Pharmacokinetics of midazolam administered concurrently with ketamine after intravenous bolus or infusion in dogs

Brown, S.A., Jacobson, J.D., Hartsfield, S.M. Pharmacokinetics of midazolam administered concurrently with ketamine after intravenous bolus or infusion in dogs. J. vet. Pharmacol. Therap. 16 , 419–425. Midazolam, a water-soluble benzodiazepine tranquilizer, has been considered by some veterinary anaesthesiologists to be suitable as a combination anaesthetic agent when administered concurrently with ketamine because of its water solubility and miscibility with ketamine. However, the pharmacokinetics of midazolam have not been extensively described in the dog. Twelve clinically healthy mixed breed dogs (22.2–33.4 kg) were divided into two groups at random and were administered ketamine (10 mg/kg) and midazolam (0.5 mg/kg) either as an intravenous bolus over 30 s (group 1) or as an i.v. infusion in 0.9% NaCl (2 ml/kg) over 15 min. Blood samples were obtained immediately before the drugs were injected and periodically for 6 h afterwards. Serum concentrations were determined using gas chromatography with electron-capture detection. Serum concentrations were best described using a two-compartment open model and indicated a t_½α of 1.8 min and t_½β.p of 27.8 min after i.v. bolus, and t_½α f 1–35 min and t_½β of 31.6 min after i.v. infusion. The calculated pharmacokinetic coefficient B was significantly smaller after i.v. infusion (429 ± 244 ng/ml) than after i.v. bolus (888 ± 130 ng/ml, P = 0.004). Furthermore, AUC was significantly smaller after i.v. infusion (29 800 ±6120 ng/h/ml) than after i.v. bolus (42 500 ± 8460 ng/h/ml, P < 0.05), resulting in a larger Cl_B after i.v. infusion (17.4 ± 4.00 ml/min/kg than after i.v. bolus (12.1 ± 2.24 ml/min/kg, P < 0.05). No other pharmacokinetic value was significantly affected by rate of intravenous administration.     

Placental transfer of etomidate in pregnant ewes after an intravenous bolus dose and continuous infusion

Etomidate (ETO) is a short-acting intravenous (IV) anaesthetic characterised by cardiopulmonary stability and favourable pharmacokinetics. Although ETO has been used satisfactorily in obstetrical anaesthesia, little is known about placental transfer and the drug's pharmacokinetics in the fetus. Placental transfer in pregnant ewes has been evaluated following the administration of an IV bolus of 1mg/kg ETO; and after a 1-h infusion of 100 microg/kg min(-1) ETO preceded by an IV bolus of 1mg/kg. In ewes, ETO concentration and AUC were higher than those found in fetuses. After the ETO bolus dose, the fetus:ewe AUC ratio was 0.45+/-0.32, and the mean residence time (MRT) was 20+/-7 min for dams and 22+/-3 min for the fetuses. After ETO infusion, the AUC ratio was 0.37+/-0.08, and MRT was 46+/-12 min for ewes and 46+/-22 min for fetuses. Although ETO crosses the placenta very rapidly and reaches the fetus in high amounts, a certain placental barrier effect limits its transfer. There is no evidence of cumulative effects of the drug in the fetus as fetal ETO elimination was as rapid as in the dam.     

Causes of anaphylactoid reactions in cattle after administration of lipoid preparations]

In 1986-1988, adverse anaphylactoid reactions (AR) were observed in animals in Czechoslovakia after the administration of oil adjuvant-containing vaccines or other lipoid drugs. Treated animals showed signs resembling the classic anaphylactic reaction, i.e. restlessness, salivation, pruritus, oedema and cyanosis of udder and vulva, and eyelid oedema, developing within a few minutes. The reactions were not elicited by the antigen alone, but by the oil adjuvant. The aim of our experiments was to identify substances eliciting the reaction in susceptible animals and to investigate possible induction mechanisms. The emulsifier Tween 80 has been demonstrated to be an AR inducing component of vaccines and drugs (Tab. I and III). Weak or moderate reactions were observed in 33% of animals treated with 5% Tween and 66% of those treated with 10% Tween showed strong reactions. On the other hand, no reactions were elicited by treatment with several paraffin oils of different quality (Tab. I) nor with an oil-in-water emulsion containing Montanid as an emulsifier (Tab. II). The role of the vegetative nervous system in the rise of AR has been confirmed. AR were suppressed in animals pretreated with parasympatholytic atropine and enhanced in a part of those pretreated with parasympathomimetic pilocarpine (Tab. III). The percentage of animals affected and the intensity of AR were also lower in animals pretreated with complement inhibitor epsilon-aminocapronic acid (Tab. IV). A major role of complement activation is suggested in the discussion of possible mechanisms of AR induction. It is possible to draw a conclusion on the basis of the results presented here and of the analysis of individual cases that a certain degree of animal susceptibility, depending on the phase of reproductive cycle, metabolism level and neurovegetative balance is necessary besides the administration of an AR inducer (Tween 80 in our case). Hence it seems that the adverse anaphylactoid reactions results from interactions of the two factors, i.e. administration of an AR inducer to susceptible animals.     

