Showing papers in "Journal of Veterinary Pharmacology and Therapeutics in 1997"
TL;DR: The major drugs used in salmonids in North America and Europe will be reviewed and some insight into future directions for drug development and use for the salmonid industry will be introduced.
Abstract: In contrast to mammalian therapeutics, the use of pharmaceutical substances is rather limited in fish. It is basically restricted to anaesthetic agents and anti-infective agents for parasitic and microbial diseases. Anaesthetic agents are used primarily in fish farm and laboratory settings to provide analgesia and immobilization of fish for minor procedures. The anti-infective agents are used for controlling diseases and the choice of drug depends on efficacy, ease of application, human safety, target animal safety including stress to the fish, environmental impact, regulatory approval, costs, and implications for marketing the fish. In this article, the major drugs used in salmonids in North America and Europe will be reviewed and some insight into future directions for drug development and use for the salmonid industry will be introduced. The mechanisms of action, pharmacokinetics, side effects, and uses of the drugs are emphasized.
250 citations
TL;DR: The comparative plasma disposition kinetics of IVM, MXD and DRM in cattle, characterized over 80 days post-treatment under standardized experimental conditions, is reported for the first time.
Abstract: The persistence of the broad-spectrum antiparasitic activity of endectocide compounds relies on their disposition kinetics and pattern of plasma/tissues exchange in the host. This study evaluates the comparative plasma disposition kinetics of ivermectin (IVM), moxidectin (MXD) and doramectin (DRM) in cattle treated with commercially available injectable formulations. Twelve (12) parasite-free male Hereford calves (180-210 kg) grazing on pasture were allocated into three groups of four animals each. Animals in each group received either IVM (Ivomec 1%, MSD AGVET, Rahway, NJ, USA), MXD (Cydectin 1%. American Cyanamid, Wayne, NJ, USA) or DRM (Dectomax 1%, Pfizer Inc., New York, NY, USA) by subcutaneous injection at a dose of 200 micrograms/kg. Jugular blood samples were collected from 1 h up to 80 days post-treatment, and plasma extracted, derivatized and analysed by high performance liquid chromatography (HPLC) using fluorescence detection. The parent molecules were detected in plasma between 1 h and either 70 (DRM) or 80 (IVM and MXD) days post-treatment. The absorption of MXD from the site of injection was significantly faster (absorption half-life (t1/2ab) = 1.32 h) than those of IVM (t1/2ab = 39.2 h) and DRM (t1/2ab = 56.4 h). MXD peak plasma concentration (Cmax) was reached significantly earlier (8.00 h) compared to those of IVM and DRM (4-6 days post-treatment). There were no differences on Cmax values: the area under the concentration-time curve (AUC) was higher for IVM (459 ng.d/mL) and DRM (627 ng.d/mL) compared to that of MXD (217 ng.d/mL). The mean plasma residence time was longer for MXD (14.6 d) compared to IVM (7.35 d) and DRM (9.09 d). Unidentified metabolites were detected in plasma: they accounted for 5.75% (DRM), 8.50% (IVM) and 13.8% (MXD) of the total amount of their respective parent drugs recovered in plasma. The comparative plasma disposition kinetics of IVM, MXD and DRM in cattle, characterized over 80 days post-treatment under standardized experimental conditions, is reported for the first time.
212 citations
TL;DR: Results of this study show that interspecies scaling is applicable to certain veterinary drugs and could have important consequences in terms of avoiding the use of dose-titration studies in Phase I of drug development, for drugs that are experimentally 'well behaved.
Abstract: Allometric scaling is widely used for the determination of first dosage regimen and the interpolation or extrapolation of pharmacokinetic parameters across many animal species during drug development. In this article, 85 drugs used in veterinary medicine obtained from the Food Animal Residue Avoidance Databank database were selected for allometric scaling analysis. Outlier species were identified by statistical methods. The results showed that 77% and 88% of drugs displayed significant correlations between total systemic clearance (CL) and volume of distribution at steady status (Vss) vs. body weight (P < 0.05) on a log-log scale, respectively. The distribution of the allometric exponent b for CL and Vss displays approximate normal distribution, with means (0.87 and 0.99) and standard deviations (0.143 and 0.157) for CL and Vss, respectively. Twelve drugs were identified to have at least one outlier species for CL and ten drugs for Vss. The human CL and Vss were predicted for selected drugs by the obtained allometric equations. The predicted CL and Vss were within a threefold error compared to observed values, except the predicted CL values for antipyrine, warfarin and diazepam. The results can be used to estimate cross-species pharmacokinetic profiles for predicting drug dosages in veterinary species, and to identify those species for which interpolation or extrapolation of pharmacokinetics properties may be problematic.
138 citations
TL;DR: The alpha 2 agonists studied induced a similar change in PaO2 at peak effect, despite their reported variable selectivity for alpha 2 vs. alpha 1 adrenoceptors, as compared to the saline treated group.
