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Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for the treatment of type 2 diabetes mellitus are known to delay gastric emptying (GE). The potential effect of the GLP-1 RA dulaglutide on the pharmacokinetics (PK) of four orally administered drugs and on the pharmacodynamic (PD) effect of warfarin was investigated. In four separate clinical pharmacology studies, digoxin, warfarin, atorvastatin and Ortho-Cyclen® were orally administered to healthy subjects with and without a subcutaneous dose of dulaglutide 1.5 mg. The effect of dulaglutide coadministration was assessed based on the PK parameters of key analytes. For warfarin PD, the effect of dulaglutide on the international normalized ratio (INR) was evaluated. Areas under the concentration–time curves (AUCs) with and without dulaglutide were similar for all analytes except atorvastatin, where it was reduced by 21%. Maximum concentrations (C max) were generally lower following coadministration with dulaglutide, with statistically significant reductions (90% confidence intervals of geometric least squares means ratios outside 0.80–1.25) for all analytes except R-warfarin. For all analytes, there was a general trend for the time to C max (t max) to increase following coadministration with dulaglutide. For warfarin, dulaglutide coadministration had no statistically significant effect on the maximum INR (INRmax); however, a 2% increase in area under the INR curve (AUCINR) was observed. Dulaglutide did not affect the absorption of the tested medications to a clinically relevant degree. Based on the PK and PD evaluations, no dose adjustments for digoxin, warfarin, atorvastatin and Ortho-Cyclen® are recommended when coadministered with dulaglutide. NCT01458210, NCT01436201, NCT01432938, and NCT01250834.

Background A large multistate outbreak of equine herpesvirus myeloencephalopathy (EHM) occurred in May 2011 among horses that participated in a competitive event. Objective To identify EHM risk factors among horses with a common exposure venue. Animals A total of 123 horses: 19 horses with EHM, 14 equine herpesvirus-1 cases with no reported neurologic signs, and 90 control horses. Methods EHM case survey data were compared with data from EHV-1 cases with no neurologic signs and healthy controls using univariable and multivariable methods. Results Significant factors associated with higher risk for EHM compared with EHV-1 cases with no neurologic signs were (1) greater number of biosecurity risks at the event, (2) female sex, (3) increasing number of classes competed in at the event, and (4) an interaction between sex and number of classes competed in. In the EHM versus controls comparison, in addition to sex and biosecurity risks, factors associated with higher EHM risk included EHV-1 vaccination in the 5 weeks before the event and increasing number of events attended in April 2011; zinc dietary supplementation was associated with decreased risk. An interaction between sex and the number of events attended in April 2011 also was significant. Conclusions and Clinical Importance Findings from this study suggest that dietary zinc supplementation may be associated with decreased risk of EHM. Several factors were associated with increased risk of EHM. Additional investigations of factors associated with risk of EHM are warranted to evaluate the importance of these factors in this complex disease of horses.

Summary Reason for performing study: Older horses have an increased risk of hyperthermia due to impaired cardiovascular function. While many studies have investigated thermoregulation in horses during exercise, none have investigated the effects of ageing. Objective: To test the hypothesis that there is a difference in thermoregulation during exercise and plasma volume (PV) in young and old horses. Methods:Study 1: 6 young (Y, 7.7 ± 0.5 years) and 5 old (O, 26.0 ± 0.8 years) unfit Standardbred mares (507 ± 11 kg, mean ± s.e.) ran on a treadmill (6% grade, velocity calculated to generate a work rate of 1625 watts) until core temperature reached 40°C. Core (CT), skin (ST), rectal temperature (RT) and heart rate (HR) were measured every min until 10 min post exertion. Packed cell volume (HCT), lactate (LA) and plasma protein (TP) were measured in blood samples collected before, at 40°C and every 5 min until 10 min post exercise. Sweat loss was estimated using bodyweight. Study 2: Plasma volume was measured in 26 young (8.2 ± 0.7 years) and 8 old (26.6 ± 0.7 years) Standardbred mares (515 ± 12 kg) using Evans Blue dye. Pre-exercise blood (rBV) and red cell (rRCV) volumes were calculated using PV and HCT. Data analysis utilised repeated measures ANOVA and t tests and data are expressed as mean ± s.e. Results: Old horses reached 40°C faster (998 ± 113 vs. 1925 ± 259 s; P 0.05) post exercise. Age did not alter (P>0.05) CT, ST, RT, LA, HCT or TP. Plasma volume was greater in Y vs. O horses (P

