In the veterinary industry, long acting oxytetracycline formulations are loosely referred to as those formulations that only require a single dose at 20 mg/kg to achieve clinical cure and to be repeated after three days only if required. Short acting oxytetracycline formulations are recommended for use once a day for four days, at a dose of 10 mg/kg IV and 10mg/kg IM on day one, 10 mg/kg IM on day two and 5 mg/kg IM on days three and four. The primary objective of this study is to demonstrate that, based on pharmacokinetics, a double dose of a conventional short acting, 135mg/ml formulation of oxytetracycline has a longer action than a single dose of the same formulation. As a secondary objective the efficacy and safety of a single, double dose of a conventional oxytetracycline formulation are compared to multiple, single doses of a conventional formulation as well against a single dose of a long-acting formulation. Factors that influence the duration of action of a parenteral oxytetracycline formulation are reviewed, as are the pharmacokinetic / pharmacodynamic relationship of oxytetracycline. A single dose, randomized, two treatment, two sequence cross-over experimental design as described by Grizzle (1965) was selected for this study. The washout period between the two sequences was determined using at least 5 half-lives (11.1 hours x 5) of conventional oxytetracycline formulation , based on a study by Davey et al (1985) Although a wash-out period of 55.5 hours for a dose rate 20 mg/kg of oxytetracycline would have sufficed to ensure the absence of any residual drug in the central compartment of the experimental animals, it was decided to extend the washout period between treatment periods to 7 days (168 hours) for mainly practical reasons. Sample size determination was based on the rejection of the null hypothesis as described by Anderson and Hauck (1983). 5 animals per treatment group were selected. The sheep were equally and randomly assigned to either the group that would receive the 10 mg/kg dose first (group 1), or the group that would receive the 20 mg/kg dose first (group 2). For the cross over treatment (phase 2), the animals remained in the groups they were allocated to for phase 1, but group 1 received the 20 mg/kg dose and group 2 received the 10 mg/kg dose. The volume of oxytetracycline was calculated based on a product oxytetracycline content of 135 mg/ml. The blood sample collection procedure was the same for phases (treatments) 1 and 2. Time 0 was the time of treatment. Samples were collected into 10ml lithium heparinized vacutainer glass tubes with 19G disposable needles at the following intervals (hrs): 0, 0.25, 0.5, 1, 2, 4, 6, 9, 12, 24, 36, 48, 72, 96. The oxytetracycline concentrations in plasma were determined using validated High Performance Liquid Chromatographic methodology. The difference between the 2 sets of results emanating from phase 1 and phase 2 of the study are used as basis for presenting the results. Three pharmacokinetic parameters were used to compare the 2 treatments: Cmax (maximum plasma concentration) , AUCinf (Total area under the concentration curve) and T>0.5 (Time that the drug concentration remains above 0.5 ìg/ml). The geometric means of the results show that: The 20mg/kg treatment maintains levels above 0.5 ìg/ml significantly longer than the 10 mg/kg treatment. (37.4 hours versus 24 hours; p value 0.0013) The 20 mg/kg dose reaches a significantly higher concentration than does the 10 mg/kg dose. (6.59ìg/ml versus 3.55ìg/ml; p value 0.000000) The 20mg/kg treatment has an AUCinf which is greater than the 10 mg/kg treatment by a highly significant margin. (120.63 ìg/ml*hr versus 71.63 ìg/ml*hr; p value 0.000001) In demonstrating that a conventional oxytetracycline formulation administered intramuscularly at double dose provides drug plasma concentrations above MIC for an average duration of 13 hours longer than a single dose, the primary objective of the study was achieved. The study demonstrated that a single dose at 20 mg/kg of a conventional oxytetracycline formulation offers an acceptable alternative to conventional treatment regimes in terms of efficacy, target animal safety, as well as convenience to the user. / Dissertation (MMedVet)--University of Pretoria, 2008. / Paraclinical Sciences / unrestricted

An ideal dexmedetomidine protocol has yet to be determined for standing sedation in horses. It was hypothesized that an intravenous (IV) bolus followed by continuous rate infusion (CRI) dexmedetomidine would have a quicker increase in plasma concentrations compared to repeated intramuscular (IM) injections. In a cross-over design, eight adult, female horses were randomly placed in two groups: the CRI group (IV bolus dexmedetomidine at 0.005 mg/kg followed by a CRI at 0.01 mg/kg/hr for 15 minutes then 0.005 mg/kg/hr for 60 minutes) and the IM group (dexmedetomidine at 0.01 mg/kg, followed by 0.005 mg/kg in 30-minute intervals for 60 minutes). Analgesia was evaluated using a mechanical pressure threshold device. Intravenous dexmedetomidine produced faster onset of sedation and increased pressure threshold compared to IM administration. Individual horses had a large variability in dexmedetomidine plasma concentrations between CRI and IM administration.

