The influence of rapid growth in broilers on florfenicol pharmacokinetics – allometric modelling of the pharmacokinetic and haemodynamic parameters

1. The aim of this study was to determine if the pharmacokinetics (PK) of florfenicol (FF) undergo age-dependent changes in broilers. Since drug elimination depends on cardiovascular functions, a haemodynamic study was performed in parallel.

2. Broilers of 0.68, 1.27, 2.45 and 5.13 kg were administered FF in a single intravenous dose of 30 mg/kg body weight. Plasma drug concentrations were determined using high-performance liquid chromatography and PK parameters were calculated using a non-compartmental model. Echocardiography was used to measure haemodynamic functions.

3. During growth, the area under the drug concentration-time curve (AUC_inf) increased from 25.7 ± 2.9 to 39.0 ± 8.0 mg h/l. Total body clearance (Cl_B) gradually decreased from 1.19 ± 0.14 to 0.80 ± 0.15 l/h/kg. Elimination half-life increased from 0.73 ± 0.08 to 1.07 ± 0.07 h, whereas volume of distribution (V_ss) remained unchanged. Haemodynamic measurements revealed an increase in cardiac output, from 495 ± 65 to 1303 ± 306 ml/min, in the respective body weight groups.

4. Allometric models for PK and haemodynamic parameters were developed and validated. All models proved to be statistically significant; however, only models for Cl_B and V_ss met stringent validation criteria. Model for Cl_B was used to calculate an optimal dose for a given age group that provides uniform AUC_inf.

5. Age-dependent change in FF kinetics may cause variability in therapeutic response under clinical conditions. A novel approach to the dosing protocol was proposed as a means of optimising therapeutic efficacy.     

Naïve averaged, naïve pooled, and population pharmacokinetics of orally administered marbofloxacin in juvenile harbor seals

OBJECTIVE: To determine the pharmacokinetics of marbofloxacin after oral administration in juvenile harbor seals (Phoca vitulina) at a dose of 5 mg/kg (2.3 mg/lb) and to compare pharmacokinetic variables after pharmacokinetic analysis by na?ve averaged, na?ve pooled, and nonlinear mixed-effects modeling. DESIGN: Original study. Animals-33 male and 22 female juvenile seals being treated for various conditions. PROCEDURES: Blood collection was limited to < or = 3 samples/seal. Plasma marbofloxacin concentrations were measured via high-pressure liquid chromatography with UV detection. RESULTS: Mean +/- SE dose of marbofloxacin administered was 5.3 +/- 0.1 mg/kg (2.4 +/- 0.05 mg/lb). The terminal half-life, volume of distribution (per bioavailability), and clearance (per bioavailability) were approximately 5 hours, approximately 1.4 L/kg, and approximately 3 mL/min/kg, respectively (values varied slightly with the method of calculation). Maximum plasma concentration and area under the plasma-time concentration curve were approximately 3 microg/mL and 30 h x microg/mL, respectively. Na?ve averaged and na?ve pooled analysis appeared to yield a better fit to the population, but nonlinear mixed-effects modeling yielded a better fit for individual seals. CONCLUSIONS AND CLINICAL RELEVANCE: Values of pharmacokinetic variables were similar regardless of the analytic method used. Pharmacokinetic variability can be assessed with nonlinear mixed-effects modeling, but not with na?ve averaged or na?ve pooled analysis. Visual observation by experienced trainers revealed no adverse effects in treated seals. Plasma concentrations attained with a dosage of 5 mg/kg every 24 hours would be expected to be efficacious for treatment of infections caused by susceptible bacteria (excluding Pseudomonas aeruginosa).     

The influence of age and body weight gain on enrofloxacin pharmacokinetics in turkeys—Allometric approach to dose optimization

Enrofloxacin is a concentration-dependent antimicrobial used in bacterial infections in poultry. During a few months of a turkey's life, pharmacokinetics of drugs undergoes substantial changes which may compromise their efficacy due to variability in internal exposure (measured by area under the concentration–time curve, AUC). The aim of this study was to describe the effects of age on the pharmacokinetics of a single intravenous (i.v.) and oral administration of enrofloxacin at a dose of 10 mg/kg to turkeys. It was found that during a 2.5-month-long period of growth from 1.4 to 14.6 kg, the AUC after i.v. administration increased almost threefold due to a significant decrease in the body clearance (from a mean of 0.76–0.28 L hr⁻¹ kg⁻¹). Over the same period, the mean elimination half-life was prolonged from 2.65 to 7.03 hr. Oral administration resulted in a similar trend in pharmacokinetic parameters. For both routes, formation of the major metabolite, ciprofloxacin, was marginal. Protein binding was not age-dependent and never exceeded 50%. Body clearance, volume of distribution and elimination half-life were subjected to an allometric analysis and a novel, nonlinear dosage protocol has been proposed to improve the internal exposure to the drug in different age groups of turkeys.     

