Pulmonary pharmacokinetics of tulathromycin in swine. Part I: Lung homogenate in healthy pigs and pigs challenged intratracheally with lipopolysaccharide of Escherichia coli

The objective of the study was to assess the pharmacokinetics of tulathromycin in lung tissue homogenate (LT) and plasma from healthy and lipopolysaccharide (LPS)‐challenged pigs. Clinically healthy pigs were allocated to two dosing groups of 36 animals each (group 1 and 2). All animals were treated with tulathromycin (2.5 mg/kg). Animals in group 2 were also challenged intratracheally with LPS from Escherichia coli (LPS‐Ec) 3 h prior to tulathromycin administration. Blood and LT samples were collected from all animals during 17‐day post‐tulathromycin administration. For LT, one sample from the middle (ML) and caudal lobes (CL) was taken. The concentration of tulathromycin was significantly lower in the ML after the intratracheal administration of LPS‐E. coli (P < 0.02). In healthy pigs and LPS‐challenged animals, the distribution of the drug into the lungs was rapid and persisted at high levels for 17‐day postadministration. The distribution of the drug within the lung seems to be homogenous, at least between the middle and caudal lobes within dosing groups. The concentration versus time profile of the drug and pharmacokinetic parameters in two different lung areas (middle and caudal lobe) were consistent within the groups. The clinical significance of these findings is unknown.     

Understanding the pharmacokinetics of tulathromycin: a pulmonary perspective

Tulathromycin is approved in the United States for the treatment of respiratory disease in bovine and swine, infectious bovine keratoconjunctivitis associated with Moraxella bovis, and interdigital necrobacillosis in bovine. This macrolide highly concentrates in lung tissue and persists in the intra‐airway compartment for a long time after a single administration. It also accumulates in inflammatory cells, including neutrophils and macrophages. This article reviews pharmacokinetic information about tulathromycin in different veterinary species with particular emphasis on the respiratory system.     

Pharmacokinetics and lung tissue concentrations of tulathromycin in swine

The absolute bioavailability and lung tissue distribution of the triamilide antimicrobial, tulathromycin, were investigated in swine. Fifty-six pigs received 2.5 mg/kg of tulathromycin 10% formulation by either intramuscular (i.m.) or intravenous (i.v.) route in two studies: study A (10 pigs, i.m. and 10 pigs, i.v.) and study B (36 pigs, i.m.). After i.m. administration the mean maximum plasma concentration (C(max)) was 616 ng/mL, which was reached by 0.25 h postinjection (t(max)). The mean apparent elimination half-life (t(1/2)) in plasma was 75.6 h. After i.v. injection plasma clearance (Cl) was 181 mL/kg.h, the volume of distribution at steady-state (V(ss)) was 13.2 L/kg and the elimination t(1/2) was 67.5 h. The systemic bioavailability following i.m. administration was >87% and the ratio of lung drug concentration for i.m. vs. i.v. injection was > or =0.96. Following i.m. administration, a mean tulathromycin concentration of 2840 ng/g was detected in lung tissue at 12 h postdosing. The mean lung C(max) of 3470 ng/g was reached by 24 h postdose (t(max)). Mean lung drug concentrations after 6 and 10 days were 1700 and 1240 ng/g, respectively. The AUC(inf) was 61.4 times greater for the lung than for plasma. The apparent elimination t(1/2) for tulathromycin in the lung was 142 h (6 days). Following i.m. administration to pigs at 2.5 mg/kg body weight, tulathromycin was rapidly absorbed and highly bioavailable. The high distribution to lung and slow elimination following a single dose of tulathromycin, are desirable pharmacokinetic attributes for an antimicrobial drug indicated for the treatment of respiratory disease in swine.     

Intra‐abdominal hypertension in horses

Intra‐abdominal hypertension (IAH) may lead to a multiple organ dysfunction syndrome associated with significant dysfunction of the cardiovascular, respiratory, renal, gastrointestinal and central nervous systems of human patients. A recent prospective multicentre epidemiological investigation in man concluded that IAH was associated with an increased risk of mortality in critically ill patients. In this review, we present current information pertaining to the potential clinical importance of IAH in the context of equine clinical practice. In conclusion, consideration of intra‐abdominal pressure should be a part of the clinical assessment of patient well‐being in critically ill equine patients.     

