Pharmacokinetics of famotidine in goats after intravenous administration.

There is currently limited pharmacokinetic data for the use of famotidine in goats for treatment and prevention of abomasal ulceration. The objective of this study was to determine the pharmacokinetic parameters after a single intravenous administration of famotidine (0.6 mg/kg). Famotidine was administered to six healthy goats and plasma samples were collected over a 24-h period. The famotidine concentration was measured using reverse phase high-performance liquid chromatography (HPLC). Non-compartmental analysis was then used to determine the pharmacokinetic parameters. The maximum plasma concentration was estimated at 5476.68 ± 1530.51 ng/mL and elimination half-life was estimated at 18.455 ± 13.26 min. The mean residence time was determined to be 19.85 ± 12.14 min with the apparent volume of distribution being estimated at 321.924 ± 221.667. The area under the curve was determined to be 54230.08 ± 24947.6 min*ng/mL. Total exposure and elimination half-life were less than what has been reported in cattle and horses. Future research evaluating the pharmacokinetics of subcutaneous administration and looking at the pharmacodynamics of famotidine in goats is needed to determine the effectiveness of famotidine on raising pH levels of the abomasum.

Pharmacokinetics of intraarticular liposomal amphotericin B in goats (Capra aegagrus hircus).

Lameness is a significant welfare concern in goats. Amphotericin B is used via intraarticular (IA) administration in models to study experimentally induced lameness in large animals. The main objective of this study was to estimate plasma pharmacokinetic (PK) parameters for amphotericin B in goats after a single IA administration. Liposomal amphotericin B was administered to ten Kiko-cross goats at a dose of 10 mg total (range: 0.34-0.51 mg/kg) via IA administration into the right hind lateral distal interphalangeal joint. Plasma samples were collected over 96 h. Amphotericin B concentrations were measured via liquid chromatography/mass spectrometry (LC-MS/MS). A non-compartmental analysis was used to derive PK parameters. Following single IA administration, maximum plasma concentration was estimated at 54.6 ± 16.5 ng/mL, and time to maximum concentration ranged from 6 to 12 h. Elimination half-life was estimated at 30.9 ± 16.5 h, and mean residence time was 45.1 ± 10.4 h. The volume of distribution after IA administration was 13.3 ± 9.4 L/kg. The area under the curve was 1481 ± 761 h*ng/mL. The achieved maximum concentration was less than the observed concentrations for other species and routes of administration. Further research is needed into the pharmacodynamics of IA liposomal amphotericin B in goats to determine specific research strategies.

Pharmacokinetics of oral clonazepam in growing commercial pigs (Sus scrofa domestica).

Clonazepam causes sedation and psychomotor impairment in people. Due to similarities between people and swine in response to benzodiazepines, clonazepam may represent a viable option to produce mild-to-moderate tranquillization in pigs. The objective of this study was to determine the pharmacokinetic profile of a single oral dose (0.5 mg/kg) of clonazepam in eight healthy, growing commercial cross pigs. Serial plasma samples were collected at baseline and up to 96 h after administration. Plasma concentrations were quantified using reverse-phase high-performance liquid chromatography, and compartment models were fit to time-concentration data. A one-compartment first-order model best fits the data. Maximum plasma concentration was 99.5 ng/mL, and time to maximum concentration was 3.4 h. Elimination half-life was 7.3 h, mean residence time 7.4 h, and apparent volume of distribution 5.7 L/kg. Achieved plasma concentrations exceeded those associated with psychomotor impairment in people although pharmacodynamic effects have not been investigated in pigs. A simulated oral regimen consisting of 0.35 mg/kg administered every 8 h to pigs would achieve plasma concentrations above 32 ng/mL which are shown to produce psychomotor impairment in people. Further studies to test the clinical efficacy of these dosages in commercial and miniature pigs are warranted.

Pharmacokinetics of nalbuphine administered intravenously and subcutaneously in goats (Capra aegagrus hircus).