Expressions of cytochrome P450 aromatase and anti-Müllerian hormone in testes of fattening pigs by the timing of the first vaccination for immunocastration

In practice, two injections of gonadotropin-releasing hormone (GnRH) vaccine are recommended for pig immunocastration for effective outcomes. The present study aimed to investigate the expressions of cytochrome P450 aromatase (P450_arom) and anti-Müllerian hormone (AMH) in testes, testicular length and testicular histomorphometry of the fattening pigs receiving the first injection of GnRH vaccine 6 weeks earlier than the standard protocol. Based on vaccination protocol, 24 pigs were equally divided into three groups: T1 was vaccinated at 15 and 19 weeks of age, T2 received vaccine at 9 and 19 weeks of age and C remained intact. P450_arom and AMH expressions were analysed using immunohistochemistry and Western blot. The results revealed that testicular length was highest in C pigs, but not different between T1 and T2 groups (6.5 ± 0.2 versus 6.9 ± 0.3 cm, p = .538). Histomorphometry demonstrated that the height of spermatogenic epithelia, the diameter of seminiferous tubules and the number of seminiferous tubules between T1 and T2 groups were not different (p > .05). For P450_arom, immunohistochemistry revealed that H-score of C group was significantly higher than that of both T1 and T2 groups. Western blot analysis showed that C group possessed the densest protein band. Moreover, H-score between T1 and T2 groups was not significantly different. Protein band intensity between both groups was not apparently different. As for AMH, C pigs had significantly lower H-score than both T1 and T2 pigs. Furthermore, T2 pigs possessed significantly higher H-score than T1 pigs. Western blot analysis showed that the most intense protein band was found in T2 group. In summary, GnRH vaccine affected testicular development and functions. The first injection could be performed either at 9 or 15 weeks of age since both protocols contributed to comparable results in aspect of testicular length, histomorphometry and expressions of P450_arom and AMH.     

Does the rate of fat deposition influence the pharmacokinetic disposition of subcutaneously administered moxidectin and ivermectin in pigs?

Body condition has been shown to affect the pharmacokinetics of subcutaneously administered macrocyclic lactone anthelmintics but the underlying mechanism is unknown. This study examined the effect of different rates of fat deposition on the pharmacokinetics of moxidectin (MXD) and ivermectin (IVM). All animals initially received a diet with a high linoleic acid content for 7 weeks. One group of animals then received a normal grower diet while the other half received a maintenance ration. Within each diet group, animals were treated with either IVM (n = 4) or MXD (n = 4) or remained as untreated controls (n = 2). There was no difference in the proportion of linoleic acid between the drug treated groups and the untreated controls at any time throughout the study. At 4 and 9 weeks after treatment there was a significantly lower proportion of linoleic acid in the pigs fed the normal ration indicating a greater fat deposition in these animals compared with those that received the maintenance diet. There was an increased persistence of MXD in the plasma of pigs fed the normal ration compared with those fed the maintenance ration. No differences were seen in the kinetic disposition of IVM between pigs fed the maintenance or normal ration. Reducing the rate of fat deposition influenced the pharmacokinetic disposition of the highly lipophilic MXD but did not influence the pharmacokinetic disposition of the less lipophilic IVM.     

Effect of Tomanol® on the pharmacokinetics and tissue distribution of penicillin G in dairy cows

Summary

Following concomitant intravenous administration of Tomanol® and sodium penicillin G to six Dutch Friesian dairy cows a significant decrease in total body clearance of penicillin (34.7%) and a prolongation of the elimination half‐life of penicillin (17.2%) was observed. Tomanol® did not affect other pharmacokinetic parameters such as rate constants of drug transfer (k₁₂/k₂₁, α en β), distribution volume of the central compartment (V₁), and extrapolated serum drug levels. Intravenous or intramuscular administration of Tomanol® had no effect on the tissue distribution of penicillin G, because neither a change in the ratios of muscle to serum and of kidney cortex to serum nor a change in an induced steady state level of low penicilline G serum concentrations was observed. From the data obtained it is concluded that concomitant Tomanol® administration with penicillin induces an elevation of the serum penicillin concentration and prolongs the persistence of penicillin residues in carcass meat and organs.     

