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Objective To evaluate the agreement between oscillometric blood pressure (OBP) measured from the tongue and invasive blood pressure (IBP), and to compare OBPs measured from the tongue with OBPs measured from the pelvic limb and tail. Study design Prospective experimental study. Animals A total of eight adult Beagle dogs weighing 11.1 ± 1.2 kg. Methods Animals were premedicated with intravenous (IV) acepromazine (0.005 mg kg−1). Anesthesia was induced with alfaxalone (3 mg kg−1) IV and maintained with isoflurane. The dorsal pedal artery was catheterized for IBP measurements. Systolic (SAP), diastolic (DAP) and mean (MAP) arterial pressure were simultaneously measured from the tongue, pelvic limb and tail. Based on invasive SAP, hypertension (>140 mmHg), normotension (90–140 mmHg) and hypotension ( Results Regardless of cuff placement, the mean bias ± standard deviation between IBP and OBP met veterinary (≤10 ± 15 mmHg) and human ( Conclusions and clinical relevance The tongue is a clinically useful site for measuring OBP in anesthetized Beagle dogs, providing reliable estimates of MAP and DAP. The tongue could replace other cuff placement sites and may be a relatively suitable site for assessing hypotension.

Granular-shaped carbonate apatite (CO3Ap) bone substitute has demonstrated good clinical results, especially in the bone augmentation procedure, because it has high osteoconductivity and can be replaced by a new bone. This study aimed to evaluate the potential usefulness of CO3Ap bone substitute for alveolar ridge preservation of beagle dogs during the 9-week follow-up period after surgery. Reconstruction of extraction sockets with CO3Ap granules (CO3Ap group) allowed approximately 1.0 mm higher alveolar bone height than that with a blood clot (control group) at 4 and 9 weeks after surgery. Additionally, the measured area at the buccal aspect of the alveolar bone in the CO3Ap group was approximately 2 mm2 larger than that in the control group at 4 and 9 weeks after surgery. Continuity from the buccal side to palatal side of the alveolar bone was restored, maintaining its contour at 4 weeks after surgery. The amount of bony tissue, especially the amount of mature bone, in the alveolar part was statistically larger than that of control group at 9 weeks after surgery even though complete replacement of CO3Ap granules with new bone was not observed within 9 weeks. In conclusion, CO3Ap granules have good potential for alveolar ridge preservation.

Objective To compare the effects of sevoflurane, propofol and alfaxalone on the neuromuscular blockade induced by a single intravenous bolus of rocuronium in dogs. Study design A randomized, prospective, crossover experimental study. Animals A total of eight adult Beagle dogs (four female, four male), weighing 8.9–15.3 kg and aged 5–7 years. Methods The dogs were anesthetized three times with 1.25× minimum alveolar concentration of sevoflurane (SEVO treatment) and 1.25× minimum infusion rate of propofol (PROP treatment) or alfaxalone (ALFX treatment) at intervals of ≥14 days. Neuromuscular function was monitored with train-of-four (TOF) stimulation of the peroneal nerve by acceleromyography. After recording the control TOF ratio (TOFRC), a single bolus dose of rocuronium (1 mg kg–1) was administered intravenously. The times from rocuronium administration to achieving TOF count 0 (onset time), from achieving TOF count 0 to the reappearance of TOF count 4 (clinical blockade period), from 25% to 75% of TOFRC (recovery index) and from achieving TOF count 0 to TOF ratio/TOFRC >0.9 (total neuromuscular blockade duration) were recorded. Results The onset time and recovery index did not differ among the treatments. The median clinical blockade period was longer in the SEVO treatment [27.3 (26.0–30.3) minutes] than in PROP [16.6 (15.4–18.0) minutes; p = 0.002] and ALFX [22.4 (18.6–23.1) minutes; p = 0.017] treatments; and longer in the ALFX treatment than in the PROP treatment (p = 0.020). The mean total neuromuscular blockade duration was longer in the SEVO treatment (43.7 ± 9.9 minutes) than in PROP (25.1 ± 2.7 minutes; p Conclusions and clinical relevance Compared with alfaxalone and propofol, sevoflurane prolonged rocuronium-induced neuromuscular blockade by a significantly greater extent in dogs.

Background Hyperadrenocorticism (HAC) is a common endocrine disorder in dogs; however, there are no reports on the use of the corticotropin‐releasing hormone test (CRHT) to differentiate between pituitary‐dependent hyperadrenocorticism (PDH) and cortisol‐producing adrenal tumors (CPATs), both causative of HAC. Objectives To evaluate the usefulness of CRHT as a tool to differentiate between PDH and CPAT in dogs and to determine the reference intervals for CRHT in healthy, PDH, and CPAT dogs. Animals Dogs diagnosed with PDH (n = 21), CPAT (n = 6), and healthy beagle dogs (n = 33). Methods This prospective study included dogs with a definitive diagnosis of PDH and CPAT and healthy beagle dogs, in which CRHT was performed, were prospectively evaluated. We investigated the correlations of CRHT (endogenous adrenocorticotropic hormone [ACTH] concentration, endogenous ACTH concentration [EAC], and poststimulation ACTH concentration [PAC]) with pituitary‐to‐brain ratio (PBR) (in PDH) and with indices of adrenal ultrasonography (smaller and larger adrenal gland dorsoventral thickness in PDH and CPAT). Results For EAC, the area under the curve (AUC) was 0.95, with a cutoff value of 26.3 pg/mL (sensitivity: 90.62%, specificity: 87.50%). The AUC for PAC was 0.96 with a cutoff value of 54.5 pg/mL (sensitivity: 100.00%, specificity: 66.67%). The 95% reference interval for CRHT in healthy (control) dogs ranged 5.00 to 79.8 pg/mL (1.10‐17.57 pmol/L) for EAC, and 1.92 to 153.42 pg/mL (0.42‐33.78 pmol/L) for PAC. There was no significant correlation between PBR and CRHT, nor adrenal size and CRHT. Conclusions and Clinical Importance CRHT appears to be a rapid and reliable test for differentiating PDH from CPAT in dogs.

Protoapigenone, a unique class of natural flavonoid, exerted significant cytotoxic and antitumoral activities. A simple, sensitive, and rapid LC–MS/MS method for the quantification of protoapigenone in plasma was developed and validated to obtain the pharmacokinetic profile of protoapigenone in beagle dogs. Ethyl acetate-10% ammonium hydroxide (2:1, v/v) was employed for liquid–liquid extraction (recovery > 90%). Under optimal conditions, chromatographic resolution was achieved on a C18 column using acetonitrile and 10 mM ammonium formate in water (9:1, v/v), as mobile phase at a flow rate of 0.5 ml/min. The established method presented good linearity, selectivity, accuracy, and precision in the range of 0.2–100 ng/ml. Finally, this method was successfully applied to a pharmacokinetic study in beagle dogs following oral administration of protoapigenone.

Objective To confirm the feasibility of visualizing upper and lower proximal lacrimal canaliculi (LC) using spectral-domain optical coherence tomography (SD-OCT). Animals studied Eight eyes of four normal Beagle dogs. Procedures To obtain an upper proximal LC image, the head was turned in the opposite direction to the eye being imaged, and the medial part of the upper eyelid was everted to expose the LC. To obtain a lower LC image, the lower eyelid was everted just below the punctum. Using "angle mode", the scan line was placed parallel on the long axis of the LC. The inlet LC width (LCW) was measured. Artificial tears (AT) were instilled, and LCW was compared before and after AT instillation. Additionally, the return time to the initial LCW inlet width was recorded. Results Before AT instillation, there was a significant difference between the mean upper and lower LCW (91.8 ± 3.2 µm and 110.1 ± 8.4 µm, respectively). After AT instillation, the mean upper and lower LCW were 236.9 ± 27.7 µm and 238.4 ± 30.4 µm, respectively. Significant differences in the LCW before and after AT instillation in both the upper and lower LCWs were observed. The mean return time of the upper and lower LCW to their initial widths after AT instillation was within 4 min. Conclusions Spectral-domain optical coherence tomography was an effective method for providing high-resolution images of the upper and lower proximal LC. This method enables observation of LC changes after instillation of eyedrops in veterinary clinical practice.

