The Surface Area to Volume Ratio Changes the Pharmacokinetic and Pharmacodynamic Parameters in the Subcutaneous Tissue Cage Model:As Illustrated by Carprofen in Sheep

Introduction: Pharmacokinetic and pharmacodynamic models can be powerful tools for predicting outcomes. Many models are based on repetitive sampling of the vascular space, due to the simplicity of obtaining samples. As many drugs do not exert their effect in the vasculature, models have been developed to sample tissues outside the bloodstream. Tissue cages are hollow devices implanted subcutaneously, or elsewhere, that are filled with fluid allowing repetitive sampling to occur. The physical dimensions of the cage, namely, the diffusible surface area to volume ratio, would be expected to change the rate of drug movement into and out of tissue cages. Methods: Seven sheep were implanted with five pairs of tissue cages, subcutaneously. Each pair of cages had a different length but a fixed diffusible surface area, so the surface area to volume ratio differed. Carrageenan was injected into half of the cages in each animal during one sampling period in a cross-over design. Samples from each cage and the bloodstream were obtained at 14-time points during two sampling periods. The concentration of carprofen was measured using LC–MS/MS and the results were modeled using nonlinear mixed-effects techniques. Prostaglandin metabolites were also measured and the change over time was analyzed using linear mixed effect modeling. Results: The presence of carrageenan within an animal changed the systemic pharmacokinetics of carprofen. The rate of drug movement into and out of the tissue cages varied with the surface area to volume ratio. The concentration time curve for prostaglandin metabolites changed with cage size. Conclusion: The surface area volume ratio of tissue cages will influence the calculated pharmacokinetic parameters and may affect calculated pharmacodynamics, thus, it is an important factor to consider when using tissue cage data for dosing regimes

A review of the pharmacology and clinical application of alfaxalone in cats

AbstractAlfaxalone-2-hydroxpropyl-β-cyclodextrin (alfaxalone-HPCD) was first marketed for veterinary use in Australia in 2001 and has since progressively became available throughout the world, including the USA, where in 2012 Food and Drug Administration (FDA) registration was granted. Despite the growing body of published works and increasing global availability of alfaxalone-HPCD, the accumulating evidence for its use in cats has not been thoroughly reviewed. The purpose of this review is: (1) to detail the pharmacokinetic properties of alfaxalone-HPCD in cats; (2) to assess the pharmacodynamic properties of alfaxalone-HPCD, including its cardiovascular, respiratory, central nervous system, neuromuscular, hepatic, renal, haematological, blood-biochemical, analgesic and endocrine effects; and (3) to consider the clinical application of alfaxalone-HPCD for sedation, induction and maintenance of anaesthesia in cats. Based on the published literature, alfaxalone-HPCD provides a good alternative to the existing intravenous anaesthetic options for healthy cats

Intravenous acetaminophen does not provide adequate postoperative analgesia in dogs following ovariohysterectomy

(1) Objective: To investigate the analgesic effects of intravenous acetaminophen after intravenous administration in dogs presenting for ovariohysterectomy. (2) Methods: 14 ASA I client-owned female entire dogs. In this randomized, blinded, clinical study, dogs were given meperidine and acepromazine intramuscularly before induction of anesthesia with intravenous propofol. Anesthesia was maintained with isoflurane in oxygen. Intravenous acetaminophen 20 mg/kg or 0.9% NaCl was administered postoperatively. Pain assessments were conducted using the Glasgow Pain Scale short form before premedication and at 10, 20, 60, 120, and 180 min post-extubation or until rescue analgesia was given. The pain scores, times, and incidences of rescue analgesia between the groups was compared. Blood was collected before and 2, 5, 10, 20, 40, and 80 min after acetaminophen administration. Acetaminophen plasma concentration was quantified by liquid chromatography-mass spectrometry. The acetaminophen plasma concentration at the time of each pain score evaluation was subsequently calculated. (3) Results: There was no significant difference in pain scores at 10 min, highest pain scores, or time of rescue analgesia between groups. In each group, 3 dogs (43%) received rescue analgesia within 20 min. (4) Conclusions: Following ovariohysterectomy in dogs, there was no detectable analgesic effect of a 20 mg/kg dosage of intravenous acetaminophen administered at the end of surgery

The lower limit of quantification in pharmacokinetic analyses

Pharmacokinetic (PK) analyses rely fundamentally on independent measurements of drug concentrations in biological matrices, traditionally using chromatographic analytical methods. These methods have imperfect performance and introduce measurement error to the experiment. Commonly, the measurement error is used to constrain the report of analytical outputs. An important issue in PK is the influence of these analytical constraints on available inferences

Physiologically based modelling of the pharmacokinetics of three beta-lactam antibiotics after intra-mammary administration in dairy cows