Summary The purpose of the present study was to determine whether the training-induced hypervolemic response seen in the horse is associated with aldosterone-mediated renal mechanisms affecting sodium conservation during the first days of training. Five healthy, Standardbred mares (weight 450–500 kg, age 4–8 years) that were unfit, but accustomed to running on the treadmill, were used to test the hypothesis that repeated submaximal exercise would alter plasma aldosterone (ALDO) concentration and renal excretion of electrolytes in horses within the first 3 days of training. The experiment consisted of a 2 week housing equilibration period followed by a 1 week control period and a 3 day exercise training period (30 min/day at 60% VO2max). During control, ALDO and renal fluid and electrolyte losses were measured for 24 h on 3 separate days. Renal function (urine volume [UV], 24 h excretion of Na+, K+ and CI- [UNA+V, UK+V, UClV], clearance of Na+ [CNa+], K+ [CK+] and Cl− [CCl-], creatinine [CCr], osmotic substances [Cosm], and solute-free water [FWC], and the fractional excretion of Na+, K+ and Cl−) and ALDO were measured for an additional 3 consecutive days during the training period. There were no differences (P>0.05) in any variable during the control period. Plasma volume increased (+18.7%, P

Dulaglutide is a long-acting glucagon-like peptide-1 receptor agonist administered as once-weekly subcutaneous injections for the treatment of type 2 diabetes (T2D). The clinical pharmacokinetics of dulaglutide were characterized in patients with T2D and healthy subjects. The pharmacokinetics of dulaglutide were assessed throughout clinical development, including conventional pharmacokinetic analysis in clinical pharmacology studies and population pharmacokinetic analyses of data from combined phase 2 and phase 3 studies in patients with T2D. The effects of potential covariates on dulaglutide population pharmacokinetics were evaluated using nonlinear mixed-effects models. Dulaglutide gradually reached the maximum concentration in 48 h and had a terminal elimination half-life of 5 days. Steady state was achieved between the second and fourth doses. The accumulation ratio was 1.56 for the 1.5 mg dose. Intra-individual variability estimates for the area under the plasma concentration–time curve and the maximum concentration were both

Older horses have an increased risk of hyperthermia due to impaired cardiovascular function. While many studies have investigated thermoregulation in horses during exercise, none have investigated the effects of ageing.To test the hypothesis that there is a difference in thermoregulation during exercise and plasma volume (PV) in young and old horses.Study 1: 6 young (Y, 7.7 ± 0.5 years) and 5 old (O, 26.0 ± 0.8 years) unfit Standardbred mares (507 ± 11 kg, mean ± s.e.) ran on a treadmill (6% grade, velocity calculated to generate a work rate of 1625 watts) until core temperature reached 40 °C. Core (CT), skin (ST), rectal temperature (RT) and heart rate (HR) were measured every min until 10 min post exertion. Packed cell volume (HCT), lactate (LA) and plasma protein (TP) were measured in blood samples collected before, at 40 °C and every 5 min until 10 min post exercise. Sweat loss was estimated using bodyweight. Study 2: Plasma volume was measured in 26 young (8.2 ± 0.7 years) and 8 old (26.6 ± 0.7 years) Standardbred mares (515 ± 12 kg) using Evans Blue dye. Pre-exercise blood (rBV) and red cell (rRCV) volumes were calculated using PV and HCT. Data analysis utilised repeated measures ANOVA and t tests and data are expressed as mean ± s.e.Old horses reached 40 °C faster (998 ± 113 vs. 1925 ± 259 s; P0.05) with a greater HR at 40 °C (184 ± 6 vs. 140 ± 5 beats/min; P0.05) and greater sweat losses (P0.05). Heart rate did not differ (P0.05) post exercise. Age did not alter (P0.05) CT, ST, RT, LA, HCT or TP. Plasma volume was greater in Y vs. O horses (P0.05, 28.5 ± 1.4 vs. 24.1 ± 1.6 l) as was rBV (41.3 ± 2.0 vs. 35.3 ± 2.3 l) and rRCV (13.3 ± 0.6 vs. 11.1 ± 0.8 l).Ageing compromises the ability to handle the combined demand of exercise and thermoregulation in part due to decreased absolute pre-exercise PV.