HAD-B1 is a Korean herbal formula designed to treat solid tumors, and through cell experiments, it has proven to have an anticancer effect. The current study aims to test the safety of HAD-B1. This experiment is under the regulation of ICH. In order to find if HAD-B1 has any effect on the CNS, 0, 500, 1000, and 2000 mg/kg/day of HAD-B1 were orally administered to male and female rats once. To discover any effect on the respiratory system, 0, 500, 1000, and 2000 mg/kg/day of HAD-B1 were orally given to male rats followed by measuring the respiratory rate, tidal volume, and minute respiratory volume. To assess the possibility of a delayed QT period as a result of the drug administration, hERG analysis was conducted at 0, 0.1, 0.3, and 1 μg/ml. To assess any effect on the cardiovascular system, 0, 500, 1000, and 2000 mg/kg/day of HAD-B1 were orally given to male beagle dogs once followed by temperature, blood pressure, ECG, and heart rate analyses. There were no clinically significant changes in both male and female rats on assessing any effects on the CNS. There were no clinically significant changes in male rats’ respiratory assessment. There were no clinically significant changes in hERG analysis results. There were no clinically significant changes in the cardiovascular system of male beagle dogs. Our results demonstrate that HAD-B1 is a safe herbal formula that does not have a clinically significant effect on the CNS, respiratory, and cardiovascular systems.

Hui-jun Wang,1 Chun-yan Zhou,1 Yan-ding Su,1 Kai-feng Gou,1 Xiao-nan Geng,1 Xiang-jun Qiu1,2 1Department of Pharmacy, School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang, 471023, People’s Republic of China; 2Functional Experiment Teaching Center, School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang, 471023, People’s Republic of ChinaCorrespondence: Xiang-jun QiuFunctional Experiment Teaching Center, School of Basic Medical Sciences, Henan University of Science and Technology, 263 Kaiyuan Avenue, Luoyang, 471023, People’s Republic of ChinaTel +8613698882699Fax +86379-64830346Email lyxiangjun@126.comBackground: A new UPLC-MS/MS technique for the determination of ripretinib in beagle dog plasma was developed, and the pharmacokinetic effects of voriconazole and itraconazole on ripretinib in beagle dogs were studied.Methods: After extraction with ethyl acetate under alkaline conditions, ripretinib was detected using avapritinib as the internal standard (IS). The mobile phases were 0.1% formic acid-acetonitrile. The scanning method was multi-reaction monitoring using ESI+ source, and the ion pairs for ripretinib and IS were m/z 509.93→ 416.85 and 499.1→ 482.09, respectively. This animal experiment adopted a three period self-control experimental design. In the first period, ripretinib was orally administered to six beagle dogs at a dose of 5 mg/kg. In the second period, the same six beagle dogs were orally given itraconazole at a dose of 7 mg/kg, after 30 min, ripretinib was orally given. In the third period, voriconazole at a dose of 7 mg/kg was given orally, and then ripretinib was orally given. At different time points, the blood samples were collected. The concentration of ripretinib was detected, and the pharmacokinetic parameters of ripretinib were calculated.Results: Ripretinib had a good linear relationship in the range of 1– 1000 ng/mL. The precision, accuracy, recovery, matrix effect and stability met the requirements of the guiding principles. After erdafitinib combined with itraconazole, the Cmax and AUC0→t of ripretinib increased by 38.35% and 36.36%, respectively, and the t1/2 was prolonged to 7.53 h. After ripretinib combined with voriconazole, the Cmax and AUC0→t of ripretinib increased by 37.44% and 25.52%, respectively, and the t1/2 was prolonged to 7.33 h.Conclusion: A new and reliable UPLC-MS/MS technique was fully optimized and developed to detect the concentration of ripretinib in beagle dog plasma. Itraconazole and voriconazole could inhibit the metabolism of ripretinib in beagle dogs and increase the plasma exposure of ripretinib.Keywords: itraconazole, voriconazole, ripretinib, UPLC-MS/MS, pharmacokinetics, beagle dog

The safety evaluation of timosaponin BII (TBII) in beagle dogs with toxicokinetic study was performed. For the acute oral toxicity study, the minimum lethal dose (MLD) of TBII was more than 2000 mg/kg and suggested the characteristics of absorption saturation. For the 28-day repeated dose oral toxicity and toxicokinetic studies, there was no significant effect on all test parameters except for prolonged APTT in the 60 and 180 mg/kg groups, which recovered after withdrawal. The increase of drug exposure of 180 mg/kg group was not proportional to the increase of administration dose, showing the characteristics of absorption saturation.

Objective The aim of this study was to investigate whether small- to medium-sized dogs with a naturally occurring unilateral hindlimb lameness show the same compensatory changes in ground reaction forces as large-breed dogs and how the changes are displayed compared with healthy small- to medium-sized dogs. Study Design Small- to medium-sized dogs (n = 15) and large-breed dogs (n = 16) with unilateral rupture of the cranial cruciate ligament were examined. The kinetic parameters peak vertical force and vertical impulse of the two groups were compared with each other and compared with healthy Beagles (n = 15) and with healthy Labrador Retrievers (n = 17), respectively. Results The healthy Beagle group showed a significantly higher weight loading on the forelimbs compared with the healthy Labrador group. The affected groups in comparison with the corresponding healthy groups showed a higher load on the non-affected body half and a significant lower weight bearing on the affected limb. Comparing the two affected groups, no significant difference could be found. Conclusion Despite a substantially different initial situation regarding weight distribution of the examined small- to medium-sized dogs and large dogs, a unilateral hindlimb lameness leads to the same compensatory changes (cranial and lateral shift of the body mass centre).

BACKGROUND Canine stomatocytosis is a well-recognized rare erythrocyte disorder characterized by nonsyndromic forms with selective erythroid involvement, syndromic forms with extra-hematologic disease, and acquired forms. OBJECTIVES We describe serial clinicopathologic changes in two dogs with stomatocytosis of breeds that are different from those previously reported. METHODS Blood samples were obtained from a 12-year-old female neutered Australian Cattle Dog and a 12-year-old male neutered Beagle for hematologic and biochemical analyses, including a morphologic examination of peripheral blood films. Serial clinicopathologic data were reviewed, including CBCs performed by the referring veterinary surgeons. RESULTS Serial CBC data in both cases reported a variable decrease in RBC numbers commonly associated with a normal hematocrit, macrocytosis, hypochromasia, changes in red cell distribution width parameters including marked histogram abnormalities in volume distribution of the RBC population, and mildly increased or normal reticulocyte counts. Morphologic examination of peripheral blood films identified variable numbers of stomatocytes, knizocytes (Case 1, Day 1, Day 4), mild anisocytosis, mild macrocytosis, and mild polychromasia. CONCLUSIONS In both cases, the changes exhibited in the erythrogram raise suspicion for an RBC membrane disorder with cell volume dysregulation and stomatocytosis, although they did not appear to cause clinically relevant hemolysis.

Meng-Jie Wang,1 Yu-Hang Zhao,2 Chen Fan,3 Ying-Jie Wang,3 Xin-Qi Wang,3 Xiang-Jun Qiu,3 Rui-Le Shen1 1Department of Neurology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan, 471003, People’s Republic of China; 2School of Medical Imaging, Hangzhou Medical College, Hangzhou, 310051, Zhejiang, People’s Republic of China; 3Department of Pharmacy, School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang, 471023, Henan, People’s Republic of ChinaCorrespondence: Xiang-Jun QiuDepartment of Pharmacy, School of Basic Medical Sciences, Henan University of Science and Technology, Luoyang, 471023, Henan, People’s Republic of ChinaEmail lyxiangjun@126.comRui-Le ShenDepartment of Neurology, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, Henan, People’s Republic of ChinaEmail yfyshenruile@126.comBackground: Upadacitinib, a novel selective Janus kinase 1 (JAK1) inhibitor, has been recently approved by the US FDA for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA). An ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method for the quantitative analysis of upadacitinib in beagle dog plasma was developed and validated.Methods: Upadacitinib and fedratinib (internal standard, IS) were extracted with ethyl acetate under alkaline condition and then separated and detected. The chromatographic column was Waters Acquity UPLC BEH C18 column (2.1 mm × 50 mm, 1.7 μm), the mobile phase was acetonitrile and 0.1% formic acid in water with gradient elution procedure, and the flow rate was 0.40 mL/min. Under the positive ion mode, upadacitinib and IS were monitored by multiple reaction monitoring (MRM) as the following mass transition pairs: m/z 447.00 → 361.94 for upadacitinib and m/z 529.82 → 141.01 for IS.Results: In the concentration range of 1– 500 ng/mL, upadacitinib had good linearity, and the lower limit of quantification (LLOQ) was 1 ng/mL. The RSD of the intra- and inter-day precision was less than 10.03%, and the RE of accuracy was − 3.79% to 2.58%. The extraction recovery of upadacitinib was more than 80%, the matrix effect was around 100%, and upadacitinib was found to be stable.Conclusion: The novel optimized UPLC-MS/MS assay was an effective tool for the determination of upadacitinib and had been successfully applied to the pharmacokinetic study of upadacitinib in beagle dogs, and this method would also be used to study DDIs.Keywords: upadacitinib, UPLC-MS/MS, pharmacokinetic, beagle dog

