP in clinically normal cats was 20.74 mmHg with the rebound tonometer and 18.4 mmHg with the applanation tonometer. Topical anesthesia did not significantly affect rebound tonometry.
Conclusions  As the rebound tonometer correlated well with direct manometry in the clinically important pressure range and was well tolerated by cats, it appears suitable for glaucoma diagnosis. The mean IOP obtained with the rebound tonometer was 2–3 mmHg higher than that measured with the applanation tonometer. This difference is within clinically acceptable limits, but indicates that the same type of tonometer should be used in follow-up examinations in a given cat.     

Bioavailability, pharmacokinetics, and tissue distribution of 14C homidium after parenteral administration to Boran cattle

The absorption, distribution and elimination characteristics of ¹⁴C homidium have been described in non-infected and Trypanosoma congolense -infected cattle treated with ¹⁴C homidium chloride by either intramuscular (i.m.) or intravenous (i.v.) injection at a dose level of 1 mg/kg body weight. Results show that the mean (± SD) elimination of the drug from plasma followed a biexponential process, with half-lives of 0.084 ± 0.006 h and 97.66 ± 16.28 h for the distribution and elimination phases after intravenous injection, respectively. Bioavailability of the intramuscular dose was 62.5% and 57.8% in non-infected and trypanosome-infected cattle, respectively. Absorption was rapid, with a t _max of 15 min and a mean C _max (± SD) of 268.4 ± 4.09 ng/mL following the intramuscular dose in non-infected cattle. The major route of excretion was via faeces. Approximately 90% of the total dose given to non-infected i.m.-treated cattle was excreted within 14 days. Following intramuscular administration of the drug, residues remained high in the major excretory organs, with the liver having concentrations of 1411 and 1199 ng/g after 14 and 28 days, respectively. Over the same period, the values in the kidneys were 649 and 448 ng/g. Concentrations in the liver 14 and 21 days following i.v. treatment were 2195 and 2454 ng/g, respectively. These results show that there was no significant difference in liver drug residues between 14 and 21 days, or 28 days depending on the treatment given, suggesting that once the drug is in this organ, it is released back into the circulation at an extremely slow rate.     

Preservation of canine and feline corneoscleral tissue in Optisol® GS

Objective The objective of the research was to determine whether preservation of corneal tissue of dogs and cats in Optisol^® GS (OGS, Bausch & Lomb Surgical, Irvine, CA, USA) is feasible for subsequent use in penetrating keratoplasty. Animals The study subjects were 33 dogs and 31 cats with no gross corneal pathology, which had been euthanised by pentobarbital overdose for reasons unrelated to this project. Procedure One cornea of each pair was evaluated immediately and the other was evaluated after storage in Optisol^® GS for either 5, 10, 15 or 20 days. The most important criterion was the preservation of the endothelial cell layer. Results Corneoscleral tissue of cats survived longer, when preserved in Optisol^® GS at 4 °C, than that of dogs. Light and scanning electron microscopy revealed good preservation of the endothelial cell layer for up to 10 days in dogs and up to 15 days in cats.     

Immunohistochemical Colocalization of Serotonin, Substance P and Met-enkephalin-Arg6-Gly7-Leu8 in the Endocrine Cells of the Ruminant Duodenum

The duodenum of various ruminants was examined by immunohistochetnical staining for serotonin, substance P and Metenkephalin-Arg⁶-Gly⁷-Leu⁸ (MENK8). Serotonin- and substance P-immunoreactive endocrine cells were detected in samples from cow, calf, sheep, goat, and barbary sheep. MENK8-immunoreactive endocrine cells were detected exclusively in samples from cow and calf. Substance P and MENK8 immunoreactivity was found in serotonin-immunoreactive endocrine cells of cattle. Substance P- and MENK8-immunoreactive nervous elements were detected in all ruminants examined. The present results suggest that the expression and/or the mechanism that controls the expression of each peptide might differ between endocrine cells and nerve cells and might also depend on animal species.     

Comparison of the pharmacokinetics and thermal antinociceptive pharmacodynamics of 20 µg kg−1 buprenorphine administered sublingually or intravenously in cats

