Pharmacodynamics and pharmacokinetics of phenylbutazone in calves

Phenylbutazone (PBZ) was administered to six calves intravenously (i.v.) and orally at a dose rate of 4.4 mg/kg in a three-period cross-over study incorporating a placebo treatment to establish its pharmacokinetic and pharmacodynamic properties. Extravascular distribution was determined by measuring penetration into tissue chamber fluid in the absence of stimulation (transudate) and after stimulation of chamber tissue with the mild irritant carrageenan (exudate). PBZ pharmacokinetics after i.v. dosage was characterized by slow clearance (1.29 mL/kg/h), long-terminal half-life (53.4 h), low distribution volume (0.09 L/kg) and low concentrations in plasma of the metabolite oxyphenbutazone (OPBZ), confirming previously published data for adult cattle. After oral dosage bioavailability (F) was 66%. Passage into exudate was slow and limited, and penetration into transudate was even slower and more limited; area under curve values for plasma, exudate and transudate after i.v. dosage were 3604, 1117 and 766 microg h/mL and corresponding values after oral dosage were 2435, 647 and 486 microg h/mL. These concentrations were approximately 15-20 (plasma) and nine (exudate) times greater than those previously reported in horses (receiving the same dose rate of PBZ). In the horse, the lower concentrations had produced marked inhibition of eicosanoid synthesis and suppressed the inflammatory response. The higher concentrations in calves were insufficient to inhibit significantly exudate prostaglandin E2 (PGE2), leukotriene B4 (LTB4) and beta-glucuronidase concentrations and exudate leucocyte numbers, serum thromboxane B2 (TxB2), and bradykinin-induced skin swelling. These differences from the horse might be the result of: (a) the presence in equine biological fluids of higher concentrations than in calves of the active PBZ metabolite, OPBZ; (b) a greater degree of binding of PBZ to plasma protein in calves; (c) species differences in the sensitivity to PBZ of the cyclo-oxygenase (COX) isoenzymes, COX-1 and COX-2 or; (d) a combination of these factors. To achieve clinical efficacy with single doses of PBZ in calves, higher dosages than 4.4 mg/kg will be probably required.     

Pharmacokinetic studies of flunixin meglumine and phenylbutazone in plasma,exudate and transudate in sheep

Flunixin meglumine (FM, 1.1 mg/kg) and phenylbutazone (PBZ, 4.4 mg/kg) were administered intravenously (i.v.) as a single dose to eight sheep prepared with subcutaneous (s.c.) tissue-cages in which an acute inflammatory reaction was stimulated with carrageenan. Pharmacokinetics of FM, PBZ and its active metabolite oxyphenbutazone (OPBZ) in plasma, exudate and transudate were investigated. Plasma kinetics showed that FM had an elimination half-life (t_½β) of 2.48 ± 0.12 h and an area under the concentration – time curve (AUC) of 30.61 ± 3.41 μg/mL.h. Elimination of PBZ from plasma was slow (t_½β = 17.92 ± 1.74 h, AUC = 968.04 ± μg/mL.h.). Both FM and PBZ distributed well into exudate and transudate although penetration was slow, indicated by maximal drug concentration (C_max) for FM of 1.82 ± 0.22 μg/mL at 5.50 ± 0.73 h (exudate) and 1.58 ± 0.30 μg/mL at 8.00 h (transudate), and C_max for PBZ of 22.32 ± 1.29 μg/mL at 9.50 ± 0.73 h (exudate) and 22.07 ± 1.57 μg/mL at 11.50 ± 1.92 h (transudate), and a high mean tissue-cage fluids:plasma AUC_last ratio obtained in the FM and PBZ groups (80–98%). These values are higher than previous reports in horses and calves using the same or higher dose rates. Elimination of FM and PBZ from exudate and transudate was slower than from plasma. Consequently the drug concentrations in plasma were initially higher and subsequently lower than in exudate and transudate.     