The purpose of this study was to evaluate the pharmacokinetics (PK) of intravenously (IV) and subcutaneously (SC) administered nalbuphine in domestic goats. Nalbuphine hydrochloride was administered at 0.8 mg/kg for both IV and SC routes in six goats with a minimum of 10-day washout period between sample collection phases. Eighteen plasma samples were collected over a 36-hour period, analyzed using reverse phase high-performance liquid chromatography (HPLC). Plasma data were analyzed using compartmental and noncompartmental approaches. Following IV nalbuphine administration, elimination half-life, area under the plasma concentration time curve from time 0 to infinity (AUC0 - ∞), concentration at time zero (C0), and total body clearance were 120.4 ± 39.1 (min-1 ± SD), 17311.01 ± 7227.32 (min·ng·mL-1 ± SD), 675.6 ± 337.13 (ng·mL-1 ± SD), and 44.5 ± 13.8 (mL·min-1·kg-1 ± SD), respectively. After SC nalbuphine administration, elimination half-life, area under the plasma concentration time curve from time 0 to infinity (AUC0 - ∞), and maximum plasma drug concentration were 129 ± 52.9 (min-1 ± SD), 20826.5 ± 14376.2 (min·ng·mL-1), and 368.03 ± 503.78 (ng·mL-1). Calculated bioavailability for the SC route was 138 ± 126 (% ± SD). Nalbuphine in goats is characterized by rapid elimination and high subcutaneous bioavailability and may be a safe analgesic opioid option in goats in the future.

Pharmacokinetics of a single oral dose of grapiprant in juvenile pigs (Sus scrofa domestica).

Both pet and research pigs can suffer from some degree of pain from surgery, injuries, or osteoarthritis (OA). Despite this, there is a paucity of data on safe and effective analgesia agents in pigs. Grapiprant is an EP4 antagonist that blocks the action of the pro-inflammatory prostanoid, PGE2 . It has shown efficacy in attenuating pain associated with ovariohysterectomy and OA in dogs. However, there are no data regarding grapiprant in pigs. Therefore, the pharmacokinetic profile of orally administered grapiprant to juvenile pigs (Sus scrofa domestica) was evaluated in this study. Seven juvenile pigs received 12 mg/kg grapiprant orally. Blood was collected from an indwelling jugular catheter using the push-pull method at set timepoints up to 48 hours. Sample analysis was performed with high-performance liquid chromatography. Mean grapiprant plasma concentration was 164.3 ± 104.7 ng/mL which occurred at 0.8 ± 0.3 h. This study demonstrated that grapiprant concentrations consistent with analgesia in dogs were reached at this dosage in pigs. Further studies are needed to evaluate the efficacy of grapiprant in pigs.

Pharmacokinetics of intramuscular maropitant in pigs (Sus scrofa domesticus).

Pigs are at risk of vomiting from medical conditions as well as the emetic side effects of drugs administered for peri-operative manipulations, but there is a lack of pharmacokinetic data for potential anti-emetic therapies, such as maropitant, in this species. The main objective of this study was to estimate plasma pharmacokinetic parameters for maropitant in pigs after a single intramuscular (IM) administration dosed at 1.0 mg/kg. A secondary objective was to estimate pilot pharmacokinetic parameters in pigs after oral (PO) administration at 2.0 mg/kg. Maropitant was administered to six commercial pigs at a dose of 1.0 mg/kg IM. Plasma samples were collected over 72 h. After a 7-day washout period, two pigs were administered maropitant at a dose of 2.0 mg/kg PO. Maropitant concentrations were measured via liquid chromatography/mass spectrometry (LC-MS/MS). A non-compartmental analysis was used to derive pharmacokinetics parameters. No adverse events were noted in any of the study pigs after administration. Following single IM administration, maximum plasma concentration was estimated at 412.7 ± 132.0 ng/mL and time to maximum concentration ranged from 0.083 to 1.0 h. Elimination half-life was estimated at 6.7 ± 1.28 h, and mean residence time was 6.1 ± 1.2 h. Volume of distribution after IM administration was 15.9 L/kg. Area under the curve was 1336 ± 132.0 h*ng/mL. The relative bioavailability of PO administration was noted to be 15.5% and 27.2% in the two pilot pigs. The maximum systemic concentration observed in the study pigs after IM administration was higher than what was observed after subcutaneous administration in dogs, cats, or rabbits. The achieved maximum concentration exceeded the concentrations for anti-emetic purposes in dogs and cats; however, a specific anti-emetic concentration is currently not known for pigs. Further research is needed into the pharmacodynamics of maropitant in pigs to determine specific therapeutic strategies for this drug.

