Sexual maturity,seasonal estrus,and gestation in female Indo-Pacific bottlenose dolphins Tursiops aduncus inferred from serum reproductive hormones

Reproductive hormones in serum concentrations of progesterone, estradiol, and testosterone in female Indo-Pacific bottlenose dolphins (Tursiops aduncus, n = 12) housed in Ocean Park Hong Kong were investigated in the present study. Results showed that, onset of puberty of captive Indo-Pacific bottlenose dolphins was at 5 years while sexual maturity was at 6. Average serum progesterone concentrations in non-pregnant sexually mature individuals was 0.33 (0.25–0.97) ng/mL (interquartile), significantly higher than in immature ones 0.26 (0.25–0.38) ng/mL. This study found significant difference in serum estradiol concentrations between individuals at the onset of puberty (9.5 ± 1.7 pg/mL, ±SD) and not (below detection limit 9 pg/mL). A slightly seasonal breeding pattern, with progesterone values tend to be higher from February to October (0.38 [0.25–1.07] ng/mL) was inferred. During pregnancy, serum progesterone concentrations range from 10.54 ± 8.74 ng/mL (indexed month post-conception [IMPC] 0) to 25.49 ± 12.06 ng/mL (IMPC 2), and display a bimodal pattern with 2 peaks in early- (25.49 ± 12.06 ng/mL, IMPC 2) and late-pregnancy (21.71 ± 10.25 ng/mL, IMPC 12), respectively. Serum estradiol concentrations can seldom be detected in early-pregnancy and increase constantly in mid- (9.45 ± 1.83 pg/mL) and late-pregnancy (11.88 ± 3.81 pg/mL), with a spike (15.45 ± 6.78 pg/mL) 1 month prior to delivery. Serum testosterone concentrations elevate significantly in IMPC 7 (0.36 ± 0.10 ng/mL) compared to other months (0.16 ± 0.10 ng/mL) of the year. The present study provides normal concentration profiles for some reproductive hormones in female Indo-Pacific bottlenose dolphins and can contribute to the breeding monitoring of this species. Also, our study would shed further light on the reproductive physiology of small cetaceans.     

超数排卵处理沼泽型水牛血清E_2和P_4浓度变化研究

研究利用3种不同的方法超数排卵处理沼泽型水牛,比较研究不同方法处理时水牛血清雌二醇(E2)、孕酮(P4)浓度变化规律。结果表明:进口FolltropinR○-V、国产FSH和PMSG超数排卵处理沼泽型水牛,血清E2浓度峰值分别出现在氯前列烯醇(PGc)处理后的48 h([142.45±94.66)pg/mL]、72 h([87.78±29.62)pg/mL]、48 h([126.38±92.33)pg/mL];血液中P4浓度最低值分别出现在PGc处理后的48 h([0.76±0.21)pg/mL]、24 h([1.18±0.12)pg/mL]和144 h([0.82±0.06)pg/mL]。     

Pharmacokinetics of a controlled‐release liposome‐encapsulated hydromorphone administered to healthy dogs

The purpose of the study was to assess the pharmacokinetics of liposome‐encapsulated (DPPC‐C) hydromorphone administered intravenously (IV) or subcutaneously (SC) to dogs. A total of eight healthy Beagles aged 12.13 ± 1.2 months and weighing 11.72 ± 1.10 kg were used. Dogs randomly received liposome encapsulated hydromorphone, 0.5 mg/kg IV (n = 6), 1.0 mg/kg (n = 6), 2.0 mg/kg (n = 6), or 3.0 mg/kg (n = 7) SC with a 14–28 day washout between trials. Blood was sampled at serial intervals after drug administration. Serum hydromorphone concentrations were measured using liquid chromatography with mass spectrometry. Serum concentrations of hydromorphone decreased rapidly after IV administration of the DPPC‐C formulation (half‐life = 0.52 h, volume of distribution = 12.47 L/kg, serum clearance = 128.97 mL/min/kg). The half‐life of hydromorphone after SC administration of DPPC‐C formulation at 1.0, 2.0, and 3.0 mg/kg was 5.22, 31.48, and 24.05 h, respectively. The maximum serum concentration normalized for dose (C_MAX/D) ranged between 19.41–24.96 ng/mL occurring at 0.18–0.27 h. Serum hydromorphone concentrations fluctuated around 4.0 ng/mL from 6–72 h after 2.0 mg/kg and mean concentrations remained above 4 ng/mL for 96 h after 3.0 mg/kg DPPC‐C hydromorphone. Liposome‐encapsulated hydromorphone (DPPC‐C) administered SC to healthy dogs provided a sustained duration of serum hydromorphone concentrations.     