Pharmacodynamics,chiral pharmacokinetics and PK-PD modelling of ketoprofen in the goat

There have been few studies of the pharmacodynamics of nonsteroidal antiinflammatory drugs (NSAIDs) using PK-PD modelling, yet this approach offers the advantage of defining the whole concentration-effect relationship, as well as its time course and sensitivity. In this study, ketoprofen (KTP) was administered intravenously to goats as the racemate (3.0 mg/kg total dose) and as the single enantiomers, S(+) KTP and R(-) KTP (1.5 mg/kg of each). The pharmacokinetics and pharmacodynamics of KTP were investigated using a tissue cage model of acute inflammation. The pharmacokinetics of both KTP enantiomers was characterized by rapid clearance, short mean residence time (MRT) and low volume of distribution. The penetration of R(-) KTP into inflamed (exudate) and noninflamed (transudate) tissue cage fluids was delayed but area under the curve values were only slightly less than those in plasma, whereas MRT was much longer. The S(+) enantiomer of KTP penetrated less readily into exudate and transudate. Unidirectional inversion of R(-) to S(+) KTP occurred. Both rac-KTP and the separate enantiomers produced marked inhibition of serum thromboxane B2 (TxB2) synthesis (ex vivo) and moderate inhibition of exudate prostaglandin E2 (PGE2) synthesis (in vivo); pharmacodynamic variables for S(+) KTP were Emax (%) = 94 and 100; IC50 (microg/mL) = 0.0033 and 0.0030; N = 0.45 and 0.58, respectively, where Emax is the maximal effect, IC50 the plasma drug concentration producing 50% of Emax and N the slope of log concentration/effect relationship. The IC50 ratio, serum TxB2:exudate PGE2 was 1.10. Neither rac-KTP nor the individual enantiomers suppressed skin temperature rise at, or leucocyte infiltration into, the site of acute inflammation. These data illustrate for KTP shallow concentration-response relationships, probable nonselectivity of KTP for cyclooxygenase (COX)-1 and COX-2 inhibition and lack of measurable effect on components of inflammation.     

Influence of marbofloxacin on the pharmacokinetics and pharmacodynamics of tolfenamic acid in calves

Pharmacokinetic and pharmacodynamic properties of tolfenamic acid (TA) in calves were determined in serum and fluids of inflamed (carrageenan administered) and non-inflamed subcutaneously implanted tissue cages after intramuscular administration both alone and in combination with marbofloxacin (MB). MB significantly altered the pharmacokinetics of TA: mean values were Cmax = 2.14 and 1.64 microg/mL, AUC = 27.38 and 16.80 microg.h/mL, Vd(area)/F = 0.87 and 1.17 L/kg, and ClB/F = 0.074 and 0.128 L/kg/h, respectively, after administration of TA alone and TA + MB. T(1/2)K10 and MRT were not significantly different for the two treatments. The pharmacodynamic properties of TA were not influenced by MB co-administration, in spite of the alterations in some TA pharmacokinetic parameters. TA inhibited prostaglandin E2 (PGE2) synthesis in vivo in inflammatory exudate by 50-88% for up to 48 h after both TA treatments. Inhibition of synthesis of serum thromboxane B2 (TxB2) ex vivo ranged from 40 to 85% up to 24 h after both TA and TA + MB. From the derived pharmacokinetic and eicosanoid inhibition data for TA, pharmacodynamic parameters for serum TxB2 and exudate PGE2 inhibition expressing efficacy (Emax = 78.1 and 97.5%), potency (IC50 = 0.256 and 0.265 microg/mL), sensitivity (N = 1.96 and 2.29) and the pharmacokinetic parameter equilibration time (t(1/2)K(e0) = 0.695 and 24.0 h), respectively, were determined. In this model TA was a nonselective inhibitor of cyclo-oxygenase (COX) (COX-1:COX-2 IC50 ratio = 1.37). TA, both alone and co-administered with MB, did not affect leucocyte numbers in exudate, transudate or blood. Partial attenuation of skin temperature rise over inflamed tissue cages and reduction of zymosan-induced skin swelling were recorded after administration of TA and TA + MB with no significant differences between the two treatments. These data provide a basis for the rational use of TA in combination with MB in calf medicine.     

