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OBJECTIVE: To report the success rate and complications of combined phacoemulsification and pars plana vitrectomy (PPV) for treatment of cataracts and retinal detachment in the Siberian Husky breed. ANIMALS STUDIED: Client-owned Siberian Husky dogs that underwent combined phacoemulsification and PPV at two veterinary referral centers. PROCEDURE: Retrospective study of 16 Siberian Husky dogs that underwent combined phacoemulsification and PPV with a minimum 3-month postoperative follow-up. Signalment and preoperative ophthalmic examination findings, intraoperative findings, and postoperative visual status and complications were recorded. Functional success was defined as the maintenance or restoration of vision. RESULTS: Seventeen eyes of 16 dogs were evaluated. Immediate postoperative anatomic success was achieved in all 17 eyes (100%), with functional success through the last known follow-up examination achieved in 88.2% of operated eyes (15/17). The most common postoperative complication was silicone oil migration into the anterior chamber (AC-SiO migration), occurring in 47.1% of eyes (8/17), followed by corneal endothelial decompensation and glaucoma each occurring in 17.6% of eyes (3/17). CONCLUSIONS: Combined phacoemulsification and PPV is a viable option in Siberian Husky dogs with cataracts and preoperative retinal detachment. Visual success was achieved in 88.2% of eyes, with the most common postoperative complication being AC-SiO migration.
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OBJECTIVE: To report the long-term (>1 year) outcome of MicroPulse transscleral diode cyclophotocoagulation (MP-TSCP) in dogs. ANIMALS STUDIED: Client owned dogs that underwent MP-TSCP at a veterinary referral center. PROCEDURE: Retrospective study of 19 dogs treated with MP-TSCP. Dogs were evaluated at a median follow-up time of 30.5 months postoperatively. Reported outcomes were intraocular pressure (IOP), retention or loss of vision, number of medications, and additional procedures performed. Variables associated with time to treatment failure were evaluated. RESULTS: Data from 19 dogs (24 eyes) was available. Median laser settings employed were 140 s and 2200 mW at 31.3% duty cycle. Long-term postoperative IOP was lower than preoperative IOP values (14 mmHg (IQR = 22 mmHg, range: 4-52 mmHg) versus 30 mmHg (IQR = 31 mmHg, range: 8-62 mmHg), respectively). Laser settings >2000 mW were associated with a significantly longer time to reported failure. MP-TSCP was the sole therapy performed in 16/24 eyes resulting in long-term IOP control in 13/24 eyes and retention of vision in 6 of the 14 sighted eyes. Repeat MP-TSCP was performed in 10/24 eyes. Eight of 24 eyes required additional procedures with long-term IOP control in 4/8 eyes. CONCLUSIONS: MicroPulse transscleral diode cyclophotocoagulation can be an effective treatment for refractory glaucoma in select cases. Higher laser settings increased time to reported failure, whereas age, glaucoma type, and preoperative IOP did not affect survival. MP-TSCP as sole therapy or coupled with additional glaucoma procedures controlled the IOP in 70% of cases.
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Enfermedades de los Perros , Glaucoma , Animales , Cuerpo Ciliar , Enfermedades de los Perros/cirugía , Perros , Glaucoma/cirugía , Glaucoma/veterinaria , Presión Intraocular , Coagulación con Láser/veterinaria , Láseres de Semiconductores/uso terapéutico , Estudios Retrospectivos , Esclerótica/cirugía , Resultado del TratamientoRESUMEN
AIM: To examine the use of prophylactic anti-glaucoma medications in the normotensive fellow eye in dogs with unilateral overt primary glaucoma by veterinary ophthalmology clinicians. METHODS: A survey of veterinary ophthalmology clinicians was distributed over two international list serves servicing veterinary ophthalmologists, trainees, and individuals whose practice consisted primarily of ophthalmic patients. The survey was developed following analysis of historical and currently available medical options for control of intraocular pressure and for neuroprotection. RESULTS: Responses from 199 veterinary ophthalmology clinicians were evaluated. While a large variety of topical anti-hypertensive drugs and protocols were used, the most commonly used medications were aqueous humor production suppressors such as dorzolamide 2.0% ophthalmic solution, timolol 0.5% ophthalmic solution, and a combination product containing both drugs. Latanoprost 0.005% ophthalmic solution was used infrequently for prophylaxis by comparison. The majority of respondents do not use concurrent anti-inflammatory medications (61.22%), although a sizeable minority used prednisolone acetate, dexamethasone, or ketorolac as prophylactic treatment. Systemically administered ocular anti-hypertensive agents were rarely used. Only 40% of respondents used neuroprotectant agents; the most commonly prescribed were the calcium channel blocker amlodipine and the nutraceutical Ocu-Glo™. Recommended intervals between re-examination by the clinician ranged from one month to one year, with most re-evaluations occurring every 3 to 6 months. The majority of respondents recommended more frequent assessments of IOP at intervals between once monthly and once every 3 months. CONCLUSIONS: Data analysis of medical therapy for the normotensive fellow eye of dogs previously diagnosed with primary glaucoma suggests that there is a great need for well-designed, prospective, controlled, multi-center studies to determine which protocols have the greatest efficacy in delaying an overt attack in the previously normotensive eye in dogs with a genetic predisposition to glaucoma. Prospective studies utilizing a carbonic anhydrase inhibitor such as dorzolamide and a prostaglandin analogue such as latanoprost would be reasonable as these two drugs are widely used in the treatment of overt glaucoma and would allow for an exploration of the impact of different mechanisms of action of lowering IOP on the pathophysiology of primary glaucoma.
