Months In Dogs Research Articles

Efficacy of Sustained-Release Formulation of Moxidectin (Guardian SR) in Preventing Heartworm Infection over 18 Months in Dogs Living in a Hyperendemic Area.

This study investigates the efficacy of a sustained-release (SR) moxidectin microsphere formulation in preventing canine heartworm infection over 18 months in Canary Hound dogs, a hunting breed common in the Canary Islands, which is a hyperendemic region. These dogs typically do not receive preventive treatments and act as reservoirs for the disease. This field study was conducted across 11 hunting kennels with 109 dogs living outdoors, none of whom were receiving heartworm prophylaxis, with Dirofilaria immitis prevalence ranging from 11.1% to 57.1% (average 36.7%). Among these, 20 clinically healthy, heartworm-negative dogs were randomly selected to receive a single subcutaneous injection of moxidectin SR (0.17 mg/kg body weight). Antigen and Knott's tests were performed at 6, 12, 18, and 24 months. All dogs completed the study without adverse reactions and remained heartworm-negative throughout. By the end of the study, kennel heartworm prevalence ranged from 14.3% to 46.7% (average 35.4%). A single subcutaneous dose of moxidectin SR at the recommended dosage may prevent patent heartworm infection in dogs for up to 18 months in hyperendemic regions. Further studies are required to confirm these findings. Extending the efficacy period of moxidectin could improve owner compliance, particularly among those with lower animal health awareness.

Effectiveness of silver diamine fluoride 38% on reduction of gingivitis in dogs: a randomized clinical trial.

Periodontal disease is a ubiquitous disease in small animal veterinary medicine. Currently regular professional dental cleaning and daily tooth brushing are considered gold standards in the prevention of periodontal disease. Efforts to find a noninvasive, cost effective and easy to use preventative for periodontal disease are ongoing. The primary objective of this double-blind randomized clinical trial was to determine if a single application of silver diamine fluoride (SDF) 38% on the buccal surface of all teeth would reduce gingivitis within 3 months in dogs with stage two periodontal disease. Twenty-nine client-owned dogs 3-12 years old, 6-35 pounds were randomized 1:1 into active and placebo-control groups. Both groups underwent a baseline treatment and a three-month follow-up under general anesthesia. Gingival Index (GI), Plaque Index (PI), and Calculus Index (CI) were assessed and recorded at each event. A single application of SDF 38% did not significantly lower GI relative to the control group. However, the GI score dropped significantly in both groups relative to baseline, with a 53% reduction in the average GI score for dogs that received SDF 38% treatment and a 44% reduction for dogs that received placebo treatment. There were no differences in PI or CI scores compared to control groups. Further research is needed to determine if a more frequent application or a longer study duration would yield a different outcome.

Presence of Gastrointestinal Paraneoplastic Syndrome at Diagnosis in Dogs With Cutaneous Mast Cell Tumors and Its Influence on Disease-Free Interval and Survival

Paraneoplastic syndrome (PNS) is a combination of signs unrelated to the physical presence of a tumor and/or its metastases. Its presence may result in poorer clinical outcomes and prognosis. Gastrointestinal ulceration is a well-known PNS in animals with cutaneous MCT. This retrospective study analyzed the occurrence of gastrointestinal (GI) PNS at the time of diagnosis. Using medical records, we attempted to correlate the occurrence of these GI signs with clinical and histologic criteria, as well as to evaluate their influence on the disease-free interval (DFI) and survival (ST) over a 6-year follow-up period (2013-2020). The medical records of 41 dogs with a confirmed diagnosis of cutaneous MCT treated between 2013 and 2014 were included. All dogs underwent surgical biopsy or tumor excision, endoscopic and histologic examination to evaluate possible GI lesions. The presence and severity of GI signs were recorded. Clinical data such as the history of recurrence, number of tumors, tumor size, presence of ulceration, local pruritus, edema and erythema, histopathological classification, and mitotic index were extracted from medical records. Clinical signs relating to the GI system were observed in 41.5% of the dogs and were classified as mild in 94.1% at the time of diagnosis. Endoscopic examination of the upper digestive tract showed evidence of inflammation, but histologic examination of the mucosa showed no serious lesions in any case. There was no significant association between the occurrence of clinical GI signs and any of the variables studied. Follow-up issues meant that only 38 dogs were included for evaluation of the ST and 32 for DFI analysis. DFI was 25.1 months for dogs with GI signs and 14.8 months for dogs without GI signs. At the end of the study, 71.1% of patients had died. Survival time for dogs with GI signs was 54.9 months and 48 months for dogs without GI signs. Over the 6 years of the study, no differences were observed between the ST and the DFI, and the presence or absence of GI PNS at the time of diagnosis.