Abstract: In the present study, the hypoxaemic potential of four alpha 2 agonists possessing different selectivity for alpha 2 adrenoceptors and of a saline placebo was studied in five clinically healthy sheep using a randomized Latin square design and equipotent sedative doses. Baseline values for heart rate (HR), mean arterial pressure (MAP), arterial oxygen (PaO2)f and carbon dioxide (PaCO2) tensions, respiration rate and maximum change in pleural pressure (delta Ppl) were obtained, followed by the intravenous administration of either: xylazine (150 micrograms/kg); romifidine (50 micrograms/kg); detomidine (30 micrograms/kg); medetomidine (10 micrograms/kg) or placebo. Subsequent recordings were made up to 60 min after drug administration. No significant (P < or = 0.05) alterations in any variable occurred with placebo. All the alpha 2 agonists significantly (P < or = 0.05) decreased PaO2 levels without a significant (P < or = 0.05) change in PaCO2. The lowest PaO2 values were 29-42 mm Hg (3.9-5.5 kPa) with no significant difference between drugs. Respiratory rate and delta Ppl increased significantly within 2 min of drug administration; the duration of this effect varied with the alpha 2 agonist, lasting longest with romifidine. As compared to the saline treated group, a significant increase in MAP was observed up to 10 min after administration of romifidine and detomidine, however, a significant decrease was seen at 10 and 45 min after xylazine and medetomidine, respectively. The alpha 2 agonists studied induced a similar change in PaO2 at peak effect, despite their reported variable selectivity for alpha 2 vs. alpha 1 adrenoceptors.
134 citations
TL;DR: The intramuscular, oral, and bath immersion disposition of enrofloxacin were evaluated following administration to a cultured population of red pacu, finding the i.m. route is the most predictable and results in the highest plasma concentrations of the drug.
Abstract: The intramuscular (i.m.), oral (p.o.), and bath immersion disposition of enrofloxacin were evaluated following administration to a cultured population of red pacu. The half-life for enrofloxacin following i.m. administration was 28.9 h, considerably longer than values calculated for other animals such as dogs, birds, rabbits, and tortoises. The 4 h maximum concentration (Cmax) of 1.64 micrograms/ml, following a single 5.0 mg/kg dosing easily exceeds the in vitro minimum inhibitory concentration (MIC) for 20 bacterial organisms known to infect fish. At 48 h post i.m. administration, the mean plasma enrofloxacin concentration was well above the MIC for most gram-negative fish pathogens. The gavage method of oral enrofloxacin administration produced a Cmax of 0.94 microgram/mL at 6-8 h. This Cmax was well above the reported in vitro MIC. A bath immersion concentration of 2.5 mg/L for 5 h was used in this study. The Cmax of 0.17 microgram/mL was noted on the 2 hour post-treatment plasma sample. Plasma concentrations of enrofloxacin exceeded published in vitro MIC's for most fish bacterial pathogens 72 h after treatment was concluded. Ciprofloxacin, an active metabolite of enrofloxacin, was detected and measured after all methods of drug administration. It is possible and practical to obtain therapeutic blood concentrations of enrofloxacin in the red pacu using p.o., i.m., and bath immersion administration. The i.m. route is the most predictable and results in the highest plasma concentrations of the drug.
79 citations
TL;DR: All administration routes at 10 mg/kg were found to yield comparable drug concentration-time curves for multiple tissue, indicating no distinct advantage of using one route over another from a kinetics perspective, and pharmacokinetic evidence to justify therapeutic efficacy trials with the lower dose is provided.
Abstract: The fluoroquinolone antibacterial family is a relatively recent group of bactericidal compounds, generally characterized by efficacy against a wide spectrum of bacterial organisms and exhibiting minimal adverse effects in treated patients. The fluoroquinolones are widely prescribed in both human and veterinary medicine, though in veterinary medicine in the USA there are currently only two approved compounds, enrofloxacin (Baytril, Bayer Animal Health, Shawnee Mission, KS) and sarafloxacin (SaraFlox, Abbott Laboratories, North Chicago, IL), both with limited species and disease label approvals. Currently, there are no approved fluoroquinolone antibacterials to treat bacterial infectious diseases in cultured fish species. Enrofloxacin was administered to juvenile Atlantic salmon as a single bolus via intraarterial (i.a.), intraperitoneal (i.p.), intramuscular (i.m.), or oral gavage routes of administration. The drug was administered via the first three routes to achieve a dose of 10 mg/kg, and via oral gavage to achieve both 10 (p.o.-10) and 5 (p.o.-5) mg/kg doses. Two-compartment model kinetics were observed with elimination of half-lives (t1/2) of 130.6, 34.32, 84.98, 105.11, and 48.24 h, area under the drug concentration-time curves (AUC) of 84.3, 75.31, 55.61, 41.68, and 38.81 micrograms x h/mL, and bioavailabilities (F) of 100, 89.34, 65.97, 49.44, and 46.04% (i.a., i.p., i.m., p.o.-10, p.o.-5, respectively). All administration routes at 10 mg/kg were found to yield comparable drug concentration-time curves for multiple tissue, indicating no distinct advantage of using one route over another from a kinetics perspective. Finally, the 5 mg/kg dose (p.o.-5) yielded comparable multiple tissue drug concentration-time curves to the 10 mg/kg dose (p.o.-10), providing pharmacokinetic evidence to justify therapeutic efficacy trials with the lower dose.