While doxorubicin (DOX) is one of the most common chemotherapeutic drugs for treating cancer, use of DOX must be managed carefully due to dose-related toxicity. Nanodiamond (ND) drug delivery system conjugated with DOX (NDX) has been reported to enhance treatment efficacy and attenuate toxicity in murine cancer models. In addition, extensive biocompatibility studies indicate that NDs seem to be well tolerated in non-human primates. Before the clinical translation of NDX, it is necessary to verify the safety of ND in large mammals. Studies of nanomedicine drug safety for large animal are not commonly reported, and this work represents a key milestone in bridging earlier advances towards clinical assessment. Herein, NDs’ safety as a drug-delivery platform was evaluated in Naive Beagle dogs. The study is performed with DOX, ND, and NDX in a dual-gender animal model using intravenous (IV) injection and hepatic portal vein (HPV) injection methods. The dogs are monitored for their health phenotype changes in continuous 5 days. Blood and urine obtained are for clinical pathology research. The results indicate that ND drug delivery platform significantly relieves DOX toxicity for Naive Beagle dog model. This study provides guidance for the pre-clinical safety assessment of NDX therapy at large animal level.

Rebamipide (RBM) is known to have a specific absorption window in the upper GI tract. However, there have been no in vivo studies reporting the regional absorption of RBM, which may lead to misjudgment in formulation development considering the many other physiological factors involved in oral absorption. Therefore, this study aimed to assess the regional absorption of RBM. Barium sulfate was incorporated into RBM-sustained release (SR) tablets as a radiopaque marker and the location of RBM-SR tablets was monitored using X-ray imaging after oral administration of RBM-SR tablets in Beagle dogs. Based on the gastric residence time (GRT) of RBM-SR tablets, dogs were divided into two groups: GRTlow for 0.25 and 1.5 h and GRThigh for 3 and 5 h. GRThigh had significantly delayed time to reach peak plasma concentration (Tmax), longer mean residence time (MRT), and higher area under the plasma concentration–time curve from time zero to the last observation time point (AUClast) than GRTlow, which indicates the presence of an absorption window in the upper GI tract. This study, for the first time, reports on the regional absorption of RBM. The findings of this study may be useful for developing RBM-SR formulations.

A simple, rapid, efficient and reproducible method based on High Performance Liquid Chromatography (HPLC) for simultaneous determination of prodrug of voriconazole (POV) and voriconazole in beagle plasma has been established and validated. Omeprazole was utilized as the sole internal standard. Analytes and internal standards were extracted through protein precipitation and separated on a Venusil XBP C18 chromatography column (4.6 × 250 mm, 5 µm). The mobile phase was methanol and 20 mmol/L potassium dihydrogen phosphate. Chromatographic separation was achieved by using an isocratic elution procedure that used 65% methanol and a flow rate of 1 mL/min. The ultraviolet (UV) detection wavelength was 256 nm and the total running time was 15 min. This method showed good linear ranges of 100–75,000 ng/mL for voriconazole prodrug and 200–100,000 ng/mL for voriconazole respectively. The precision and accuracy were acceptable. Analytes in plasma samples are stable under different temperatures and storage conditions. The developed HPLC method has been successfully applied to the studies of toxicokinetics of POV after intravenous drip in beagle and provided important information for the further development and application.

Background Otitis externa is a commonly diagnosed disorder in dogs and can carry a high welfare impact on affected animals. This study aimed to report the prevalence and explore the role of breed and aural conformation as predisposing factors for canine otitis externa in the UK. The study used a cohort design of dogs under UK primary veterinary care at clinics participating in the VetCompass Programme during 2016. Risk factor analysis used multivariable logistic regression modelling. Results The study included a random sample of 22,333 dogs from an overall population of 905,554 dogs under veterinary care in 2016. The one-year period prevalence of otitis externa was 7.30% (95% confidence interval [CI]: 6.97 to 7.65). Breed and ear carriage were the highest ranked risk factors. Compared with crossbred dogs, sixteen breed types showed increased odds, including: Basset Hound (odds ratio [OR] 5.87), Chinese Shar Pei (OR 3.44), Labradoodle (OR 2.95), Beagle (OR 2.54) and Golden Retriever (OR 2.23). Four breeds showed protection (i.e. reduced odds) of otitis externa: Chihuahua (OR 0.20), Border Collie (OR 0.34), Yorkshire Terrier (OR 0.49) and Jack Russell Terrier (OR 0.52). Designer breed types overall had 1.63 times the odds (95% CI 1.31 to 2.03) compared with crossbred dogs. Compared with breeds with erect ear carriage, breeds with pendulous ear carriage had 1.76 times the odds (95% CI 1.48 to 2.10) and breeds with V-shaped drop ear carriage had 1.84 times the odds (95% CI 1.53 to 2.21) of otitis externa. Conclusions Breed itself and breed-associated ear carriage conformation are important predisposing factors for canine otitis externa. Greater awareness of these associations for both predisposed and protected breeds could support veterinary practitioners to promote cautious and low-harm approaches in their clinical advice on preventive care for otitis externa, especially in predisposed breeds., Plain English Summary Otitis externa is a common and often painful condition of the ears of dogs. The probability of otitis externa varies widely between dogs depending on their tendency towards other skin problems such as allergic skin disease. However, breed-related anatomical features such as the degree and point of folding of the ear flap or the overall size of the dog can act to further predispose towards otitis externa. Greater understanding of these predisposing factors could lead to opportunities for breeders to breed away from predisposing features and also help owners and veterinarians to predict which dogs are most at risk of this painful condition. Veterinarians record clinical notes when dogs visit for veterinary care, and these clinical notes can act as a rich source of information on the health of these dogs. This study accessed anonymised clinical records of almost a million dogs in the UK to identify dogs diagnosed with otitis externa. The breed, age, bodyweight and other information available on these dogs were used to explore why certain dog types were predisposed to otitis externa. A random sample of 22,333 dogs was selected for analysis. Of these, 7.30% (over 7 in a hundred) were diagnosed with otitis externa in a single year. There were 16 breeds with higher risk of otitis externa compared with crossbred dogs. Breeds with the highest risk were Basset Hound (× 5.87), Chinese Shar Pei (× 3.44), Labradoodle (× 2.95), Beagle (× 2.54) and Golden Retriever (× 2.23). Four breeds showed reduced risk: Chihuahua (× 0.20), Border Collie (× 0.34), Yorkshire Terrier (× 0.49) and Jack Russell Terrier (× 0.52). Breeds with pendulous ear carriage (× 1.76) and V-shaped drop ear carriage (× 1.84) had higher risk of otitis externa compared with breeds with erect ear carriage. Breed itself and also breed-associated ear carriage conformation are associated with differing probability of otitis externa in dogs. Better understanding about how these factors affect the probability of otitis externa in dogs can help veterinary practitioners to promote cautious and low-harm approaches to preventing otitis externa (e.g., by advocating ear cleaning with a dry paper cloth, judicious use of ear cleaners with antimicrobial properties and avoidance of overzealous ear-cleaning) and can also assist breeders to breed away from features of dogs that predispose to otitis externa.