Clinical presentation, diagnostics, treatment, and outcome of goats diagnosed with presumptive cerebrospinal nematodiasis at a veterinary teaching hospital.

This retrospective study describes clinical presentation, diagnostic approach, treatment, and outcome for goats with presumptive cerebrospinal nematodiasis. A presumptive diagnosis was made based on neurologic signs, results of cerebrospinal fluid analysis, and response to treatment. Six goats were identified that met inclusion criteria. Cerebrospinal fluid analysis revealed eosinophilic pleocytosis (total nucleated cell count: 12 to 430/µL, 33 to 89% eosinophils). All 6 goats were treated with fenbendazole and anti-inflammatory drugs (NSAIDs ± corticosteroids) and 4 received physical rehabilitation therapy. At discharge or follow-up, all 6 goats were ambulatory and had minimal neurologic deficits. Key clinical message: In goats, cerebrospinal nematodiasis caused by Parelaphostrongylus tenuis is often a presumptive diagnosis based on neurologic signs, shared habitat with white-tailed deer, eosinophilic pleocytosis, and response to anthelmintic therapy. Presumptive cases in goats have many similarities to confirmed cases in camelids. Further study is indicated to characterize the clinical signs and optimize the diagnosis and treatment of goats infected with P. tenuis.

Présentation clinique, diagnostic, traitement et devenir des chèvres diagnostiquées avec une nématodose cérébro-spinale présumée dans un hôpital d'enseignement vétérinaire. Cette étude rétrospective décrit la présentation clinique, l'approche diagnostique, le traitement et les résultats pour des chèvres atteintes de nématodose cérébro-spinale présumée. Un diagnostic présomptif a été posé sur la base des signes neurologiques, des résultats de l'analyse du liquide céphalo-rachidien et de la réponse au traitement. Six chèvres ont été identifiées qui répondaient aux critères d'inclusion. L'analyse du liquide céphalo-rachidien a révélé une pléocytose éosinophile (nombre total de cellules nucléées : 12 à 430/µL, 33 à 89 % d'éosinophiles). Les six chèvres ont été traitées avec du fenbendazole et des anti-inflammatoires (AINS ± corticostéroïdes) et quatre ont reçu une thérapie de réadaptation physique. À la sortie ou au suivi, les six chèvres étaient ambulatoires et présentaient des déficits neurologiques minimes.Message clinique clé :Chez les chèvres, la nématodose cérébro-spinale causée par Parelaphostrongylus tenuis est souvent un diagnostic présomptif basé sur des signes neurologiques, un habitat partagé avec des cerfs de Virginie, une pléocytose éosinophile et une réponse à un traitement anthelminthique. Les cas présumés chez les chèvres présentent de nombreuses similitudes avec les cas confirmés chez les camélidés. Une étude plus approfondie est indiquée pour caractériser les signes cliniques et optimiser le diagnostic et le traitement des chèvres infectées par P. tenuis.(Traduit par Dr Serge Messier).

Toward compact high-efficiency grating couplers for visible wavelength photonics.

Although grating couplers have become the de-facto standard for optical access to integrated silicon photonics platforms, their performance at visible wavelengths, in moderate index contrast platforms such as silicon nitride, leaves significant room for improvement. In particular, the index contrast governs the diffraction efficiency per grating tooth and the resulting overall coupler length. In this work, we develop two approaches to address this problem: a dielectric grating that sums multiple optical modes to increase the overall output intensity; and an embedded metal grating that enhances the attainable refractive index contrast, and therefore reduces the on-chip footprint. We present experimental results that can be developed to realize compact efficient visible wavelength photonic interconnects, with a view toward cryogenic deployment for quantum photonics, where space is constrained and efficiency is critical.