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Enfermedades de los Perros/prevención & control , Glaucoma/veterinaria , Soluciones Oftálmicas/uso terapéutico , Sulfonamidas/uso terapéutico , Tiofenos/uso terapéutico , Timolol/uso terapéutico , Animales , Enfermedades de los Perros/tratamiento farmacológico , Perros , Femenino , Glaucoma/tratamiento farmacológico , Glaucoma/prevención & control , Encuestas de Atención de la Salud , Masculino , Soluciones Oftálmicas/administración & dosificación , Sulfonamidas/administración & dosificación , Tiofenos/administración & dosificación , Timolol/administración & dosificaciónRESUMEN
OBJECTIVE: To investigate veterinary ophthalmologists' use of presumed neuroprotective therapies for degenerative retinal and optic nerve diseases in dogs. PROCEDURES: An online survey was sent to 663 board-certified veterinary ophthalmologists who were Diplomates of the American College of Veterinary Ophthalmologists (ACVO), Asian College of Veterinary Ophthalmologists (AiCVO), Latin American College of Veterinary Ophthalmologists (Colegio Latinoamericano de Oftalmólogos Veterinarios, CLOVE), or European College of Veterinary Ophthalmologists (ECVO). The survey was created using Qualtrics® software and focused on the prescription of presumed neuroprotective treatments for canine glaucoma, sudden acquired retinal degeneration syndrome (SARDS), progressive retinal atrophy (PRA), and retinal detachment (RD). RESULTS: A total of 165 completed surveys were received, representing an overall response rate of 25%, which was comparable across the four specialty colleges. Of all respondents, 140/165 (85%) prescribed some form of presumed neuroprotective therapies at least once in the last five years: 114/165 (69%) for glaucoma, 51/165 (31%) for SARDS, 116/165 (70%) for PRA, and 50/165 (30%) for RD. The three most recommended neuroprotective reagents were the commercial Ocu-GLO™ Vision Supplement for animals, amlodipine, and human eye supplements. CONCLUSIONS: Despite lack of published clinical efficacy data, the majority of surveyed board-certified veterinary ophthalmologists previously prescribed a presumed neuroprotective therapy at least once in the last five years in dogs with degenerative retinal and optic nerve diseases.
