Nonsteroidal anti-inflammatory agents: Species differences in pharmacodynamics

The disposition kinetics and systemic availability of nonsteroidal anti-inflammatory (NSAI) agents as well as their antipyretic and anti-nociceptive properties are reviewed in different species. The anti-inflammatory versus bradykinin, serotonin and kaolin oedema activities of aspirin (ASA), phenylbutazone (PBZ) and indomethacin (IDM) explain their large use in veterinary medicine. The low analgesic effect versus NO₃Ag arthritis, radiant heat and tail pressure of indomethacin and oxyphenbutazone contrasts with the widespread activity of phenazone. The comparative inhibitory effect of NSAI agents on the rat fundus contraction due to arachidonic acid is an indication of their relative inhibition of prostaglandin biosynthesis. Among the side-effects of NSAI agents, the long-lasting hyperactivity and hypomotility induced by a parenteral injection of phenylbutazone in the dog is of importance despite the fact that in this species, as in the horse, the average half life is only 6 h due to side-chain hydroxylation (versus 42 h in man for whom conjugation is a major pathway). Initiation of therapy with a loading dose followed by maintenance doses (each half the size of the loading dose) at constant intervals equal to the half-life of the drug has been shown to be suitable for most drugs with long half-life values. According to this a tentative harmless dosage regimen can be calculated for NSAI therapy in different species.     

Renal clearance: Species differences and similarities

Species differences and differences between newborn and adults in glomerular filtration rate (GFR), active tubular secretion and back-diffusion in the kidney are described. Measuring the renal clearance of drugs — organic acids or organic bases — and relating this clearance to the GFR, the processes involved in the renal handling of a drug are described. The main principles involved in the renal handling of drugs are the same in the various, animal species and age-groups, but the quantitative influence of these processes may vary considerably from one animal species to another and from neonates to adults.     

Species differences in the hepatic biotransformation of zearalenone

Zearalenone (ZEA), a Fusarium toxin, is frequently found in animal feed materials. It is known to exert oestrogenic effects in all animals tested but susceptibility varies between species, possibly reflecting differences in the metabolic processing of ZEA, which predominantly involves hydroxylations, assumed to be catalysed by 3alpha- and 3beta- hydroxysteroid dehydrogenases, as well as conjugation with glucuronic acid. In this study, the biotransformation of ZEA by hepatic subcellular fractions of various domestic animals was investigated and compared to the rat. Notable inter-species differences in terms of the rate of absolute and relative metabolite production in the different subcellular fractions were identified. The highest amount of alpha-zearalenol (alpha-ZOL) was produced by pig hepatic microsomes (V(max)=795.8+/-122.7pmol/mg/min), whereas in chicken microsomes the highest amounts of beta-zearalenol (beta-ZOL) (V(max)=1524+/-29.7pmol/mg/min) could be measured. Except for sheep and cattle, the efficiency of alpha-ZOL production (expressed as the ratio of apparent V(max)/k(m)) was higher in the microsomal fraction compared to the post-mitochondrial fraction. In contrast, the apparent efficiency of beta-ZOL production was high in pigs, cattle, chickens and rats, but very low in sheep. Conjugation of ZEA with glucuronic acid was investigated, and the results indicated significant inter-species differences in the rate of glucuronidation, which was saturable at low concentrations in all species tested, except pigs. The significant differences between the percentages of glucuronidation of ZEA, alpha-ZOL, and beta-ZOL suggest not only differences in the affinity of the individual substrate, but might also indicate the presence of different isoforms of uridine diphosphate glucuronyl transferases (UDPGTs). The results are of clinical relevance, as they contribute to the understanding of the species-specific susceptibility towards exposure to ZEA.     