Characterization of a sterile soft-tissue inflammation model in Thoroughbred horses

This paper describes the use of subcutaneously-placed tissue chambers as a sterile soft-tissue inflammation model in Thoroughbred horses. Acute, nonimmune inflammation was initiated by injecting a sterile lambda carrageenan solution into a tissue chamber. This model was used to study the temporal changes in oxygen and carbon dioxide tensions, pH, bicarbonate, protein, albumin, prostaglandin E₂ (PGE₂) and leukotriene B₄ (LTB₄) concentrations, cell counts and differential counts in tissue fluid from inflamed tissue chambers and control chambers. Skin temperatures over control and inflamed chambers were also compared. Carrageenan-induced inflammation resulted in significant increases in tissue-fluid carbon dioxide tension, leucocyte count, albumin, and PGE₂ and LTB₄ concentrations. It also resulted in a significant decrease in tissue fluid pH and HCO₃- concentration. Inflammation did not result in significant changes in tissue-fluid protein concentration, differential cell counts or skin temperature over the chambers. The use of this type of tissue chamber is wellsuited for studying the pathophysiology of a self-contained, non-immune inflammatory process. The model described in this paper could prove to be very useful in studies of the distribution of anti-inflammatory drugs and the effects of such drugs on various aspects of the inflammatory process.     

Development and validation of a tissue cage model of acute inflammation in the cat

Four cylindrical silicon tissue cages (TC, internal volume: 6.7 ± 0.11 cm(3)) were inserted subcutaneously in 29 young healthy cats. A mild inflammatory reaction was induced by intracaveal injection of 1 mL of a 2%λ-carrageenan solution. TC exudate was subsequently sampled at predetermined times (up to 120 h) to measure exudate leucocyte counts and the concentrations of protein and eicosanoids. TC remained in situ for 9-10 months and were well tolerated. Leucocyte counts peaked at 34 h (50.1 ± 57.6 × 10(3) cells/mm(3) ) and returned towards baseline after 72 h. Protein concentration increased from 26.2 ± 2.7 g/L to a peak of 35.9 ± 6.0 g/L at 12 h before returning to baseline at 48 h. Exudate prostaglandin (PG)E(2) concentration peaked at 24 h (11.7 ± 13.7 ng/mL) and returned to baseline by 120 h. Repeated collection of fluid from noninjected cages did not increase transudate PGE(2). Ketoprofen (2 mg/kg, subcutaneously) suppressed exudate PGE(2) at 24 h. The carrageenan-stimulated TC model is an ethical and novel means of investigating soft tissue inflammation in the cat, in which exudate PGE(2) acts as surrogate marker of cyclooxygenase-2 activity. This model will facilitate the investigation of in vivo pharmacokinetics and pharmacodynamics of anti-inflammatory drugs in this species.     

Pharmacokinetic and pharmacodynamic interactions of tolfenamic acid and marbofloxacin in goats

Pharmacokinetic and pharmacodynamic properties in goats of the non-steroidal anti-inflammatory drug tolfenamic acid (TA), administered both alone and in combination with the fluoroquinolone marbofloxacin (MB), were established in a tissue cage model of acute inflammation. Both drugs were injected intramuscularly at a dose rate of 2 mg kg⁻¹. After administration of TA alone and TA + MB pharmacokinetic parameters of TA (mean values) were C_max = 1.635 and 1.125 μg ml⁻¹, AUC = 6.451 and 3.967 μg h ml⁻¹, t_1/2K₁₀ = 2.618 and 2.291 h, Vdarea/F = 1.390 and 1.725 L kg⁻¹, and ClB/F = 0.386 and 0.552 L kg⁻¹ h⁻¹, respectively. These differences were not statistically significant. Tolfenamic acid inhibited prostaglandin (PG)E₂ synthesis in vivo in inflammatory exudate by 53-86% for up to 48 h after both TA treatments. Inhibition of synthesis of serum thromboxane (Tx)B₂ ex vivo ranged from 16% to 66% up to 12 h after both TA and TA + MB, with no significant differences between the two treatments.From the pharmacokinetic and eicosanoid inhibition data for TA, pharmacodynamic parameters after dosing with TA alone for serum TxB₂ and exudate PGE₂ expressing efficacy (E_max = 69.4 and 89.7%), potency (IC₅₀ = 0.717 and 0.073 μg ml⁻¹), sensitivity (N = 3.413 and 1.180) and equilibration time (t_1/2K_e0 = 0.702 and 16.52 h), respectively, were determined by PK-PD modeling using an effect compartment model. In this model TA was a preferential inhibitor of COX-2 (COX-1:COX-2 IC₅₀ ratio = 12:1). Tolfenamic acid, both alone and co-administered with MB, did not affect leucocyte numbers in exudate, transudate or blood. Compared to placebo significant attenuation of skin temperature rise over inflamed tissue cages was obtained after administration of TA and TA + MB with no significant differences between the two treatments. Marbofloxacin alone did not significantly affect serum TxB₂ and exudate PGE₂ concentrations or rise in skin temperature over exudate tissue cages. These data provide a basis for the rational use of TA in combination with MB in goat medicine.     