Introduction: Vital pulp therapy has been known as one of the treatment optionsto preserve pulp vitality after being exposed by trauma or caries. Aim: This experimentexplored the effect of injectable-Platelet Rich Fibrin on marginal adaptation of two pulp capping agents (Mineral Trioxide Aggregate and Bioactive Bone Graft). Materials andmethods: A total of 64 teeth were used out of 8 healthy male beagle dogs. The teethwere randomly assigned into four groups, they were exposed and capped with differentcapping agents. Group A; capped with Mineral Trioxide Aggregate (MTA), Group B;capped with MTA+ i-PRF, Group C; capped with Bioactive Bone Graft (BBG), Group D; capped with BBG+i-PRF. Finally the access cavity was restored with IntermediateRestorative Material (IRM). At each predetermined interval, the dogs were sacrificed(1 month, and 3 months). The samples were then prepared for electron microscopicscanning evaluation. To compare between the gap percentage of four groups at eachinterval, Kruskal-wallis test; was used. Mann-Whitney U test; was used to pair-wisecomparison when Kruskal-wallis test is significant. Bonferroni’s correction was utilizedfor the pair-wise comparisons. Statistical significance was considered at P area between the capping materials and dentin, followed by group C (BBG), with theleast value recorded in group A (MTA). Conclusion: the findings from the current studysuggested that i-PRF provided a better marginal adaptation of either MTA or BBG tothe pulp and dentin, which improved with time from one month to three months.

Background:. The effectiveness of bronchial thermoplasty (BT) has been reported in patients with severe asthma. This study compared the effects of BT and cryoballoon ablation (CBA) therapy on the airway smooth muscle (ASM). Methods:. Eight healthy male beagle dogs were included in this experiment. In the preliminary experiment, one dog received BT treatment for both lower lobe bronchus, another dog received CBA treatment for 7 s on the upper and lower lobe of right bronchus, and 30 s on the left upper and lower lobe. The treatments were performed twice at an interval of 1 month. In subsequent experiments, the right lower lobe bronchus was treated with BT, and the left lower lobe bronchus was treated with CBA. The effects of treatment were observed after 1 (n = 3) month and 6 months (n = 3). Hematoxylin-eosin staining, Masson trichrome staining, and immunohistochemical staining were used to compare the effects of BT and CBA therapy on the ASM thickness, collagen fibers synthesis, and M3 receptor expression after treatment. One-way analysis of variance with Dunnett post hoc test was used to analyze the differences among groups. Results:. In the preliminary experiment, the ASM ablation effect of 30-s CBA was equivalent to that of 7-s CBA (ASM thickness: 30.52 ± 7.75 μm vs. 17.57 ± 15.20 μm, P = 0.128), but the bronchial mucociliary epithelium did not recover, and large numbers of inflammatory cells had infiltrated the mucosal epithelium at 1-month post-CBA with 30-s freezing. Therefore, we chose 7 s as the CBA treatment time in our follow-up experiments. Compared with the control group (35.81 ± 11.02 μm), BT group and CBA group (13.41 ± 4.40 μm and 4.81 ± 4.44 μm, respectively) had significantly decreased ASM thickness after 1 month (P

Like humans, weight control in overweight dogs is associated with a longer life expectancy and a healthier life. Dietary supplements are one of the best strategies for controlling obesity and obesity-associated diseases. This study was conducted to assess the potential of black ginseng (BG) and silkworm (SW) as supplements for weight control in diet-induced overweight beagle dogs. To investigate the changes that occur in dogs administered the supplements, different obesity-related parameters, such as body condition score (BCS), blood fatty acid profile, transcriptome, and microbiome, were assessed in high energy diet (HD) and HD with BG + SW supplementation (HDT) groups of test animals. After 12 weeks of BG + SW supplementation, total cholesterol and triglyceride levels were reduced in the HDT group. In the transcriptome analysis, nine genes (NUGGC, EFR3B, RTP4, ACAN, HOXC4, IL17RB, SOX13, SLC18A2, and SOX4) that are known to be associated with obesity were found to be differentially expressed between the ND (normal diet) and HD groups as well as the HD and HDT groups. Significant changes in some taxa were observed between the HD and ND groups. These data suggest that the BG + SW supplement could be developed as dietary interventions against diet-induced obesity, and obesity-related differential genes could be important candidates in the mechanism of the anti-obesity effects of the BG + SW supplement.

The aim of the present study was to assess the duration of dentin tubule occlusion by the calcium phosphate precipitation (CPP) method in the vital teeth of beagle dogs. Vital teeth were treated using the CPP method, potassium oxalate, or a bonding agent (Liner bond II) after cavity preparation and acid etching. The dentin tubules of all groups, except for the bonding agent, opened more widely with time in the absence of plaque control. Dentin tubules treated with the CPP method were open and no precipitate remained in the absence of plaque control. Differences were observed in dentin tubule occlusion when plaque control was achieved by daily tooth brushing. The majority of dentin tubules were occluded with an apatitic precipitate seven days after the CPP method with plaque control. The present results demonstrated that the CPP method is useful with proper plaque control.

The aim of this study was to investigate histologically the amount of peri-implant tissue augmentation after volume-stable porcine collagen matrix transplantation. Six male beagle dogs were used in the experiment. P2, P4, and M1 distal roots were extracted under general anesthesia. After 6 months, implants were placed in the same sites, and volume-stable porcine collagen matrix transplantation was performed. Impressions were taken at 1 and 2 weeks and at 1, 2, and 3 months after transplantation. The dogs were euthanized at 3 months, and their mandibles were removed and scanned using micro-computed tomography. Standard Triangulated Language data were also obtained. Using preoperative models as a reference, the data for all time points were compared, and changes in the thickness of the cross-section of the implant sites were measured. The model created at 3 months was then compared with the mandible data, and the thickness of collected peri-implant soft tissue was measured under optical microscopy. Increased thickness was found at some of the sites on the buccal side. Regarding the peri-implant soft tissue, the thickness of the measured sites on the buccal side was significantly increased at 3 months in the experimental group. Histological observations of the internal structures of the tissue in the experimental group revealed irregular collagen fibers and a remnant collagen matrix. Endogenous tissue was observed within the collagen matrix, indicating good fusion with the surrounding autologous tissue. These results suggest that volume-stable porcine collagen matrix transplantation promotes peri-implant tissue augmentation on the buccal side.

The objectives of the study were to evaluate the pharmacokinetics and tolerance of grapiprant, a substrate of the human P-gp transporter, in collies homozygous for MDR1-1Δ when administered at the labeled dosage of 2 mg/kg once daily for 28 days. Twelve collie dogs with homozygous for MDR1-1Δ genotype from a commercial colony were used in the study, eight in the treated group and four as placebo-treated controls. The only treatment-related clinical sign was self-limiting vomiting (in 2/8 treated animals) and the only treatment-related clinical pathological changes seen were a slight decrease in serum albumin in one dog (2.6 g/dL; reference 2.7 to 3.9 g/dL) and total protein (5.1 g/dL; reference 5.5 to 7.7 g/dL). Absorption of grapiprant was rapid with a median Tmax of 1 h, Cmax of 5.2 μg/mL, AUC0-24 of 17.3 ± 7.1 h* μg/mL and median terminal t½ of 4.3 h after the first dose. To determine whether MDR1-1Δ animals handle grapiprant differently from normal dogs, a population pharmacokinetic analysis was performed utilizing data from the collies and historical beagle data. Volume of the peripheral compartment of collies was estimated to be 45% that of beagles, and clearance from the central compartment was 71% less in collies than in beagles. Self-liming vomiting events occurred at a numerically higher rate (2/8; 25%) in this group of P-gp-deficient dogs than seen in a clinical study (17%) composed of various dog breeds but limited numbers in this PK study make comparisons difficult. Grapiprant was otherwise well tolerated in collies homozygous for MDR1-1Δ despite increased drug exposure compared to dogs without this mutation.

Pharyngeal collapsibility has been used as diagnostic criteria in dogs, whereas the normal range and quantitative method have not been studied. Dynamic and static computed tomography (CT) was performed in 23 normal Beagle dogs to quantify the nasopharyngeal collapsibility at different locations. Using dynamic CT, maximum and minimum nasopharyngeal cross-sectional areas (CSAs) were measured at the level of the cranial end of the soft palate, pterygoid hamulus, foramen lacerum, bony labyrinth, and caudal end of the soft palate. The ratio of all maximum and minimum CSA to nasopharyngeal CSA at the level of the caudal hard palate (rCSAmax and rCSAmin) and the nasopharyngeal collapsibility were calculated. The differences of rCSAmax, rCSAmin, and nasopharyngeal collapsibility were analyzed at various locations. The nasopharyngeal collapsibility at the level of foramen lacerum, bony labyrinth, and caudal end of soft palate were higher than the others. At the level of the caudal end of the soft palate, rCSAmin was lower than that of the foramen lacerum and bony labyrinth, whereas rCSAmax at foramen lacerum was higher than that of the caudal end of the soft palate. These results indicated that the nasopharynx at the level of foramen lacerum and caudal end of the soft palate were considered notable locations for evaluating collapsibility. Dynamic CT could show the nasopharyngeal dynamic profile and will be an adequate modality for evaluating nasopharynx. Our results will be helpful for further comparative studies in dogs with and without nasopharyngeal collapse.