71 citations
TL;DR: It was concluded that both opioids are equally suitable analgesics for postoperative analgesia for the elective arthrotomy in dogs.
Abstract: The aim of this study was to compare morphine with the partial agonist, buprenorphine, for postoperative analgesic effects, when administered preoperatively for elective arthrotomy in dogs. Fifty two dogs were anaesthetized for stifle, elbow, or hock arthrotomy. The dogs were premedicated 30 min prior to induction of anaesthesia with 0.03 mg/kg acepromazine intramuscularly, and either 0.3 mg/kg morphine or 0.01 mg/kg buprenorphine intramuscularly (allocated randomly). Anaesthesia was induced with thiopentone and maintained with halothane in an oxygen/nitrous oxide mixture. Pain and sedation were assessed preoperatively, and 0.5, 1, 2, 3, 5, and 7 h after the halothane was switched off, with a visual analogue scale scoring system. Pain scores did not differ significantly (morphine group median postoperative score from 30 to 40 mm, buprenophine group median postoperative score from 36 to 43 mm) and analgesia was considered adequate in the majority of cases (score less than 40 mm). Morphine produced significantly more sedation at 0.5 h after anaesthesia only. It was concluded that both opioids are equally suitable analgesics for postoperative analgesia for the elective arthrotomy in dogs.
70 citations
TL;DR: The chirality of drugs, with particular reference to agents used in veterinary medicine, is reviewed and the implications for drug product development and approval by registration authorities are discussed.
Abstract: The chirality of drugs, with particular reference to agents used in veterinary medicine, is reviewed. Basic concepts of chirality and aspects of the methodology for the separation of enantiomers are considered. Chiral compounds are in common use in animals and their pharmacological actions and side-effects (pharmacodynamics) and absorption into and fate within the body (pharmacokinetics) are of fundamental importance; pharmacodynamic and pharmacokinetic properties of enantiomeric pairs commonly differ and this has major implications for their effective and safe therapeutic use. As examples of the particular significance of chirality in veterinary medicine, the following drug classes are reviewed; benzimidazole anthelmintics, cloprostenol, verapamil, ketamine, halogenated hydrocarbon anaesthetics and 2-arylpropionic acid anti-inflammatory drugs. The implications of chirality for drug product development and approval by registration authorities are discussed.
70 citations
TL;DR: The findings reported in this article show that fasting prior to treatment notably affects the bioavailability and disposition kinetics of ABZ and its metabolites in cattle.
Abstract: The influence of fasting on the bioavailability and disposition kinetics of albendazole (ABZ) and its metabolites in cattle was investigated. ABZ (10 mg/ kg) was given by intraruminal (i.r.) (Experiment 1) and intravenous (i.v.) (Experiment 2) administration to Holstein calves either fed ad libitum (control) or subjected to a 48 h fasting period (fasted group) prior to treatment. The rate of passage of digesta through the gastrointestinal (GI) tract was evaluated by measurement of cobalt faecal excretion following the oral administration of the sodium-cobalt-ethylendiamine-tetracetic acid complex to calves subjected to the feeding conditions above described. Jugular blood and abomasal fluid (via cannula) samples were collected over 120 h post-treatment; samples were analysed by high performance liquid chromatography (HPLC) for ABZ, ABZ sulphoxide (ABZSO) and ABZ sulphone (ABZSO2). Fasting the animals prior to the i.r. treatment resulted in pronounced modifications to the plasma and abomasal fluid disposition kinetics of ABZ and its metabolites. A greater extent of GI absorption with significantly higher CmaX (150%) and AUC (310%) values for ABZSO in plasma, was observed in fasted compared to fed animals following the i.r. administration of ABZ. Extended detection of ABZ metabolites resulting in significantly longer plasma t 1/2el and MRT was also obtained in fasted compared to fed calves. These results correlated with the substantially enhanced availability of ABZ and its metabolites (AUCs over 200% greater) in the abomasal fluid of the fasted animals. Fasting did not induce changes to the plasma disposition of either ABZ or its metabolites after the i.v. treatment. The digesta passage rate, measured by the amount of cobalt excreted in faeces, was significantly lower in fasted compared to animals fed ad libitum. A delayed GI transit time that decreases the rate of passage of the drug down the digestive tract, may have accounted for enhanced ABZ dissolution and absorption in fasted compared to fed calves. The findings reported in this article show that fasting prior to treatment notably affects the bioavailability and disposition kinetics of ABZ and its metabolites in cattle.
53 citations
TL;DR: The dosage of enrofloxacin should be adjusted according to age when administered to very young calves, as shown by the pharmacokinetic behaviour and mean volume of distribution and clearance in newborn calves.
Abstract: The pharmacokinetic behaviour of enrofloxacin was compared in four one-day-old and four one-week-old calves in order to find out if there were any age-related differences. Mean volume of distribution (Vd(ss)) and clearance (Cl) were significantly smaller in newborn calves: Vd(ss) was 1.8 and 2.3 L/kg, while clearance was 0.19 and 0.39 L/kg.h in newborn and one-week-old calves, respectively. Mean elimination half-life (t1/2 beta) did not differ significantly in newborn and in one-week-old calves: mean t1/2 beta was 6.6 h and 4.9 h, respectively. Enrofloxacin was metabolized to ciprofloxacin both by newborn and one-week-old calves, but the maximum concentration (Cmax) of ciprofloxacin was lower and the time when maximum concentration was reached (tmax) later in newborn calves. We conclude that the dosage of enrofloxacin should be adjusted according to age when administered to very young calves.