Ultrasonography and digital radiography findings in sheep with clinical disease associated with small ruminant lentivirus infection.

Digital radiography and ultrasonographic images were used in this case series to evaluate 4 ewes from a single flock for chronic weight loss and ill-thrift. On examination, all displayed tachypnea, dyspnea, coughing, and normothermia with abnormal thoracic auscultations. Three of the 4 animals were diagnosed with chronic respiratory disease associated with Maedi-visna (MV) infection confirmed via serologic testing. Diagnostic thoracic imaging identified characteristics consistent with pathological lesions associated with interstitial pneumonia in the 3 MV affected animals; these findings were absent in the animal that tested negative for MV. Key clinical message: Diagnostic imaging may be useful to clinicians looking to obtain further visualization of lung pathologies and as a reliable means of detecting thoracic lesions indicative of interstitial pneumonia on-farm. These results can be used to aid the practitioner in determining appropriate further diagnostic testing and treatment strategies while awaiting confirmatory test results for diagnosis of MV.

Résultats de l'échographie et de la radiographie numérique chez des ovins atteints d'une maladie clinique associée à une infection à lentivirus des petits ruminants. La radiographie numérique et les images échographiques ont été utilisées dans cette série de cas pour évaluer quatre brebis d'un seul troupeau présentant une perte de poids chronique et un retard de croissance. À l'examen, tous les animaux présentaient une tachypnée, une dyspnée, une toux et étaient normothermiques avec des auscultations thoraciques anormales. Trois des quatre animaux ont été diagnostiqués avec une maladie respiratoire chronique associée à une infection Maedi-visna (MV) confirmée via des tests sérologiques. L'imagerie thoracique diagnostique a identifié des caractéristiques compatibles avec des lésions pathologiques associées à une pneumonie interstitielle chez les trois animaux atteints de MV; ces résultats étaient absents chez l'animal qui a été testé négatif pour MV.Message clinique clé :L'imagerie diagnostique peut être utile aux cliniciens qui cherchent à obtenir une visualisation plus poussée des pathologies pulmonaires et comme un moyen fiable de détecter les lésions thoraciques indiquant une pneumonie interstitielle à la ferme. Ces résultats peuvent être utilisés pour aider le praticien à déterminer d'autres tests de diagnostic appropriés et des stratégies de traitement en attendant les résultats des tests de confirmation pour le diagnostic de MV.(Traduit par Dr Serge Messier).

Pharmacokinetics and pharmacodynamics of doxycycline in a Streptococcusequi subsp. zooepidemicus infection model in horses.

The objectives of this study were to investigate the pharmacokinetics (PK), pharmacodynamics (PD), and the efficacy of oral administration of doxycycline (DXC) in horses with Streptococcus zooepidemicus tissue infections. Tissue chambers (TC) were implanted subcutaneously in the cervical region of 7 horses and inoculated with a single S. zooepidemicus isolate with a minimum inhibitory concentration (MIC) of 0.25 µg/ml, determined by agar dilution. Doxycycline hyclate (10 mg/kg, orally, q 12 h, for 5 days) mixed with poloxamer gel was started following inoculation. The TC fluid was sampled prior to and following inoculation for cytology analysis, quantitative culture, and DXC determination. Plasma DXC concentrations were measured over 48 h following the last dose of DXC administered. The mean plasma peak concentration (Cmax ) of DXC was 0.32 µg/ml, and concentrations above the MIC were only reached in 3 TC samples. In plasma, mean T > MIC was 2.4 h, mean Cmax /MIC was 1.30, and mean AUClast /MIC was 11.63 h. These PK/PD indices did not reach the suggested targets for DXC treatments of infections, and the TC abscessed in all horses. This is the first study to evaluate the recommended dose of DXC in horse in an infection model.