Background Bio-Oss® collagen (BC) has been used in clinical applications for years but the ridge preservation property of BC remains controversial. There is no animal model accurately simulates the extraction socket in people. The aim of this study was to assess the ridge preservation of a novel extraction sockets with a thin buccal plate using BC. Materials and methods Two beagle dogs were used to assess the characterization of the novel extraction socket. The width and height of the socket were measured and biopsies of the socket were collected for histologic examination. Four beagle dogs were used to assess the ridge preservation property of BC. BC was placed in the socket and socket left untreated was set as control group (CT). Cone-beam computed tomography analysis, histological examination, and micro-CT analysis were used to evaluate the ridge preservation. Results The novel extraction socket had obvious larger volume with a markedly narrow buccal wall than mandible extraction sockets. At 12 weeks, the width of the crest of the alveolar ridge preservation ratios was 34% for the CT and 82% for the BC. BC group had larger socket volume compare to CT group. BC group had a significant higher bone density in the middle and apical areas of the alveolar bone. Socket placed with BC showed significantly less vertical bone loss compared with CT group. Conclusion Extraction site with a significantly larger dimension and a very thin buccal plate was established. Extraction sockets filled with BC exhibit excellent maintenance of alveolar bone volume.

Purpose: This study was designed to evaluate the autogenous bone grafting (ABG) alone or in combination with intra-marrow penetration (IMP) in the treatment of one osseous wall defects in dog model .Material and methods: This current study was conduct on 8 Beagle dogs that were alienated randomly into two groups: Group I: received open flap debridement with autogenous bone graft, Group П: received open flap debridement with autogenous bone graft and IMP. Each animal received two treatment modalities, one for each jaw. Each jaw divided into two halves (right and left). The surgery intervention was performed at base line in the left side. The right side received the same treatment after 6 weeks. All experimental defects were followed up through histological analysis. Results: Histomorphometric analysis showed significantly increased bone neogenesis within the experimental groups at 14, 60 days. The total area percent of newly formed bone in group I was 38.46+7.71% while it was 33.17+7.3% in group II with non-significant difference between two groups throughout the study intervals. Conclusion: The regenerative therapy using either autogenous bone graft alone or in combination with IMP showed an improvement in the treatment outcome of one osseous wall defects.

The pharmacokinetics of enflicoxib were evaluated in both a bioavailability study and a multi-dose safety study in Beagle dogs. When administered at 8 mg/kg, the oral bioavailability (F) of enflicoxib was 44.1% in fasted dogs, but F increased to 63.4% under post prandial conditions. Enflicoxib is rapidly metabolised. After the first 48 h, the plasma levels of its pyrazol metabolite were much higher and persistent than those of the parent compound. Following intravenous administration, the total body plasma clearance of enflicoxib was of 140 ml/h/kg and the volume of distribution based on the terminal phase was 4 L/kg. Plasma protein binding for both compounds was approximately 99%. The blood to plasma ratio for the pyrazol metabolite showed saturable kinetics with higher blood cell affinity at lower total blood concentrations which ranged from 2.49 to 0.95 for concentrations from 1 to 15 µg/ml. Enflicoxib and its pyrazol metabolite exhibited dose-proportional pharmacokinetics for single oral doses of 8-40 mg⁄kg and for multiple oral doses of 4-20 mg⁄kg. After 7 months of repeated weekly administrations, pre-dose plasma concentrations (Cmin,ss ) remained constant throughout the study, with no trend to any significant over-accumulation. The mean terminal elimination half-life (t½ ) was 20 h for enflicoxib and 17 days for the pyrazol metabolite. The pharmacokinetic profile of enflicoxib and its pyrazol metabolite in dogs supports the proposed dosing regimen in which doses are separated by 1 week.

Aim To determine the healing outcome following grafting with deproteinized porcine bone mineral (DPBM) with or without collagen membrane coverage in two‐wall (both buccal and lingual)‐damaged extraction sockets. Materials and methods Distal roots of three mandibular premolars in six beagle dogs were extracted, and the whole buccal and lingual bony walls were surgically removed. Three treatment protocols were then applied according to the following group allocation: no graft (None), grafting DPBM (BG), and grafting DPBM with coverage by a collagen membrane (BG + M). Two observational periods (2 and 8 weeks) were used with the split‐mouth design, and quantitative and qualitative analyses were performed by microcomputed tomography and histology. Results The dimensions of the alveolar ridge at both grafted sites (BG and BG + M) remained similar to those of the pristine ridge in the histologic and radiographic analyses, whereas the ungrafted sites (None) collapsed both vertically and horizontally. Both grafting protocols produced substantial bony regeneration, but the addition of a covering membrane enhanced the proportion of mineralized tissue within the augmented area, and the BG + M group also showed a significantly larger area of regenerated ridge than the None group (p

OBJECTIVE The aim of the study was to evaluate safety and efficacy of topically administered 0.02% netarsudil-0.005% latanoprost fixed-dose combination (FDC) (Rocklatan™; Aerie Pharmaceutical) in normal and glaucomatous dogs with ADAMTS10-open-angle glaucoma (ADAMTS10-OAG). ANIMALS STUDIED Five normal and five glaucomatous beagle dogs with ADAMTS10-OAG were the study animals. PROCEDURES In each dog, left (OS) or right eye (OD) was randomly selected for netarsudil-latanoprost FDC treatment. Contralateral eyes served as latanoprost-treated controls. The study was divided into four consecutive study periods: following a 4-day baseline period, two sequential 8-day study periods followed with once daily (q24h) and twice daily (q12h) treatments and ending with a washout period. Efficacy was measured by diurnal intraocular pressure (IOP) and pupil diameter. Safety was assessed by routine ophthalmic examination, gonioscopy, and pachymetry. Differences in least square means of quantitative outcome measures were compared between FDC and latanoprost treatments by using the linear Gaussian model. RESULTS Baseline IOPs were 13.6 ± 0.7 mmHg (mean ± SEM) in normal and 28.3 ± 1.4 mmHg in OAG-affected dogs. There was a significant decrease in mean diurnal IOP following FDC administration in both normal (q24h: -2.1 mmHg; q12h: -4.1 mmHg) and glaucomatous dogs (q24h: -14.2 mmHg; q12h: -17.7 mmHg; p

Progression of unilateral laryngeal paralysis (LP) was quantified in an asymptomatic 4-year-old beagle during spontaneous breathing stimulated with inhaled 10% CO(2). Laryngeal evaluation was performed sequentially to track progression of LP over an 18-month period. Videos of the larynx during CO(2)-stimulated breathing were obtained under propofol anaesthesia. Maximal inspiratory normalised glottal gap area (NGGA) was determined on each occasion for left and right hemiglottis. Left NGGA was smaller than the right side throughout the period of follow-up. After 18 months, LP had progressed to such a degree that the left arytenoid was completely paralysed with no movement during inspiration. This case report demonstrates the possibility of early detection of LP, and quantification of progression. Early detection may allow regenerative surgical strategies for LP to maintain glottic area and reduce postoperative complication rates.

Knowledge about energy requirements (ER) of dogs is important in order to provide dogs with an appropriate energy supply. In this study, the oral 13 C-bicarbonate technique (o13 CBT) was used to estimate energy expenditure (EE) in 50 privately owned dogs of different body sizes (small: Danish-Swedish Farmdog (DSF, n = 16), medium: Beagle (n = 15), large: Labrador Retriever (n = 19)), of different ages (adult: 2-7 years (n = 33), senior: ≥8 years (n = 17)). The aim was to evaluate the feasibility of the method in the field and to get more information about ER of dogs. All dogs were measured twice, on two separate days under standardized, resting conditions. The dogs were fasted overnight prior to measurements, which were carried out in home environment. Only measurements of dogs resting calmly were included in the statistical analyses. No significant difference (p > 0.05) in EE was found between days of measurements. The EE measured in Labrador Retrievers (405 kJ (97 kcal)/kg BW0.75 /day) was significantly lower (p 0.05) between adult (548 kJ (131 kcal)/kg BW0.75 /day) and senior (499 kJ (119 kcal)/kg BW0.75 /day) Beagles. This study suggests that when measured under standardized resting conditions, the o13 CBT can provide reliable results of EE and be a helpful tool to get more knowledge about ER of dogs of different sizes, breeds and ages.