52 citations
TL;DR: Relationships between the antimicrobial activities of sulfonamides and physicochemical properties including the acid dissociation constant (pKa) and the hydrophobicity constant (pi) indicated a bilinear relation between pKa and MIC and model-based equations showed that the antibacterial activity was governed by the extracellular ionic concentration of the sulf onamides.
Abstract: Relationships between the antimicrobial activities of sulfonamides and physicochemical properties including the acid dissociation constant (pKa) and the hydrophobicity constant (pi) were determined The minimal inhibitory concentrations (MIC) of sulfonamides against Actinobacillus pleuropneumoniae, a gram-negative veterinary pathogen, were used High performance liquid chromatography was applied for the determination of the electronic and hydrophobic parameters Empirically determined relationships pointed out the dominant role of the degree of ionization on the antimicrobial activity The data indicate that hydrophobic properties of sulfonamides, characterized by pi, are of minor importance for the in vitro antibacterial activity Because of the restricted pKa range (49-77) it could not be established whether the relationship between pKa and activity was linear or bilinear Whenever o,m-disubstituted sulfonamides were included correlations decreased substantially Relationships based on multicompartment equilibrium models were derived and indicated a bilinear relation between pKa and MIC Model-based equations showed that the antibacterial activity was governed by the extracellular ionic concentration of the sulfonamides whenever different intra and extracellular pH values were assumed in the equilibrium model The antimicrobial activities of the sulfonamides against gram-positive organisms were also related to the degree of ionization of the sulfonamides in the agar medium
TL;DR: Donkeys required less guaifenesin than horses to produce recumbency, but cleared it more rapidly than horses, which was significantly different from 313 (SD, 62) for horses.
Abstract: Five donkeys and three horses were given guaifenesin, intravenously, by gravity administration, until recumbency was produced. The time and dose required to produce recumbency, recovery time to sternal and standing were recorded. Blood samples were collected for guaifenesin assay at 10, 20, 30, 40, 50, 60 min, and 2, 3, 4 and 6 h after guaifenesin administration. Serum was analysed for guaifenesin using HPLC and pharmacokinetic values were calculated using a computer software package (RSTRIP). In donkeys, heart and respiratory rates and blood pressures were recorded before and at 5-min intervals during recumbency. Arterial blood samples were collected before and at 5 and 15 min intervals during recumbency for analysis of pH, CO2, and O2. ANOVA was used to evaluate dynamic data, while t-tests were used for kinetic values. Respiratory rate was decreased significantly during recumbency, but no other significant changes from baseline occurred. The mean (+/- SD) recumbency dose of guaifenesin was 131 mg/kg (27) for donkeys and 211 mg/kg (8) for horses. Recovery time to sternal (min) was 15 (SD, 11) for donkeys and 34 (SD, 1.4) for horses. Time to standing was 32 min for donkeys and 36 min for horses. Calculation of AUC (area under the concentration-time curve) microgram/mL) (dose-dependent variable) was 231 (SD, 33) for donkeys and 688 (SD, 110) for horses. The clearance (CL) (mL/h.kg) was 546 (SD, 73) for donkeys, which was significantly different from 313 (SD, 62) for horses. Mean residence time (MRT) (h) was 1.2 (SD, 0.1) for donkeys and 2.6 (SD, 0.5) for horses. Volume of distribution Vd(area) (mL/kg) was 678 (SD, 92) for donkeys and 794 (SD, 25) for horses. At the rate of administration used in this study, donkeys required less guaifenesin than horses to produce recumbency, but cleared it more rapidly.
TL;DR: There was minimal accumulation of drug in serum as assessed by Cmax, and serum concentrations were dose-proportional after the multiple dosing regimen, and the AUC0-infinity was dose- Proportional from 1.1-2.2 mg CFAE/kg body weight.
Abstract: Twelve (12) lactating dairy goats (46-71 kg body wt at study initiation) were divided into four treatment groups and dosed with ceftiofur sodium at 11 mg ceftiofur free acid equivalents (CFAE)/kg or 22 CFAE/kg using a complete two route (intravenous, iv; intramuscular, im), two-period crossover design, with a 2-week washout between injections After another 2-week washout period, the goats were dosed with ceftiofur sodium im for 5 consecutive days at either 11 or 22 mg CFAE/kg The goats from the 22 mg/kg multiple dose group were dried off and the iv kinetic study repeated After all injections, blood samples were obtained serially for determination of combined serum concentrations of ceftiofur and metabolites After intravenous doses of 11 and 22 mg/kg, the harmonic means of the terminal phase half-lives were 1718 and 233 min, respectively, for lactating does The harmonic mean of the terminal phase half-life after an iv dose of 22 mg/kg in non-lactating does was 254 min The AUC0-infinity was significantly less and the clearance significantly greater during lactation After im doses of 11 and 22 mg/kg, the harmonic mean terminal phase half-lives were 163 and 156 min, respectively The im bioavailability of ceftiofur sodium in goats was 100%, and the AUC0-infinity was dose-proportional from 11-22 mg CFAE/kg body weight After five daily im doses of ceftiofur sodium at either 11 or 22 mg CFAE, there was minimal accumulation of drug in serum as assessed by Cmax, and serum concentrations were dose-proportional after the multiple dosing regimen
TL;DR: The data indicate that equine digital veins possess both post-synaptic alpha1 and alpha2-adrenoceptors.