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Enfermedades de los Perros/prevención & control , Fármacos Neuroprotectores/administración & dosificación , Oftalmólogos , Enfermedades del Nervio Óptico/veterinaria , Pautas de la Práctica en Medicina/estadística & datos numéricos , Degeneración Retiniana/veterinaria , Veterinarios , Animales , Asia , Perros , Europa (Continente) , América Latina , Enfermedades del Nervio Óptico/prevención & control , Degeneración Retiniana/prevención & control , Encuestas y Cuestionarios , Estados UnidosRESUMEN
OBJECTIVE: To describe ocular surface complications following micropulse transscleral cyclophotocoagulation (MP-TSCPC) in dogs. ANIMALS STUDIED: Eighteen dogs treated with MP-TSCPC at two institutions for glaucoma management. PROCEDURES: MP-TSCPC was applied to each eye (avoiding 3 and 9 o'clock positions) with 31.3% duty cycle, 2000-3000 mW energy, and 90-180 seconds duration per hemisphere. Central corneal tactile sensation (CTS) and Schirmer tear test-1 (STT-1) were measured at baseline and ≥2 post-operative visits in each dog. RESULTS: Corneal sensitivity decreased in 16/18 dogs (89%) by an average of 10%-42% (up to 100% in 4 dogs). CTS decline was rapid (≤1 week) and only fully recovered in 50% of dogs within 8-180 days. Patients' age, glaucoma duration, laser energy, and total energy delivered did not affect CTS at any visit. However, brachycephalic dogs had significantly lower CTS and likelihood to recover full sensation compared with nonbrachycephalic dogs. Aqueous tear deficiency (STT-1 < 15 mm/min) occurred in 8/18 dogs (44%) within 7-270 days, and concurrent signs of keratoconjunctivitis sicca were noted in 2/18 dogs (11%). Neurotrophic corneal ulcers developed in 6/18 dogs (33.3%) and required 16-53 days to heal. CONCLUSIONS: Corneal hypoesthesia is a common complication of MP-TSCPC in dogs, and can lead to serious adverse effects such as aqueous tear deficiency and neurotrophic corneal ulcers. Brachycephalic dogs represent a population at higher risk. Close monitoring of ocular surface health is recommended for months following MP-TSCPC in dogs.
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Enfermedades de la Córnea/veterinaria , Enfermedades de los Perros/cirugía , Glaucoma/veterinaria , Hipoestesia/veterinaria , Coagulación con Láser/veterinaria , Complicaciones Posoperatorias/veterinaria , Animales , Enfermedades de la Córnea/etiología , Perros , Glaucoma/cirugía , Hipoestesia/etiología , Coagulación con Láser/efectos adversos , Lágrimas/fisiologíaRESUMEN
OBJECTIVE: To compare complication rates and visual outcomes following phacoemulsification in Pugs versus dogs of other breeds. ANIMALS STUDIED: Thirty-two pure-bred Pugs (55 eyes) and 32 dogs of other breeds (56 eyes) undergoing phacoemulsification. PROCEDURES: Multi-institutional retrospective medical record review of perioperative factors, postoperative complications, and visual outcomes. The reference population of dogs of varying breeds included surgical cases following each Pug case at the same institutions. Perioperative risk factors and postoperative complication rates were compared between the two populations. RESULTS: Pigmentary keratitis and diabetes mellitus were the most common preoperative comorbidities, found in 75% (P < .001) and 72% (P = .12) of Pugs, respectively. No perioperative factors were significantly associated with postoperative complications in Pugs. Postoperative complication rates were similar between groups; however, the most common complication in Pugs was corneal ulceration (15% of operated eyes), whereas glaucoma was most common in the reference population (13% of operated eyes). Three months postoperatively, vision was preserved in 91% of eyes of Pugs (50/55) and 95% of the reference population (53/56). One year postoperatively, 80% (32/40) of Pug eyes and 82% (28/34) of eyes in the reference population remained sighted. CONCLUSIONS: Comorbidities and complications of cataract surgery in Pugs of this study demonstrate a predisposition for corneal disease. This highlights the importance of preoperative evaluation of factors associated with PK and corneal clarity, and postoperative monitoring for corneal ulceration in this breed.
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Enfermedades de los Perros/cirugía , Glaucoma/veterinaria , Facoemulsificación/veterinaria , Animales , Perros , Femenino , Glaucoma/epidemiología , Masculino , New York/epidemiología , Linaje , Facoemulsificación/efectos adversos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/veterinaria , Registros/veterinaria , Estudios Retrospectivos , Factores de RiesgoRESUMEN
OBJECTIVE: The purpose of this study was to report the preliminary results of a novel micropulse transscleral diode laser cyclophotocoagulation (MP-TSCP) as primary therapy for glaucomatous dogs. ANIMAL STUDIED: Client owned dogs undergoing MP-TSCP therapy at a veterinary referral center. PROCEDURE: Retrospective study of dogs with glaucoma that were treated with MP-TSCP with a minimum of 1 month (range: 1-18 months) of follow-up. Reported outcomes were intraocular pressure (IOP), treatment parameters, reduction in medications, complications, and incidence of repeat therapy. RESULTS: Thirty dogs (35 eyes) were evaluated. The mean age was 9.0 years. Mean preoperative IOP was 34.5 mm Hg. Mean postoperative IOP at 1 month (35/35 eyes) was 22 mm Hg, 2 months (26/35 eyes) was 20.5 mm Hg, 4 months (20/35 eyes) was 19 mm Hg, 6 months (10/35 eyes) was 19 mm Hg, 12 months (8/35 eyes) was 21 mm Hg. First treatment success rate was 19/35 eyes (54.3%). Repeat laser was performed in 11 eyes with 4/11 eyes responding favorably for a total IOP control of 23/35 eyes (65.7%). Mean energy levels employed were 137.5 seconds and 2351 mW at 31.3% duty cycle. Reduction in medications was from a mean of 3.6 medications preoperatively to 3.1 medications postoperatively. Complications included corneal ulcers 5/35 eyes (14.3%), uncontrolled IOP in 12/35 eyes (34.3%) and repeat treatment in 11/35 eyes (31.4%). CONCLUSIONS: MP-TSCP was successful in controlling IOP in most patients as well as to reduce postoperative medications with minimal resultant intraocular inflammation and complications. The micropulse procedure also can be repeated. Future investigations to study effective treatment parameters are warranted in a larger series of patients over a longer period of evaluation.