Abstract 6347: Preliminary results of an exploratory phase I clinical trial of anchored canine interleukin-12 (cANK-101) in dogs with advanced oral malignant melanoma

Abstract Background: Malignant melanoma is the most common form of oral cancer in canines with a median survival of 3 months for dogs with stage III or IV disease. Currently, there are limited effective systemic treatment options for these patients with advanced disease. We have developed an anchored immunotherapy approach in which canine interleukin-12 is stably linked to aluminum hydroxide (cANK-101). The anchored IL-12 forms a stable, functional depot of IL-12 and is expected to increase therapeutic responses with limited systemic toxicity. We report the preliminary results of an exploratory Phase I study of cANK-101 in dogs with advanced melanoma. Methods: The clinical study was approved by the University of Illinois IACUC, conducted at the College of Veterinary Medicine, and all pet owners provided written informed consent. The primary objective of the trial was to determine the safety and tolerability of cANK-101 in dogs with advanced melanoma. A standard 3+3 dose-escalation design was used with three dose levels (1, 3, and 10 µg/kg) cANK-101 given by intratumoral injection every three weeks for 4 cycles. In the absence of overt clinical progression, dogs were allowed to receive a second course of four cycles. Dogs were monitored for adverse events via VCOG-CTCAE and clinical responses were measured using RECISTv1.1. Serum was collected for pharmacokinetic (PK) and immunogenicity analyses. In addition, serial tumor biopsy and lymph node cytology were performed. Serum cytokines were assayed via ELISA while immunophenotyping of PBMC and lymph node aspirates were assessed by flow cytometry. Tumor-infiltrating lymphocyte (TIL) analysis was performed by immunohistochemistry (IHC) and gene expression profiling (Nanostring). Descriptive statistics were used for analyses. Results: As of November 16, 2022, 8 dogs have been enrolled and all dogs remain on treatment. Thirteen adverse events have been reported in 6 dogs, all being grade 1. However, only two are considered related to the study drug (tumor site inflammation and pain). Treatment was associated with increases in serum IFNγ and IL-10, as well as increases in peripheral CD4+ T and CD21+ T cells. Additional data on PK analyses, anti-drug antibody levels, gene expression, and clinical responses will be presented. Conclusions: Thus far, cANK-101 appears to be safe and tolerable in dogs with advanced melanoma. Data from this trial will help inform human clinical trials and may represent a new therapeutic option for dogs with advanced melanoma and perhaps other solid tumors. Our experience further suggests that companion animal trials could serve as relevant translational models for early immuno-oncology drug development. Citation Format: Matheus Moreno Passos Barbosa, Angel J. Lopez, Rachel Uyehara, Rebecca L. Kamerer, Michael Schmidt, Sailaja Battula, Howard L. Kaufman, Timothy M. Fan. Preliminary results of an exploratory phase I clinical trial of anchored canine interleukin-12 (cANK-101) in dogs with advanced oral malignant melanoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6347.