Little is known about the analgesic action of buprenorphine (BUP) in cats. Relative to man, the cat has a more alkaline oral pH, which may make this an effective route for administering BUP in this species. This study aimed to assess and compare the pharmacokinetics and pharmacodynamics of sublingual (S‐L) and IV administration of BUP. Thermal threshold (TT) was measured and blood samples were collected following IV or S‐L administration (20 µg kg^?1) of the injectable formulation. Six cats (five spayed females, one castrated male, 4.1–6.6 kg) were used. Each cat received both treatments in a randomized cross‐over study design with 1 month between experiments. Twenty‐four hours prior to each study, the lateral thorax of each of the cats was shaved, cephalic and jugular catheters placed, and oral pH measured. On the day of the study, TT was measured using a ‘thorax‐mounted’ thermal threshold‐testing device specifically developed for cats. The cats were free to move around. Skin temperature was recorded before each test, then the heater activated. When the cat responded by flinching, turning, or jumping, the stimulus was terminated and the threshold temperature was recorded. The thermal threshold cut‐off point was 55.5 °C. Three baseline thresholds were recorded before treatment with S‐L or IV (via cephalic catheter) BUP (20 µg kg^?1). Blood was withdrawn (jugular) at 1, 2, 4, 6, 10, 15, 30, 45, 60 minutes and at 2, 4, 6, 8, 12, and 24 hours post‐administration. TT was measured every 30 minutes?6 hours, 1–12 hours, and at 24 hours post‐administration. Plasma was immediately separated, stored at ?20.5 °C, and assayed within 4 months using a commercially available ¹²⁵I radioimmunoassay. Threshold data were analyzed using anova with a repeat factor of time. No adverse effects were noted. Pupils were dilated for up to 9 hours post‐BUP. Behavioral changes were calm euphoria. Measured oral pH was 9 in each cat. Pre‐treatment mean threshold (±SD) was 41.2 ± 0.9 °C in the S‐L group and 40.8 ± 0.85 °C in the IV group. There were no significant differences between the groups with respect to thresholds over time (p = 0.72). Thresholds were significantly increased from 30 to 360 minutes in both the groups (>44.615 °C). Peak plasma BUP (C_max) was lower (11 ± 6.7 ng mL^?1vs. 92.9 ± 107.9 ng mL^?1) and occurred later (T_max) (30 minutes vs. 1 minute) after S‐L compared to IV administration, respectively. BUP (20 µg kg^?1)‐administered S‐L or IV provided antinociception between 30 and 360 minutes after administration. Plasma levels did not correspond to TT.     

Safety and tolerability of 3-week and 6-month dosing of Deramaxx® (Deracoxib) chewable tablets in dogs

Although non-steroidal anti-inflammatory drugs (NSAIDs) are effective in reducing pain and inflammation, these agents have adverse effects. Selective inhibitors of COX-2 are an alternative to traditional NSAIDs. Deramaxx^® [Novartis Animal Health US, Inc. (NAH), Greensboro, NC, USA] contains the selective COX-2 inhibitor, deracoxib, and is approved for the relief of pain and inflammation associated with orthopedic surgery and osteoarthritis in dogs. The safety of Deramaxx was evaluated in two target animal safety studies: 40 dogs (four dogs/sex/group) received 0, 4, 6, 8, or 10 mg/kg/day deracoxib once daily for 21 days; and 60 dogs (five dogs/sex/group) received 0, 2, 4, 6, 8, or 10 mg/kg/day deracoxib once daily for 6 months. There was a dose-dependent trend towards increased blood urea nitrogen (BUN) in treated dogs, however mean BUN values remained within the reference range at the labeled doses. In both trials, histopathology revealed focal renal tubular degeneration/regeneration in some dogs receiving ≥6 mg/kg/day deracoxib. Focal renal papillary necrosis was seen in one dog treated with 8 mg/kg/day and in three dogs receiving 10 mg/kg/day deracoxib on the 6-month study. No other parameters of renal function were adversely affected for either study. Results show that Deramaxx is safe and well-tolerated in dogs when administered as directed.     

Abundance of intestinal Na+/glucose cotransporter (SGLT1) in roe deer (Capreolus capreolus)