Intra‐uterine Infection with Babesia bovis in a 2‐day‐old Calf

Infection with Babesia bovis was diagnosed in a 2‐day‐old female calf apparently transmitted in utero. The calf was born as the second calving to a cross‐bred beef cow permanently on pasture. Diagnosis was based upon identification of B. bovis in peripheral blood smears and clinical signs which included fever, jaundice, pale mucous membranes and convulsions. Anaemia, leucocytosis, thrombocytopenia and lymphocytosis were noted at the febrile acute stage of the disease. The blood smears revealed evidence of regeneration of toxic neutrophils with a left shift, severe spherocytosis and high degree of basophilic stippling. Elevated concentration of aspartate aminotransferase, lactate dehydrogenase, and creatine kinase were also noted, and were probably the result of haemolysis, dehydration and muscle damage because of recumbancy. Elevated total bilirubin concentration following haemolysis resulted in jaundice. The neurological symptoms observed were probably caused by sludging of parasitized erythrocytes in the brain capillaries. The calf recovered following treatment with diminazene aceturate and the recovery was followed up clinically, haematologically and biochemically.     

Expression of Progesterone Receptor in the Utero‐tubal Junction After Intra‐uterine and Deep Intra‐uterine Insemination in Sows

The aim of this study was to investigate the expression of progesterone receptor (PR) in the utero‐tubal junction (UTJ) of sows at 24 h after intra‐uterine insemination (IUI) and deep intra‐uterine insemination (DIUI) compared with conventional artificial insemination (AI) in pigs. Fifteen multiparous sows were used: AI (n = 5), IUI (n = 5) and DIUI (n = 5). The sows were inseminated with a single dose of diluted semen during the second oestrus after weaning at 6–8 h prior to ovulation (AI: 3000 × 10⁶ spermatozoa, IUI: 1000 × 10⁶ spermatozoa and DIUI: 150 × 10⁶ spermatozoa). The UTJ was collected and subject to immunohistochemical staining using avidin‐biotin immunoperoxidase technique with mouse monoclonal antibody to PR. In the oviductal part of the UTJ, the intensity of PR in the tunica muscularis and the proportion of PR‐positive cells in the surface epithelium after DIUI were lower than AI (p < 0.05). The intensity and the proportion of PR‐positive cells between AI and IUI in all compartments of the UTJ did not differ significantly (p > 0.05). When comparing between tissue compartments, prominent staining was observed in the muscular layer of the UTJ. It could be concluded that the expression of PR in the UTJ prior to fertilization after DIUI with a reduced number of spermatozoa was lower than that after AI. This might influence sperm transportation and the fertilization process.     

Population pharmacokinetics of valnemulin in swine

This study was carried out in 121 pigs to develop a population pharmacokinetic (PPK) model by oral (p.o.) administration of valnemulin at a single dose of 10 mg/kg. Serum biochemistry parameters of each pig were determined prior to drug administration. Three to five blood samples were collected at random time points, but uniformly distributed in the absorption, distribution, and elimination phases of drug disposition. Plasma concentrations of valnemulin were determined by high‐performance liquid chromatography–tandem mass spectrometry (HPLC‐MS/MS). The concentration–time data were fitted to PPK models using nonlinear mixed effect modeling (NONMEM) with G77 FORTRAN compiler. NONMEM runs were executed using Wings for NONMEM. Fixed effects of weight, age, sex as well as biochemistry parameters, which may influence the PK of valnemulin, were investigated. The drug concentration–time data were adequately described by a one‐compartmental model with first‐order absorption. A random effect model of valnemulin revealed a pattern of log‐normal distribution, and it satisfactorily characterized the observed interindividual variability. The distribution of random residual errors, however, suggested an additive model for the initial phase (<12 h) followed by a combined model that consists of both proportional and additive features (≥12 h), so that the intra‐individual variability could be sufficiently characterized. Covariate analysis indicated that body weight had a conspicuous effect on valnemulin clearance (CL/F). The featured population PK values of K_a, V/F and CL/F were 0.292/h, 63.0 L and 41.3 L/h, respectively.     