Anti-inflammatory effects of carprofen,carprofen enantiomers,and N(G)-nitro-L-arginine methyl ester in sheep

OBJECTIVE: To assess anti-inflammatory effects of carprofen (CPF), CPF enantiomers, and N(G)-nitro-L-arginine methyl ester (LNAME) in sheep. ANIMALS: 8 sheep. PROCEDURE: Sheep with SC tissue cages were used. After intracaveal injection of 1% carrageenan, sheep were given single doses of racemic (Rac; 50:50 mixture of S[+] and R[-] enantiomers)-CPF (4.0 mg/kg), R(-)CPF (2.0 mg/kg), S(+)CPF (2.0 mg/kg), LNAME (25 mg/kg), and placebo (PLB) IV in a crossover design. RESULTS: Rac-CPF and S(+)CPF inhibited serum thromboxane2 (TXB2) and exudate prostaglandin (PG)E2 generation significantly for 32 hours. Maximal inhibitory effect for serum TXB2 was 79+/-3% for Rac-CPF and 68+/-6% for S(+)CPF. The Rac-CPF and S(+)CPF induced 50 to 98% reversible inhibitory effect for exudate PGE2 generation during a 4- to 32-hour period. The R(-)CPF and LNAME attenuated serum TXB2 generation significantly. The R(-)CPF did not affect exudate PGE2 production, whereas L-NAME potentiated exudate, PGE2 generation by 30% during 4 to 32 hours. The S(+)CPF and LNAME increased leukotriene B4 generation and WBC recruitment in exudate although significance was achieved only at a few time points. Increase in skin temperature over inflammatory cages was effectively inhibited by Rac-CPF and S(+)CPF but not by R(-)CPF CONCLUSIONS AND CLINICAL RELEVANCE: Carprofen is a potent cyclooxygenase inhibitor in vivo in sheep, and its anti-inflammatory effects are attributable only to S(+)CPF in Rac-CPF. Nitric oxide may enhance eicosanoid production and accelerate the acute inflammatory process.     

Pharmacodynamics and pharmacokinetics of ketoprofen enantiomers in sheep

OBJECTIVE: To establish pharmacokinetic and pharmacodynamic properties of a racemic mixture and individual R(-) and S(+) enantiomeric forms of ketoprofen (KTP) in sheep and determine pharmacodynamic variables of KTP by pharmacokinetic-pharmacodynamic modeling. ANIMALS: 8 female Dorset crossbred sheep. PROCEDURE: A tissue cage model of inflammation was used. Carrageenan was administered into tissue cages. Time course of cyclooxygenase (COX)-2 inhibition was determined in vivo by measurement of exudate prostaglandin E2 (PGE2) concentrations. Time course of COX-1 inhibition was determined ex vivo by measurement of serum thromboxane B2 (TXB2) concentrations. In addition, plasma concentration-time course and penetration of KTP enantiomers into inflammatory exudate and transudate (noninflamed tissue cage fluid) were investigated. Four treatments were compared: placebo, racemic mixture (rac-KTP [3 mg/kg of body weight, IV]), S(+) KTP (1.5 mg/kg, IV),and R(-) KTP (1.5 mg/kg, IV). RESULTS: Both KTP enantiomers had elimination half-life and mean residence time measurements that were short and volume of the central compartment and steady state volume of distribution that were low. Clearance was rapid, particularly for R(-) KTP Elimination of both enantiomers from exudate was > 10 times slower than from plasma. Both rac-KTP and the individual enantiomers significantly inhibited serum TXB2 concentrations for 12 hours. Rac-KTP and S(+) KTP, but not R(-) KTP, also significantly inhibited PGE2 synthesis in exudate for 12 hours. CONCLUSIONS AND CLINICAL RELEVANCE: Inhibition of serum TXB2 concentration and exudate PGE2 synthesis for similar time courses after S(+) KTP administration indicates that it is a nonselective inhibitor of COX in sheep.     