Determination of volatile fatty acids in the blood plasma of cattle before and after an infusion of propionate and butyrate

Before and after infusion of propionate and butyrate the concentrations of volatile fatty acids (VFA) in the blood of heifers were determined by gas chromatography, in order to indicate activity and regulation of the carbohydrate metabolism. 14 heifers were loaded after food deprivation with intravenous infusions of propionate and butyrate. Concentrations of acetate, propionate, isobutyrate, butyrate, and valerate were measured in blood samples which were taken later on. The methods used for clearance and extraction as well as for gas chromatographic analysis are described. Retention times and blood concentrations are given for each VFA. Concentrations prior to infusion were for: acetate 10.14 +/- 2.51 microliters/ml; propionate 0.42 +/- 0.35 microliters/ml; iso-butyrate 3.72 +/- 1.37 microliters/ml; butyrate 3.44 +/- 0.68 microliters/ml blood plasma. The concentrations of the infused VFA showed a 100 (butyrate) to 1000 (propionate) fold increase followed by a subsequent decrease to the initial values. These investigations on the profile of VFA elucidated criteria of the energy metabolism.     

Stability and storage characteristics of enzymes in cattle blood

The stability and storage characteristics were studied of 11 bovine enzymes of potential clinical significance, namely, aldolase, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, acetylcholinesterase, creatine kinase, gamma glutamyltransferase, glutathione peroxidase (GSH-Px), alpha-hydroxybutyrate dehydrogenase, lactate dehydrogenase and superoxide dismutase (SOD). Enzyme activities in fresh serum were compared with those in plasma containing various anticoagulants including lithium heparin, EDTA and oxalate/fluoride. The same preservatives were assessed for their effects on the whole blood activities of GSH-Px and SOD. Stabilities of enzymes in plasma and serum stored at room (+20 degrees C), refrigerator (4 degrees C) or deep freeze (-20 degrees C) temperatures were also compared. In addition, SOD and GSH-Px activities in samples stored, at the same temperatures, as whole blood or aqueous lysates were monitored.     

Non-linear pharmacokinetics of ofloxacin after a single intravenous bolus dose in pigs

The pharmacokinetics of ofloxacin (OFLX) was investigated after intravenous administration of 3, 10 and 30 mg/kg of body weight in pigs. Plasma OFLX concentration-time course collected from the highest dosage showed a convex decline, indicating a capacity-limited process in drug elimination (Michaelis-Menten elimination). Dose-normalized area under curve (AUC/Dose) and mean resident time (MRT) were dose-dependent, indicating a classical pattern of non-linear elimination pharmacokinetics. Based on simultaneous curve fitting from three doses, non-linear pharmacokinetic parameters were as follows: 0.87 mg/h/kg for maximum velocity, 2.20 microg/mL in Michaelis-Menten constant and 2.06 L/kg for apparent volume of distribution. Based on a model-independent analysis, the apparent volume of distribution at steady-state (Vdss) was dose-independent whereas total body clearance (CLtot) was dose-dependent, mainly contributed by renal clearance (CLr) with the regression line of CLtot=1.14xCLr+0.09 (r=0.92). The intercept of the regression line indicates non-renal clearance (CLnr), corresponding to the value of observed CLnr without dose-dependency. Because of a higher CLr compared with glomerular filtration rate (GFR) in spite of drug reabsorption, the CLr must contain the renal active tubular secretion. With increasing dosage, the level of saturation of tubular secretion of OFLX decreased the CLr, resulting in the decrease in CLtot. The plasma protein binding to OFLX was dose-independent: mean free fraction (fp)=0.73, with probably no influential effect on OFLX disposition. In conclusion, the degree of saturation in the renal active tubular secretion of OFLX could be a major causal factor in the alteration of CLr in an increasing dosage of OFLX. Accordingly, the alteration of CLr could directly induce the non-linear pharmacokinetics of OFLX in pigs, an important consideration in clinical therapeutics.     