Prevalence of pelvic fractures in cat and dogs: A retrospective study in 183 cases (2016-2020)

This study aims to classify radiographically diagnosed pelvic fractures in cats (n = 103) and dogs (n = 80). The pelvic bone resembles a box structurally, and as a result of the trauma of this bone, multiple fractures usually occur. Radiographs of cats and dogs exposed to various traumas were evaluated and classified as ilium, ischium, pubis, acetabulum, sacroiliac luxations and symphysis pubis fractures. The mean age of the cases included in the study was 16.9 months in cats and 19.2 months in dogs. Pelvic fractures were more common in females than males (♀=57.9%, ♂= 42.1%). In this context, it was constituted 18.7% ilium fractures, 12.6% pubis fractures, 18.9% ischial fractures, 11.3% acetabulum fractures, 29.2% sacroiliac luxation and 9% symphysis pelvis fractures of pelvic fractures. As a result, it was revealed that multiple fractures could be seen in traumas taken to the pelvic area and their rates.

Investigating Flubendazole as an Anthelmintic Treatment for Guinea Worm (Dracunculus medinensis): Clinical Trials in Laboratory-Reared Ferrets and Domestic Dogs in Chad.

ABSTRACT.Dracunculus medinensis (Guinea worm [GW]), a zoonotic nematode targeted for eradication, has been managed using interventions aimed at humans; however, increases in domestic dog GW infections highlight the need for novel approaches. We conducted two clinical trials evaluating the efficacy of subcutaneously injected flubendazole (FBZ) as a treatment of GW infection. The first trial was conducted administering FBZ to experimentally infected ferrets; the second trial involved administering FBZ or a placebo to domestic dogs in the Republic of Tchad (Chad). We found contrasting results between the two trials. When adult gravid female GW were recovered from ferrets treated with FBZ, larvae presented in poor condition, with low to no motility, and an inability to infect copepods. Histopathology results indicated a disruption to morulae development within uteri of worms from treated animals. Results from the trial in Chadian dogs failed to indicate significant treatment of or prevention against GW infection. However, the difference in treatment intervals (1 month for ferrets and 6 months for dogs) or the timing of treatment (ferrets were treated later in the GW life-cycle than dogs) could explain different responses to the subcutaneous FBZ injections. Both trials provided valuable data guiding the use of FBZ in future trials (such as decreasing treatment intervals or increasing the dose of FBZ in dogs to increase exposure), and highlighted important lessons learned during the implementation of a field-based, double-blinded randomized control trial in Chadian dogs.

Evaluation of Serum and Urine Amino Acids in Dogs with Chronic Kidney Disease and Healthy Dogs Fed a Renal Diet.

This observational study aimed to evaluate serum and urinary amino acid (AA) concentrations in healthy dogs and dogs with chronic kidney disease (CKD) fed a commercial therapeutic renal diet with reduced protein and phosphorus levels. Ten dogs with CKD stages 3 or 4 composed the study group and received the renal diet for 180 days (RG T180). A control group (CG T30) composed of seven healthy dogs was fed a renal diet for 30 days. When comparing serum AA between RG T180 and CG T30, histidine, isoleucine, leucine, lysine, phenylalanine, tryptophan, cysteine, citrulline, ornithine, taurine, branched-chain amino acids (BCAA), and total essential amino acids (EAA) were higher in RG T180. Meanwhile, arginine, asparagine, aspartate, glutamine, serine, and tyrosine were higher in CG T30. Serum phenylalanine, tryptophan, and hydroxyproline were higher in RG T0 (dogs with CKD before consuming a renal diet) when compared to RG T180. In addition, the serum ratios of arginine/citrulline, tyrosine/phenylalanine, and serine/glycine were higher in CG T30 than in RG T180. Concerning urinary AA concentrations in CKD dogs, isoleucine, phenylalanine, tryptophan, aspartate, cysteine, and BCAA were higher in RG T180. In urine, the total EAA/total non-essential AA ratio in RG T180 was higher than in CG T30 as well as tyrosine/phenylalanine ratio higher in CG T30. In conclusion, the combination of renal diet and conservative treatment over 6 months in dogs with CKD stages 3 or 4 affected the AAs metabolism when compared to healthy adult dogs.