Pharmacokinetics and pharmacodynamics of danofloxacin in serum and tissue fluids of goats following intravenous and intramuscular administration

OBJECTIVE: To determine the pharmacokinetics and pharmacodynamics of danofloxacin in goats and the concentrations required to induce bacteriostasis, bactericidal activity, and bacterial elimination. ANIMALS: 6 healthy British Saanen goats. PROCEDURE: Danofloxacin (1.25 mg/kg of body weight) was administered i.v. and i.m. in a cross-over design with 14 days between treatments. A tissue cage was used for evaluation of drug distribution into transudate and exudate. The ex vivo antibacterial activity of danofloxacin in serum, exudate, and transudate against a caprine isolate of Mannheimia haemolytica was determined. Pharmacokinetic and pharmacodynamic data were integrated to determine the ratio of the area under the concentration versus time curve to the minimum inhibitory concentration of danofloxacin (AUIC). RESULTS: Elimination half-lives of danofloxacin in serum were 4.67 and 4.41 hours after i.v. and i.m. administration, respectively. Volume of distribution was high after administration via either route, and bioavailability was 100% after i.m. administration. Rate of penetration into exudate and transudate was slow, but elimination half-lives from both fluids were approximately twice that from serum. Drug concentrations in serum, exudate, and transudate for 9 to 12 hours after administration induced marked ex vivo antibacterial activity. For serum, AUIC24h values required for bacteriostasis, bactericidal effect, and bacterial elimination were 22.6, 29.6, and 52.4, respectively. Similar values were obtained for exudate and transudate. CONCLUSIONS AND CLINICAL RELEVANCE: Integration of danofloxacin pharmacokinetic and pharmacodynamic data obtained in goats may provide a new approach on which to base recommendations for therapeutic dosages.     

辛夷油的药理学研究

向大白鼠胸腔注入角叉菜胶诱发胸膜炎,8h后处死动物，测定其胸腔渗出液中白细胞数、蛋白质及前列腺素E2（PGE2）的含量，体内白细胞介素1（IL-1）和肿瘤坏死因子（TNF）的含量。结果显示，事先灌服辛夷油的试验组动物，其胸腔渗出液中白细胞数、蛋白质和PGE2的含量均显著小于模型对照组；IL-1和TNF的含量也明显小于模型组，说明辛夷油能抑制炎症介质的产生，具有抗炎效应。     

Pharmacodynamics and pharmacokinetics of tolfenamicacid in ruminating calves: Evaluation in models of acute inflammation

Injections of mild irritants intradermally (carrageenan, zymosan and dextran) and intracaveally (carrageenan)in a tissue cage model of inflammation were used in studies of the pharmacodynamics and pharmacokinetics of tolfenamic acid administered intramuscularly in calves. Inhibition of serum thromboxane (TX) B₂ and inflammatory exudate prostaglandin (PG) E₂ were used as indicators of the magnitude and time course of blockade of cyclo-oxygenase isoforms COX-1 and COX-2, respectively. Single doses of 2, 4 and 8mgkg⁻¹ tolfenamic acid partially inhibited irritant-induced rises in skin temperature (non-dose dependently) and skin oedema (dose-dependently). These doses also markedly inhibited serum TXB₂ synthesis and the duration of inhibition was dose-related. A dose of 2mgkg⁻¹ tolfenamic acid also attenuated skin temperature rise over carrageenan-injected tissue cages, and markedly inhibited exudate PGE₂ synthesis, even though drug penetration into both exudate and tissue cage transudate was limited. Tolfenamic acid pharmacokinetics were characterized by a relatively short t_max (0.94–2.0411), a high estimated Vdarea (1.79–3.20Lkg⁻¹), an estimated ticase 1/2β of 8.01–13.5011 and Cl_β of 0.142–0.175Lkg⁻¹h⁻¹. The actions of tolfenamic acid in inhibiting PGE₂ synthesis and in attenuating two of the cardinal signs of inflammation (heat and swelling) suggest that a dosage of 2mgkg⁻¹ administered intramuscularly should be effective clinically as an anti-inflammatory agent.     