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Enfermedades de los Perros/cirugía , Glaucoma/veterinaria , Coagulación con Láser/veterinaria , Animales , Perros , Femenino , Estudios de Seguimiento , Glaucoma/cirugía , Presión Intraocular , Coagulación con Láser/métodos , Láseres de Semiconductores , Masculino , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Canine glaucoma is a group of disorders that are generally associated with increased intraocular pressure (IOP) resulting in a characteristic optic neuropathy. Glaucoma is a leading cause of irreversible vision loss in dogs and may be either primary or secondary. Despite the growing spectrum of medical and surgical therapies, there is no cure, and many affected dogs go blind. Often eyes are enucleated because of painfully high, uncontrollable IOP. While progressive vision loss due to primary glaucoma is considered preventable in some humans, this is mostly not true for dogs. There is an urgent need for more effective, affordable treatment options. Because newly developed glaucoma medications are emerging at a very slow rate and may not be effective in dogs, work toward improving surgical options may be the most rewarding approach in the near term. This Viewpoint Article summarizes the discussions and recommended research strategies of both a Think Tank and a Consortium focused on the development of more effective therapies for canine glaucoma; both were organized and funded by the American College of Veterinary Ophthalmologists Vision for Animals Foundation (ACVO-VAF). The recommendations consist of (a) better understanding of disease mechanisms, (b) early glaucoma diagnosis and disease staging, (c) optimization of IOP-lowering medical treatment, (d) new surgical therapies to control IOP, and (e) novel treatment strategies, such as gene and stem cell therapies, neuroprotection, and neuroregeneration. In order to address these needs, increases in research funding specifically focused on canine glaucoma are necessary.
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Enfermedades de los Perros/terapia , Glaucoma/veterinaria , Animales , Enfermedades de los Perros/diagnóstico , Perros , Glaucoma/diagnóstico , Glaucoma/terapia , Presión IntraocularRESUMEN
An 18-month-old intact female lioness (Panthera leo) was referred to the Clinica Veterinaria Roma Sud for evaluation of bilateral cataracts. Phacoemulsification and implantation of +30 diopter intraocular lens (IOL) were performed bilaterally. Seven years after surgery, the IOL remained centrally positioned and the patient had normal activity.
Phaco-émulsification bilatérale et implantation d'une lentille intra-oculaire chez une jeune lionne africaine (Panthera leo) . Une lionne entière âgée de 18 mois (Panthera leo) a été dirigée à la Clinica Veterinaria Roma Sud pour l'évaluation de cataractes bilatérales. La phaco-émulsification et l'implantation de lentilles intraoculaires dioptriques +30 (LID) ont été réalisées bilatéralement. Sept années après la chirurgie, les LID sont demeurées en position centrale et la patiente s'adonnait à des activités normales.(Traduit par Isabelle Vallières).