Communications: Validation of a Solid-Phase Enzyme Immunoassay Technique for the Measure of Plasma Cortisol in Rainbow Trout

Abstract

A kit for a solid-phase enzyme immunoassay (SOPHEIA®) of cortisol in human sera was evaluated and validated for measuring cortisol in plasma of rainbow trout Oncorhynchus mykiss. The accuracy of the SOPHEIA was demonstrated by the recovery of exogenous cortisol concentrations of 25, 50, 100, and 250 ng/mL in charcoal-stripped fish plasma. The amounts (mean ± SE) recovered from triplicate samples were 29.9 ± 2.75, 47.5 ± 3.41, 101.7 ± 12.08, and 232.0 ± 11.06 ng/mL, respectively. The intra- and interassay coefficient of variation (CV = 100 × SD/mean) for cortisol levels in undisturbed fish (26.6 ± 1.18 ng/mL) were 14 and 10%, respectively. The intra- and interassay CV for elevated cortisol levels in stressed fish (330.8 ± 19.90 ng/mL) were 8 and 13%, respectively. Cross-reactivity determined for nine steroids in teleostean fish was negligible. Cortisol concentrations in serial dilutions of pooled fish plasma were parallel to the standard curve. Sensitivity (minimum detection limit) was 3.04 ng/mL. The SOPHEIA compared favorably to radioimmunoassay measurements of cortisol (r = 0.98; P < 0.001).     

Pharmacokinetics of erythromycin after the administration of intravenous and various oral dosage forms to dogs

The purpose of this study was to describe and compare the pharmacokinetic properties of different formulations of erythromycin in dogs. Erythromycin was administered as lactobionate (10 mg/kg, IV), estolate tablets (25 mg/kg p.o.) and ethylsuccinate tablets or suspension (20 mg/kg p.o.). After intravenous (i.v.) administration, the principal pharmacokinetic parameters were (mean ± SD): AUC_(0–∞) 4.20 ± 1.66 μg·h/mL; C_max 6.64 ± 1.38 μg/mL; V_z 4.80 ± 0.91 L/kg; Cl_t 2.64 ± 0.84 L/h·kg; t_½λ 1.35 ± 0.40 h and MRT 1.50 ± 0.47 h. After the administration of estolate tablets and ethylsuccinate suspension, the principal pharmacokinetic parameters were (mean ± SD): C_max, 0.30 ± 0.17 and 0.17 ± 0.09 μg/mL; t_max, 1.75 ± 0.76 and 0.69 ± 0.30 h; t_½λ, 2.92 ± 0.79 and 1.53 ± 1.28 h and MRT, 5.10 ± 1.12 and 2.56 ± 1.77 h, respectively. The administration of erythromycin ethylsuccinate tablets did not produce measurable serum concentrations. Only the i.v. administration rendered serum concentrations above MIC₉₀ = 0.5 μg/mL for 2 h. However, these results should be cautiously interpreted as tissue erythromycin concentrations have not been measured in this study and, it is recognized that they can reach much higher concentrations than in blood, correlating better with clinical efficacy.     

Intravenous disposition kinetics, oral and intramuscular bioavailability and urinary excretion of norfloxacin nicotinate in donkeys

An aqueous solution of norfloxacin nicotinate (NFN) was administered to donkeys (Aquus astnus) intravenously (once at 10 mg/kg), intramuscularly and orally (both routes once at 10 and 20 mg/kg, and for 5 days at 20 mg/kg/day). Blood samples were collected at predetermined times after each treatment and urine was sampled after intravenous drug administration. Serum NFN concentrations were determined by microbiological assay. Intravenous injection of NFN over 45–60 s resulted in seizures, profuse sweating and tachycardia. The intravenous half-life (t_1/2β was 209 ± 36 min, the apparent volume of distribution (V_d(area)) was 3.34 ± 0.58 L/kg, the total body clearance (Cl_E) was 1.092 ± 0.123 ± 10^--²mL/min/kg and the renal clearance (C1_R) was 0.411 ± 0.057 ± 10^--²mL/min/kg. Oral bioavailability was rather poor (9.6% and 6.4% for the 10 and 20 mg/kg doses respectively). Multiple oral treatments did not result in any clinical gastrointestinal disturbances. After intramuscular administration (20 mg/kg), serum NFN concentrations > 0.25 μg/mL (necessary to inhibit the majority of gram-negative bacteria isolated from horses) were maintained for 12 h. The intramuscular bioavailability was 31.5% and 18.8% for the 10 and 20 mg/kg doses respectively. After multiple dosing some local swelling was observed at the injection site. About 40% of the intravenous dose was recovered in the urine as parent drug. The results of comprehensive haematological and blood biochemistry tests indicated no abnormal findings except elevation in serum CPK (creatine phosphokinase) values after multiple intramuscular dosing. On the basis of the in vitro-determined minimum inhibitory concentrations of the drug and serum concentrations after multiple dosing, the suggested intramuscular dosage schedules for the treatment of gram-negative bacterial infections in Equidae are 10 mg/kg every 12 h or 20 mg/kg every 24 h.     