Double-cut center of rotation of angulation–based leveling osteotomy for treatment of cranial cruciate ligament deficiency and excessive tibial plateau angle secondary to growth anomaly in two dogs

A 4-year-old female Staffordshire Bull Terrier (dog 1) and a 6-year-old male Yorkshire Terrier (dog 2) were evaluated because of left pelvic limb lameness. Both dogs had a partial rupture of the left cranial cruciate ligament associated with a unilateral excessive tibial plateau angle (51° in dog 1 and 41° in dog 2) secondary to a growth anomaly. Both dogs underwent a double-cut center of rotation of angulation-based leveling osteotomy combining rotation of the proximal fragment with a cranial closing wedge ostectomy. The procedure allowed leveling of the tibial plateau to a final angle of 11° in one dog and 10° in the other without perioperative complications. Both dogs had excellent functional outcomes ≤ 4 months after the surgery. No postoperative complications were reported during follow-up (12 months and 9 months for dogs 1 and 2, respectively). Results for these dogs suggested that double-cut center of rotation of angulation-based leveling osteotomy can be considered as a viable treatment option for cranial cruciate ligament deficiency associated with excessive tibial plateau angle.

Nutritional adjuvants with antioxidant properties in the treatment of canine leishmaniasis

Clinical improvement of dogs treated for canine leishmaniasis (CanL) requires reducing Leishmania infantum loads, which depend on intracellular oxidant compounds to destroy the parasite. However, oxidative species’ excess and antioxidants consumption can culminate in oxidative stress, resulting in increased, widespread inflammation. We aimed to evaluate if early or late addition of nutritional adjuvants (NAs) – omega-3 polyunsaturated fatty acids and B vitamins – to anti-Leishmania drugs (ALDs) in the treatment of CanL would be clinically beneficial. For that, serum biomarkers including oxidative stress parameters were analyzed during 12 months in dogs allocated to two treatment groups: (G1) NAs administered from 30 days prior to the beginning of ALDs; and (G2) NAs administered from 61 days after the beginning of ALDs. Both G1 and G2 continued to receive NAs until the 12th month. The ALDs administered were metronidazole associated with ketoconazole (40 days), followed by allopurinol from day 41 until the 12th month. G1 exhibited superior inflammation control, with reduced globulins (p = 0.025), specific anti-Leishmania immunoglobulins (p = 0.016), total protein (p = 0.031), and an increased serum albumin/globulin ratio (p = 0.033), compared to G2. The early use of NAs associated with ALDs is clinically beneficial in treating dogs with CanL.

Maintaining long-term odor memory and detection performance in dogs

Detection dogs represent an essential resource for security and defense sectors, yet logistical and security constraints limit the frequency in which relevant maintenance training can occur. Further, the extents and limits of canine odor memory are unknown. The aims of this study were to examine the duration of long-term odor memory in detection dogs, and to evaluate effects of single-target maintenance training on the recall of previously trained targets, as well as generalization to a set of related but untrained targets. Detection dogs (n = 18) were trained on a set of 10 target odors followed by an assessment of baseline performance in odor discrimination and operational search tests. During the subsequent 12 months, half of the dogs received minimal intermittent odor detection maintenance training (approximately 30 min total per month) with a single target odor from the trained set, while the other half received commensurate training not involving odor detection (i.e., obedience training). Detection of the targets not experienced over the 12-mo period was then re-assessed. Generalization to untrained variants of the trained targets, a critical aspect of optimal detection that may be affected by extensive training with specific odors, was also assessed at baseline and after the 12-mo period. Accuracy in the odor discrimination test significantly decreased from 99 % (SE = .25) at baseline to 72 % (SE = 4.36) after 12 months for dogs that received no odor detection maintenance training, and significantly increased from 94 % (SE = 1.57) to 99 % (SE = .53) for dogs that received single-odor maintenance training over the 12-mo period. However, the maintenance training did not appear to maintain operational search performance. Further, results from the generalization test were less straightforward, suggesting that single-target maintenance training may not be sufficient for optimal operational detection of untrained variants. Our results indicate that long-term odor memory is largely robust in dogs, and that odor discrimination accuracy can be effectively maintained and even improved through minimal maintenance training using a single target odor, but that the task of searching in operational environments may require more regular maintenance.

Congenital ocular malformations in dogs and cats: 123 cases.