Species differences in hepatic biotransformation of the anthelmintic drug flubendazole

Flubendazole (FLBZ) is a broad‐spectrum benzimidazole anthelmintic used in pigs, poultry, and humans. It has been proposed as a candidate for development for use in elimination programmes for lymphatic filariasis and onchocerciasis in humans. Moreover, FLBZ has shown promise in cancer chemotherapy, particularly for neuroblastoma. This work investigated the hepatic carbonyl‐reducing pathway of FLBZ in different species, including humans. Microsomal and cytosolic fractions were obtained from sheep, cattle, pig, hen, rat, and human liver. Both subcellular fractions of each species converted FLBZ into a reduced metabolite (red‐FLBZ). The rate of microsomal red‐FLBZ production was highest in sheep (1.92 ± 0.13 nmol/min.mg) and lowest in pigs (0.04 ± 0.02 nmol/min.mg); cytosolic red‐FLBZ production ranged from 0.02 ± 0.01 (pig) to 1.86 ± 0.61 nmol/min.mg (sheep). Only subcellular fractions from sheep liver oxidized red‐FLBZ to FLBZ in a NADP⁺‐dependent oxidative reaction. Liver microsomes from both pigs and humans transformed FLBZ to red‐FLBZ and a hydrolyzed metabolite. Very significant differences in the pattern of FLBZ metabolism were observed among the tested species and humans. These results reinforce the need for caution in extrapolating data on metabolism, efficacy, and safety of drugs derived from studies performed in different species.     

Comparative Morphology of Trigeminal Ganglion in Some Species of Vertebrates

Introduction:  The mammalian digital end organ has developed in three basic functional forms, i.e., claw, hoof and nail. Whereas detailed information on the ontogeny and phylogeny of the equine and bovine hooves, and the human nail, respectively, are on hand, such data are still not available for the canine claw. Because phylogenetically the carnivore claw is considered as a primary form of digital end organ, data on the organogenesis of the canine claw will complement current knowledge on onto- and phylogeny of the carnivore claw, and digital end organs in general.
Materials and Methods:  Light and electron microscopy of 18 canine fetuses of 40–150 mm crown-rump-length and five puppies aged 1 day–4 weeks post-partum.
Results:  The development of the canine claw can be divided into four periods. The first stage is initiated by the differentiation of the connective tissue layers of the claw anlage. The second stage is characterized by formation of the specific claw shape, and the third stage by further regional function-related modifications resulting in the development of the five different segments of the digital end organ. The fourth stage proceeds post-natally when the influence of increasing body weight and weight bearing leads to the final functional adaptation of the papillary body.
Conclusion:  The organogenesis of the canine claw resembles that of the feline claw in many aspects, but also shows some specific deviations. In particular, the development of the dorsal ridge – characteristic for the carnivore claw – differs between both species. The results of our study therefore raise the question whether the current hypothesis on allocation of the different segments of the canine claw has to be reconsidered.     

三种盐生境植物叶表的扫描电镜观察（简报）

用Ｈｉｔａｃｈｉ Ｓ４３０扫描电镜观察温室培养的小花碱茅，野大麦和碱蓬幼苗在ＮａＣｌ胁迫下的叶表结构，结果表明，碱茅叶表腺毛稀疏，腊被密度中等，气孔下陷，随盐浓度增加，腺毛数显著增加，野大麦叶表腺毛数为１３２￣１９６个／ｍｍ＾２，划被略疏于碱茅，腺毛数随盐浓度增加的变化不大，但形状有所改变，气孔亦下陷。碱蓬叶表有浓密的腊被，气孔数达２３６个／ｍｍ＾２，说明植物在盐渍环境下有相应的调整外部结构的适应     