Pharmacokinetics of ketamine in plasma and milk of mature Holstein cows

Sellers, G., Lin, H. C., G. Riddell, M. G., Ravis, W. R., Lin, Y. J., Duran, S. H., Givens, M.D. Pharmacokinetics of ketamine in plasma and milk of mature Holstein cows. J. vet. Pharmacol. Therap. 33 , 480–484. The purpose of this study was to evaluate the pharmacokinetics of ketamine in mature Holstein cows following administration of a single intravenous (i.v.) dose. Plasma and milk concentrations were determined using a high‐performance liquid chromatography assay. Pharmacokinetic parameters were estimated using a noncompartmental method. Following i.v. administration, plasma T_max was 0.083 h and plasma C_max was 18 135 ± 22 720 ng/mL. Plasma AUC was 4484 ± 1,398 ng·h/mL. Plasma t_½β was 1.80 ± 0.50 h and mean residence time was 0.794 ± 0.318 h with total body clearance of 1.29 ± 0.70 L/h/kg. The mean plasma steady‐state volume of distribution was calculated as 0.990 ± 0.530 L/kg and volume of distribution based on area was calculated as 3.23 ± 1.51 L/kg. The last measurable time for ketamine detection in plasma was 8.0 h with a mean concentration of 24.9 ± 11.8 ng/mL. Milk T_max was detected at 0.67 ± 0.26 h with C_max of 2495 ± 904 ng/mL. Milk AUC till the last time was 6593 ± 2617 ng·h/mL with mean AUC milk to AUC plasma ratio of 1.99 ± 2.15. The last measurable time that ketamine was detected in milk was 44 ± 10.0 h with a mean concentration of 16.0 ± 9.0 ng/mL.     

Noradrenergic Control of Arginine Vasopressin Release from the Ewe Hypothalamus In Vitro: Sensitivity to Oestradiol

The present study aims at ascertaining the influence of α₁‐adrenoreceptors on arginine vasopressin (AVP) release in vitro and determine whether E₂ modulates the α₁‐adrenoreceptor and AVP interaction. Ten minutes after ewe killing, sagittal midline hypothalamic slices (from the anterior preoptic area to the mediobasal hypothalamus with the median eminence, 2 mm thick, 2 per sheep) were dissected, placed in oxygenated minimum essential media‐α (MEM‐α) at 4°C and within 2 h were singly perifused at 37°C with oxygenated MEM‐α (pH 7.4; flow rate 0.15 ml/min), either with or without E₂ (24 pg/ml). After 4 h equilibration, 10 min fractions were collected for 4 h interposed with 10 min exposure at 60 min to a specific α₁‐adrenoreceptor agonist or antagonist at various doses (0.1–10 mm ). At the end of all perifusions, slices responded to KCl (100 mm ) with AVP efflux (p < 0.05). Release of AVP was enhanced (p < 0.05) by the α₁‐adrenoreceptor agonist (methoxamine 10 mm ; no E₂, n = 7 perifusion chambers: from 14.3 ± 2.7 to 20.9 ± 3.9, with E₂, n = 10: from 10.7 ± 1.2 to 18.4 ± 3.4 pg/ml) or the antagonist (thymoxamine 10 mm ; no E₂, n = 5: from 9.5 ± 3.1 to 30.4 ± 6.0, with E₂, n = 10: from 10.8 ± 0.9 to 39.1 ± 6.3 pg/ml). With the agonist, the response occurred only at 80 min (p < 0.05) both in the presence and absence of E₂. Whereas, after the antagonist, values were higher (p < 0.05) throughout the post‐treatment period (80–170 min) without E₂, but declined by 150 min in the presence of E₂. Furthermore, the response to the α₁‐adrenoreceptor antagonist was greater (p < 0.05; 90–140 min) than the agonist only in the presence of E₂. In conclusion, these results reveal direct α₁‐adrenoreceptor‐mediated control of the hypothalamic AVP neuronal system which is modulated by E₂.     

Leptin and ghrelin levels in colostrum,milk and blood plasma of sows and pig neonates during the first week of lactation

Radioimmunology was used to determine leptin and ghrelin levels in sow colostrum and milk in relation to those in sow and neonatal pig blood plasma and to the body weight of piglets during the first week of lactation. The highest concentration of leptin was found in colostrum on the second day of lactation (69.3 ± 6.3 ng/mL). Leptin concentrations in sow plasma were significantly lower than in colostrum/milk (2.19 ± 0.9 ng/mL, P = 0.7692) and were stable in the first 7 days of lactation. Total and active ghrelin concentrations in colostrum/milk were stable in the measured time points (6734 ± 261 pg/mL, P = 0.3397; 831 ± 242 pg/mL, P = 0.3988, respectively). Total ghrelin concentrations in sow plasma were lower than in colostrum/milk. These results indicate that pigs follow a unique species‐specific pattern of leptin and ghrelin synthesis, release and existence, and that the mammary gland is an important source of leptin and ghrelin contained in colostrum/milk.     