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Summer flounder, Paralichthys dentatus, culture is becoming increasingly popular in the United States because of high market prices and consumer demand. In addition, flounder is a marine fish species that can tolerate a wide range of salinities, allowing for inland intensive fish culture. Oxytetracycline (OTC) is one of two available FDA-approved antibiotics for use in foodfish in the United States. Oxytetracycline was chosen for these studies because it is excreted primarily unchanged through the urine and the absorption, distribution and elimination of this drug may be influenced by environmental and physiological conditions. Four experiments were conducted to investigate: 1) pharmacokinetic parameters of oxytetracycline (50 mg/kg) following intravascular (IV), intraperitoneal (IP), intramuscular (IM) and per os (PO) administration in summer flounder maintained at 28 ppt salinity and 20°C; 2) pharmacokinetic parameters of OTC (50 mg/kg) following IM and PO administration in summer flounder maintained at three different salinity levels of 0 ppt, 15 ppt and 32 ppt and the physiological adjustments summer flounder make to acclimate to environmental salinity; 3) OTC retention times in muscle tissue from summer flounder maintained at three different salinity levels (0 ppt, 15 ppt, 32 ppt) and treated with a single 50 mg/kg OTC dose via IM and PO administration; and 4) pharmacokinetic parameters of OTC (50 mg/kg) following IM and PO administration in clinically healthy and clinically diseased summer flounder maintained at 28 ppt and 20°C. Oxytetracycline plasma concentrations were determined using high performance liquid chromatography (HPLC) and analyzed using a non-compartmental pharmacokinetic model for all routes of drug administration. Statistical comparisons were not made between the different routes of OTC exposure, but results from experiment one indicated that IV administration of OTC resulted in the largest area under the curve (AUC) value (8147.9 µg·h/ml) and the highest maximum plasma concentration (Cmax) of 1173.2 µg/ml OTC at 5 min post-injection. Intramuscular injections of OTC resulted in prolonged total body elimination half-life (T ½) of 301.3 h and high fish-to-fish variability (0.6). Per os administration resulted in low Cmax (0.2 µg/ml OTC) and poor systemic bioavailability (0.2 %). Results from experiment two demonstrated that when OTC is administered IM AUC estimates are significantly (p<0.05) lower in summer flounder held at 0 ppt (1684.8 µg·h/ml) than fish maintained at 15 ppt or 32 ppt salinity (2067.8 µg·h/ml and 2241.3 µg·h/ml, respectively). Although not significantly different from other salinity treatments, time to maximum plasma concentration (Tmax) was longer in fish held at 15 ppt and 32 ppt (312 h and 168 h, respectively) compared to cohorts in freshwater (0.5 h) and Cmax values were higher in animals held at 15 ppt and 32 ppt (8.4 µg/ml OTC and 9.2 µg/ml OTC, respectively) than freshwater fish (4.9 µg/ml OTC) when OTC was administered via IM injection. No significant differences were detected in any of the pharmacokinetic parameters following PO dosing of OTC, however, the AUC estimates were lower in the 32 ppt acclimated fish (127.7 µg·h/ml) than in the 0 ppt or 15 ppt acclimated fish (190.2 µg·h/ml and 180.7 µg·h/ml, respectively). In addition, the T ½ was longer in the higher salinity groups (278.1 h and 266.0 h, respectively) than in the freshwater fish group (256.9 h). Physiological adjustments made by summer flounder including plasma and urine osmolality, urine flow rate and urine character, gill chloride cell size and density, and Na+ - K+ ATPase activity demonstrated trends that suggested physiological differences among the salinity groups. Plasma and urine osmolalities were typically significantly (p<0.05) higher in fish maintained at 32 ppt salinity than at the lower salinity treatments. In addition, urine flow rates were generally significantly (p<0.05) greater in freshwater adapted fish (0.13 - 0.21 ml of urine/kg/hour) in comparison to fish in the salinity treatments of 15 ppt and 32 ppt (0.06 - 0.12 ml of urine/kg/hour and 0.09 – 0.11 ml of urine/kg/hour, respectively). Changes in gill chloride cell size and density and enzyme activity of Na+ - K+ ATPase revealed no significant differences between the salinity treatments but summer flounder in saltwater had numerically larger and more chloride cells than summer flounder in freshwater, but enzyme activity was greater in freshwater acclimated summer flounder compared to fish in seawater. Experiment three results revealed similar OTC muscle tissue pharmacokinetic parameters in summer flounder following IM injection. However, there were significant differences (p<0.05) in the AUC parameters of the plasma and muscle OTC concentrations between fish maintained at different salinities following IM OTC treatment. These effects may be the result of a "depot" effect in the muscle tissue or may be related to the reduced solubility of OTC in the muscle tissue of marine fish. A single PO dose administration of OTC at 50 