The influence of ageing on muscarinic receptors, β-adrenoceptors and adenylate cyclase activity in the bovine lung

Muscarinic and -adrenoceptors were identified in airway epithelium, smooth muscle and lung parenchyma from Holstein-Friesian calves and cows and were characterized with [³H]quinuclidinyl benzilate and [³H]dihydroalprenolol, respectively. The muscarinic receptor density in the smooth muscle of cows (B _max=4803±245 fmol/mg protein) was 33% greater (p<0.01) than in calves. Low receptor numbers were detected in the epithelium and parenchyma. In both calves and cows, the density of epithelial -adrenoceptors was twice as high as in smooth muscle and parenchyma. The quantity of -adrenoceptors in the tracheal epithelium (B _max=994±83 fmol/mg protein) and smooth muscle (B _max=492±41 fmol/mg protein) in cows was respectively 37% (p<0.001) and 35% (p<0.01) lower than in calves. Adenylate cyclase (AC) assays indicated that the basal and the (–)-isopropylnoradrenaline- (ISO-) stimulated cAMP production were not significantly different between the calves and cows. After stimulation with NaF, significantly higher cAMP production was found in all tissues from cows. Significant correlations were found between absolute AC responses to NaF and -adrenoceptor density in epithelium (r=–0.75,p<0.001) and smooth muscle (r=–0.63,p<0.01). It seems that, in older animals, the production of cAMP is independent of the number of receptors, indicating the presence of fully active compensatory mechanisms.Abbreviations AC adenylate cyclase - cAMP intra-cellular adenosine monophosphate - G-protein GTP binding protein - GTP guanosine 5-triphosphate - ISO isopropylnoradrenaline - M muscarine - QNB quinuclidinyl benzilate     

The influence of the tracer injection–acquisition interval on the distribution of 99mTc-ECD in the brain of laboratory cats

Single-photon emission computed tomography (SPECT) can be used to study the regional distribution of the cerebral blood flow in the feline brain without interference of anesthetics. When the tracer, ^99mtechnetium-ethyl cysteinate dimer (^99mTc-ECD), is injected in the awake animal, the acquisition can be performed afterward under general anesthesia, whereas the tracer distribution still represents the regional cerebral blood flow (rCBF) in the awake animal. The aim of this study was to look at the in vivo stability of ^99mTc-ECD in the feline brain. For this purpose, 6 cats (n = 6) were used, and 3 serial acquisitions were performed starting at 40 (T40), 60 (T60), and 85 (T85) minutes after tracer injection. Total counts and perfusion indices (PIs), normalized to the total brain and to the cerebellum, were calculated. When T85 was compared with T40, total counts decreased, depending on the brain region, with 29% (left thalamus) to 51% (bulbus olfactorius). These regional differences in tracer clearance resulted in significantly altered PIs at T85 as compared with T40. This study shows that ^99mTc-ECD SPECT can be used in cats for studying the rCBF and that the clearance of ^99mTc-ECD in the feline brain is region dependent. As a result, the acquisition should be started between 40 and 60 minutes after tracer injection.     

The influence of tiller age and time of year on the growth of Themeda tri andra and Sporobolus fimbriatus in semi‐arid grassveld

Abstract

Sequential growth measurements were made on successive populations of Themeda triandra and Sporobolus fimbriatus tillers initiated at different times of the year. The independent influences of tiller age and time of year on tiller growth were isolated by deriving growth indices for tillers of the same age at different times of the year and for tillers of all ages at each time of the year respectively.

Isolating the effect of plant age on growth showed that T. triandra is most productive under a regime of long periods of undisturbed growth, while S. fimbriatus is better suited to frequent interruptions in growth. Isolating the effect of time of year shows that both species are particularly sensitive to perturbations in spring. However, the photosynthetic efficiency of T. triandra is strongly influenced by time of year while S. fimbriatus seems to be a more opportunistic assimilator of sunlight.     

Immunolocalization of steroidogenic enzymes P450scc, 3betaHSD, P450c17, and P450arom in Göttingen miniature pig testes

The objective of this study was to investigate immunolocalization of steroidogenic enzymes in G?ttingen miniature (GM) pig testes. Testes of 6 adult GM pigs were obtained in September 1996 (n=2), February (n=2) and June (n=2), 1997. Steroidogenic enzymes were immunolocalized using polyclonal antisera raised against bovine adrenal cholesterol side-chain cleavage cytochrome P450 (P450scc), human placental 3beta-hydroxysteroid dehydrogenase (3betaHSD), porcine testicular 17alpha-hydroxylase cytochrome P450 (P450c17), and human placental aromatase cytochrome P450 (P450arom). Histologically, all types of spermatogenic cells including mature-phase spermatozoa in seminiferous tubules were observed in all testes throughout the year. Moreover, P450scc, 3betaHSD, P450c17and P450arom were identified in Leydig cells but not in Sertoli cells of all testes. These results suggested that adult GM pig testes have the ability to produce germ cells throughout the year, and the synthesis of progestin, androgen and estrogen occurs in the Leydig cells of GM pig testes.     