Ketoprofen in the cat: pharmacodynamics and chiral pharmacokinetics

The non-steroidal anti-inflammatory drug ketoprofen (KTP) was administered as the racemate to cats intravenously (IV) and orally at clinically recommended dose rates of 2 and 1 mg/kg, respectively, to establish its chiral pharmacokinetic and pharmacodynamic properties.After IV dosing, clearance was more than five times greater and elimination half-life and mean residence time were approximately three times shorter for R(-) KTP than for S(+) KTP. Absorption of both S(+) and R(-) enantiomers was rapid after oral dosing and enantioselective pharmacokinetics was demonstrated by the predominance of S(+) KTP, as indicated by plasma AUC of 20.25 (S(+)KTP) and 4.09 (R(-)KTP) microg h/mL after IV and 6.36 (S(+)KTP) and 1.83 (R(-)KTP) microg h/mL after oral dosing. Bioavailability after oral dosing was virtually complete. Reduction in ex vivo serum thromboxane (TX)B(2) concentrations indicated marked inhibition of platelet cyclo-oxygenase (COX)-1 for 24 h after both oral and IV dosing and inhibition was statistically significant for 72 h after IV dosing. Both oral and IV rac-KTP failed to affect wheal volume produced by intradermal injection of the mild irritant carrageenan but wheal skin temperature was significantly inhibited by IV rac-KTP at some recording times. Possible reasons for the disparity between marked COX-1 inhibition and the limited effect on the cardinal signs of inflammation are considered.In a second experiment, the separate enantiomers of KTP were administered IV, each at the dose rate of 1mg/kg. S(+)KTP again predominated in plasma and there was unidirectional chiral inversion of R(-) to S(+)KTP. Administration of both enantiomers again produced marked and prolonged inhibition of platelet COX-1 and, in the case of R(-)KTP, this was probably attributable to S(+)KTP formed by chiral inversion.     

Cetirizine in horses: pharmacokinetics and pharmacodynamics following repeated oral administration

The pharmacokinetics of the histamine H(1)-antagonist cetirizine and its effect on histamine-induced cutaneous wheal formation were studied in six healthy horses following repeated oral administration. After three consecutive administrations of cetirizine (0.2 mg/kg body weight, bw) every 12h, the trough plasma concentration of cetirizine was 16+/-4 ng/mL (mean+/-SD) and the wheal formation was inhibited by 45+/-23%. After four additional administrations of cetirizine (0.4 mg/kg bw) every 12 h, the trough plasma concentration was 48+/-15 ng/mL and the wheal formation was inhibited by 68+/-11%. The terminal half-life was about 5.8 h. A pharmacokinetic/pharmacodynamic link model showed that the maximal inhibition of wheal formation was about 95% and the EC(50) about 18 ng/mL. It is concluded that cetirizine in doses of 0.2-0.4 mg/kg bw administered at 12 h intervals exhibits favourable pharmacokinetic and pharmacodynamic properties without causing visible side effects, and the drug may therefore be a useful antihistamine in equine medicine.     

Metocurine pharmacokinetics and pharmacodynamics in goats

Non-depolarizing muscle relaxants can facilitate surgery and anaesthesia in numerous species, and volatile inhalational anaesthetics such as isoflurane potentiate their action. We studied the effect of isoflurane on the pharmacodynamics and pharmacokinetics of metocurine in six goats. Each was studied twice: once during barbiturate-opiate anaesthesia and once during isoflurane anaesthesia. The evoked response to sciatic nerve stimulation was measured using a force transducer attached to the hoof. Metocurine was infused until approximately 80–90% blockade. Plasma metocurine concentration was determined by high-performance liquid chromatography. Isoflurane increased the potency of metocurine significantly; IC₅₀ (the concentration in the effect compartment at 50% paralysis) was 70 ± 15 ng/mL during isoflurane anaesthesia and 129 ± 42 ng/mL during barbiturate-opiate anaesthesia ( P < 0.03). Volume of distribution (63 ± 18 mL/kg), clearance (1.6 ± 0.4 mL/min±kg) and elimination half-life (99 ± 9 min) during barbiturate-opiate anaesthesia were not significantly different during isoflurane anaesthesia: 64 ± 25 mL/kg, 1.5 ± 0.7 mL/kgmin, 116 ± 16 min respectively. We conclude that, relative to barbiturate-opiate anaesthesia, isoflurane potentiates metocurine in goats.     

Pharmacokinetics and pharmacodynamics in the newborn

Pharmacokinetics and pharmacodynamics in the newborn are multifaceted: maturation processes of the systems committed to absorption, distribution, metabolism, and excretion partially overlap, making the newborn an extremely dynamic system, especially if compared with adults. In this short note, some of the relevant variables able to regulate these processes are reviewed according to published literature data.

     

Pharmacokinetics and pharmacodynamics in the newborn

Pharmacokinetics and pharmacodynamics in the newborn are multifaceted: maturation processes of the systems committed to absorption, distribution, metabolism, and excretion partially overlap, making the newborn an extremely dynamic system, especially if compared with adults. In this short note, some of the relevant variables able to regulate these processes are reviewed according to published literature data.