Evaluation of the therapeutic activity of tulathromycin against swine respiratory disease on farms in Europe

The clinical efficacy of tulathromycin in the treatment of natural outbreaks of swine respiratory disease (SRD) was evaluated at five European sites. Pigs (1 to 6 months of age) exhibiting clinical signs of SRD were treated intramuscularly with tulathromycin (n = 247) at 2.5 mg/kg on day 0 versus either tiamulin (n = 102) at 15 mg/kg on days 0, 1, and 2 (Germany, the Netherlands, and the United Kingdom) or florfenicol (n = 20) at 15 mg/kg on days 0 and 2 (France). Actinobacillus pleuropneumoniae, Pasteurella multocida, and Mycoplasma hyopneumoniae infections were the most frequently diagnosed pathogens. For both tulathromycin-treated animals and those treated with tiamulin or florfenicol, there were significant (P = .0001) reductions in mean rectal temperature and the severity of abnormal clinical signs on days 2 and 10 compared with day 0. There were no significant differences (P > .05) between treatments in average daily weight gain. Tulathromycin was found to be safe and highly effective in the treatment of natural outbreaks of SRD.     

Intra‐abdominal cystic lymphangiomatosis in a Thoroughbred foal

Cystic lymphangiomas are rare malformations of the lymphatics that result in the formation of a cystic mass. Where multiple cysts are seen, the condition is termed cystic lymphangiomatosis. This case describes the diagnosis and unique management of cystic lymphangiomatosis in a 10‐day‐old Thoroughbred foal. Ultrasonography, histopathology and laparoscopy were essential for diagnosis and appreciation of the extent of disease. Ultimately, the cystic lymphangiomatosis was so extensive in this foal that complete surgical excision was considered impossible and the presence of adhesions within the abdomen indicated a very poor long‐term prognosis; the owners elected for euthanasia at age 14 weeks. Although rare, lymphangioma and lymphangiomatosis should be considered as a differential diagnosis for an intra‐abdominal mass in a young horse.     

The influence of Actinobacillus pleuropneumoniae infection on tulathromycin pharmacokinetics and lung tissue disposition in pigs

A tulathromycin concentration and pharmacokinetic parameters in plasma and lung tissue from healthy pigs and Actinobacillus pleuropneumoniae (App)‐infected pigs were compared. Tulathromycin was administered intramuscularly (i.m.) to all pigs at a single dose of 2.5 mg/kg. Blood and lung tissue samples were collected during 33 days postdrug application. Tulathromycin concentration in plasma and lung was determined by high‐performance liquid chromatography with tandem mass spectrometry (LC‐MS/MS) method. The mean maximum plasma concentration (C_max) in healthy pigs was 586 ± 71 ng/mL, reached by 0.5 h, while the mean value for C_max of tulathromycin in infected pigs was 386 ± 97 ng/mL after 0.5 h. The mean maximum tulathromycin concentration in lung of healthy group was calculated as 3412 ± 748 ng/g, detected at 12 h, while in pigs with App, the highest concentration in lung was 3337 ± 937 ng/g, determined at 48 h postdosing. The higher plasma and lung concentrations in pigs with no pulmonary inflammation were observed at the first time points sampling after tulathromycin administration, but slower elimination with elimination half‐life t_1/2el = 126 h in plasma and t_1/2el = 165 h in lung, as well as longer drug persistent in infected pigs, was found.     

Intra‐thoracic gossypiboma (textiloma) in a 6‐year‐old cocker spaniel

This report documents the first case of gossypiboma (textiloma) identified within the thorax of a dog. CT findings, surgical removal and histopathology are described. Intra‐thoracic gossypiboma has not previously been reported in dogs and is rarely reported in the human medical literature, where it is most commonly associated with previous cardiac or pulmonary surgery. This dog had previously had a thoracotomy for attempted surgical correction of a persistent right aortic arch and left ligamentum arteriosum 6 years prior to presentation. A brief review of the previous literature and recommendations for prevention of this condition are provided.     