Characterization of Endocrine Events During the Periestrous Period in Sheep After Estrous Synchronization with Controlled Internal Drug Release (CIDR) Device

The Controlled Internal Drug Releasing (CIDR) device is an intravaginal pessary containing progesterone (P₄) designed for synchronizing estrus in ruminants. To date, there has been little information available on the timing, duration, and quality of the follicular phase after CIDR removal and how those characteristics compare with natural periovulatory endocrine events. The present communication relates the results of methods we used to characterize the endocrine events that followed CIDR synchronization. Breeding-season ewes were given an injection (10 mg) of Lutalyse (PGF_2α), and then studied during three consecutive estrous cycles, beginning in the luteal phase after the estrus induced by PGF_2α. Cycle 1 estrus was synchronized with 1 CIDR (Type G) inserted for 8 d beginning 10 d after PGF_2α. Cycles 2 and 3 were synchronized with two CIDRs for 8 d beginning 10 d after previous CIDR removal. Cycle 1 estrous behavior and serum gonadotropins showed a follicular phase (the interval from CIDR withdrawal to gonadotropin surge [surge] peak) of 38.2 ± 1.5 hr. Two CIDRs lengthened the interval to 46.2 ± 1.5 hr (P < 0.0001). At CIDR removal, circulating P₄ concentrations were higher in ewes treated with two CIDRs (5.1 ± 0.3 and 6.4 ± 0.4 ng/mL in Cycles 2 and 3 vs. 2.7 ± 0.3 ng/mL in Cycle 1), whereas estradiol concentrations were higher in the 1 CIDR cycle (3.3 ± 0.5 pg/mL in Cycle 1 vs. 0.5 ± 0.1, and 0.7 ± 0.2 pg/mL in Cycles 2 and 3), suggesting that the lower levels of P₄ achieved with one CIDR was not sufficient to arrest follicular development. There were no differences in any other endocrine variable. Both one and two CIDR synchronization concentrated surges within a 24-hr period in 92% of the ewes in Cycles 1 and 2. Cycle 3 ewes were euthanized at estimated luteal, early follicular, late follicular, LH surge, and secondary FSH rise timepoints. Endocrine data and ovaries showed that 88% of the ewes synchronized with two CIDRs were in the predicted stage of the estrous cycle. These data demonstrate that the CIDR device applied during the luteal phase effectively synchronizes estrus and results in a CIDR removal-to-surge interval of similar length to a natural follicular phase.     

Endothelin receptor subtype A blockade does not affect the haemodynamic recovery from haemorrhage during xenon/remifentanil or isoflurane/remifentanil anaesthesia in dogs

ObjectiveTo test the compensatory role of endothelin-1 when acute blood loss is superimposed on anaesthesia, by characterizing the effect of systemic endothelin receptor subtype A (ET_A) blockade on the haemodynamic and hormonal responses to haemorrhage in dogs anaesthetized with xenon/remifentanil (X/R) or isoflurane/remifentanil (I/R).Study designProspective experimental randomized controlled study.AnimalsSix female Beagle dogs, 13.4 ± 1.3 kg.MethodsAnimals were anaesthetized with remifentanil 0.5 μg kg^?1 minute^?1 plus either 0.8% isoflurane (I/R) or 63% xenon (X/R), with and without (Control) the systemic intravenous endothelin receptor subtype A antagonist atrasentan (four groups, n = 6 each). After 60 minutes of baseline anaesthesia, the dogs were bled (20 mL kg^?1) over 5 minutes and hypovolemia was maintained for 1 hour. Continuous haemodynamic monitoring was performed via femoral and pulmonary artery catheters; vasoactive hormones were measured before and after haemorrhage.ResultsIn Controls, systemic vascular resistance (SVR), vasopressin and catecholamine plasma concentrations were higher with X/R than with I/R anaesthesia at pre-haemorrhage baseline. The peak increase after haemorrhage was higher during X/R than during I/R anaesthesia (SVR 7420 ± 867 versus 5423 ± 547 dyne seconds cm^?5; vasopressin 104 ± 23 versus 44 ± 6 pg mL^?1; epinephrine 2956 ± 310 versus 177 ± 99 pg mL^?1; norepinephrine 862 ± 117 versus 195 ± 33 pg mL^?1, p < 0.05). Haemorrhage reduced central venous pressure from 3 ± 1 to 1 ± 1 cmH₂O (I/R, ns) and from 8 ± 1 to 5 ± 1 cmH₂O (X/R, p < 0.05), but did not reduce mean arterial pressure, nor cardiac output. Atrasentan did not alter the haemodynamic and hormonal response to haemorrhage during either anaesthetic protocol.Conclusions and clinical relevanceSelective ET_A receptor blockade with atrasentan did not impair the haemodynamic and hormonal compensation of acute haemorrhage during X/R or I/R anaesthesia in dogs.     