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Catarata/veterinaria , Implantación de Lentes Intraoculares/veterinaria , Lentes Intraoculares/veterinaria , Leones/cirugía , Animales , Catarata/diagnóstico , Catarata/terapia , Electrorretinografía/veterinaria , Femenino , Facoemulsificación/veterinariaRESUMEN
OBJECTIVE: To evaluate effectiveness and safety of debulking and diode laser photocoagulation (DPC) for the treatment of limbal melanoma (LM). PROCEDURE: Retrospective multi-institutional case series. Medical records of animals diagnosed with LM at the Centro Veterinario Specialistico (CVS) and at the Long Island Veterinary Specialists from 1994 to 2014 were retrieved. Signalment, location, extent of tumors, recurrence rate, and early and late complications were reported. Patient follow-up information was obtained from veterinary ophthalmologists, primary care veterinarians, and where appropriate, owners. RESULTS: Twenty-one eyes of 21 dogs (13 females and 8 males) were included in this study. The dogs' average age was 6 years (range: 7 months-11 years). The follow-up period ranged from 1-108 months (median 48 months) after the last DPC procedure. Long-term follow-up was obtained by telephone interviews in 6 of 20 cases and by clinical re-evaluations in 14 of 20 cases. The most common early complications were a moderate anterior uveitis and peripheral corneal edema (21/21 eyes). Late complications included corneal fibrosis and/or pigmentation (20/21). In one case, a severe bullous keratopathy associated with extensive corneal fibrosis was observed (1/21). One case was blind due to concurrent Sudden Acquired Retinal Degeneration (SARD). However, after surgery 2 of 20 eyes lost vision and one of these was enucleated. CONCLUSIONS: Debulking, in addition to diode laser photocoagulation, was technically straightforward to perform, minimally invasive, well tolerated, and highly successful in this case series.
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Cirugía Laser de Córnea/veterinaria , Procedimientos Quirúrgicos de Citorreducción/veterinaria , Enfermedades de los Perros/cirugía , Neoplasias del Ojo/veterinaria , Coagulación con Láser/veterinaria , Limbo de la Córnea/cirugía , Melanoma/veterinaria , Animales , Coagulación con Plasma de Argón , Terapia Combinada , Perros , Neoplasias del Ojo/cirugía , Femenino , Láseres de Semiconductores , Masculino , Melanoma/cirugía , Estudios RetrospectivosRESUMEN
PURPOSE: The purpose of this study was to describe breed, age, gender, and weight distribution of dogs affected with sudden acquired retinal degeneration (SARD) and to investigate whether SARD is more common in small breed dogs. METHODS: Medical records of dogs diagnosed with SARD confirmed by an electroretinogram were reviewed. Breed, age, gender, and weight were recorded when available. The same data were obtained for dogs with SARD described in the veterinary literature. RESULTS: Three hundred and two dogs were included from the ophthalmology practices and 193 dogs from the veterinary literature. Sixty breeds were present in the study. Mixed-breed dogs were the most common at 108 dogs (21.8%), followed by the Dachshund (68, 13.7%), Chinese Pug (44, 8.9%), Miniature Schnauzer (39, 7.9%), Maltese (23, 4.6%), Cocker Spaniel (22, 4.4%), Bichon Frise (18, 3.6%), Beagle (16, 3.2%), Brittany (15, 3.0%), and Pomeranian (10, 2.0%). Fifty other breeds were represented by 1-9 dogs each. The median age was 9 years (range = 10 months-16 years). The weight was known for 197 dogs. About 60.9% of dogs were less than 25 pounds, 31.5% were between 25 and 50 pounds, and 7.6% were greater than 50 pounds. Gender was recorded in 393 dogs: 217 female dogs and 176 male dogs. CONCLUSIONS: As previously reported, SARD is most common in middle-aged to older dogs. Smaller dogs of less than 25 pounds appear overrepresented, while large/giant breed dogs of greater than 50 pounds are infrequently diagnosed. In this study, there was no statistical significance between female and male dogs.