Albendazole sulphoxide enantiomeric ratios in plasma and target tissues after intravenous administration of ricobendazole to cattle

The comparative concentration profiles of the (+) and (-) albendazole sulphoxide (ABZSO) enantiomers obtained in plasma and in selected target tissues/fluids after intravenous (i.v.) administration of a racemic formulation of ricobendazole (RBZ) to cattle were characterised. Fourteen Holstein calves received RBZ (racemic solution, 150 mg/mL) by i.v. administration at 7.5 mg/kg. Jugular blood samples were collected over 48 h post-treatment (plasma kinetic trial) and two animals were sacrificed at either 4, 12, 20, 28 or 32 h post-treatment to obtain samples of abomasal/small intestine mucosal tissue, abomasal/small intestine fluids, bile, liver and lung tissue (tissue distribution study). The (-)ABZSO enantiomer was depleted significantly faster from plasma compared with the (+)ABZSO antipode. The plasma AUC for (+)ABZSO (38.3 microg. h/mL) was significantly higher (P < 0.05) compared with that obtained for (-)ABZSO (20.5 microg. h/mL). The (+)ABZSO enantiomer was the predominant antipode measured in bile, abomasal fluid and abomasal mucosa. For instance, at 12 h post-treatment the (+)/(-) concentration ratios were: 12.9 (plasma), 1.62 (abomasal mucosa), 13.0 (abomasal fluid), 2.92 (intestinal mucosa), 9.87 (intestinal fluid) and 21.5 (bile). No marked differences between the concentration profiles of both enantiomers were observed in the liver tissue. Albendazole (ABZ) was recovered from the liver, lung and gastrointestinal (GI) mucosal tissues of RBZ-treated calves up to 32 h post-treatment, probably produced by a GI microflora-mediated sulphoreduction of RBZ. An enantioselective kinetic behaviour may account both for the faster depletion of the (-) enantiomer and for the higher availabilities of the (+) antipode observed in plasma and in most of the tissues/fluids investigated. The simultaneous evaluation of the plasma kinetics and tissue concentration profiles of both enantiomeric forms reported here, may help to interpret the relationship between chiral behaviour and pharmacological action for sulphoxide derivatives of benzimidazole (BZD) methylcarbamate anthelmintics.     

Plasma pharmacokinetics of alfaxalone in dogs after an intravenous bolus of Alfaxan-CD RTU

OBJECTIVE: To determine the pharmacokinetic parameters of alfaxalone in dogs after the intravenous (IV) administration of clinical and supra-clinical doses of a 2-hydroxypropyl-beta-cyclodextrin (HPCD) alfaxalone formulation (Alfaxan-CD RTU). EXPERIMENTAL DESIGN: Prospective two-period crossover design. Animals Eight (four male and four female) young adult healthy Beagle dogs. Methods The steroid anaesthetic alfaxalone was administered IV at two doses in a crossover design (2 and 10 mg kg(-1)) with a washout period of 21 days. Blood samples were collected before and up to 8 hours after dosing. Plasma concentrations of alfaxalone were assayed using a liquid chromatograph/mass selective detector technique and analyzed to estimate the main pharmacokinetic parameters by noncompartmental analysis. Results were expressed as mean +/- SD. RESULTS: The mean duration of anaesthesia from endotracheal intubation to extubation was 6.4 +/- 2.9 and 26.2 +/- 7.5 minutes, for the 2 and 10 mg kg(-1) doses, respectively. The plasma clearance of alfaxalone for the 2 and 10 mg kg(-1) doses differed statistically at 59.4 +/- 12.9 and 52.9 +/- 12.8 mL kg(-1) minute(-1), respectively (p = 0.008) but this difference was deemed clinically unimportant; the harmonic mean plasma terminal half-lives (t(1/2)) were 24.0 +/- 1.9 and 37.4 +/- 1.6 minutes respectively. The volume of distribution was between 2 and 3 L kg(-1) and did not differ between the two doses. No sex effect was observed. CONCLUSIONS AND CLINICAL RELEVANCE: Alfaxalone, as an HPCD formulation (Alfaxan-CD RTU) administered in the dog provides rapid and smooth induction of anaesthesia, satisfactory conditions for endotracheal intubation and a short duration of anaesthesia. There was no clinically significant modification of the pharmacokinetic parameters between sexes and between the clinical (2 mg kg(-1)) and supra-clinical (10 mg kg(-1)) doses.     