Understanding the pharmacokinetics of intra-mammary antibiotics is important for the prediction of drug residues in milk and for the design of optimal dosage regimens. Unfortunately, compartmental pharmacokinetic models are not valid for this unique system. A minimal physiologically based pharmacokinetic model is presented incorporating the physiology of milk secretion, drug administration at the quarter level, drug absorption and dispersion, drug retention during the inter-milking interval and episodic drug elimination at milking. The primary objective of the study was the development and exploration of a model for major factors controlling drug concentration in milk, rather than generation of rigorously predictive pharmaco-statistical models for any particular drug. This model was implemented in a two-stage approach, using published concentration data for penicillin, cefuroxime, cephapirin and desacetyl-cephapirin in milk of healthy cows. Model simulations evaluated sensitivity and developed predictions of drug residues. The model successfully predicted both drug concentrations and drug residues in milk. The postmilking residual milk volume did not adequately explain antibiotic pharmacokinetics, requiring additional considerations for drug retention. Local sensitivity analysis indicated that increasing the number of quarters treated, the dosage, or the duration of the inter-milking interval prolonged both the persistence of drug residues and the duration that antibiotic concentration exceeded typical minimum inhibitory concentrations. The model was flexible across different beta-lactam drugs as a general description of intra-mammary pharmacokinetics. This model is suitable for the design and analysis of dosage regimens, and could be applied for the prediction of withholding periods when these antibiotic preparations are used off-label. The final model indicates that explicit consideration of the milking regimen is fundamental to the design and interpretation of pharmacokinetic studies of antibiotics in bovine milk

General Pharmacology of Anesthetic and Analgesic Drugs

Anesthesia and pain management are two branches of veterinary clinical medicine that inarguably are inextricably intertwined with clinical pharmacology. This chapter introduces these fundamental pharmacological concepts as they relate to the practice of anesthesia. It talks about the classic receptor and the receptor state theories. The chapter illustrates the study of receptor structures using a few examples only of receptors that have a particular importance in the field of anesthesia. The discussion is limited to some membrane receptors, ion channels, and G-protein receptors. Background knowledge of the pharmacokinetics (PK) of a drug is necessary to permit the proper use of that drug in clinical cases. Constant rate therapy is used when maintenance of a specific plasma concentration and its consequent effect is desired. Combinations of drugs may occasionally result in drug-drug interactions, which can be synergistic, antagonistic, or additive. These interactions can be explained by three mechanisms: physicochemical, PK, and pharmacodynamics (PD)

A survey of injuries that occurred in veterinary teaching hospitals during 2017

Knowing the frequency, extent or severity of injuries that occur to students and staff within veterinary teaching hospitals (VTHs) is necessary for proactive management of their safety. This study surveyed contemporaneously-captured incident reports likely to cause or causing injury to students and staff of veterinary teaching hospitals in Europe, the United States of America (USA), Canada, Australia, and New Zealand, recorded in 2017. Four different severities of incident were evaluated within four different cohorts of people, precipitated by five categories for cause. Within each cause-category, further subdivision was based on the nature of the incident. All colleges of veterinary medicine accredited by the American Veterinary Medical Association (AVMA) Council on Education (COE) or the Australasian Veterinary Boards Council were surveyed. Responses were received from (7/7, 100%) schools in Australia and New Zealand, 12/30 (40%) the United States of America, 1/4 (25%) Canada, 1/1 (100%) Mexico, and 1/3 (33%) United Kingdom, and no responses were received from the AVMA–COE accredited schools in the European Union. The mean incidence of incidents caused by horses was (0.4/1,000 cases), followed by food animals (0.1/1,000 cases), other animals (0.1/1,000 cases), and small animals (0.074/1,000 cases). Within veterinary teaching hospitals at many institutions, veterinary students and veterinarians are particularly at risk of injuries caused by hand-held instruments, such as scalpels and needles. Non-veterinary staff are more at risk than students or veterinarians from injuries caused by small animals. Recording and reporting of incidents is not uniform and may be lacking in detail. Some institutions’ systems for record management preclude easy evaluation, and therefore may be insufficient for proactive management of health and safety as required by accreditation bodies

A controlled randomized clinical trial to assess postoperative analgesia after thiopental–isoflurane anaesthesia or total intravenous anaesthesia with alfaxalone in dogs

Alfaxalone, a synthetic neuroactive steroid, has been attributed with properties including sedation, anaesthesia and analgesia. The clinical relevance of any analgesic properties of alfaxalone has not been demonstrated. This study was a prospective, blinded, randomized, negative control clinical trial in 65 healthy dogs presented for ovariohysterectomy. Anaesthesia was induced and maintained, for Group 1 (TIVA) dogs (n = 30) with intravenous alfaxalone alone and for Group 2 dogs (n = 35) with thiopental followed by isoflurane in 100% oxygen inhalation. After ovariohysterectomy, quantitative measures of pain or nociception were recorded at 15 min intervals for 4 hr using three independent scoring systems, a composite measure pain scale (CMPS), von Frey threshold testing and measures of fentanyl rescue analgesia. The mean CMPS scores of Group 2 (THIO/ISO) dogs remained higher than Group 1 (TIVA) dogs from 15 to 135 min post-surgery but this difference was not statistically significant. There were no significant differences between groups in the proportions of dogs requiring rescue fentanyl analgesia, the total fentanyl dose used or the time to first fentanyl dose. The Von Frey threshold testing was found to be unsuitable for measurement of pain in this experimental model. When administered as total intravenous anaesthesia, alfaxalone did not provide analgesia in the postoperative period

Study design synopsis: Designing and performing pharmacokinetic studies for systemically administered drugs in horses

The goal of this editorial is to discuss best practice design, execution and reporting of a pharmacokinetic (PK) study in horses. Our target readers are clinicians who plan to perform this type of research, in a field, clinic or research setting but we also hope that this article might help readers of such work to appraise the articles and understand the quality of the studies. Our emphasis will be on appropriate study design and analytical method, drug and drug formulation choice and route of administration, animal choice, sample collection, storage and shipping, and reporting, rather than the PK data analysis itself