Abstract: Rings of equine digital vein examined under conditions of isometric tension recording constricted to alpha-adrenoceptor agonists with an order of potency of 5-bromo-6-[2-imidazolin-2-yl-amino]-quinoxaline bitartrate (UK 14304) = noradrenaline > 6-Allyl-2-amino-5,6,7,8-tetrahydro-4H-thiazolo-(4,5-d) azepine (BHT-920) > phenylephrine > dopamine > methoxamine. The maximum force generated was greatest for the non-selective agonist noradrenaline and lowest for the alpha2-selective agonist BHT-920 with the other agonists between these two extremes. Selective inactivation of alpha1-adrenoceptors (achieved by treating yohimbine-protected tissues with phenoxybenzamine) reduced the maximum responses of all agonists, the EC50 values of UK 14304, BHT-920 and noradrenaline and increased the EC50 values of phenylephrine and methoxamine. Prazosin (30 nM) had no inhibitory effect on responses to low concentrations of BHT-920 and UK 14304 and caused competitive inhibition of responses to phenylephrine and noradrenaline giving pKb values of 8.49 +/- 0.18 and 8.23 +/- 0.14, respectively. Yohimbine (0.1 microM) caused significant competitive inhibition of responses to BHT-920 and noradrenaline with calculated pKb values of 8.43 +/- 0.11 for BHT-920 and 7.43 +/- 0.31 for noradrenaline and non-competitive inhibition of responses to UK 14304. 2-[2-methoxy-1,4-benzodioxan-2-yl]-2-imidazoline (RX 821002; 10 nM) caused competitive inhibition of responses to BHT-920 (pKb 9.04 +/- 0.27) and dopamine (pKb 8.2 +/- 0.2). These data indicate that equine digital veins possess both post-synaptic alpha1 and alpha2-adrenoceptors.
TL;DR: Results of this study suggest fluconazole can effectively be administered to cats at 50 mg per cat per day, as suggested by non-compartmental analysis of data.
Abstract: The pharmacokinetics of fluconazole following intravenous (i.v.) and oral (p.o.) administration and the penetration of fluconazole into cerebrospinal fluid, aqueous humour and epithelial lining fluid (ELF) of the lungs were evaluated in adult male cats. Pharmacokinetic parameters were calculated from serum concentration-time data obtained following i.v. and p.o. administration of 50 mg per cat using a cross-over study design. Fluconazole concentrations were measured using a high-performance liquid chromatography assay. Mean total body clearance of fluconazole was 37.7 mL/h.kg, mean volume of distribution at steady state was 1.14 L/kg, mean residence time was 31.0 h and mean half-life of elimination was 25 h as derived by non-compartmental analysis of data. Absorption was complete. Mean ratios of fluid:serum fluconazole concentrations following administration of 50 mg fluconazole per day for 8 days were as follows: cerebrospinal fluid, 0.88; aqueous humour 0.79; ELF, 1.20. Fluconazole concentrations in cerebrospinal fluid, aqueous humour and ELF exceeded reported minimum inhibitory concentrations of fluconazole for pathogenic fungi. Results of this study suggest fluconazole can effectively be administered to cats at 50 mg per cat per day.
TL;DR: Midazolam reduced the hormonal stress response commonly observed during halothane anaesthesia and appears to have a good potential for use in horses.
Abstract: Six Welsh gelding ponies were premedicated with 0.03 mg/kg of acepromazine intravenously (i.v.) prior to induction of anaesthesia with midazolam at 0.2 mg/kg and ketamine at 2 mg/kg i.v.. Anaesthesia was maintained for 2 h using 1.2% halothane concentration in oxygen. Heart rate, electrocardiograph (ECG), arterial blood pressure, respiratory rate, blood gases, temperature, haematocrit, plasma arginine vasopressin (AVP), dynorphin, beta-endorphin, adrenocorticotropic hormone (ACTH), cortisol, dopamine, noradrenaline, adrenaline, glucose and lactate concentrations were measured before and after premedication, immediately after induction, every 20 min during anaesthesia, and at 20 and 120 min after disconnection. Induction was rapid, excitement-free and good muscle relaxation was observed. There were no changes in heart and respiratory rates. Decrease in temperature, hyperoxia and respiratory acidosis developed during anaesthesia and slight hypotension was observed (minimum value 76 +/- 10 mm Hg at 40 mins). No changes were observed in dynorphin, beta-endorphin, ACTH, catecholamines and glucose. Plasma cortisol concentration increased from 220 +/- 17 basal to 354 +/- 22 nmol/L at 120 min during anaesthesia; plasma AVP concentration increased from 3 +/- 1 basal to 346 +/- 64 pmol/L at 100 min during anaesthesia and plasma lactate concentration increased from 1.22 +/- 0.08 basal to 1.76 +/- 0.13 mmol/L at 80 min during anaesthesia. Recovery was rapid and uneventful with ponies taking 46 +/- 6 min to stand. When midazolam/ketamine was compared with thiopentone or detomidine/ketamine for induction before halothane anaesthesia using an otherwise similar protocol in the same ponies, it caused slightly more respiratory depression, but less hypotension. Additionally, midazolam reduced the hormonal stress response commonly observed during halothane anaesthesia and appears to have a good potential for use in horses.