Dimethyl fumarate reduces TNF and Plasmodium falciparum induced brain endothelium activation in vitro.

BACKGROUND: Cerebral malaria (CM) is associated with morbidity and mortality despite the use of potent anti-malarial agents. Brain endothelial cell activation and dysfunction from oxidative and inflammatory host responses and products released by Plasmodium falciparum-infected erythrocytes (IE), are likely the major contributors to the encephalopathy, seizures, and brain swelling that are associated with CM. The development of adjunctive therapy to reduce the pathological consequences of host response pathways could improve outcomes. A potentially protective role of the nuclear factor E2-related factor 2 (NRF2) pathway, which serves as a therapeutic target in brain microvascular diseases and central nervous system (CNS) inflammatory diseases such as multiple sclerosis was tested to protect endothelial cells in an in vitro culture system subjected to tumour necrosis factor (TNF) or infected red blood cell exposure. NRF2 is a transcription factor that mediates anti-oxidant and anti-inflammatory responses. METHODS: To accurately reflect clinically relevant parasite biology a unique panel of parasite isolates derived from patients with stringently defined CM was developed. The effect of TNF and these parasite lines on primary human brain microvascular endothelial cell (HBMVEC) activation in an in vitro co-culture model was tested. HBMVEC activation was measured by cellular release of IL6 and nuclear translocation of NFκB. The transcriptional and functional effects of dimethyl fumarate (DMF), an FDA approved drug which induces the NRF2 pathway, on host and parasite induced HBMVEC activation was characterized. In addition, the effect of DMF on parasite binding to TNF stimulated HBMVEC in a semi-static binding assay was examined. RESULTS: Transcriptional profiling demonstrates that DMF upregulates the NRF2-Mediated Oxidative Stress Response, ErbB4 Signaling Pathway, Peroxisome Proliferator-activated Receptor (PPAR) Signaling and downregulates iNOS Signaling and the Neuroinflammation Signaling Pathway on TNF activated HBMVEC. The parasite lines derived from eight paediatric CM patients demonstrated increased binding to TNF activated HBMVEC and varied in their binding and activation of HBMVEC. Overall DMF reduced both TNF and CM derived parasite activation of HBMVEC. CONCLUSIONS: These findings provide evidence that targeting the NRF2 pathway in TNF and parasite activated HBMVEC mediates multiple protective pathways and may represent a novel adjunctive therapy to improve infection outcomes in CM.

Particle size and gastrointestinal absorption influence tiotropium pharmacokinetics: a pilot bioequivalence study of PUR0200 and Spiriva HandiHaler.

AIMS: Plasma pharmacokinetics permit the assessment of efficacy and safety of inhaled drugs, and possibly their bioequivalence to other inhaled products. Correlating drug product attributes to lung deposited dose is important to achieving equivalence. PUR0200 is a spray-dried formulation of tiotropium that enables more efficient lung delivery than Spiriva® HandiHaler® (HH). The ratio of tiotropium lung-to-oral deposition in PUR0200 was varied to investigate the impact of particle size on tiotropium pharmacokinetics, and the contribution of oral absorption to tiotropium exposure was assessed using charcoal block. METHODS: A seven-period, single-dose, crossover study was performed in healthy subjects. PUR0200 formulations differing in dose and aerodynamic particle size were administered in five periods and Spiriva HH in two periods. In one period, Spiriva HH gastrointestinal absorption was blocked with oral charcoal. Tiotropium plasma concentrations were assessed over 8 h after inhalation. RESULTS: PUR0200 pharmacokinetics were influenced by aerodynamic particle size and the ratio of lung-to-oral deposition, with impactor sized mass (ISM) correlating most strongly with exposure. Formulation PUR0217a (3 µg tiotropium) lung deposition was similar to Spiriva HH (18 µg) with and without charcoal block, but total PUR0200 exposure was lower without charcoal. The Cmax and AUC0-0.5h of Spiriva HH with and without charcoal block were bioequivalent; however, Spiriva HH AUC0-8h was lower when gastrointestinal absorption was inhibited with oral charcoal administration. CONCLUSIONS: Pharmacokinetic bioequivalence indicative of lung deposition and efficacy can be achieved by matching the reference product ISM. Due to reduced oral deposition and more efficient lung delivery, PUR0200 results in a lower AUC0-t than Spiriva HH due to reduced absorption of drug from the gastrointestinal tract.