Intramuscular Selenium Administration in Selenium-Deficient Cattle

Nine recently weaned Hereford heifers were randomly assigned to a control group (n = 3) or a treatment group (n = 6). The animals were selenium (Se) deficient (mean ± SD blood Se concentration = 0.024 ± 0.012 μg/mL). They were maintained on a selenium-deficient diet, and on day 0 of the study the treatment group was given 0.05 mg Se/kg body weight intramuscularly, while the control group received a placebo. The Se concentration of blood, serum, and urine as well as the glutathione peroxidase (GSH-Px) activity of blood and serum was measured over an 84-day period. Peak blood Se and serum Se concentrations (mean ± SD) in the treatment group occurred at 5 hours postinjection and were 0.131 ± 0.028 μg/mL and 0.154 ± 0.027 μg/mL, respectively. The mean blood Se concentration of the treatment group was greater (P < .05) than that of the control group for the first 28 days after injection. The mean serum Se concentration of the treatment group was greater (P < .05) than that of the control group for all times after injection, except for day 56. The mean (±SD) blood GSH-Px activity of the treatment group (12.0 ± 2.3 mU/min/mg hemoglobin) was increased (P < .05) over the control group (2.0 ± 1.4 mU/min/ mg hemoglobin) by day 28 and continued to be greater (P < .05) throughout the 84 day postinjection period. The blood GSH-Px activity and the blood Se concentrations in the treatment group heifers did not reach concentrations considered indicative of Se adequacy (30 mU/min/mg hemoglobin and 0.10 μg/mL, respectively) except briefly, at 5 hours postinjection when the blood Se concentration of the treatment group was 0.131 ± 0.028 μg/mL. The mean serum GSH-Px activity of the treatment group did not differ at any time from that of the control group (P≥ .17). The mean (±SD) fractional excretion (FE) of Se, as an estimate of Se excretion, was greater (P < .05) in the treatment group heifers (n = 5; 6.2 ± 2.5%) than in the control heifers (n = 3; 1.3 ± 0.6%) at 24 hours postinjection. The mean (±SD) weight gain, from day 0 to day 84, for the treatment group heifers was 63.0 ± 18.1 kg and the mean weight gain for the control group heifers was 53.1 ± 7.3 kg at 84 days postinjection and there was no difference between the groups (P < .39). Conclusions drawn from this study include: 1) the increase in blood GSH-Px activity occurs approximately 28 days after Se injection given to Se-deficient heifers, 2) a single label dose of injectable Se does not result in blood Se concentrations or blood GSH-Px activity normally considered to be adequate, 3) the label dose of injectable Se, although therapeutically beneficial for nutritional myodegeneration (NMD), does not seem to be a desired method for long-term Se supplementation of cattle consuming a Se-deficient diet, and 4) blood Se is a better predictor of Se status than serum Se. (Journal of Veterinary Internal Medicine 1993; 7:342–348. Copyright © 1993 by the American College of Veterinary Internal Medicine.)     

Pharmacokinetics and adverse effects of oral meloxicam tablets in healthy adult horses

The objective of this study was to assess the pharmacokinetic profile and determine whether any adverse effects would occur in seven healthy adult horses following oral meloxicam tablet administration once daily for 14 days at a dose of 0.6 mg/kg·bwt. Horses were evaluated for health using physical examination, complete blood count, serum chemistry, urinalysis, and gastroscopy at the beginning and end of the study. Blood was collected for the quantification of meloxicam concentrations with liquid chromatography and mass spectrometry. The mean terminal half‐life was 4.99 ± 1.11 h. There was no significant difference between the mean C_max, 1.58 ± 0.71 ng/mL at T_max 3.48 ± 3.30 h on day 1, 2.07 ± 0.94 ng/mL at T_max 1.24 ± 1.24 h on day 7, and 1.81 ± 0.76 ng/mL at 1.93 ± 1.30 h on day 14 (P = 0.30). There was a statistically significant difference between the T_max on the sample days (P = 0.04). No statistically significant increase in gastric ulcer score or laboratory analytes was noted. Oral meloxicam tablets were absorbed in adult horses, and adverse effects were not statistically significant in this study. Further studies should evaluate the adverse effects and efficacy of meloxicam tablets in a larger population of horses before routine use can be recommended.     