TL;DR: It is shown, both on theoretical grounds and using Monte Carlo simulations, that the main assumptions for the correct use of linear regression do not hold when a tissue depletion curve is under investigation.
Abstract: The aim of this article is to review current issues concerning the statistical determination of a withdrawal time for a veterinary drug. Special attention has been paid to the Food and Drug Administration (FDA) approach which consists of using a regression method to estimate a 99th percentile of the population with a 95% confidence level. The different assumptions of the simple regression techniques are reviewed. It is shown, both on theoretical grounds and using Monte Carlo simulations, that the main assumptions for the correct use of linear regression do not hold when a tissue depletion curve is under investigation. Finally, it is suggested that methods other than the regression technique must be evaluated, especially a revised version of the so-called simpler approach, which consists of using a non-parametric strategy to estimate a withdrawal time.
TL;DR: The results suggest that when treating sheep and goats, the pharmacokinetic differences between the two species must be considered in order to optimize the therapeutic doses of ampicillin and oxytetracycline.
Abstract: In this investigation the pharmacokinetics of three commonly used antibiotics, ampicillin trihydrate (10 mg/kg), gentamicin sulphate (3 mg/kg) and oxytetracycline hydrochloride (5 mg/kg), given intravenously, were each studied in five Nubian goats and five desert sheep. The pharmacokinetic parameters were described by a two-compartment open model. The results indicated that there were significant differences between the two species in some kinetic parameters of ampicillin and oxytetracycline but not gentamicin. Ampicillin elimination half life (t1/2β) in goats (1.20 h) was shorter than that in sheep (2.48 h), and its clearance (Cl) significantly higher in goats (2921mL/h·kg) compared to sheep (262 mL/h·kg) (P < 0.01). Ampicillin volume of distribution (Vdarea) was found to be significantly larger in goats (5673 mL/kg) than in sheep (992 mL/kg) (P < 0.01). For oxytetracycline, the t1/2β in goats (3.89 h) was significantly shorter than that in sheep (6.30 h) and the Cl value in goats (437 mL/h·kg) was significantly higher than in sheep (281 mL/h·kg). The results suggest that when treating sheep and goats, the pharmacokinetic differences between the two species must be considered in order to optimize the therapeutic doses of ampicillin and oxytetracycline.
TL;DR: Results indicate that infusion of pentoxifylline will increase 6-keto-prostaglandin F1 alpha and significantly suppress endotoxin-induced tumour necrosis factor activity in horses during the period of infusion.
Abstract: Pentoxifylline (7.5 mg/kg) was bolused intravenously to eight healthy horses and was immediately followed by infusion (1.5 mg/kg/h) for 3 h. Clinical parameters were recorded and blood samples were collected for 24 h. Plasma was separated and concentrations of pentoxifylline, its reduced metabolite I, and 6-keto-prostaglandin F1 alpha were determined. Heparinized whole blood was also incubated ex vivo with 1 ng Escherichi coli endotoxin/mL blood for 6 h before determination of plasma tumour necrosis factor activity. The peak plasma concentrations of pentoxifylline and metabolite I occurred at 15 min after bolus injection and were 9.2 +/- 1.4 and 7.8 +/- 4.3 micrograms/mL, respectively. The half-life of elimination (t1/2 beta) of pentoxifylline was 1.44 h and volume of distribution (Vdarea) was 0.94 L/kg. The mean plasma concentration of 6-keto-prostaglandin F1 alpha increased over time, with a significant increase occurring 30 min after the bolus administration. Ex vivo plasma endotoxin-induced tumour necrosis factor activity was significantly decreased at 1.5 and 3 h of infusion. These results indicate that infusion of pentoxifylline will increase 6-keto-prostaglandin F1 alpha and significantly suppress endotoxin-induced tumour necrosis factor activity in horses during the period of infusion.
TL;DR: The locomotor chamber is a useful, sensitive and highly reproducible tool for measuring spontaneous locomotor activity in the horse, which allows investigators to determine an agent's average time of onset, duration and intensity of effect on movement.