Provide epidemiological data regarding the prevalence of congenital ocular malformations in dogs and cats. A population of 32974 dogs and 13977 cats that presented for consultation at the veterinary teaching hospital. Medical records from 2011 to 2018 were reviewed. A retrospective and prospective epidemiological clinical study addressing congenital ocular malformations was conducted. Signalment, medical history, reason for presentation, clinical findings, vision impairment, and treatment options were analyzed. From the total of cases analyzed, 103 dogs (0.3%) and 20 cats (0.1%) met the inclusion criteria. The majority of dogs were mixed breed, the most common breed being the French Bulldog, while the majority of cats were European domestic shorthair. The median age of diagnosis was 12months for dogs and 6months for cats. Sex predisposition was not found. The most frequently identified abnormalities were as follows: congenital cataract (dogs: 31.1%; cats: 30.0%), microphthalmia (dogs: 35.0%, cats: 25.0%), and persistent pupillary membrane (dogs: 27.2%, cats: 40.0%). Some of the concurrently observed malformations were significantly associated. A statistically significant association was found between ocular dermoids and the French Bulldog breed (P<.001). Even though congenital ocular malformations are uncommon, knowledge about their prevalence is important, since they can cause vision impairment or even blindness. Moreover, some human ocular disease phenotypes are similar to the ones presented by dogs and cats, so they can be used as models to investigate pathophysiology and therapeutic approaches.

The One Health Consortium: Design of a Phase I Clinical Trial to Evaluate M032, a Genetically Engineered HSV-1 Expressing IL-12, in Combination With a Checkpoint Inhibitor in Canine Patients With Sporadic High Grade Gliomas.

As the most common and deadly of primary brain tumors, malignant gliomas have earned their place within one of the most multifaceted and heavily-funded realms of medical research. Numerous avenues of pre-clinical investigation continue to provide valuable insight, but modeling the complex evolution and behavior of these tumors within a host under simulated circumstances may pose challenges to extrapolation of data. Remarkably, certain breeds of pet dogs spontaneously and sporadically develop high grade gliomas that follow similar incidence, treatment, and outcome patterns as their human glioma counterparts. The most malignant of these tumors have been refractory to limited treatment options despite aggressive treatment; outcomes are dismal with median survivals of just over 1 year in humans and 2 months in dogs. Novel treatments are greatly needed and combination therapies appear to hold promise. This clinical protocol, a dose-escalating phase I study in dogs with sporadic malignant glioma, represents a first in comparative oncology and combination immunotherapy. The trial will evaluate M032, an Interleukin-12 expressing Herpes Simplex virus, alone and combined with a checkpoint inhibitor, Indoximod. Extensive pre-clinical work has demonstrated safety of intracranial M032 administration in mice and non-human primates. M032 is currently being tested in humans with high-grade malignant gliomas. Thus, in a novel fashion, both canine and human trials will proceed concurrently allowing a direct “head-to-head” comparison of safety and efficacy. We expect this viral oncolytic therapy to be as safe as it is in human patients and M032 to (a) infect and kill glioma cells, producing a virus and tumor cell antigen-rich debris field; (b) provide an adjuvant effect due to liberation of viral DNA, which is rich in unmethylated CpG sequences that “toggle” TLR-9 receptors; and (c) express IL-12 locally, stimulating induction of TH1 lymphocytes. The resultant immune-mediated anti-viral responses should, through cross-epitope spreading, translate into a strong response to tumor antigens. The ability to compare human and dog responses in real time affords the most stringent test of suitability of the dog as an informative model of human brain tumors. Subsequent studies will allow canine trials to properly inform the design of human trials.