Intra‐ovarian dynamic blood flow in pseudopregnant rabbits during prostaglandin F2α‐induced luteolysis

In the present study, we evaluated the dynamic changes of intra‐ovarian blood flow, by real‐time colour‐coded and pulsed Doppler ultrasonography, as well as the immunopresence of prostaglandin F2α (PGF2α) receptor (FP) and peripheral plasma progesterone concentrations in pseudopregnant rabbit after PGF2α treatments at either early‐ (4 days) and mid‐luteal (9 days) stages. During the pre‐treatment observation interval of one hour, the ovarian blood flows showed a fluctuating pattern. Independently of luteal stage, PGF2α administration caused a fourfold decline in the blood flow within 40 min that was followed 50 min later by a reactive hyperaemia that lasted several hours, while the resistive index showed an opposite trend. Twenty‐four hour later, the blood flow was one half that measured before PGF2α injection. At day 4 of pseudopregnancy, PGF2α did not affect peripheral plasma progesterone concentrations, but at day 9, it caused functional luteolysis as progesterone levels declined 6 hr later to reach basal values after 24 hr. The changes in the ovarian blood flows of pseudopregnant rabbits receiving PGF2α were accompanied by simultaneous changes in the resistance index. This biphasic response in the blood flow and vascular resistances likely reflects reactive hyperaemia following vasoconstriction. By immunohistochemistry, strong positive immune reaction for FP was detected in the cytoplasm of endothelial cells of ovarian arteries, veins and capillaries. In conclusion, these results suggest that PGF2α could acutely regulate the ovarian blood flow of pseudopregnant rabbits, even if there is no evidence of a blood flow reduction anticipating luteolysis.     

Intra‐Articular Use of a Platelet‐Rich Product in Normal Horses: Clinical Signs and Cytologic Responses

Objectives

(1) To report the clinical and synovial effects of a platelet‐rich product (PRPr) in normal equine joints, (2) to assess the persistence of platelets within synovial fluid after intra‐articular injection, (3) to compare responses to different preparations of that product, and (4) to evaluate a gravity filtration system for PRPr preparation in horses.

Study Design

Experimental.

Methods

A platelet‐rich saline product (PRPr) was prepared from 7 normal horses using a proprietary preparation device and was divided into 3 treatments: resting, CaCl₂‐activated (23 mM, final), and bovine thrombin‐activated (10 U/mL, final). Each horse had 3 concurrent randomly assigned intra‐articular PRPr treatments administered in their metacarpophalangeal/metatarsophalangeal joints; the fourth limb was injected with saline (0.9% NaCl) solution as a control. Clinical assessments, cytologic analysis of synovial fluid and hemograms were performed at 6, 24, 48, and 96 hours after injection. PRPr composition and growth factor content were analyzed.

Results

The gravity filtration system produced a moderately concentrated PRPr. At 6 and 24 hours, when compared to control values, all PRPr treatments caused a significant increase in synovial WBC concentration (P < .0059) and neutrophil percentage (P < .0005). Bovine thrombin‐activated PRPr injection consistently caused increased effusion scores and periarticular signs. At all time points, the synovial WBC concentration after thrombin‐activated PRPr was significantly greater (P < .001) than for the control, CaCl₂‐activated or resting PRPr. Intact platelets could be observed in synovial fluid for up to 5 days after intra‐articular PRPr injection.

Conclusions

Resting and CaCl₂‐activated PRPr may be safely used to treat equine joints, but bovine thrombin activation is not recommended at 10 U/mL. A PRPr can be prepared using a gravity filtration system, eliminating the need for centrifugation.     

Disposition of sulfonamides in food-producing animals: pharmacokinetics of sulfathiazole in swine

Disposition of sulfathiazole in plasma and urine of swine was determined following single intravenous and oral doses. Pharmacokinetics of the drug were described by a 1-compartment open model. The drug was rapidly eliminated, mainly by renal excretion of unchanged sulfathiazole and metabolism to acetylsulfathiazole, with a biological half-life of 1.4 hours. Sulfathiazole (in solution) was absorbed rapidly (half-life 0.8 hour) and relatively completely (73%) following oral administration.