Summary Reasons for performing study: Recombinant human erythropoietin (rhuEPO) causes an increase in red blood cell production and aerobic capacity in other species; however, data are lacking on effects in the horse. Hypothesis: This study tested the hypothesis that rhuEPO administration would alter red cell volume (RCV), aerobic capacity (VO2max) and indices of anaerobic power. Methods: Eight healthy, unfit mares accustomed to the laboratory and experimental protocols were randomly assigned to either a control (CON, n=4; 3 ml saline 3 times/week for 3 weeks) or EPO group (EPO, n = 4, 50 iu/kg bwt rhuEPO/3 ml saline 3 times/week for 3 weeks). Exercise tests (GXT) were performed on a treadmill (6% incline), 1 week before and 1 week after treatment. The GXT started at 4 m/sec, with a 1 m/sec increase every 60 sec until the horse reached fatigue. Oxygen uptake was measured via an open flow indirect calorimeter. Blood samples were collected before, during (each step) and 2 and 15 min post GXT to measure packed cell volume (PCV), haemoglobin concentration (Hb), blood lactate concentration (LA) and plasma protein concentration (TP). Plasma volume (PV) was measured using Evans Blue dye. Blood volume (BV) and RCV were calculated using PCV from the 8 m/sec step of the GXT. Results: There were no alterations (P>0.05) in any parameters in CON horses. By week 3, EPO produced increases (P 0.05) due to decreased PV (-11%, P

To analyze myoelectric activity of the cecum and proximal loop of the ascending colon (PLAC) in cows after spontaneous cecal dilatation/dislocation (CDD) and compare it with that in healthy cows after surgical evacuation of the cecum.12 cows with spontaneous CDD and 6 healthy cows (group C). Cows with spontaneous CDD were retrospectively assigned to 2 groups: delayed recovery from surgery or recurrence (group A; n = 3), and normal recovery (group B; n = 9).After surgical evacuation of the cecum, 8 pairs of bipolar, retrievable electrodes were implanted in the ileum, cecum, and PLAC. Cows were evaluated daily from postoperative day 1 to 7, using routine clinical methods and computer-based analysis of myoelectric activity of the cecum, and PLAC. Parameters of myoelectric activity included rate of spike bursts, duration of individual spike bursts, duration of overall spike burst activity per electrode, rate of propagated spike burst sequences, and ratio of orally propagated spike burst sequences.Rate of spike bursts, duration of cecocolic spike burst activity, and ratio of orally to aborally propagated spike burst sequences did not vary among groups during the 7-day recording period. However, cows with delayed recovery had a typical, uniform pattern of myoelectric activity of the cecum and PLAC at days 1 and 2 after surgery that consisted of repeated, propagated spike burst sequences, made up of spike bursts of significantly (P0.05) increased duration at postsurgical day 1 and substantially prolonged duration at postsurgical day 2, interrupted by periods of little or no activity.Delayed recovery and recurrence of CDD in cows after spontaneous CDD is not caused by hypomotility of the cecum and PLAC.Postoperative treatment, intended to reduce recurrence of CDD or delayed recovery after surgical evacuation of the cecum, should address propagation of digesta in the spiral colon.

106 cattle with retained placenta were treated either with Vetisept-bolus or Tetran-bolus (controls) after an attempt to remove fetal membranes. Uterine involution judged by rectal palpation on the 28th day was the same in both groups, but more treatments were necessary for cows of the experimental group. Cows treated with Vetisept came in heat nine days earlier than controls (p0.05). The pregnancy rate of the controls (91.6%) was better (p0.05) than in the experimental group (60.7%). No significant differences between the two groups were encountered for pregnancy index, total index, and service period. Of 82 cows after single calving 50 got pregnant again. In 18 of the remaining cattle another pregnancy was not attempted. The other 14 were bred but did not conceive. Treatment with tetracycline seems to be slightly superior and safer than the treatment with PVP-iodine. It is uncertain, whether the higher (p0.05) losses of animals in the experimental group than in the controls is due to the different treatment, for most of the cows had been slaughtered because of insufficient milk production. Therapy with iodine is a recommended alternative to the treatment with tracycline for certain indications.

In recent years the relationship between stress and illness has received support from studies of psychosocial influences on immunity. Initial findings from human studies indicate that decreases in measures of immune status accompany a variety of stressful life events. Research also demonstrates how emotional distress, individual differences, and social support may mediate the impact of stress on the immune system. Although statistically significant findings have been widely reported, a predominance of retrospective and cross-sectional research has produced little evidence that psychoimmunological changes are clinically significant. Future studies involving longitudinal designs and multimodal assessment can contribute greatly to a deeper understanding of the processes involved. Psychologists, especially well-qualified to measure psychosocial factors of immunomodulating potential, can have valuable roles within the expanding interdisciplinary field of psychoimmunology.