Breed-specific pro-inflammatory cytokine production as a predisposing factor for susceptibility to sepsis in the dog

Objective: To determine whether 2 dog breeds with a high risk for parvoviral enteritis, a disease associated with sepsis, produce stronger pro‐inflammatory cytokine responses to a stimulus than dogs with a lower risk. Design: Blinded comparison. Setting: University outpatient clinic. Animals: Healthy, unrelated, purebred Doberman Pinschers (n=10) and Rottweilers (n=9) with age‐matched mixed‐breed dogs (n=7). Interventions: Heparinized, whole‐blood samples were collected from each dog and incubated for 6 hours with lipopolysaccharide. Plasma was collected, and bioassays were used to determine the concentrations of TNF‐α and IL‐6. The mean values obtained from the high‐risk breeds were compared with the mean obtained from the mixed‐breeds. Measurements and main results: The mean TNF‐α production from dogs with a high risk for parvoviral enteritis (1321±161 pg/mL; Doberman Pinscher and Rottweiler) was greater (P<0.05) than that from lower risk, mixed‐breed dogs (674±186 pg/mL). There were no differences in TNF‐α levels between Doberman (1128±247 pg/mL) and Rottweiler (1563±pg/mL) breeds or between any breeds with regard to IL‐6 production. Conclusions: The magnitude of TNF‐α production by peripheral blood monocytes was the greatest in the dogs with breed‐related risk for parvoviral enteritis. However, additional studies are needed to prove a causal relationship between high TNF and predilection for parvoviral enteritis. Regardless, breed appears to be a predisposing factor for variations in cytokine production that could impact the host response to infection and other inflammatory insults.     

Pharmacokinetics and milk secretion of gabapentin and meloxicam co‐administered orally in Holstein‐Friesian cows

Malreddy, P. R., Coetzee, J. F., KuKanich, B., Gehring, R. Pharmacokinetics and milk secretion of gabapentin and meloxicam co‐administered orally in Holstein‐Friesian cows. J. vet. Pharmacol. Therap.  36 , 14–20. Management of neuropathic pain in dairy cattle could be achieved by combination therapy of gabapentin, a GABA analog and meloxicam, an nonsteroidal anti‐inflammatory drug. This study was designed to determine specifically the depletion of these drugs into milk. Six animals received meloxicam at 1 mg/kg and gabapentin at 10 mg/kg, while another group (n = 6) received meloxicam at 1 mg/kg and gabapentin at 20 mg/kg. Plasma and milk drug concentrations were determined over 7 days postadministration by HPLC/MS followed by noncompartmental pharmacokinetic analyses. The mean (±SD) plasma C_max and T_max for meloxicam (2.89 ± 0.48 μg/mL and 11.33 ± 4.12 h) were not much different from gabapentin at 10 mg/kg (2.87 ± 0.2 μg/mL and 8 ± 0 h). The mean (±SD) milk C_max for meloxicam (0.41 ± 80.16 μg/mL) was comparable to gabapentin at 10 mg/kg (0.63 ± 0.13 μg/mL and 12 ± 6.69 h). The mean plasma and milk C_max for gabapentin at 20 mg/kg P.O. were almost double the values at 10 mg/kg. The mean (±SD) milk to plasma ratio for meloxicam (0.14 ± 0.04) was lower than for gabapentin (0.23 ± 0.06). The results of this study suggest that milk from treated cows will have low drug residue concentration soon after plasma drug concentrations have fallen below effective levels.     

Pharmacokinetics of gamithromycin in cattle with comparison of plasma and lung tissue concentrations and plasma antibacterial activity