A review of the off-label use of selamectin (Stronghold?/Revolution?) in dogs and cats

Since its introduction approximately seven years ago, selamectin (Stronghold^®/Revolution^®, Pfizer Inc.) has been used off-label to treat a number of ecto- and endoparasite conditions in dogs and cats. It has been used as a successful prophylactic against Dirofilaria repens and as a treatment for Aelurostrongylus abstrusus in cats. It has also been used to treat notoedric mange, infestation with the nasal mite Pneumonyssoides caninum, Cheyletiella spp. and Neotrombicula autumnalis infestations and larval Cordylobia anthropophaga infection. However, to date attempts to treat generalised canine demodicosis have not been successful. In all cases, treatment was apparently well tolerated by the host.     

Effects of trilostane on the pituitary-adrenocortical and renin–aldosterone axis in dogs with pituitary-dependent hypercortisolism

The medical records of 63 dogs with pituitary-dependent hypercortisolism (PDH) before and during treatment with trilostane were reviewed retrospectively. The correct trilostane dosage in dogs with PDH was based on the resolution of clinical signs and the results of an adrenocorticotropic hormone (ACTH) stimulation test. The mean (±SD) dose rate of trilostane to achieve good clinical control was 2.8 ± 1.0 mg/kg bodyweight. Trilostane treatment resulted in a significant decline in basal plasma cortisol concentrations. The median plasma ACTH concentration (39 pmol/L, range 7–132 pmol/L; n = 60) at the optimal trilostane dosage time was significantly higher (P < 0.001) than before treatment (13 pmol/L, range 2–102 pmol/L). These values did not overlap with plasma ACTH concentrations (range 212–307 pmol/L) of five PDH dogs with trilostane-induced hypocortisolism.The median cortisol/ACTH ratio in well-controlled dogs (0.23, range 0.03–2.5; n = 46) was significantly lower (P < 0.001) than before treatment (2.59, range 0.27–13.25). Trilostane treatment resulted in an insignificant decrease in plasma aldosterone concentration (PAC), but the median plasma renin activity (PRA) at the time the trilostane dosage was considered optimal (265 fmol/L/s, range 70–3280 fmol/L/s; n = 18) was significantly higher (P < 0.001) than prior to treatment (115 fmol/L/s, range 15–1330 fmol/L/s). Similarly, the median PAC/PRA ratio during trilostane treatment (0.16, range 0.003–0.92; n = 17) was significantly lower (P < 0.001) than before treatment (median 0.44, range 0.04–1.33). Trilostane affected both the hypothalamic-pituitary-adrenocortical and the renin–aldosterone axes. The results also suggested that basal plasma ACTH concentration may be used to detect trilostane overdosage.     

Effects of perioperative saphenous and sciatic nerve blocks,lumbosacral epidural or morphine–lidocaine–ketamine infusion on postoperative pain and sedation in dogs undergoing tibial plateau leveling osteotomy

ObjectiveTo compare the quality of postoperative analgesia and sedation after preoperative saphenous and sciatic nerve blockade, preoperative lumbosacral epidural injection and perioperative intravenous (IV) morphine, lidocaine and ketamine infusions in dogs undergoing stifle arthroscopy and tibial plateau leveling osteotomy (TPLO) under general anesthesia.Study designProspective, blinded, randomized, clinical comparison study.AnimalsA total of 45 dogs weighing 33.9 (15.9–56.7) kg and aged 5.2 (1.0–12.0) years, mean (range), undergoing elective unilateral TPLO for spontaneous cranial cruciate ligament rupture.MethodsClient-owned dogs were enrolled. Dogs were randomly assigned to one of three groups: group MLK, perioperative IV morphine, lidocaine and ketamine infusion; group EPID, lumbosacral epidural with ropivacaine and morphine; or group SSNB, saphenous and sciatic nerve blockade with ropivacaine. Routine stifle arthroscopy followed by TPLO surgery was performed. Sedation and pain scores were assessed at 0, 2, 4, 8 and 24 hours following extubation. Rescue analgesia was administered as prescribed by Glasgow composite pain score–short form score >5.ResultsSedation scores for MLK were higher than EPID and SSNB. Pain scores for SSNB were lower than those for EPID and MLK. No significant differences were found in anesthesia duration or surgery duration among groups. No dogs required rescue analgesia.Conclusions and clinical relevanceAlthough analgesia was adequate in all groups, the best combination of analgesia without increased sedation was recorded for SSNB.     