mg/kg did not result in plasma or tissue concentrations higher than the FDA tissue tolerance limit of 2 ppm. Results of the fourth experiment demonstrated that following IM OTC administration healthy fish had significantly (p<0.05) higher AUC (4700.6 µg·h/ml) values than diseased cohorts (2576.2 µg·h/ml). Maximum plasma concentrations were also higher in the healthy fish than in the diseased fish, although values were not significantly different (23.4 µg OTC/ml and 20.2 µg OTC/ml, respectively for healthy and diseased fish). Additionally, in diseased fish, the mean resident time (MRT) (293.7 h) and T ½ (203.5 h) parameters were longer compared to parameters in healthy fish (253.2 h and 175.4 h, respectively), although values were not significantly different. No significant differences were detected in any of the pharmacokinetic parameters following PO OTC administration, however, healthy fish achieved higher maximum plasma OTC concentrations (1.0 µg OTC/ml) than diseased fish (0.7 µg OTC/ml). Fish-to-fish variation was greater in diseased animals than in healthy regardless of route of drug administration. The results of these experiments indicated that OTC pharmacokinetic parameters are influenced by route of drug administration, environmental salinity and fish health status. These factors must be considered by veterinarians and governmental regulators when developing treatment regimens for summer flounder. / Ph. D.

Objective: To describe the pharmacokinetics of buprenorphine in dogs following administration of a high-concentration formulation of buprenorphine. Study design: Prospective, randomized, crossover study. Animals: A total of six healthy male intact Beagle dogs, 9–13 months of age and weighing 10.3 ± 1.4 kg (mean ± standard deviation). Methods: Dogs were randomized to be administered buprenorphine (0.12 mg kg−1; Simbadol, 1.8 mg mL−1) via the intravenous (lateral saphenous) or subcutaneous (dorsal interscapular) route followed by the alternative route of administration after a 14 day interval. Blood was sampled before administration and at set times up to 72 hours after injection. Plasma buprenorphine concentration was measured using liquid chromatography–tandem mass spectrometry. Results: A 3-compartment model with zero or biphasic rapid and slow first order input in (intravenous or subcutaneous data, respectively) and first-order elimination from the central compartment best fitted the data. The rapid first order input accounted for 63% of the dosage absorption. Typical values (% interindividual variability) for the three compartment volumes were 900 (33), 2425 (not estimated) and 6360 (28) mL kg−1. The metabolic and two distribution clearances were 25.7 (21), 107.5 (74) and 5.7 (61) mL minute−1 kg−1. The absorption half-life for the fast absorption phase was 8.9 minutes with a 0.7 (103) minute delay. The absorption half-life for the slow absorption phase was 347 minutes with a 226 (42) minutes delay. Median (range) bioavailability calculated from noncompartmental analysis was 143 (80–239) %. Calculated terminal half-life was 963 minutes. Conclusions and clinical relevance: The high-concentration formulation of buprenorphine administered subcutaneously had a large volume of distribution and a rapid absorption phase followed by slower, delayed absorption. The high estimate of bioavailability should be interpreted with caution as values above 100% are most commonly related to experimental issues. / Master of Science / Opioids are ever-increasingly difficult to obtain for veterinary usage, although there is an FDA-approved and veterinary-specific formulation of buprenorphine (Simbadol) commercially available. Although only approved in cats, it has been used off-label in dogs due to its availability, despite minimal empirical evidence for its usage. Design: Six male beagle dogs were utilized in a randomized crossover study to evaluate the plasma concentrations of buprenorphine after intravenous and subcutaneous administration. Methodology: All dogs were anesthetized for central venous catheter placement. Following administration of the dosage (intravenous or subcutaneous), whole blood was sampled at set time points from one minute to three days. Blood was centrifuged and plasma removed for analysis of buprenorphine concentration, allowing pharmacokinetic modeling and creation of time-concentration curves. Results: Side effects were mild and associated with sedation. Appetite was transiently decreased in multiple dogs. A biphasic absorption model was determined from the subcutaneous data, with a rapid first phase accounting for the majority of absorption and a slower second phase occurring several hours later. Conclusions: The high-concentration formulation of buprenorphine administered subcutaneously resulted in a long terminal half-life and high estimate of bioavailability, although the latter should be interpreted cautiously. Relevance: The present study showed that the high-concentration formulation of buprenorphine is absorbed from subcutaneous administration in dogs with mild side effects. Further study is warranted on this formulation in dogs.