Prednisolone is used for treatment of inflammatory, allergic, neoplastic, and immune-mediated diseases in dogs. As a glucocorticoid, prednisolone has biochemical effects, which may interfere with the interpretation of biochemistry test results. The aim of this study is to investigate the effects of prednisolone treatment in an anti-inflammatory dose on common biochemical analytes in dogs and to evaluate the clinical relevance of the changes. Ten beagle dogs, enrolled in a cross-over study, were treated with oral prednisolone (1 mg/kg 24 h) for 10 days. Blood samples were collected at day 0, 1, 3, 6, 9, 10, 12, 16, and 20. Data was analyzed using a general linear model with time and treatment as fixed factors. Pairwise comparisons were done between prednisolone and control period for each dog and sampling. Significant results were further evaluated for clinical relevance using laboratory-specific reference intervals and reference change values (RCVs), when available. Statistically significant changes were observed for ALP activity and iron concentration, which increased to levels exceeding the RCV, and several results were outside reference intervals. Phosphate and bile acids increased significantly, while amylase, lipase, and cholesterol decreased significantly, but with mean/median results remaining within reference intervals. Anti-inflammatory prednisolone treatment did not induce significant changes in ALT, GLDH, GGT, cPLI, glucose, or calcium. Treatment with an anti-inflammatory dose of prednisolone induced changes in several analytes. Only the increases in ALP and iron were of such magnitude that they are expected to affect the clinical interpretation of test results.

The objective of this study was to develop a novel acetaminophen and tramadol hydrochloride-loaded soft capsule (ATSC) with enhanced bioavailability of tramadol. The ATSC was manufactured in a pilot-scale batch size with the capsule contents composed of tramadol, acetaminophen, PEG 400 and Capmul MCM at a weight ratio of 37.5:325:177.5:30. Moreover, its dissolution, stability and pharmacokinetics in beagle dogs were carried out compared to commercial tablet. The dissolved amounts of acetaminophen from the ATSC and commercial tablet were not significantly different. However, compared to the latter, the former had significantly higher dissolution rate of tramadol at the initial times. In beagle dogs, the ATSC provided no significant difference in plasma concentrations and AUC of acetaminophen than did the commercial tablet; however, it significantly improved those of tramadol compared to the other, indicating the enhanced oral bioavailability of tramadol. Compared to the commercial tablet, the ATSC had a larger AUC value for tramadol (55.27 ± 11.06 vs. 92.62 ± 21.52 h·ng/ml). In the accelerated long-term stability, the ATSC offered higher than 96% drug content of acetaminophen and tramadol, suggesting that it was stable for at least six months. Therefore, this ATSC would be a recommendable candidate with enhanced oral bioavailability and excellent stability.

A rapid and sensitive High-Performance Liquid Chromatography-tandem Mass Spectrometry (HPLC/MS/MS) method for determining apremilast in beagle dog plasma and urine samples was developed and validated using clopidogrel as the internal standard (IS). Apremilast was extracted from the plasma and urine samples by liquid–liquid extraction using methyl tert-butyl ether. Chromatographic separation was performed using a C8 column with gradient elution and a mobile phase containing methanol and 0.1% formic acid. Quantification was achieved in multiple reaction monitoring (MRM) mode with a transition of m/z 461.3→178.2 for apremilast and m/z 322.2→184.1 for clopidogrel (IS). This method was validated regarding its specificity, linearity, precision, accuracy, and stability. The lower limit of quantification (LLOQ) for this method was 5 ng/mL, and the calibration curve was linear over 5–1,000 ng/mL. The intra- and inter-run coefficients of variance (CV) of aprelimast in plasma samples were less than 12.92% and 10.64%, respectively, while in urine samples, the CV were less than 11.84% and 10.20%, respectively. The samples were stable under the tested conditions. This method was successfully applied to a pharmacokinetic study in beagle dogs following oral administration of 10 mg of apremilast.

Determine the protein content and volume of tears sampled by Schirmer strips wetness ranging from 20 to 35 mm.Ten healthy beagle dogs.Each dog underwent 20 tear collections per day (10 sessions in each eye, spaced by ≥1 h) for 4 separate days, providing 200 tear samples for each length of wetness evaluated: 20, 25, 30, and 35 mm. A Schirmer strip was placed in each eye until the selected mm-mark was reached, calculating the volume absorbed (VA) as the difference between the post- and pre-collection weight (assuming 1 mg~1 µL for tear fluid), and the volume recovered (VR) as the amount pipetted from the tube following centrifugation. Total protein content (TPC) was measured with infrared spectroscopy. Outcome measures were compared with the Kruskal-Wallis test.Median values for VA (µL), VR (µL) and TPC (mg/mL) were as follows: 20 mm (18, 10, 5.94), 25 mm (22, 12.5, 5.97), 30 mm (25.5, 16, 5.89), and 35 mm (31, 22.5, 7.13). Both VA and VR were significantly greater (p .001) for Schirmer strips wetness of 35»30»25»20 mm. TPC was significantly greater (p .001) for 35 20-30 mm, but not among other groups (p = 1.000).The study established normative data to consider when canine studies use Schirmer strips to collect tears for bioanalytical purposes (eg, proteomics, pharmacokinetics). Although 35 mm yielded higher VA and VR, the higher TPC could be explained by greater disruption of ocular surface homeostasis. Absorption to 20-30 mm is the suggested length of strip wetness for bioanalytical tear collection in dogs.

Aims The aim of this study was to investigate the potential of low-dose rhBMP-2 combined with Hydroxyapatite (HAp)/β-tricalcium phosphate (TCP)/ Collagen (Col) composite in repairing the peri-implant critical size defect and to determine the optimal rhBMP-2 concentration. Materials and methods Fifty saddle-type alveolar defects (10 mm mesiodistally and 4 mm apicocoronally) were surgically prepared on edentulous ridges in ten beagle dogs. Following implant placement, the defects with vertically exposed implant fixtures either received (a) no graft, (b) HAp/TCP/Col composite, (c) HAp/TCP/Col +0.02 mg/ml rhBMP-2, (d) HAp/TCP/Col +0.08 mg/ml rhBMP-2 or (e) HAp/TCP/Col +0.2 mg/ml rhBMP-2. After healing for 4 or 8 weeks, bone regeneration and mineralization were assessed through radiography, micro-CT, fluorescence labelling and histologic analyses. Implant stability was measured through resonance frequency analysis. Results It was evident HAp/TCP/Col with 0.2 mg/ml rhBMP-2 manifested strong osteogenic potential in this large animal model, as significantly more and faster new bone formation with better implant stability was identified compared to the HAp/TCP/Col-alone control group (adjusted p Conclusions Our results highlight the constructs of HAp/TCP/Col +0.2 mg/ml rhBMP-2 without barrier membranes as a promising tool for peri-implant ridge augmentation.