Abstract 4568: The One Health Consortium and combination immunotherapy: evaluating M032, a genetically engineered HSV-1 expressing Il-12, in combination with a checkpoint inhibitor in canine glioma patients

Abstract Introduction: Malignant gliomas are the most common primary brain tumors in humans, accounting for approximately 30% of all primary CNS tumors in adults (Levin et al., 2001). Interestingly, pet dogs spontaneously and sporadically develop malignant glial brain tumors that resemble high-grade gliomas in humans; with similar incidence, treatments, and outcome patterns. (Priester and McKay, 1980; Snyder et al., 2006; Ostrom et al., 2013; Ostrom et al., 2014; Hicks et al., 2017) The most malignant of these tumors have been refractory to limited treatment options. Despite aggressive treatment, outcomes are dismal with median survivals just over one year in humans and two months in dogs. Novel treatments are greatly needed and combination therapies appear to hold promise. Background: This pre-clinical protocol, a dose-escalating phase I study in dogs with sporadic malignant glioma, represents a first in comparative oncology and combination immunotherapy. The trial is evaluating M032, an Interleukin-12 expressing Herpes Simplex virus, alone and combined with a checkpoint inhibitor, Indoximod. Note, prior studies have demonstrated human IL-12 to generate effective anti-tumoral response in canine patients (Pavlin et al., 2012). M032 is currently being tested in humans with high-grade malignant gliomas. Thus, in a novel fashion, both canine and human trials are proceeding concurrently, allowing a direct “head-to-head” comparison of safety and efficacy. Methods: Stage 1 of the trial, which is presently ongoing, involves catheter-based administration of MO32 alone into the tumor resection cavity at escalating doses in subsequent cohorts of dogs to establish maximum tolerable dose (MTD), detect dose limiting toxicities (DLT), quantify immune response via serum assays, and determine survival benefit. Stage 2 will involve administration of a fixed dose of MO32 derived from Stage 1 data followed by 4 weeks of daily Indoximod administration at a pre-determined dose, with interval comparative immune assays, neurological monitoring, and imaging surveillance. Indoximod is expected to blunt suppressive cellular (Tregs, MDSCs) immune response components, allowing a longer time for effective anti-viral responses and via cross-epitope spreading, an anti-tumor response that will be more durable than that observed with administration of virus alone. In all cases, tumor is collected, processed, and archived for future studies, including whole genome and RNA sequencing. Results: Preliminary data from Stage 1 have demonstrated a median survival of 188 days among all canines following infusion of M032 HSV (95% confidence interval of 83.2 to 292.8 days). Nine canines have died and eight are still alive following treatment. Current dose is 1 x 109 plaque-forming units. No dose limiting toxicities have been observed with infusion of M032 alone. Conclusions: The ability to compare human and dog responses in real time affords the most stringent test of suitability of the dog as a valid and informative model of human brain tumors. The results of this and subsequent studies will allow canine trials to properly inform the design of human trials and further support bi-translational studies and the One Medicine approach to clinical research and application. Citation Format: M. R. Chambers, R. T. Bentley, David Crossman, Jeremy B. Foote, J. W. Koehler, James M. Markert, Simon R. Platt, Nidal B. Omar, D. M. Self, Andy Shores, Don Sorjonen, Alicia M. Waters, Amy B. Yanke, G Y. Gillespie. The One Health Consortium and combination immunotherapy: evaluating M032, a genetically engineered HSV-1 expressing Il-12, in combination with a checkpoint inhibitor in canine glioma patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4568.

Clinical features and outcome of functional thyroid tumours in 70 dogs.

To describe the clinical features and outcome of functional thyroid tumours in dogs. Retrospective multi-institutional study of 70 dogs diagnosed with thyroid mass and concurrent hyperthyroidism. Clinical data regarding presentation, treatment, outcome and functional thyroid status were retrieved. Overall median survival of dogs with functional thyroid tumours was 35.1 months and 1- and 3-year survival rates were 83 and 49%, respectively. Median survival time was 72.6 months for dogs treated with surgical excision and 15.7 months for dogs that did not receive surgery. Of the 50 dogs treated by surgery and for which thyroid status was known following treatment, 64% developed hypothyroidism after surgery. Histopathologically confirmed metastasis was identified in 3% of dogs. Dogs with functional thyroid tumours may survive a long time after surgical excision, although post-operative hypothyroidism is common.

Nonclinical Pharmacokinetic and Pharmacodynamic Assessment of Bimatoprost Following a Single Intracameral Injection of Sustained-Release Implants.