A series of novel alpha-aminoxy peptides have been recently developed, and showed a therapeutic potential for the treatment of CI- channel dysfunctional diseases. The present study aimed to investigate the pharmacokinetics of five structural related tx-aminoxy peptides (P1 to P5), and effect of structural modifications on their pharmacokinetic properties. / P1 showed significantly low intestinal permeability due to P-gp-mediated efflux. Structural modifications resulted in alterations of transport mechanisms from P-gp-mediation (P1, P2) to multidrug resistance-associated protein (MRP)-mediation (P3), MRP plus breast cancer resistance protein (BCRP)-mediation (P4) active transport, or even passive paracellular diffusion (P5) without any efflux transporters involved. Comparing with P1, the absorbable permeability in Caco-2 monolayer increased to about 7-fold (P3), 4-fold (P4) and 11-fold (P5), respectively, and the absorption through intestine in SPIP model significantly increased to about 36-fold (P2), 42-fold (P3), 55-fold (P4) and 102-fold (P5), respectively. P1 was unstable in the GI tract with 41% degradation in SGF within 1 h and 47% degradation in SIF within 3 h. The other four peptides were much more stable than P1 with degradation less than 6% under the same incubated conditions. For the hepatic metabolism, about 31% of P1 was metabolized by rat liver S9 within 30 min, while the metabolic stability was significantly improved to 3.3-fold (P3), 2.9-fold (P4) and 7.5-fold (P5), respectively with no metabolism for P2. Their metabolism was mainly via oxidation catalyzed by CYP enzymes to form hydroxylated metabolites. After i.v. administration (5 mg/kg), both P1 and P5 was eliminated rapidly. P1 mainly distributed to liver and lung, while P5 to kidney and intestine. P1 was cleared mainly through metabolism via oxidation followed by sulphation (&sim;80% of the dose), while P5 was mainly eliminated as an intact form (&sim;53% of the dose). Oral bioavailability of P1 was low (0.36%) due to instability in the GI tract and poor intestinal absorption mediated by P-gp efflux transport. Oral bioavailability of P5 was improved to about 3-fold comparing with P1 but still low mainly because of poor intestinal absorption through passive diffusion and some unknown factor(s). / The present studies demonstrated that our rationale for the structural modifications of the designed cc-aminoxy peptides is an effective way to improve their intestinal absorption, gastrointestinal and metabolic stability, and appropriate pharmacokinetic properties. Our findings also provide scientific evidence to support further development of better alpha-aminoxy peptide cadidates with high oral bioavailability and appropriate pharmacokinetic properties. / Three absorption models, including Caco-2 cell monolayer, Ussing chamber and in situ rat single-pass intestinal perfusion (SPIP) model, were used. The stability in gastrointestinal (GI) tract was determined using simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). The hepatic metabolism was investigated in rat liver subcellular fractions and human liver microsome. P1 and P5 were selected for pharmacokinetic study in rats. / Ma, Bin. / Adviser: Ge Lin. / Source: Dissertation Abstracts International, Volume: 73-04, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 199-215). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

The pharmacokinetics of two antimicrobials were investigated in alpacas. Six healthy alpacas were each administered a single dose of 10 mg/kg of oxytetracycline by IV injection and IM injection. In addition, a single dose of 20 mg/kg of florfenicol by IV administration was given to alpacas in a separate study. The pharmacokinetic parameters of oxytetracycline and florfenicol in alpacas were compared to the results previously obtained in llamas. There were significant differences between llamas and alpacas in several of oxytetracycline pharmacokinetic parameters but there were no significant differences in all of florfenicol pharmacokinetic parameters in these two animals. It can be concluded that llamas and alpacas have different oxytetracycline disposition kinetics while they have similar disposition kinetics of florfenicol. The pharmacokinetics of clorsulon, a narrow-spectrum anthelmintic agent, was investigated in llamas following oral administration at a single dose of 14 mg/kg. The plasma levels of clorsulon produced by this dose was lower than the values reported in the clorsulon pharmacokinetic studies carried out in sheep and goats following oral administration at a single dose of 7 mg/kg This suggests the entire dose of clorsulon is not absorbed in llamas. Since the differential equations describing one-compartment system with first-order input and two-compartment system after IV administration with nonlinear elimination kinetics cannot be solved, there is no mathematical expression for the AUC for drugs following these models. The AUC values calculated from the proposed preliminary AUC equations for drugs following these models were compared to the AUC calculated using the trapezoidal rule method based on computer-generated data using the fourth-order Runge-Kutta method. Except for a few exceptions, the predicted AUC from the proposed equations matched the values calculated from the theoretically generated data. / Graduation date: 2004