Pharmacokinetics and pharmacokinetic/pharmacodynamic integration of marbofloxacin in calf serum,exudate and transudate

Marbofloxacin is a fluoroquinolone antimicrobial drug used in cattle for the treatment of respiratory infections. In this investigation the pharmacokinetics (PK) of marbofloxacin were determined after intravenous and intramuscular dosing at a dosage of 2 mg/kg. In addition the ex vivo pharmacodynamics (PD) of the drug were determined in serum and three types of tissue cage fluid (transudate, inflammatory exudate generated by carrageenan and exudate generated by lipopolysaccharide). Marbofloxacin PK was characterized by a high volume of distribution after dosing by both routes (1.28 L/kg intravenous and 1.25 L/kg intramuscular). Corresponding area under the concentration-time curve (AUC) and elimination half-life (t(1/2)el) values were 9.99 and 10.11 microg h/mL and 4.23 and 4.33 h, respectively. Values of AUC for carrageenan-induced exudate, lipopolysaccharide-induced exudate and transudate were, respectively, 8.28, 7.83 and 7.75 microg h/mL after intravenous and 8.84, 8.53 and 8.52 microg h/mL after intramuscular dosing. Maximum concentration (Cmax) values were similar for the three tissue cage fluids after intravenous and intramuscular dosing. For in vivo PK data values of AUC: minimum inhibitory concentration (MIC) (AUIC) ratio for serum were 250 and 253, respectively, after intravenous and intramuscular dosing of marbofloxacin against a pathogenic strain of Mannheimia haemolytica (MIC=0.04 microg/mL). For all tissue cage fluids AUIC values were >194 and >213 after intravenous and intramuscular dosing, and Cmax/MIC ratios were 9 or greater, indicating a likely high level of effectiveness in clinical infections caused by M. haemolytica of MIC 0.04 microg/mL or less. This was confirmed by both in vitro (serum) and ex vivo (serum, exudate and transudate) measurements, which demonstrated a concentration-dependent killing profile for marbofloxacin against M. haemolytica. Ex vivo, after 24-h incubation, virtually all bacteria were killed (<10 cfu/mL) in all samples collected up to 9 h (serum), 24 h (carrageenan-induced exudate and transudate) and 36 h (lipopolysaccharide-induced exudate). Application of the sigmoid Emax equation to the ex vivo antibacterial data provided, for serum, AUIC24 h values of 37.1 for bacteriostasis, 46.3 for bactericidal activity and 119.6 for elimination of bacteria. These data may be used as a rational basis for setting dosing schedules which optimize clinical efficacy and minimize the opportunities for emergence of resistant organisms.     

A pharmacodynamic and pharmacokinetic study with vedaprofen in an equine model of acute nonimmune inflammation