Background Coagulation status is poorly understood in dogs with chronic inflammatory enteropathy (CIE). Fibrinolytic activity and platelet dynamics have not been evaluated in CIE dogs. Objectives To assess coagulation status and fibrinolysis in normoalbuminemic CIE dogs (CIE‐N) and CIE dogs with protein‐losing enteropathy (CIE‐PLE) compared to healthy controls (HC). To evaluate thromboelastography (TEG) variable differences between groups and for correlations with clinicopathologic data. To report platelet dynamics in CIE dogs. Animals Twenty‐five client‐owned dogs with CIE (n = 16 CIE‐N; n = 9 CIE‐PLE); 14 HC beagle dogs. Methods All dogs had tissue factor + tissue plasminogen activator TEG. Nine of 25 CIE dogs had whole blood impedance platelet aggregometry. The TEG variables and coagulation data were compared between all CIE vs HC dogs, CIE‐N dogs vs HC, and CIE‐PLE dogs vs HC. Clinicopathologic and coagulation data were available for CIE dogs and assessed for correlation to TEG variables. Results Dogs with CIE had higher maximum amplitude (MA; P

Objective To describe a novel in-plane ultrasound (U/S)-guided temporal approach to peribulbar block in dogs. Study Design Prospective experimental cadaver study. Animals A group of 10 Beagle cadavers. Methods After describing the U/S anatomy, peribulbar injection was performed bilaterally in 10 thawed Beagle cadavers by two randomly assigned operators. A 5–8 MHz microconvex U/S probe was positioned caudal to the orbital ligament in the longitudinal plane. Using an in-plane technique, methylene blue dye was injected in five dogs (10 eyes total), while methylene blue dye and iohexol contrast mixture (50:50) were injected in the remaining five dogs. Injection volume was 0.2 mL cm−1 of cranial length. A computed tomography (CT) scan was performed on dogs injected with dye and contrast to identify spread of contrast. Dissection to visualize dye spread in the orbit was performed in all dogs. Injection success was defined as spread of contrast into the peribulbar space. The pattern of distribution of contrast-dye was also assessed. Comparisons between operator and bilateral injections were assessed using a Student t test (p Results Peribulbar spread was noted in 19/20 injections (95%) on dissection. CT imaging (five dogs) illustrated peribulbar contrast spread in 9/10 injections (90%), with mixed peribulbar/retrobulbar spread for the remaining injection. Contrast was present at the rostral alar foramen in 4/10 (40%) injections, orbital fissure in 5/10 (50%), oval foramen in 1/10 (10%), maxillary nerve in 3/10 (30%) and intracranial in 5/10 (50%). Coverage of the maxillary nerve was noted on 3/20 (15%) injections on dissection. No further dye spread was noted. Conclusions and clinical relevance This technique demonstrated peribulbar spread of injectate in 100% of injections for the 10 canine cadavers studied. Further studies are required to evaluate this technique clinically.

Background Inhalation treatment frequently is used in dogs and cats with chronic respiratory disease. Little is known however about the performance of delivery devices and the distribution of aerosolized drugs in the lower airways. Objective To assess the performance of 3 delivery devices and the impact of variable durations of inhalation on the pulmonary and extrapulmonary deposition of nebulized 99mtechnetium‐diethylenetriamine‐pentaacetic acid (99mTc‐DTPA). Animals Ten university‐owned healthy Beagle dogs. Methods Prospective crossover study. Dogs inhaled the radiopharmaceutical for 5 minutes either through the Aerodawg spacer with a custom‐made nose‐muzzle mask, the Aerochamber spacer with the same mask, or the Aerodawg spacer with its original nose mask. In addition, dogs inhaled for 1 and 3 minutes through the second device. Images were obtained by 2‐dimensional planar scintigraphy. Radiopharmaceutical uptake was calculated as an absolute value and as a fraction of the registered dose in the whole body. Results Mean (±SD) lung deposition for the 3 devices was 9.2% (±5.0), 11.4% (±4.9), and 9.3% (±4.6), respectively. Differences were not statistically significant. Uptake in pulmonary and extrapulmonary tissues was significantly lower after 1‐minute nebulization, but the mean pulmonary/extrapulmonary deposition ratio (0.38 ± 0.27) was significantly higher than after 5‐minute nebulization (0.16 ± 0.1; P = .03). No significant differences were detected after 3‐ and 5‐minute nebulization. Conclusion and Clinical Importance The performance of a pediatric spacer with a custom‐made mask is comparable to that of a veterinary device. One‐minute nebulization provides lower pulmonary uptake but achieves a better pulmonary/extrapulmonary deposition ratio than does 5‐minute nebulization., Journal of Veterinary Internal Medicine, 35 (2)

Mycophenolic acid (MPA) is an immunomodulating agent commonly used in human medicine for the treatment of immune-mediated diseases. There is growing evidence that the immunomodulating properties of mycophenolate mofetil (MMF), a prodrug of MPA, are therapeutically beneficial for the treatment of immune-mediated diseases in dogs. A narrow therapeutic index and high inter-and intra-patient pharmacokinetic (PK) variability complicate the use of MMF. A better characterization of MPA pharmacokinetics is needed to help establish dosing regimens and standardized treatment protocols for canine patients. The purpose of this study was to evaluate the pharmacokinetics of MPA in dogs. MMF oral suspension (10 mg/kg) was administered to five healthy beagle dogs. Serial blood samples were collected from 0 to 18 hours after administration. The simultaneous quantification of MPA, and its metabolites MPA-7-O-glucuronide (MPAG), and acyl glucuronide (AcMPAG) was determined by liquid chromatography (LC)-mass spectrometry (MS)/MS. MPA peak concentrations were achieved rapidly (median Tmax of 0.5 h). Concentrations fell through 3 hours post-dose and then plateaued around 20% of Cmax. The mean elimination half-life was rapid (5.8 hours) and notable variability was observed in all PK parameters. The PK profiles for the MPAG and AcMPAG metabolites followed a similar pattern as MPA concentration. Future repeat-dose studies will be needed to evaluate steady-state PK parameters and to define therapeutic MPA dose levels.

The aim of this pilot study was to evaluate the effect of the timing of postoperative orthodontic force application on bone remodeling during tooth movement into surgical alveolar defects with bone grafts in beagle dogs.Six beagle dogs underwent surgery for buccal dehiscence-type defects (width, 5 mm; height, 6 mm) on the distal root of maxillary second premolars bilaterally for 12 defects. After 1-month healing, bone-augmentation procedures were undertaken at the dehiscence defects. The second premolars were protracted buccally for 6 weeks into the surgical sites immediately (F-0), at 4 weeks (F-4), or 8 weeks (F-8) after grafting. Orthodontic tooth movement was monitored using digital models. Remodeling of alveolar bone was evaluated by histology, histomorphometry, immunohistochemistry, microcomputed tomography, and fluorescence microscopy.Group F-0 showed significant expansion (mean, 2.42 mm) and tipping (mean, 9.03°) after completing orthodontic tooth treatment. The vertical bone defect was significantly lower in groups F-4 and F-8 than that in group F-0 (mean, 2.1, 2.7, and 4.5 mm, respectively). In group F-4, the formation of new bone and mineralization were significantly greater than those in groups F-0 and F-8 (P 0.05). Group F-4 showed a minimal amount of bone-material remnants. Immunohistochemistry showed the highest expression of collagen-1 and osteopontin in group F-4, followed by group F-8 and group F-0, which demonstrated high osteoblast activity and enhanced bone remodeling in group F-4.Orthodontic force application at 4 weeks after an augmentation procedure provided the best functional stimulation for an alveolar bone graft. This strategy enhanced new-bone regeneration and degradation of bone substitutes and, eventually, promoted bone remodeling in the bone-grafted area.

A sensitive and selective ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS-MS) method for the determination of apremilast in beagle dog plasma has been developed and successfully validated in the current study. Clopidogrel was employed as an internal standard (IS), and liquid-liquid extraction by tert-butylmethyl ether was used for sample preparation. Chromatographic separation was achieved on a UPLC BEH Shield RP18 column (50 mm × 2.1 mm, 1.7 μm) with 5 mM ammonium formate water and 5 mM ammonium formate methanol as the mobile phase with gradient elution. Calibration plots were linear in the range of 2–3000 ng/mL for apremilast in beagle dog plasma. Mean recoveries of apremilast in beagle dogs plasma ranged from 87.4% to 97.4%. The intrarun and interrun precision was less than 6% and 9%, respectively, with the accuracy between 92.4% and 101.1%. The method has also been successfully applied in the pharmacokinetics study of apremilast. The mean t1/2Z was 5.41 h for 30 mg·day−1 for beagle dogs after oral administration. The AUC0-t increased linearly from 3.51 to 1802.13 μ g L − 1 ∗ h after administration of single doses.