Effects of experimentally induced respiratory disease on the pharmacokinetics and tissue residues of tulathromycin in meat goats.

Tulathromycin is a macrolide antibiotic commonly used for the treatment of respiratory disease in food animal species including goats. Recent research in pigs has suggested that the presence of disease could alter the pharmacokinetics of tulathromycin in animals with respiratory disease. The objectives of this study were (a) compare the plasma pharmacokinetics of tulathromycin in healthy goats as well as goats with an induced respiratory disease; and (b) to compare the tissue residue concentrations of tulathromycin marker in both groups. For this trial, disease was induced with Pasteurella multocida. Following disease induction, tulathromycin was administered. Samples of plasma were collected at various time points up to 312 hr posttreatment, when study animals were euthanized and tissue samples were collected. For PK parameters in plasma, Vz (control: 28.7 ± 11.9 ml/kg; experimental: 57.8 ± 26.6 ml/kg) was significantly higher (p = 0.0454) in the experimental group than the control group, and nonsignificant differences were noted in other parameters. Among time points significantly lower plasma concentrations were noted in the experimental group at 168 hr (p = 0.023), 216 hr (p = 0.036), 264 hr (p = 0.0017), 288 hr (p = 0.0433), and 312 hr (p = 0.0486). None of the goats had tissue residues above the US bovine limit of 5 µg/g at the end of the study. No differences were observed between muscle, liver, or fat concentrations. A significantly lower concentration (p = 0.0095) was noted in the kidneys of experimental goats when compared to the control group. These results suggest that the effect of respiratory disease on the pharmacokinetics and tissue residues appear minimal after experimental P. multocida infection, however as evidenced by the disparity in Cmax , significant differences in plasma concentrations at terminal time points, as well as the differences in kidney concentrations, there is the potential for alterations in diseased versus clinical animals.

Comparative plasma and interstitial fluid pharmacokinetics and tissue residues of ceftiofur crystalline-free acid in cattle with induced coliform mastitis.

Ceftiofur (CEF) is a third-generation cephalosporin that is the most widely used antimicrobial in the dairy industry. Currently, violative meat residues in cull dairy cattle are commonly associated with CEF. One potential cause for violative residues is altered pharmacokinetics of the drug due to disease, which could increase the time needed for the residue to deplete. The objectives of this study were (a) to determine the absolute bioavailability of CEF crystalline-free acid (CFA) in healthy versus diseased cows; (b) to compare the plasma and interstitial fluid pharmacokinetics and plasma protein binding of CEF between healthy dairy cows and those with disease; and (c) to determine the CEF residue profile in tissues of diseased cows. For this trial, disease was induced through intramammary Escherichia coli infusion. Following disease induction and CEF CFA administration, for plasma concentrations, there was not a significant effect of treatment (p = 0.068), but the treatment-by-time interaction (p = 0.005) was significant. There was a significantly greater concentration of CEF in the plasma of the DIS cows at T2 hr (p = 0.002), T8 hr (p < 0.001), T12 hr (p = 0.001), and T16 hr (p = 0.002). For PK parameters in plasma, the slope of the terminal phase of the concentration versus time curve was significantly lower (p = 0.007), terminal half-life was significantly longer (p = 0.014), and apparent volume of distribution during the elimination phase was significantly higher (p = 0.028) diseased group. There was no difference in plasma protein binding of CEF and interstitial fluid pharmacokinetics. None of the cows had kidney CEF residues above the US tolerance level following observation of the drug's withdrawal period, but one cow with a larger apparent volume of distribution and longer terminal half-life had tissue residues slightly below the tolerance. Whereas these findings do not support the hypothesis that severely ill cows need longer withdrawal times, alterations in the terminal half-life suggest that it is theoretically possible.