PurposeTo assess the pharmacokinetic (PK)/pharmacodynamic (PD) relationship following intracameral Bimatoprost sustained-release (SR) implants (8, 15, 30, and 60 µg) in dogs to determine the optimal investigative dose in humans.MethodsForty-four male normotensive beagle dogs were assigned to 1 of 8 groups receiving 8-, 15-, 30-, and 60-µg implants (PD assessment [n = 8/group, 4 groups]; PK assessment [n = 3/group, 4 groups]). Intraocular pressure (IOP) in PD animals and aqueous humor/blood concentrations of bimatoprost and its acid in PK animals were assessed. PK/PD correlation analysis was performed using steady-state data. Residual implants were recovered to assess polymer degradation.ResultsDose-dependent IOP lowering was observed for all dose groups for at least 3 months postdose. Blood concentrations of bimatoprost and bimatoprost acid were below the limit of quantification (<0.25 ng/mL), whereas dose-dependent concentration-time profiles were observed in the aqueous humor. At steady state, observed and predicted correlation between aqueous humor drug concentration and IOP lowering was similar and translatable to findings in humans following topical bimatoprost eyedrop administration. Implants at all doses were well tolerated and polymer degradation was apparent.ConclusionsDose-dependent IOP lowering with Bimatoprost SR was maintained for at least 3 months in dogs, and the implants were well tolerated. The established PK/PD relationship appears to translate to humans. Doses between 8 and 15 µg appear to provide the best benefit/risk profile for clinical development of the implants.Translational RelevanceThe close PK/PD relationship between dog and human helps inform which bimatoprost dose should be investigated in clinical studies.

Evaluation of Electrolyte Concentration and Pro-Inflammatory and Oxidative Status in Dogs with Advanced Chronic Kidney Disease under Dietary Treatment.

An integrated study on the effect of renal diet on mineral metabolism, fibroblast growth factor 23 (FGF-23), total antioxidant capacity, and inflammatory markers has not been performed previously. In this study, we evaluated the effects of renal diet on mineral metabolism, oxidative stress and inflammation in dogs with stage 3 or 4 of chronic kidney disease (CKD). Body condition score (BCS), muscle condition score (MCS), serum biochemical profile, ionized calcium (i-Ca), total calcium (t-Ca), phosphorus (P), urea, creatinine, parathyroid hormone (PTH), FGF-23, interleukin 6 (IL-6), interleukin 10 (IL-10), tumor necrosis factor alpha (TNF-α) and total antioxidant capacity (TAC) were measured at baseline (T0) and after 6 months of dietary treatment (T6). Serum urea, P, t-Ca, i-Ca, PTH, FGF-23, IL-6, IL-10, TNF-α and TAC measurements did not differ between T0 and T6. Serum creatinine (SCr) was increased at T6 and serum PTH concentrations were positively correlated with serum SCr and urea. i-Ca was negatively correlated with urea and serum phosphorus was positively correlated with FGF-23. Urea and creatinine were positively correlated. The combination of renal diet and support treatment over 6 months in dogs with CKD stage 3 or 4 was effective in controlling uremia, acid–base balance, blood pressure, total antioxidant capacity, and inflammatory cytokine levels and in maintaining BCS and MCS.

In vitro assessment of the long-term stability of the inhibitory effects of canine and feline plasma on MMP 2 and 9.

To evaluate the effect of increasing storage time on the inhibitory effects of canine and feline plasma on matrix metalloproteinases (MMP) 2 and 9 in vitro. Matrix metalloproteinases 2 and 9 activity in the presence of canine plasma stored for 57, 155, 222, 316, 367, and 438days, and feline plasma stored for 17, 198, 565, and 954days was assayed using a commercially available colorimetric assay kit. For canine plasma, the MMP 2 activity for older samples was not significantly different than the 57-day sample (P=0.2025-0.9033). Two canine samples had significantly lower MMP 9 activity than the 57-day sample (367days: P=0.0099, 438days: P=0.0348, others P=0.0778-0.9928). For feline plasma, storage time did not significantly affect inhibition of MMP 2 and MMP 9 activity (ANOVA, P=0.2688 and P=0.2404, respectively). Increasing storage time does not significantly decrease the inhibiting activity of plasma on MMP 2 and 9 for up to 14months in dogs and 31months in cats.