Introduction Based on morphological and physiological differences in their digestive systems H ofmann and S tewart (1972) classified ruminants into three feeding types: concentrate selectors (CS), grass and roughage eaters (GR) and intermediate, opportunistic, mixed feeders (IM). In evolutionary terms CS most closely resemble the original ruminants (H ofmann 1989). They have a relatively small forestomach with large openings between the different parts of the stomach. The retention time of ingesta is short and therefore less suited to optimizing cellulose digestion. They have relatively large saliva glands, producing high volumes of saliva (F ickel et al. 1998), which may facilitate the passage of soluble nutrients down their highly developed ventricular groove. The CS ruminants choose easily digestible forage, especially dicotyledons, which are rich in soluble plant cell contents (PCC, T ixier et al. 1997; D uncan et al. 1998). With evolution, the forestomach of the ruminants became larger relative to body size, and also more subdivided. These evolutionary adaptations optimized the selective retention of feed particles and increased retention time, leading to improvement of cellulose digestion. Large GR are well adapted to digest plant cell walls (PCW), i.e. structural carbohydrates (cellulose); they consequently feed mainly on monocotyledons. Roe deer (Capreolus capreolus) are very small ruminants which select concentrated feed. As energy requirements increase proportional to metabolic body weight (K leiber 1961) roe deer require relatively more energy per unit body mass for maintenance compared to that required by large ruminants (V an S oest 1994; D uncan et al. 1998). Easily digestible forage is not sufficient to satisfy the energy requirements of roe deer. It is proposed therefore that these animals may have other methods of avoiding energy losses due to microbial fermentation, either bypassing nutrients down the ventricular groove (rumen bypass) or by ruminal escape of unfermented and/or partially fermented nutrients (H ofmann 1989). The relatively high content of polyunsaturated fatty acids present in the depot fat of roe deer due to only partial rumen biohydrogenation (M eyer et al. 1998) supports the alternative hypothesis of rumen bypass or ruminal escape. Once reaching the small intestine, partially fermented or bypassed soluble carbohydrates can be further hydrolysed by maltase and sucrase to monosaccharides. These monosaccharides are then available for absorption. The intestinal sodium-dependent glucose cotransporter (SGLT1) in the brush border membrane (BBM) of the enterocytes is a stable indicator for the presence of sugars in the small intestine. The expression and activity of SGLT1 protein are regulated by the level of sugars reaching the small intestine (F erraris and D iamond 1989). Infusion of d -glucose into the intestinal lumen of ruminant sheep for 2 h stimulates the expression of SGLT1 which can be detected 4 days later in the newly formed mature enterocytes (S hirazi -B eechey et al. 1995). When dietary carbohydrate is removed, it takes 3 days before the brush border glucose uptake capacity decreases significantly from control values (F erraris 1994). This reflects the time of physiological cell renewal. In GR, such as sheep, the capacity of the intestine to absorb sugars decreases up to 500-fold during development (S hirazi -B eechey et al. 1995). This decrease in the intestinal absorptive capacity is a reflection of the decline in SGLT1 transport activity and protein abundance. It is not due to modifications in the structure of the absorptive surface and cannot be explained in terms of an age-related process (S hirazi -B eechey et al. 1991). It has been shown that there is a direct correlation between the level of monosaccharides reaching the lumen of the small intestine and the expression of functional SGLT1 protein (D yer et al. 1997). Therefore in this study we aimed to investigate the presence of functional SGLT1 in the small intestine of roe deer as a stable indicator of the availability of glucose in the luminal content of the small intestine. The presence of SGLT1 protein in the small intestine will support the hypothesis of rumen bypass and/or ruminal escape of nutrients. Furthermore we measured the maltase activities in the BBM, as part of the carbohydrates reach the intestinal lumen as polysaccharides and have to be broken down to monosaccharides before absorption.     

Agreement of SpO2, SaO2 and ScO2 in anesthetized cynomolgus monkeys (Macaca fascicularis)

Objective To assess the agreement between three measurements of arterial oxygen saturation (SpO₂, SaO₂ and ScO₂) in anesthetized cynomolgus monkeys. Study Design Prospective study. Animals Eleven mature, male cynomolgus monkeys (Macaca fasicularis). Methods Monkeys were anesthetized with intramuscular ketamine followed by intravenous propofol. The trachea of each was intubated and the lungs ventilated. Arterial oxygen saturation was measured with a Nonin 8500 V pulse oximeter, using a lingual clip on the cheek. Arterial blood samples were taken from an indwelling catheter. Inspired oxygen concentration was varied from 12 to 20%, and 88 paired arterial blood samples and saturation measurements were taken. Arterial oxygen saturation in the blood samples was measured using a cooximeter. The saturation was also calculated from the arterial oxygen tension using the Adair equation. The results were compared using Bland and Altman's method. Results The pulse oximeter readings were 2.7% higher than that of the cooximeter, with a limit of agreement of ?3.9 to 9.3%. The pulse oximeter readings were 1.8% higher than the calculated saturation, with a limit of agreement of ?6.5% to 10.1%. The cooximeter readings were 0.9% lower than the calculated saturation, with a limit of agreement of ?5.6% to 3.8%. Conclusions The agreement between SpO₂ and other measurements of arterial oxygen saturation in this study is typical for this technique. The bias and limits of agreement are consistent with reports in other species. Clinical relevance The Nonin 8500 V is a useful pulse oximeter for clinical use in primates.     

Relaciones Moefofuncionales entre Islotes Pancreáticos Y Allocortex1

The high zinc content found in pancreatic islet cells and in the hippocampus suggestsa functional relationship. Two cross-over experiments using rats were conducted in whichalternating lesions on the endocrine pancreas and in the ammon's horn were created.     

妥曲珠利微晶体的制备及其在家兔体内的药动学

采用反溶剂法制备妥曲珠利微晶体,利用显微镜观察妥曲珠利微晶体与妥曲珠利原药显微特征差异,并在25℃条件下测定两者体外溶出速率差异。将12只家兔随机分为2组,每组6只,分别按药物剂量10mg/kg灌胃,单剂量给药,采用HPLC检测血药浓度;用DAS2.0药代动力学程序计算药代动力学参数。结果显示,成功制备了妥曲珠利微晶体,微晶体与原药的显微特征差异明显,体外溶出速率明显加快;家兔单剂量灌胃妥曲珠利和微晶体后,主要药动学参数Cmax分别为（8.925±0.360）mg/L和（12.510±0.525）mg/L,tmax均为24h,AUC（0-∞）分别为（411.605±20.918）mg/（L·h）和（578.650±11.664）mg/（L·h）,相对生物利用度为140.6%,药时数据符合一级吸收二室模型。结果表明,HPLC法适用于妥曲珠利血浆浓度的测定;妥曲珠利微晶体与妥曲珠利原药相比,体内吸收速率和吸收程度有较大的提高。