Adverse reactions to fentanyl transdermal patches in calves: a preliminary clinical and pharmacokinetic study.

OBJECTIVE: To describe adverse reactions and measure plasma fentanyl concentrations in calves following administration of a fentanyl transdermal patch (FTP). STUDY DESIGN: Prospective, experimental clinical study. ANIMALS: Six female Holstein calves and one male Angus calf. Four calves were healthy experimental animals and three calves were clinical patients. METHODS: Plasma fentanyl concentrations were measured in blood collected from a jugular vein. FTP 2 µg kg-1 hour-1 and 1 µg kg-1 hour-1 was applied to four and three calves, respectively. Heart rate, respiratory rate, temperature and ataxia were recorded at the same times as blood collection (0, 2, 4, 6, 12, 24, 36, 48, 60, 72, 84 and 96 hours). Substance P concentrations were determined via radioimmunoassay for two calves. RESULTS: After the FTP (2 µg kg-1 hour-1) application, two calves developed tachycardia, hyperthermia, excitement and ataxia within 6 hours; no adverse effect was observed in the other two calves. The three calves administered FTP (1 µg kg-1 hour-1) exhibited tachycardia and excitement, and the FTP were removed at 4 hours. Naloxone was administered to two calves before the adverse clinical signs ceased, while adverse events in the other three calves resolved within 2 hours of FTP removal. Variables returned to previous baseline values by 2-4 hours after FTP removal. Maximum plasma fentanyl concentrations were variable among calves (0.726-6.923 ng mL-1). Substance P concentrations measured in two calves were not consistently depressed during FTP application. Fentanyl concentrations at 4 and 6 hours were significantly associated with the appearance of adverse effects. CONCLUSIONS AND CLINICAL RELEVANCE: FTP (1-2 µg kg-1 hour-1) administered to calves may result in adverse behavioral and cardiovascular effects. Patch removal and treatment with an opioid antagonist may resolve these adverse effects. Additional research is needed to determine optimal FTP dosing for cattle.

ASPIRATION PNEUMONIA IN TWO TIBETAN YAK BULLS ( BOS GRUNNIENS) AS A COMPLICATION OF KETAMINE-XYLAZINE-BUTORPHANOL ANESTHESIA FOR RECUMBENT CASTRATION.

Among members of the genus Bos, aspiration pneumonia has been described in domestic cattle ( Bos taurus and Bos indicus). In these species, aspiration pneumonia is most commonly a sequelae to oral administration of fluids or medications, as well as aspiration during procedures under anesthesia. Management of aspiration pneumonia secondary to complications from anesthesia for short duration surgical procedures is minimally reported in the Tibetan yak ( Bos grunniens). Although regurgitation under anesthesia has been reported in the yak, there are no reports of aspiration pneumonia treatment. This case report describes the diagnosis and management of aspiration pneumonia in two Tibetan yaks undergoing castration under injectable ketamine-xylazine-butorphanol anesthesia. This case report also describes the gross and pathologic characteristics of anesthesia-induced aspiration pneumonia in one Tibetan yak, as well as successful treatment in another.

Femoral head ostectomy for the treatment of acetabular fracture and coxofemoral joint luxation in a Potbelly pig.