Huang, R. A., Letendre, L. T., Banav, N., Fischer, J., Somerville, B. Pharmacokinetics of gamithromycin in cattle with comparison of plasma and lung tissue concentrations and plasma antibacterial activity. J. vet. Pharmacol. Therap. 33 , 227–237. The pharmacokinetics (PK) and dose proportionality of gamithromycin (ZACTRAN^®), a novel azalide, after a single intravenous (i.v.) dose of 3 mg/kg or subcutaneous (s.c.) injection at 3, 6 and 9 mg/kg body weight were studied in 13 male castrate and 13 female Angus cattle. Following i.v. administration, the mean area under the curve extrapolated to infinity (AUC_inf) was 4.28 ± 0.536 μg·h/mL, and mean elimination half‐life (t_1/2) was 44.9 ± 4.67 h, with a large volume of distribution (V_ss) of 24.9 ± 2.99 L/kg and a high clearance rate (Cl_obs) of 712 ± 95.7 mL/h/kg. For cattle treated with s.c. injection of 3, 6 or 9 mg/kg, mean AUC_inf values were 4.55 ± 0.690, 9.42 ± 1.11 and 12.2 ± 1.13 μg·h/mL, respectively, and the mean elimination half‐lives (t_1/2) were 51.2 ± 6.10, 50.8 ± 3.80 and 58.5 ± 5.50 h. Gamithromycin was well absorbed and fully bioavailable (97.6–112%) after s.c. administration. No statistically significant (α = 0.05) gender differences in the AUC_Inf or elimination half‐life values were observed. Dose proportionality was established based on AUC_Inf over the range of 0.5 to 1.5 times of the recommended dosage of 6 mg/kg of body weight. Further investigations were conducted to assess plasma PK, lung/plasma concentration ratios and plasma antibacterial activity using 36 cattle. The average maximum gamithromycin concentration measured in whole lung homogenate was 18 500 ng/g at first sampling time of 1 day (～24 h) after treatment. The ratios of lung to plasma concentration were 265, 410, 329 and 247 at 1, 5, 10 and 15 days postdose. The lung AUC_inf was 194 times higher than the corresponding plasma AUC_inf. The apparent elimination half‐life for gamithromycin in lung was 90.4 h (～4 days). Antibacterial activity was observed with plasma collected at 6 h postdose with a corresponding average gamithromycin plasma concentration of 261 ng/mL. In vitro plasma protein binding in bovine plasma was determined to be 26.0 ± 0.60% bound over a range of 0.1–3.0 μg/mL of gamithromycin. The dose proportionality of AUC, high bioavailability, rapid and extensive distribution to lung tissue and low level of plasma protein binding are beneficial PK parameters for an antimicrobial drug used for the treatment and prevention of bovine respiratory disease.     

Variability of estradiol concentration in normal dogs

Estradiol concentrations are evaluated in canine serum as part of an adrenal panel used to diagnose atypical Cushing’s syndrome and other endocrine abnormalities. Estradiol concentrations are often elevated in dogs without clinical signs of hyperestrogenism, and the significance of this elevation is unknown. The purpose of this study was to estimate the variation in estradiol concentrations in normal dogs. Ten neutered male and female dogs were enrolled in the study. Blood was collected from each dog at 2 h intervals, four times during a given day. This was repeated approximately 1 (week 2) and 5 weeks later (week 6). There was no attempt for a given dog to be started at the exact time or day each week. Results showed that estradiol concentrations ranged from 44.6 to 120.3 pg/mL with a mean of 70.4 pg/mL, which is greater than the upper limit of normal for our laboratory (69 pg/mL). The mean difference between the highest and lowest concentrations for each dog was 28.8 pg/mL, with a range of 12.5–53.5 pg/mL. Mean estradiol concentrations from week 6 (63.2 pg/mL) were significantly lower than those from week 1 (71.4 pg/mL; P = 0.015) and week 2 (76.5 pg/mL; P = 0.0004). These data show a wide range of variability in estradiol concentration both within and between dogs and that these measurements often exceed the normal ranges established by the laboratory. Therefore, diagnosis of hyperestrogenism or atypical Cushing’s syndrome based on increased estradiol concentrations should require compatible clinical presentation of hyperestrogenism together with elevated serum estradiol.     

Pharmacokinetics and bone tissue concentrations of lincomycin following intravenous and intramuscular administrations to cats

Albarellos, G. A., Montoya, L., Denamiel, G. A. A., Velo, M. C., Landoni, M. F. Pharmacokinetics and bone tissue concentrations of lincomycin following intravenous and intramuscular administrations to cats. J. vet. Pharmacol. Therap.  35 , 534–540. The pharmacokinetic properties and bone concentrations of lincomycin in cats after single intravenous and intramuscular administrations at a dosage rate of 10 mg/kg were investigated. Lincomycin minimum inhibitory concentration (MIC) for some gram‐positive strains isolated from clinical cases was determined. Serum lincomycin disposition was best‐fitted to a bicompartmental and a monocompartmental open models with first‐order elimination after intravenous and intramuscular dosing, respectively. After intravenous administration, distribution was rapid (T_1/2(d) = 0.22 ± 0.09 h) and wide as reflected by the volume of distribution (V_(d(ss))) of 1.24 ± 0.08 L/kg. Plasma clearance was 0.28 ± 0.09 L/h·kg and elimination half‐life (T_1/2) 3.56 ± 0.62 h. Peak serum concentration (C_max), T_max, and bioavailability for the intramuscular administration were 7.97 ± 2.31 μg/mL, 0.12 ± 0.05 h, and 82.55 ± 23.64%, respectively. Thirty to 45 min after intravenous administration, lincomycin bone concentrations were 9.31 ± 1.75 μg/mL. At the same time after intramuscular administration, bone concentrations were 3.53 ± 0.28 μg/mL. The corresponding bone/serum ratios were 0.77 ± 0.04 (intravenous) and 0.69 ± 0.18 (intramuscular). Lincomycin MIC for Staphylococcus spp. ranged from 0.25 to 16 μg/mL and for Streptococcus spp. from 0.25 to 8 μg/mL.     