Abstract: This report describes the development of a behaviour chamber and the validation of the chamber of measure locomotor activity of a horse. Locomotor activity was detected by four Mini-beam sensors and recorded on a data logger every 5 min for 22 h. Horses were more active during daytime than in the evening, which was at least partially related to human activity in their surroundings. To validate the ability of the chambers to detect changes in activity, fentanyl citrate and xylazine HCl, agents well-characterized as a stimulant and a depressant, respectively, were administered to five horses. Fentanyl citrate (0.016 mg/kg) significantly increased locomotor activity which persisted for 30 min. Xylazine HCl (1 mg/kg) significantly reduced locomotor activity for 90 min. Amitraz produced a dose-dependent decrease in locomotor activity, lasting 75 min for the 0.05 mg/kg dose, 120 min for the 0.10 mg/kg dose, and 180 min for the 0.15 mg/kg dose. In a separate experiment, yohimbine administration immediately reversed the sedative effect of amitraz. This suggests there is a similarity in the mode of action of amitraz, xylazine and detomidine, as yohimbine acts primarily by blocking central alpha 2 -adrenoceptors that are stimulated by agents like xylazine. There was also a significant decrease in locomotor activity following injection of detomidine (0.02, 0.04 and 0.08 mg/kg) for 1.5, 3.5 and 5.0 h, respectively. The locomotor chamber is a useful, sensitive and highly reproducible tool for measuring spontaneous locomotor activity in the horse, which allows investigators to determine an agent's average time of onset, duration and intensity of effect on movement.
TL;DR: No synergistic effects were observed after i.v. infusion of polymyxin B with pentoxifylline, and this lack of synergy may be due to the production and release of pro-inflammatory cytokines other than TNF-alpha.
Abstract: The purpose of this study was to assess whether polymyxin B together with pentoxifylline, had beneficial effects on the acute-phase-response to E. coli endotoxin in the dwarf goat (n = 6). Polymyxin B partly neutralizes E. coli endotoxin by forming inactive polymyxin B-lipopolysaccharide (LPS) complexes; pentoxifylline has been reported to suppress the LPS-induced production of tumour necrosis factor (TNF-alpha). E. coli LPS (0.0067 microgram/kg/min over 30 min) induced fever, tachycardia, inhibition of rumen motility, a decline in WBC, lymphopenia, and decreases in plasma zinc and iron concentrations. Most of the haematological, blood biochemical and clinical effects of E. coli LPS were significantly reduced by polymyxin B pretreatment (0.1 mg/kg/min over 30 min, i.v.). Pentoxifylline (0.3 mg/kg/min over 30 min, i.v.) did not reduce the clinical and blood biochemical effects of E. coli LPS, however, it modulated the number of circulating neutrophils. No synergistic effects were observed after i.v. infusion of polymyxin B with pentoxifylline. The lack of synergy may be due to the production and release of pro-inflammatory cytokines other than TNF-alpha.
TL;DR: A simple and understandable non-parametric method which allows the control of the risk in the estimation of the withdrawal time of a veterinary drug.
Abstract: The study of a veterinary drug for use in a food producing animal requires the estimation of the withdrawal time which is defined as the time when it can be assessed with a controlled risk that a given percentage (less than 100(1-alpha)%) of animals have a concentration below the Maximal Limit of Residue (MRL). A simple and understandable non-parametric method which allows the control of the risk is presented. This method does not require the assumptions needed for the correct use of the current method of estimation to be met. A simple example which illustrates the use of this method is presented.
TL;DR: The study shows that ST-91 and clonidine produce a greater degree of Hypoxaemia than occurs with diazepam sedation, and that the hypoxaemic effect of alpha 2 adrenoceptor agonists in sheep are mainly mediated by peripheral alpha 2 Adrenoceptors.
Abstract: The cardiopulmonary effects of the intravenous administration of clonidine (15 micrograms/kg), ST-91 (30 micrograms/kg) and diazepam (04 mg/kg) were compared in five healthy sheep using a randomized cross-over design, to determine whether the hypoxaemic effects of alpha 2 adrenoceptor agonists are due to sedation, or to peripheral alpha 2 adrenoceptor stimulation All three drugs significantly lowered arterial oxygen tension (PaO2) levels within 2 min of their administration; however, clonidine and ST-91 produced long lasting and severe hypoxaemia with mean PaO2 levels of approximately equal to 40 mm Hg and 50 mm Hg (53 kPa and 66 kPa), respectively The fall in PaO2 was considerably less with diazepam (63 mm Hg or 84 kPa at 2 min) and by 15 min the values did not differ from placebo treated animals None of the drugs increased arterial carbon dioxide tension (PaCO2) levels when compared to saline treatment and the acid base variables did not show any significant change A significant increase was recorded in the packed cell volume of the ST-91 treated group throughout the study Within 2 min of their administration, all drugs caused a significant increase in mean arterial pressure (MAP) as compared to the placebo treated group The MAP remained significantly increased for 5 and 60 min after clonidine and ST-91 treatment, respectively The study shows that ST-91 and clonidine produce a greater degree of hypoxaemia than occurs with diazepam sedation, and that the hypoxaemic effect of alpha 2 adrenoceptor agonists in sheep are mainly mediated by peripheral alpha 2 adrenoceptors
TL;DR: Minimum inhibitory concentrations for 35 antimicrobial agents against 100 Fusobacterium necrophorum isolates from hepatic abscesses in sheep and cattle were determined.