Persistence of ivermectin in plasma and faeces following administration of a sustained-release bolus to cattle

Six calves (weight 210 to 230 kg) were dosed with an intra-ruminal slow-release bolus prepared to deliver ivermectin at a low daily dosage for 135 days. Ivermectin concentrations in jugular blood 160 days post-treatment were determined by high performance liquid chromatography (HPLC) using fluorescence detection. Ivermectin plasma concentrations increased gradually to achieve the steady-state concentration (20 ng ml(-1)) at approximately four days post-treatment, which was maintained for 120 days. The ivermectin peak plasma concentration (28.5 ng ml(-1)) was attained at 15 days post-administration of the bolus. The faecal ivermectin concentration rose to a maximal concentration of 4.1 microg g(-1) at four days post-treatment, dropping to a steady-state concentration of around 1.18 microg g(-1) which was maintained up to 120 days post-treatment. Ivermectin was detected in both plasma (0.05 ng ml(-1)) and faeces (2.67 ng g(-1)) up to 160 days. The high levels of ivermectin recovered in faeces indicate that a large proportion of the dose released by the bolus (80 to 90 per cent) is excreted in faeces.     

奶牛乳房内灌注头孢噻呋钠的消除动力学研究

在奶牛乳房内灌注头孢噻呋钠后,采用超高效液相色谱一串联质谱法测定牛乳中头孢噻呋的浓度,对其消除动力学进行了研究。3头实验奶牛按每个乳房0．3g头孢噻呋灌注,牛乳中药物达到的最高浓度Cmax=107．89μg／mL,达峰时间Tmax=8h,药物半衰期T1/2=13．97h。在乳房内用药后的最初56h内,头孢噻呋浓度快速下降;最后一次给药88h后,所有乳腺中头孢噻呋的浓度都低于允许限量（0．1μg／mL）。故建议头孢噻呋在牛奶中的休药期为4d。     

Comparative plasma kinetics of orally administered sulfamethazine in clinically parasitized and parasitism-treated lambs

Sulfamethazine was administered at a dosage of 99 mg/kg body weight to lambs with a naturally acquired parasitism and again at 37 days following treatment with an anthelmintic. Blood samples were analyzed for sulfonamides over a 72 h period following sulfamethazine administration in both phases of the study. Pharmacokinetic parameter estimates of the sulfonamide blood data demonstrated significantly lower peak levels, longer times to peak and higher blood levels of the drug as time after dosing increased, in the parasitized as compared with the parasitism-treated lambs.     

Elimination of homologous and heterologous (bovine) serum albumin from the blood circulation in the dog

The elimination of intravenously administered I¹³¹-labelled bovine serum albumin has been compared to the elimination rate of relabelled homologous serum albumin in normal and bled dogs, which had lost considerable blood volumes. The investigation shows that during the first four to five days after the administration the elimination is similar of heterologous and homologous serum albumin. This proves that bovine serum albumin can be regarded to be an equivalent plasma expander to homologous serum albumin in the dog. Elimination of homologous as well as heterologous serum albumin follows a simple exponential curve during four to five days after administration. The intravascular half-lives for homologous serum albumin were 6.4 ±1.5 days and 6.4 ± 0.6 days respectively in control and bled dogs. Corresponding values for heterologous (bovine) serum albumin were 5.0 ± 0.3 and 4.8 ± 0.4 days respectively.The quote for cencentrations of homologous and heterologous serum albumin in different tissues was found to be relatively constant approximately 1.4. An exception was the stomach wall in bled dogs which had a quote of 1.1 only.