The influence of in ovo injection with the prebiotic DiNovo~? on the development of histomorphological parameters of the duodenum,body mass and productivity in large-scale poultry production conditions

Background: Among various feed additives currently used in poultry nutrition, an important role is played by bioactive substances, including prebiotics. The beneficial effect of these bioactive substances on the gastrointestinal tract and immune system give rise to improvements in broiler health and performance nutrition, thus increasing the productivity of these birds. An innovative method for introducing bioactive substances into chickens is the in ovo injection into eggs intended for hatching. The aim of the study was to evaluate the development of histomorphological parameters of the duodenum and productivity in chickens injected in ovo with the prebiotic DiNovo~?(extract of Laminaria species of seaweed, BioA tlantis Ltd., Ireland) on d 12 of incubation, under large-scale, high density poultry production conditions.Results: There was no significant impact of the injection of DiNovo~? prebiotic on the production parameters of broiler chickens(body weight, FCR, EBI and mortality) obtained on d 42 of rearing. No significant impact of the DiNovo~? injection on the duodenum weight and length was observed, as wel as on the CSA, diameter and muscular layer thickness of the duodenum. The in ovo injection of DiNovo~? significantly increased the width of the duodenal vil i(P 0.05) and crypt depth(P 0.01) of chickens on d 21 of rearing. Other histomorphological parameters of duodenal vil i at d 42 of chickens rearing such as: the height, width, and cross section area of vil i were significantly greater in chickens from the control group compared to those from the DiNovo~? group(P 0.05 and P 0.01).Conclusions: In conclusion, this study demonstrates that injection of DiNovo~? prebiotic into the air chamber of egg significantly influences the histomorphological parameters on d 21 of rearing without negatively affecting productivity in chickens at the end of rearing.     

The influence of trilostane on steroid hormone metabolism in canine adrenal glands and corpora lutea—an in vitro study

Trilostane is widely used to treat hyperadrenocorticism in dogs. Trilostane competitively inhibits the enzyme 3-beta hydroxysteroid dehydrogenase (3β-HSD), which converts pregnenolone (P5) to progesterone (P4) and dehydroepiandrosterone (DHEA) to androstendione (A4). Although trilostane is frequently used in dogs, the molecular mechanism underlying its effect on canine steroid hormone biosynthesis is still an enigma. Multiple enzymes of 3β–HSD have been found in humans, rats and mice and their presence might explain the contradictory results of studies on the effectiveness of trilostane. We therefore investigated the influence of trilostane on steroid hormone metabolism in dogs by means of an in vitro model. Canine adrenal glands from freshly euthanized dogs and corpora lutea (CL) were incubated with increasing doses of trilostane. Tritiated P5 or DHEA were used as substrates. The resulting radioactive metabolites were extracted, separated by thin layer chromatography and visualized by autoradiography. A wide variety of radioactive metabolites were formed in the adrenal glands and in the CL, indicating high metabolic activity in both tissues. In the adrenal cortex, trilostane influences the P5 metabolism in a dose- and time-dependent manner, while DHEA metabolism and metabolism of both hormones in the CL were unaffected. The results indicate for the first time that there might be more than one enzyme of 3β-HSD present in dogs and that trilostane selectively inhibits P5 conversion to P4 only in the adrenal gland.     

A comparative study by age and gender of the pituitary adenoma and ACTH and α-MSH secretion in dogs with pituitary-dependent hyperadrenocorticism

Pituitary-dependent hyperadrenocorticism (PDH) is frequent in dogs. Little is known about its presentation in different age groups and its characteristics. Dividing the population under study (n = 107) into three age groups we observed that 11.2% were young, 51.4% adults and 37.4% aged. Using magnetic resonance, pituitary tumours were intra-sellar (IS) in 30.8% and extra-sellar (ES) in 62.6% and the pars intermedia (PI) was affected in 6.5%. ES are predominant in females and IS in males (p < 0.0001). In the adult-aged population, the ES and PI are predominant, while in the young, the IS predominate (p < 0.0001). ACTH concentration was greater in the ES vs. IS (p < 0.05). α-MSH did not present significant differences according to tumour size, showing a negative correlation (r = −0.47; p < 0.01) vs. ACTH. Differences in adenoma size according to gender and their age-related frequency of apparition could be because of different origins of the corticotrophinoma.