Relationship between serum leptin concentrations and the marbling scores in Japanese Black Cattle

The objective of this study was to investigate the relationship between marbling and serum leptin concentrations. First, we compared serum leptin concentrations between Japanese Black cattle and Holstein calves, and found that the mean serum concentration was significantly higher (P < 0.05) in Japanese Black cattle (2.67 ± 0.41 ng/mL, n = 13) than in Holstein calves (1.79 ± 0.43 ng/mL, n = 5). We then examined the effects of roughage intake or vitamin A on the serum leptin concentrations in Japanese Black cattle. Although the leptin concentrations for the high roughage group were significantly higher than those for the low roughage group at 4, 7 and 20 months old, there was no significant difference in the carcass characteristics of the two groups. In addition, although there was a significant difference in the marbling score between the high vitamin A group and low vitamin A group, there was no significant difference in serum leptin concentrations between the groups. These results suggest that although serum leptin concentrations were not significantly correlated to the marbling scores they may be related to the genetic advantage for marbling in Japanese Black cattle.     

Effect of eCG dose on ovarian haemodynamics,hormonal profiles and prolificacy rate when oestrus was induced during low-breeding season in Beetal goats

The objectives of the experiment were to determine the effect of two doses of equine chorionic gonadotropin (eCG) in a standard synchronization protocol based on a short-term progesterone (P₄) priming on ovarian structures and haemodynamics, concentrations of steroid hormones and prolificacy rate when oestrus was induced during low-breeding season (LBS) in Beetal dairy goats. We hypothesized that inclusion of eCG in a short-term P₄ priming-based synchronization protocol would increase the blood perfusion to ovarian structures leading to enhance oestrous and ovulatory responses and prolificacy rate in goats. Forty-two multiparous acyclic goats were blocked by body condition and, within block, assigned randomly to receive saline as control (CON), low eCG (L-eCG; 300 IU) or high eCG (H-eCG; 600 IU) dose. Initially, a controlled internal drug release (CIDR) device was placed in the anterior vagina on d −8, followed by removal of CIDR on d −3, concurrent with the administration of PGF_2α and eCG according to their respective treatments. Goats were monitored for oestrous response. B-mode and Doppler ultrasonography was performed with 12-h interval, starting from day −3 until natural breeding (day 0), and then on days 5, 10, 15 and 20 post-breeding to monitor follicular and luteal dynamics and blood flow, respectively. Blood was sampled at 0, 12, 24, 36 and 60 h after CIDR removal to quantify plasma concentrations of estradiol-17β (E₂), whereas plasma concentrations of P₄ were assayed at days 5, 10, 15 and 20 after breeding. Pregnancy and prolificacy rates were determined at day 30 and 150 after breeding, respectively. Data were analysed with mixed-effects models, and orthogonal contrasts were used to evaluate the effect of treatment [Con vs. (½ L-eCG + ½ H-eCG)] and dose of eCG (L-eCG vs. H-eCG). Data are presented in sequence as CON, L-eCG, H-eCG (LSM ± SEM). The oestrous intensity score (152.9 vs. 182.7 vs. 186.5 ± 15.1; p = .02) was greater in eCG-treated goats as compared to CON. Administration of eCG reduced the intervals to standing oestrus (66.2 vs. 41.8 vs. 48.9 h ± 5.5; p = .05), breeding (70.2 vs. 44.4 vs. 45.4 h ± 4.5; p = .03) and ovulation (84.5 vs. 61.2 vs. 63.4 h ± 6.2; p = .05) compared with CON goats. The mean growth rate of pre-ovulatory follicle was greater (1.11 vs. 1.49 vs. 1.45 mm ± 0.08; p = .01) in eCG-treated goats resulting in an increased diameter of pre-ovulatory follicle (6.27 vs. 7.20 vs. 7.31 mm ± 0.07; p < .01) and corpora lutea (6.75 vs. 8.26 vs. 8.07 mm ± 0.42; p = .04) than CON. The mean follicular blood flow did not differ among treatments; however, the mean luteal blood flow was greater in L-eCG-treated goats (0.81 vs. 1.61 vs. 1.07 cm² ± 0.12; p = .001). The mean concentrations of E₂ (4.03 vs. 5.21 vs. 4.78 pg/ml ± 0.42; p = .04) and P₄ (4.85 vs. 6.39 vs. 6.22 ng/ml ± 0.34; p = .04) were greater in eCG-treated goats. The twinning rate did not differ between treatments; nevertheless, prolificacy rate was greater (p = .04) in L-eCG-treated goats. Collectively, our data suggest that the administration of eCG improves the induction of oestrous and ovarian dynamics. Administration of L-eCG enhances prolificacy rate, therefore, a low dose of eCG might be practically beneficial to improve reproduction during LBS in acyclic Beetal dairy goats.