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Enfermedades de los Perros/diagnóstico , Degeneración Retiniana/veterinaria , Animales , Enfermedades de los Perros/genética , Perros , Electrorretinografía/veterinaria , Femenino , Predisposición Genética a la Enfermedad , Masculino , Degeneración Retiniana/diagnóstico , Degeneración Retiniana/genética , Estudios Retrospectivos , Especificidad de la EspecieRESUMEN
A review of avian cataracts at the Wildlife Conservation Society's Bronx Zoo between 1992 and 2011 was conducted. Ninety cataracts in 54 birds from 42 species were identified. Cataracts were found primarily during examination for ocular abnormalities (29/54, 53.7%) or opportunistically (13/54, 24.1%) and were most commonly diagnosed as mature (22/90, 24.4%). Systemic medical conditions diagnosed in these birds included West Nile virus (4/54, 7.4%), head trauma (3/54, 5.6%), plumbism and Salmonella Pullorum (1/54, 1.9%), Marek's disease (1/54, 1.9%), leukocytosis (1/54, 1.9%), and hyperglycemia (1/54, 1.9%). Cataracts were progressive in seven birds of four species. Unilateral enucleation was performed in 2/54 (3.7%) birds, and 12/54 (22.2%) underwent cataract removal (phacoemulsification in 16 eyes and standard extracapsular cataract extraction in 2 eyes). Concurrent ocular abnormalities, such as corneal scarring and lens-induced uveitis, were seen in 2/18 (11.1%) eyes preoperatively in the group undergoing cataract removal, 2/2 (100%) eyes preoperatively in the group undergoing enucleation, and 33/70 (47.1%) of eyes that did not undergo surgery. For birds undergoing cataract removal, complications included successfully treated cardiorespiratory arrest intraoperatively (1/12, 8.3%) as well as postanesthetic complications of acute respiratory distress and tracheal stricture (2/12, 16.7%). The most common postoperative ocular abnormalities included posterior capsular opacity (4/18 eyes, 22.2%) and corneal scarring (2/18 eyes, 11.1%). Lens cortical regrowth and marked posterior lens capsular opacity occurred in one eye of one bird after phacoemulsification, necessitating a second ocular surgery. A successful outcome, as determined by improved postoperative visual acuity, was seen in 10/12 (83.3%) birds undergoing cataract removal, and 5/12 (41.7%) of these birds were alive >3 yr after surgery. The results of this review will aid clinicians in identifying common stages of cataracts, determining eligibility for cataract surgery, and managing postoperative complications in avian patients.
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Animales de Zoológico , Enfermedades de las Aves/terapia , Extracción de Catarata/veterinaria , Catarata/veterinaria , Animales , Aves , Catarata/diagnóstico , Catarata/patología , Extracción de Catarata/métodos , Estudios Retrospectivos , Especificidad de la EspecieRESUMEN
OBJECTIVE: To evaluate a rapid and efficacious procedure to anchor the prolapsed gland of the third eyelid in dogs. METHODS: This is a retrospective study of 100 affected dogs (122 eyes) with third eyelid gland prolapse that were surgically anchored with a nonabsorbable suture around the insertion of the ventral rectus muscle. RESULTS: Hundred dogs (122 eyes) were included in this study. Twenty-three pure-bred and several mixed-breed dogs were represented with the right eye affected in 60 cases and the left eye in 62 cases. Thirty-four eyes (27.9%) were previously operated on at another facility prior to referral. The average age of the patients was 2.2 years (57 days to 11 years). No recurrences of gland prolapse were observed over the course of study. Minor intraoperative conjunctival perforations were observed and easily repaired at the time of the surgery in 21 cases (17.2%). Five cases demonstrated preexistent keratoconjunctivitis sicca (KCS), and all had improved Schirmer tear test following surgical correction and medical therapy. CONCLUSIONS: The suture anchor placement technique provides a cosmetic, rapid, and successful replacement of the prolapsed gland of the third eyelid in dogs. No recurrences were noted. Complications were easily addressed.
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Enfermedades de los Perros/cirugía , Glándulas Exocrinas/cirugía , Enfermedades de los Párpados/veterinaria , Membrana Nictitante/cirugía , Técnicas de Sutura/veterinaria , Animales , Perros , Enfermedades de los Párpados/cirugía , Femenino , Masculino , Prolapso , Estudios RetrospectivosRESUMEN
We report here the discovery of a novel series of selective mTOR kinase inhibitors and the identification of CC214-2, a compound with demonstrated anti-tumor activity upon oral dosing in a PC3 prostate cancer xenograft model. A series of 4,6-disubstituted-3,4-dihydropyrazino[2,3-b]pyrazine-2(1H)-ones were discovered through a core modification of our original compound series. Analogs from this series have excellent mTOR potency and maintain selectivity over the related PI3Kα lipid kinase. Compounds such as CC214-2 were found to block both mTORC1(pS6) and mTORC2(pAktS473) signaling in PC3 cancer cells, in vitro and in vivo.