A 6-month-old female beagle dog, assigned to the low-dose group in a toxicity study, was evaluated for compound toxicity, and spontaneous hyperadrenocorticism was suspected. The animal had an externally apparent distended abdomen on clinical examination upon arrival. Pre-dose clinical pathology showed slightly higher erythroid parameters and stress leukogram on hematology; plasma biochemistry showed higher total protein, gamma-glutamyl transferase, total cholesterol, and triglyceride levels than the reference data. On necropsy, a prominent increase in adipose tissues of the subcutis and abdomen and increased weight of the adrenal gland and liver were observed. Histopathology revealed diffuse hyperplasia of adrenocortical cells in the zona fasciculata and reticularis, cortical atrophy of the thymus, and abundant glycogen accumulation in the hepatocytes. These findings were incidental and not test-substance-related. Electron microscopy of the adrenocortical cells in the zona fasciculata revealed decreased typical translucent lipid droplets, increased electron-dense lipid droplets, and abundant smooth endoplasmic reticulum and lysosomes. Additionally, increased numbers of various sizes and forms of mitochondria with tubular, vesicular, or lamellar cristae compared to that of normal animals were observed. These ultrastructural characteristics of the adrenocortical cells suggested hyperfunction. The pre-dose plasma cortisol levels were slightly higher than those of other females assigned to the toxicity study, while plasma adrenocorticotropic hormone levels were within the normal range. These findings indicate that hyperadrenocorticism is a possible cause of the systemic changes in this case.

Objective: To develop a reliable and sensitive high-performance liquid chromatographytandem mass spectrometry (HPLC-MS/MS) method for the quantification of selegiline in Beagle dog plasma and apply the validated method to study the pharmacokinetics and bioavailability of oral selegiline lyophilizate in Beagle dogs. Methods: Following alkalization with 1 M sodium hydroxide solution, selegiline and the Internal Standard (IS) zolmitriptan were extracted using tert-butyl methyl ether and separated on a CAPCELL PAK C18 column under isocratic conditions. They were detected by MS/MS using electrospray ionization (ESI) in the positive mode. Quantification was performed using multiple reaction monitoring (MRM) with transitions of m/z 188.05→90.9 for selegiline and m/z 288.05→57.95 for IS. Results: Calibration curves were constructed in the concentration range of 0.2–200 ng/mL with a lower limit of quantification (LLOQ) of 0.21 ng/mL. The matrix effect of dog plasma on the selegiline signal ranged from 98.8 to 105.6%, and the mean extraction recovery ranged from 79.0% to 81.4% at concentrations of 1.04, 20.8, and 166 ng/mL. The intra-day precision was lower than 6.86% and the inter-day precisions were lower than 4.63%. Conclusion : The validation results demonstrated the reliability of this bioanalytical method, which was successfully applied to study the pharmacokinetics and bioavailability of 1.25 mg of orally administered selegiline lyophilizate in Beagle dogs. The pharmacokinetic results were also compared with those obtained following intragastric (i.g.) and intravenous (i.v.) administration. Buccal delivery of selegiline was found to significantly increase its bioavailability.

Objective Treatment of mandibular lesions sometimes leads to the formation of large defects in the bone. Mandible reconstruction using grafted tissue, bone, and/or medical implants is required following the resection of such lesions. However, such grafts may not completely restore the continuity of the mandible. Facial transplantations using allografts are common, but mandibular allotransplantation has not been performed in humans, due to the unstable immune reaction of the complex tissue. In this study, mandibular transplantations performed under the effect of the immunosuppressive agent, FK506, were evaluated in dogs. Methods Mandibular allotransplantations were performed in 21 pairs of sex-blind beagle dogs. The left side of the mandible in the donor dog was transplanted to the left side of the mandible in the recipient dog. The FK506 doses were 0 mg for 3 dog pairs, 0.08 mg/kg/day for 3, 0.12 mg/kg/day for 5, 0.16 mg/kg/day for 5, and 0.32 mg/kg/day for 5 pairs. Twelve weeks after transplantation, the dogs were euthanized. Computed tomography (CT) and histological examinations of the transplanted sides were performed. Results Successful graft acceptance was dependent on immunosuppressive agent doses, and dogs administered more than 0.16 mg/kg/day FK506 showed 100 % survival. However, dogs administered 0.32 mg/kg/day FK506 showed significant weight loss 12 weeks after the surgery. CT findings showed thick mandibular cortical bone in the transplanted sites. Conclusions These results indicate that 0.16 mg/kg/day FK506 was the ideal dose for allotransplantations. Bone hyperplasia was observed in the transplanted sides, but it is not a disadvantage for allotransplantations.

Oncolytic virotherapy is an emerging strategy that uses replication-competent viruses to kill tumor cells. We have reported the oncolytic effects of TG6002, a recombinant oncolytic vaccinia virus, in preclinical human xenograft models and canine tumor explants. To assess the safety, biodistribution and shedding of TG6002 administered by the intravenous route, we conducted a study in immune-competent healthy dogs. Three dogs each received a single intravenous injection of TG6002 at 105 PFU/kg, 106 PFU/kg or 107 PFU/kg, and one dog received three intravenous injections at 107 PFU/kg. The injections were well tolerated without any clinical, hematological or biochemical adverse events. Viral genomes were only detected in blood at the earliest sampling time point of one-hour post-injection at 107 PFU/kg. Post mortem analyses at day 35 allowed detection of viral DNA in the spleen of the dog which received three injections at 107 PFU/kg. Viral genomes were not detected in the urine, saliva or feces of any dogs. Seven days after the injections, a dose-dependent antibody mediated immune response was identified. In conclusion, intravenous administration of TG6002 shows a good safety profile, supporting the initiation of clinical trials in canine cancer patients as well as further development as a human cancer therapy.

Objective To describe an approach for ethmoidal nerve block (EBLOCK) and to compare the effects of a maxillary nerve block (MBLOCK), EBLOCK and their combination (M-EBLOCK) on heart rate (HR), systolic (SAP), mean (MAP), diastolic (DAP) arterial pressures and respiratory rate (fR) during nasal stimulation in dogs. Study design Prospective, blinded, randomized, crossover placebo-controlled study. Animals Beagle dogs (five cadavers, nine live dogs), with a median (interquartile range) weight of 10.5 (10.3–11.0) kg. Methods The accuracy of iohexol injections (each 1 mL) at the maxillary and ethmoidal foramina in cadavers was evaluated using computed tomography. Then, anesthetized dogs were administered four bilateral treatments separated by 1 week, saline or 2% lidocaine 1 mL per injection: injections of saline at the maxillary and ethmoidal foramina (Control), injections of lidocaine at the maxillary foramina and saline at the ethmoidal foramina (MBLOCK), injections of saline at the maxillary foramina and lidocaine at the ethmoidal foramina (EBLOCK) and injections of lidocaine at all foramina (M-EBLOCK). The ventral nasal meatus was bilaterally stimulated using cotton swabs, and HR, SAP, MAP, DAP and fR were continuously recorded. Values for each variable were compared before and after stimulation using Wilcoxon signed-rank test. Changes in variables among treatments were analyzed using Mann–Whitney U and Kruskal–Wallis tests (p ≤ 0.05). Results Computed tomography revealed iohexol distribution around the openings of the target foramina in all cadavers. In living dogs, HR, SAP, MAP, DAP and fR significantly increased after stimulation within each treatment (p Conclusions and clinical relevance Concurrent injections of lidocaine at the maxillary and ethmoidal foramina attenuated HR, arterial pressure and fR responses to nasal stimulation in Beagle dogs.

Highlights • HAD-B1 is used in Korean medicine to treat lung cancer patients. • The acute and Sub-chronic toxicity of HAD-B1 was evaluated in Beagle dogs. • No toxicologically significant effects were found. • The NOAEL was ≥2000 mg/kg/day for both genders, with no target organ effect., HAD-B1 is a herbal formula originated from Korean Traditional Medicine that used to treat lung cancer patients. Herein we assessed acute and sub-chronic toxicity of HAD-B1 in beagle dogs. Acute study, 4 weeks dose rate finding (DRF) study and sub chronic toxicity study for 13 weeks were done by oral administration at doses of 0, 500, 1000, and 2000 mg/kg. Neither oral acute toxicity study nor DRF study showed any significant clinical signs, death, or weight changes. Based on that, a sub-chronic study for 13-weeks was performed. As a result, HAD-B1 caused a decrease of mean daily feed consumption in females, infiltration of intestinal inflammatory cells in both sexes, a significant decrease in total cholesterol (TCHO) in females, Kupffer cell hypertrophy/hyperplasia in the liver as well as dilation of the sinusoid. However, there were no significant toxic effects in the treated group compared to the control group. Therefore, the No Observed Adverse Effect Level (NOAEL) of the HAD-B1 is at least 2000 mg/kg/day when administrated orally for 13 consecutive weeks. These results demonstrate that HAD-B1 consumption is relatively non-toxic and safe for clinical usage.