Heart-fatty acid binding protein in dogs with degenerative valvular disease and dilated cardiomyopathy

The study objective was to investigate heart-fatty acid binding protein (HFABP) concentrations in dogs with degenerative valvular disease (MVD) and dilated cardiomyopathy (DCM), and its potential as a prognostic factor. Plasma HFABP, N-terminal pro brain natriuretic peptide (NTproBNP) and serum cardiac troponin I (cTnI) levels were measured in 21 control dogs, 23 dogs with MVD and 13 dogs with DCM, with repeated sampling at 1 and 3 months after initial presentation. All dogs were followed up after 6 and 12 months to verify survival.Heart-fatty acid binding protein concentrations were significantly higher in dogs with MVD and DCM than controls at initial presentation, and after 1 month in dogs with MVD. For dogs with DCM, a significant reduction in HFABP levels over time was observed. Comparing ACVIM stages, highest HFABP concentrations were detected in ACVIM stage C dogs compared to stage B, with the lowest levels seen in controls, and a reduction over time in stage C dogs was present. Similarly, cTnI concentrations were higher in DCM and stage C in comparison to control dogs and reduced over time, while NTproBNP concentrations were only higher in diseased dogs at 1 month. Heart-fatty acid binding protein and cTnI levels at initial presentation and ACVIM disease stage were independent predictors of survival in a univariate analysis. The elevation of HFABP in dogs with MVD and DCM in comparison to controls, its association with disease severity, and its potential in predicting reduced survival, suggest that HFABP might be useful as marker for canine MVD and DCM.

Evolution of Radiographic Parameters of Canine Passive Hip Laxity at 4, 6 and 12 months: A Study of 306 Dogs.

This article evaluates the variation in the distraction index (DI) and Norberg angle measurement with the femur in a neutral position and the hips distracted (distraction Norberg angle [DNA]) between 4, 6 and 12 months of age. Radiographic data from dogs (n = 306) line-bred for favourable characteristics, including hip conformation, were reviewed. Dogs underwent stress radiographs, using a Vezzoni distractor, at 4, 6 and 12 months of age. The DI and DNA were calculated, and their evolution was studied for the total population and the sub-category of hips with a DI > 0.7. For the total population, the DI showed a significant increase from 4 to 6 months and a significant decrease at 12 months. For the hips with a DI > 0.7 at 4 months, DI at 6 and 12 months showed a significant decrease (0.14 and 0.26, respectively, on average). For the total population, the DNA followed the same pattern as the DI, and the values are significantly associated (p < 0.001). The DI varies significantly from 4 to 12 months in dogs, and the time of radiographic evaluation of hip laxity may strongly influence the value of the DI. The DNA is strongly related to the DI, and its use as a more convenient indicator of hip laxity in dogs should be further investigated.

Design and Synthesis of Clinical Candidate PF-06751979: A Potent, Brain Penetrant, β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor Lacking Hypopigmentation.

A major challenge in the development of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors for the treatment of Alzheimer's disease is the alignment of potency, drug-like properties, and selectivity over related aspartyl proteases such as Cathepsin D (CatD) and BACE2. The potential liabilities of inhibiting BACE2 chronically have only recently begun to emerge as BACE2 impacts the processing of the premelanosome protein (PMEL17) and disrupts melanosome morphology resulting in a depigmentation phenotype. Herein, we describe the identification of clinical candidate PF-06751979 (64), which displays excellent brain penetration, potent in vivo efficacy, and broad selectivity over related aspartyl proteases including BACE2. Chronic dosing of 64 for up to 9 months in dog did not reveal any observation of hair coat color (pigmentation) changes and suggests a key differentiator over current BACE1 inhibitors that are nonselective against BACE2 in later stage clinical development.