OBJECTIVE: To report the successful surgical treatment of a comminuted left acetabular fracture, a dorsally luxated left femoral head, and avulsion of the ligament of the femoral head by femoral head ostectomy (FHO) and physical therapy in a companion Potbelly pig. STUDY DESIGN: Case report. ANIMALS: A 1-year-old, 13 kg, castrated male, companion Potbelly pig. METHODS: The pig presented with a nonweight bearing left pelvic limb lameness of 3 weeks' duration that was noticed shortly after the pig got caught under a fence. Under general anesthesia a lateral approach was made to the fractured limb. A FHO was performed as described for dogs. Following surgery, a period of physical therapy was initiated based on protocols described for dogs. RESULTS: The canine surgical procedure with the approach modified for pigs was successfully performed in our pig. Following surgery, the pig was comfortable and weight bearing. A physical therapy regimen of supervised activity, stairs, and water therapy was used to rehabilitate the leg, as well as a weight management protocol to maintain ideal body condition. The owner was highly satisfied with the outcome. Telephone follow-up with the owner at 12 months after surgery revealed no impairment to movement, and the pig was maintaining normal ambulation without lameness. No complications were observed with this case. CONCLUSION: FHO, as described for dogs, provided a favorable outcome for hip luxation caused by acetabular fracture, luxation, and avulsion of the femoral head ligament in this small size Potbelly pig.

Off-Target drug effects resulting in altered gene expression events with epigenetic and "Quasi-Epigenetic" origins.

This review synthesizes examples of pharmacological agents who have off-target effects of an epigenetic nature. We expand upon the paradigm of epigenetics to include "quasi-epigenetic" mechanisms. Quasi-epigenetics includes mechanisms of drugs acting upstream of epigenetic machinery or may themselves impact transcription factor regulation on a more global scale. We explore these avenues with four examples of conventional pharmaceuticals and their unintended, but not necessarily adverse, biological effects. The quasi-epigenetic drugs identified in this review include the use of beta-lactam antibiotics to alter glutamate receptor activity and the action of cyclosporine on multiple transcription factors. In addition, we report on more canonical epigenome changes associated with pharmacological agents such as lithium impacting autophagy of aberrant proteins, and opioid drugs whose chronic use increases the expression of genes associated with addictive phenotypes. By expanding our appreciation of transcriptomic regulation and the effects these drugs have on the epigenome, it is possible to enhance therapeutic applications by exploiting off-target effects and even repurposing established pharmaceuticals. That is, exploration of "pharmacoepigenetic" mechanisms can expand the breadth of the useful activity of a drug beyond the traditional drug targets such as receptors and enzymes.

Development of clinical decision support alerts for pharmacogenomic incidental findings from exome sequencing.

PURPOSE: Electronic health records (EHRs) and their associated decision support tools are potentially important means of disseminating a patient's pharmacogenomic profile to his or her health-care providers. We sought to create a proof-of-concept decision support alert system generated from pharmacogenomic incidental findings from exome sequencing. METHODS: A pipeline for alerts from exome sequencing tests was created for patients in the New EXome Technology in (NEXT) Medicine study at the University of Washington. Decision support rules using discrete, machine-readable incidental finding results were programmed into a commercial EHR rules engine. An evaluation plan to monitor the alerts in real medical interactions was established. RESULTS: Alerts were created for 48 actionable pharmacogenomic variants in 11 genes and were launched on 24 September 2014 for University of Washington inpatient care. Of the 94 participants enrolled in the NEXT Medicine study, 49 had one or more pharmacogenomic variants identified for return. CONCLUSION: Reflections on the process reveal that while incidental findings can be used to generate decision support alerts, substantial resources are required to ensure that each alert is consistent with rapidly evolving pharmacogenomic literature and is customized to fit in the clinical workflow unique to each incidental finding.

Applying a weed risk assessment approach to GM crops.

Current approaches to environmental risk assessment of genetically modified (GM) plants are modelled on chemical risk assessment methods, which have a strong focus on toxicity. There are additional types of harms posed by plants that have been extensively studied by weed scientists and incorporated into weed risk assessment methods. Weed risk assessment uses robust, validated methods that are widely applied to regulatory decision-making about potentially problematic plants. They are designed to encompass a broad variety of plant forms and traits in different environments, and can provide reliable conclusions even with limited data. The knowledge and experience that underpin weed risk assessment can be harnessed for environmental risk assessment of GM plants. A case study illustrates the application of the Australian post-border weed risk assessment approach to a representative GM plant. This approach is a valuable tool to identify potential risks from GM plants.