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Antineoplásicos/química , Inhibidores de Proteínas Quinasas/química , Pirazinas/química , Serina-Treonina Quinasas TOR/antagonistas & inhibidores , Administración Oral , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Semivida , Humanos , Masculino , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Inhibidores de las Quinasa Fosfoinosítidos-3 , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Inhibidores de Proteínas Quinasas/farmacocinética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pirazinas/farmacocinética , Pirazinas/uso terapéutico , Pirazinas/toxicidad , Transducción de Señal/efectos de los fármacos , Serina-Treonina Quinasas TOR/metabolismo , Trasplante HeterólogoRESUMEN
In this Letter we describe the discovery of potent, selective, and orally active aminopurine JNK inhibitors. Improving the physico-chemical properties as well as increasing the potency and selectivity of a subseries with rat plasma exposure, led to the identification of four structurally diverse inhibitors. Differentiation based on PK profiles in multiple species as well as activity in a chronic efficacy model led to the identification of 1 (CC-930) as a development candidate, which is currently in Phase II clinical trial for IPF.
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Ciclohexanoles/química , Ciclohexanoles/farmacología , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , MAP Quinasa Quinasa 4/antagonistas & inhibidores , Purinas/química , Purinas/farmacología , Administración Oral , Animales , Dominio Catalítico , Ciclohexanoles/administración & dosificación , Perros , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/administración & dosificación , Haplorrinos , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Concentración 50 Inhibidora , Modelos Moleculares , Estructura Molecular , Purinas/administración & dosificación , Ratas , Relación Estructura-ActividadRESUMEN
OBJECTIVE: To determine the outcome and effect of a partial ligation of the transposed parotid duct at the level of the parotid gland in four dogs with excessive salivation and ocular irritation. METHODS: Four dogs were previously diagnosed with absolute keratoconjunctivitis sicca. After a parotid duct transposition (PDT) surgery, these dogs experienced excessive saliva production and abundant salivary precipitates, which resulted in epiphora, moist dermatitis, blepharospasm, and keratitis. In an effort to decrease saliva production, a partial ligation of the transposed duct at the level of the parotid gland was performed. Two or three accessory branches to the primary parotid duct were ligated at the level of the salivary gland. RESULTS: The four cases were three Yorkshire terriers and a Chihuahua. The average age of the four patients was 2.5 years. Partial ligation of accessory branches of the parotid duct at the level of the parotid gland after a PDT in this study demonstrated improved ocular comfort, decreased salivary precipitates, and adequate Schirmer tear test results without marked epiphora in three of the four animals. The male Yorkshire had epiphora after the initial partial ligations of two accessory branches were placed at the level of the parotid gland. To correct the excessive salivary flow, two additional ligatures were placed at a later date, which resolved the epiphora. CONCLUSION: Partial ligation of the parotid duct at the level of the parotid gland proved to be an effective technique in moderating the salivation in these four patients with excessive salivary secretions after PDT.
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Enfermedades de los Perros/cirugía , Queratoconjuntivitis Seca/veterinaria , Aparato Lagrimal/cirugía , Glándula Parótida/cirugía , Saliva/metabolismo , Animales , Perros , Femenino , Queratoconjuntivitis Seca/cirugía , Masculino , Procedimientos Quirúrgicos Oftalmológicos , Lágrimas/fisiologíaRESUMEN
To retrospectively evaluate the effectiveness and outcome of lamellar keratoplasty using acellular bioengineering cornea (BioCorneaVetTM) for the treatment of feline corneal sequestrum (FCS). The medical records of cats diagnosed with FCS that underwent lamellar keratoplasty with BioCorneaVetTM between 2018 and 2021 with a minimum of 3 months of follow-up were reviewed. Follow-up examinations were performed weekly for 3 months, and then optical coherence tomography (OCT) examination was performed on select patients at 0, 3, 6, and 12 months post-operatively. A total of 61 cats (30 left eyes and 32 right eyes) were included. The Persian breed was overrepresented, 48/61 (78.69%). Four different thicknesses of acellular bioengineering cornea were used (200, 300, 400, or 450 microns), and the mean graft size was 8.23 mm (range, 5.00-12.00 mm). Minor complications were composed of partial dehiscence, and protrusion of the graft occurred in 7/62 eyes (11.29%). The median postoperative follow-up was 12.00 months (range, 3-41 months). A good visual outcome was achieved in 60/62 eyes (96.77%), and a mild to moderate corneal opacification occurred in 2/62 (3.23%). No recurrence of corneal sequestrum was observed. From the results, lamellar keratoplasty using acellular bioengineering cornea (BioCorneaVetTM) is an effective treatment for FCS, providing a good tectonic support and natural collagen framework, and resulting in satisfactory visual and cosmetic effects.