The pharmacodynamics and enantioselective pharmacokinetics of vedaprofen were studied in six ponies in a two period cross-over study, in which a mild acute inflammatory reaction was induced by carrageenan soaked sponges implanted subcutaneously in the neck. Vedaprofen, administered intravenously at a dosage of 1 mg/kg, produced significant and prolonged inhibition of ex vivo serum thromboxane B₂ (TXB₂) synthesis and short-lived inhibition of exudate prostaglandin E₂ (PGE₂) and TXB₂ synthesis. Vedaprofen also partially inhibited oedematous swelling and leucocyte infiltration into exudate. Vedaprofen dis-played enantioselective pharmacokinetics, plasma concentrations of the R(–) enantiomer exceeding those of S(+) vedaprofen. The plasma concentration ratio, R:S, increased from 69: 31 at 5 min to 96: 4 at 3 h and plasma mean AUC values were 7524 and 1639 ng.h/mL, respectively. Volume of distribution was greater for S(+) vedaprofen, whilst elimination half-life (t_½β) and mean residence time were greater for R(–) vedaprofen. The penetration of vedaprofen into inflammatory exudate was also enantioselective. For R(–) and S(+) veda-profen maximum concentration (C_max) values were 2950 and 1534 ng/mL, respectively, and corresponding AUC values were 9755 and 4400 ng.h/mL. Vedaprofen was highly protein bound (greater than 99%) in both plasma and exudate. The significance of these data for the therapeutic use of vedaprofen is discussed.     

Pharmacokinetic and pharmacodynamic modelling of marbofloxacin administered alone and in combination with tolfenamic acid in calves

In a four-period, cross-over study, the fluoroquinolone antibacterial drug marbofloxacin (MB) was administered to calves, alone and in combination with the nonsteroidal anti-inflammatory drug tolfenamic acid (TA). Both drugs were administered intramuscularly (IM) at doses of 2 mg/kg. A tissue cage model of inflammation, based on the actions of the mild irritant carrageenan, was used to evaluate the pharmacokinetics (PK) of MB and MB in combination with TA. MB mean values of area under concentration-time curve (AUC) were 15.1 μg·h/mL for serum, 12.1 μg·h/mL for inflamed tissue cage fluid (exudate) and 9.6 μg·h/mL for noninflamed tissue cage fluid (transudate). Values of C(max) were 1.84, 0.35 and 0.31 μg/mL, respectively, for serum, exudate and transudate. Mean residence time (MRT) of 23.6 h (exudate) and 22.6 h (transudate) also differed significantly from serum MRT (8.6 h). Co-administration of TA did not affect the PK profile of MB. The pharmacodynamics of MB was investigated using a bovine strain of Mannheimia haemolytica. Time-kill curves were established ex vivo on serum, exudate and transudate samples. Modelling the ex vivo serum time-kill data to the sigmoid E(max) equation provided AUC(24 h) /MIC values required for bacteriostatic (18.3 h) and bactericidal actions (92 h) of MB and for virtual eradication of the organism was 139 h. Corresponding values for MB + TA were 20.1, 69 and 106 h. These data were used to predict once daily dosage schedules for a bactericidal action, assuming a MIC(90) value of 0.24 μg/mL, a dose of 2.6 mg/kg for MB and 2.19 mg/kg for MB + TA were determined, which are similar to the currently recommended dose of 2.0 mg/kg.     

Stereospecific pharmacodynamics and pharmacokinetics of carprofen in the dog

The non-steroidal anti-inflammatory drug (NSAID) carprofen (CPF) contains single chiral centre. It was administered orally to Beagle dogs as a racemate (rac-CPF) at a dose of 4 mg per kg body weight and as individual (-)(R) and (+)(S) enantiomers at 2 mg per kg body weight. Each of the enantiomers achieved similar plasma bioavailability following administration as the race-mate as they did following their separate administration. Only the administered enantiomers were detectable when the drug was given in the (-)(R) or (+) (S) form, indicating that chiral inversion did not occur in either direction. Higher plasma concentrations of the (-)(R) (C_max 18 μg/ml, AUC_0–24 118 μg h/ml) than the (+)(S) (C_max 14 μg/ml, AUC_0–24 67 μg h/ml) enantiomer were achieved following administration of the racemate. Both enantiomers distributed into peripheral subcutaneous tissue cage fluids, but C_max and AUC values were lower for both transudate (non-stimulated tissue cage fluid) and exudate (induced by the intracaveal administration of the irritant carrageenan) than for plasma. Drug concentrations in transudate and exudate were similar, as indicated by C_max and AUC values, although CPF penetrated more rapidly into exudate than into transudate. Neither rac-CPF nor either enantiomer inhibited thromboxane B₂ (T × B2) generation by platelets in clotting blood (serum T × B₂, or prostaglandin E₂, (PGE,) and 12-hydroxyeicosatetraenoic acid (1 2-HETE) synthesis in inflammatory exudate. Since other studies have shown that rac-CPF at the 4 mg/kg dose rate possesses analgesic and anti-inflammatory effects in the dog, it is concluded that the principal mode of action of the drug must be by mechanisms other than cyclooxygenase or 12-lipoxygenase inhibition.     