Abstract: Minimum inhibitory concentrations for 35 antimicrobial agents against 100 Fusobacterium necrophorum isolates from hepatic abscesses in sheep and cattle were determined. Twelve of the thirteen beta-lactam antibiotics tested inhibited growth of 100% of strains tested. Of the remaining antimicrobial agents, extensive susceptibility was found for: spiramycin, josamycin, lincomycin, tylosin, oxytetracycline, chlortetracycline, rufloxacin, metronidazole, cotrimoxazole, sulfadimethoxine, virginiamycin and fosfomycin.
TL;DR: Both ointments were well tolerated and no gross or histopathologic abnormalities developed during the trial and no itraconazole could be detected in the aqueous humour in either treatment group.
Abstract: The objectives of this study were to determine the concentration of itraconazole achieved in corneal tissue and aqueous humour after topical application of a 1% itraconazole ointment: to determine the effect of including dimethyl sulphoxide (DMSO) in the ointment on achievable ocular tissue itraconazole concentrations; and to assess if any gross or histopathologic ocular toxicity results from the topical application of 1% itraconazole with or without the addition of DMSO. The experimental trial consisted of 6 horses considered to have normal eyes. Each horse had one eye treated with 0.3 mL of 1% ultra-micronized itraconazole ointment and the fellow eye with 0.3 mL of 1% itraconazole/ 30% DMSO ointment. The ointment was applied every 6 h for a total of 28 treatments. Both ointments were well tolerated and no gross or histopathologic abnormalities developed during the trial. Corneal tissue and aqueous humour concentrations of itraconazole were determined using high performance liquid chromatography. Corneal tissue concentration averaged 1.1 (+/- 0.4) micrograms/g in horses treated with the 1% ultramicronized itraconazole ointment and 7.9 (+/- 3.3) micrograms/g for those treated with the 1% itraconazole/30% DMSO ointment: there was a statistically significant difference between ointments (P = 0.005) No itraconazole could be detected in the aqueous humour in either treatment group.
TL;DR: In this review, the design and evaluation of bioequivalence studies are presented with special attention given to scientific issues.
Abstract: A bioequivalence trial is a statistically based comparison of two formulations to demonstrate with a controlled consumer (patient) risk that two formulated drug products are interchangeable. The basic assumption underlying a bioequivalence trial is that essentially the same plasma time-course leads to essentially the same effect allowing two formulations to be interchanged. Bioequivalence is generally assessed using kinetic end points and in practice, two formulations in which bioavailability parameters (rate and extent) differ by 20% or less, with a 90% degree of confidence, are considered to be bioequivalent. In this review, the design and evaluation of bioequivalence studies are presented with special attention given to scientific issues.
TL;DR: It is shown that severe adverse drug-reactions sometimes occur in Swedish veterinary practice and adverse effects to vaccines were the most frequently reported reactions in cats and dogs.
Abstract: The present article gives a summary of suspected adverse reactions reported by Swedish veterinarians during the period 1991-1995. The summary shows that severe adverse drug-reactions sometimes occur in Swedish veterinary practice. In horses, several cases of acute reactions in animals treated with procaine benzylpenicillin were reported and seven horses died within a few minutes after intramuscular injections of the drug. In cattle and swine most reports referred to the use of antimicrobial agents. In dogs reactions to vaccines were the most frequently reported adverse effects. The reactions were, however, usually rather mild. In dogs there were also several reports of severe reactions related to treatments with non-steroid anti-inflammatory drugs (NSAID) and alpha 2-receptor agonists. Amongst the reports six deaths were observed for each of these groups of drugs. In cats, as in dogs, adverse effects to vaccines were the most frequently reported reactions.
TL;DR: From data, it appears that a 20 mg/kg dose administered every 8 h by the s.c. route would optimize the pharmacodynamic profile of ofloxacin and provide an appropriate regimen for the treatment of many susceptible organisms which commonly infect this species.
Abstract: Limited information exists regarding the disposition of ofloxacin in rabbits. Pharmacokinetic information is necessary for the design of appropriate therapeutic regimens for the treatment of organisms (e.g. Pasteurella multocida) commonly infecting this species. This study evaluated the pharmacokinetics of ofloxacin following intravenous (i.v.) and subcutaneous (s.c.) administration. Two groups of three female New Zealand White rabbits received a single dose of 20 or 40 mg/kg by the i.v. and s.c. routes. Samples were collected prior to drug administration, then 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, and 8 h postdose. Ofloxacin concentrations in serum were determined using a validated HPLC assay. Mean maximum concentrations were 66.86 +/- 10.83 mg/L and 14.1 +/- 2.20 mg/L for the i.v. and s.c. administration of 20 mg/kg. The 40 mg/kg dose produced maximum concentrations of 154.96 +/- 35.45 mg/L and 23.83 +/- 4.01 mg/L for the i.v. and s.c. doses, respectively. The area under concentration-time curve increased proportionally with the dose, while the half-life was unaltered and ranged from 1.5-1.9 h. From these data, it appears that a 20 mg/kg dose administered every 8 h by the s.c. route would optimize the pharmacodynamic profile of ofloxacin and provide an appropriate regimen for the treatment of many susceptible organisms which commonly infect this species.