RESUMEN
Acute myeloid leukemia (AML) is marked by significant unmet clinical need due to both poor survival and high relapse rates where long-term disease control for most patients with relapsed or refractory AML remain dismal. Inspired to bring novel therapeutic options to these patients, we envisioned protein degradation as a potential therapeutic approach for the treatment of AML. Following this course, we discovered and pioneered a novel mechanism of action which culminated in the discovery of CC-90009. CC-90009 represents a novel protein degrader and the first cereblon E3 ligase modulating drug to enter clinical development that specifically targets GSPT1 (G1 to S phase transition 1) for proteasomal degradation. This manuscript briefly summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and efficacy data for CC-90009, which is currently in phase 1 clinical development.
Asunto(s)
Acetamidas/uso terapéutico , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Antineoplásicos/uso terapéutico , Isoindoles/uso terapéutico , Leucemia Mieloide Aguda/tratamiento farmacológico , Factores de Terminación de Péptidos/antagonistas & inhibidores , Piperidonas/uso terapéutico , Ubiquitina-Proteína Ligasas/metabolismo , Acetamidas/química , Acetamidas/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Humanos , Isoindoles/química , Isoindoles/farmacología , Macaca fascicularis , Masculino , Ratones , Estructura Molecular , Factores de Terminación de Péptidos/química , Factores de Terminación de Péptidos/metabolismo , Piperidonas/química , Piperidonas/farmacología , Proteolisis/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
The PKC-θ isoform of protein kinase C is selectively expressed in T lymphocytes and plays an important role in the T cell antigen receptor (TCR)-triggered activation of mature T cells, T cell proliferation, and the subsequent release of cytokines such as interleukin-2 (IL-2). Herein, we report the synthesis and structure-activity relationship (SAR) of a novel series of PKC-θ inhibitors. Through a combination of structure-guided design and exploratory SAR, suitable replacements for the basic C4 amine of the original lead (3) were identified. Property-guided design enabled the identification of appropriately substituted C2 groups to afford potent analogs with metabolic stability and permeability to support in vivo testing. With exquisite general kinase selectivity, cellular inhibition of T cell activation as assessed by IL-2 expression, a favorable safety profile, and demonstrated in vivo efficacy in models of acute and chronic T cell activation with oral dosing, CC-90005 (57) was selected for clinical development.
Asunto(s)
Ciclohexanoles/uso terapéutico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Proteína Quinasa C-theta/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Animales , Células CACO-2 , Proliferación Celular/efectos de los fármacos , Ciclohexanoles/síntesis química , Ciclohexanoles/metabolismo , Humanos , Factores Inmunológicos/síntesis química , Factores Inmunológicos/metabolismo , Activación de Linfocitos/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Estructura Molecular , Unión Proteica , Proteína Quinasa C-delta/antagonistas & inhibidores , Proteína Quinasa C-delta/metabolismo , Proteína Quinasa C-theta/metabolismo , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/metabolismo , Pirimidinas/síntesis química , Pirimidinas/metabolismo , Relación Estructura-Actividad , Linfocitos T/efectos de los fármacosRESUMEN
OBJECTIVE: To describe feline periocular cutaneous mast cell tumor (CMCT) clinical features, rates of local tumor recurrence and metastases, and cat survival time following surgical excision. ANIMALS STUDIED: Thirty-three cats with periocular CMCTs. PROCEDURES: Medical records of cats diagnosed with periocular CMCTs were reviewed; cats were included if CMCTs were surgically excised and the diagnosis confirmed by histopathology. The appearance, size, location and histopathology findings of CMCTs were recorded. Rates of local recurrence, metastasis, and survival time following surgical excision were collected when available. RESULTS: All periocular CMCTs were restricted to the eyelids. In addition to surgical excision, three cats were treated with adjunctive therapy (strontium-90 irradiation or cryotherapy) intraoperatively. Local tumor control was achieved in 22/23 cats with a minimum follow-up of 30 days (median follow-up time of 711 days); one cat developed disseminated CMCTs but no local recurrence. Cats with periocular CMCTs had a median survival time of 945 days. Metastatic disease involving peripheral lymph nodes or abdominal viscera was not detected in any cat at any time during the study. All periocular CMCTs were classified as low-grade based on histopathology, and complete excision was achieved in approximately 50% of cases. CONCLUSIONS: Surgical excision of periocular CMCTs in cats is an effective treatment option with rare local recurrence and metastases, even following incomplete surgical excision.