Examination of possible transmission of sheep scab mitePsoroptes ovis between host species

Examination of possible transmission of the Irish strain of the sheep scab mite (Psoroptes ovis) of ovine origin between host species involved calves and goats being placed with infected sheep and also directly challenged with live mites. Although mites remained on recipient species for up to a week, they failed to produce disease in either of these species. Calves and goats that had live mites placed on them likewise failed to infect sheep with which they were housed.     

The point prevalence of gastro-intestinal parasites in calves, sheep and goats in Magadi division, south-western Kenya

Helminths cause great economic loss in livestock in Africa, and can be categorized as either direct or indirect losses. Arid and semi-arid lands (ASAL) in Kenya comprise 71% of total land area and harbour the largest population of cattle, sheep and goats. However, little information on the distribution and impact of gastro-intestinal (GIT) parasitism in these animals is available. This survey was conducted to establish the prevalence of GIT parasites infecting calves, sheep and goats and their relative importance in Magadi division, which is semi-arid. Faecal samples were obtained directly from the rectum of 109 calves, 133 goats and 20 sheep and submitted to the laboratory for faecal worm egg counts, and coccidial oocysts examination using a modified McMaster method. The significance of differences in mean egg count per gram (epg) between animal species and herds (farms) were assessed using analysis of variance. The overall prevalence of nematodes in the calves, sheep and goats was 69.2%, 80% and 82%, respectively. About 10% of sheep and goats had epgs higher than 1 000, the remainder having light to moderate infections. The overall prevalence of coccidial oocysts in calves, sheep and goats was 30%, 44% and 45%, respectively. Poor productivity in ASAL areas, where nutrition is often poor, is likely to be pronounced in the presence of parasite infections. These findings indicate that viable internal parasite control should be implemented in the study area in order to increase the productivity of the livestock there.     

Arachidonic acid metabolites in carrageenin-induced equine inflammatory exudate

The presence of cyclooxygenase products of arachidonic acid metabolism in carrageenin-induced inflammatory exudate was investigated in ponies using two models. In the first model, an inflammatory response was stimulated by injecting carrageenin into subcutaneously implanted polypropylene tissue cages and exudates were collected at five predetermined times between 3 and 48 h. In the second model, exudates were harvested at 6, 12 and 24 h from carrageenin-impregnated polyester sponges which had also been inserted beneath the skin. Prostaglandin (PG) E2, thromboxane (TX) B2 and the stable breakdown-product of prostacyclin (PGI2), 6-keto-PGF1 alpha, in exudates were measured by radio-immunoassay (RIA); PGE2-like and PGF2 alpha-like activities were bioassayed following an acid-lipid extraction technique which provided a recovery rate of 78%. Agreement between RIA and bioassay was within acceptable limits. In Model 1, using RIA, mean PGE2 concentration reached 197 ng X ml-1 at 12 h decreasing to less than 12 ng X ml-1 at 24 h. Mean TXB2 and 6-keto-PGF1 alpha levels were highest at 48 h (22.3 and 34.2 ng X ml-1, respectively) after considerable fluctuations and with wide standard errors prior to this time. In the sponge model, however, PGE2 levels were surprisingly low for each group (mean 12.8 ng X ml-1 at 12 h) and TXB2 and 6-keto-PGF1 alpha were similarly lower (means of 3.3 and 8.1 ng X ml-1 respectively at 12 h). Mean total leucocyte counts and total protein concentrations were increased in both models after carrageenin stimulus. PGF2 alpha was not detected in measurable quantities in any exudate.(ABSTRACT TRUNCATED AT 250 WORDS)