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1.
PLoS One ; 8(8): e73128, 2013.
Article in English | MEDLINE | ID: mdl-24015292

ABSTRACT

BACKGROUND: Late infantile neuronal ceroid lipofuscinosis (LINCL), one form of Batten's disease is a progressive neurodegenerative disorder resulting from a CLN2 gene mutation. The spectrum of ophthalmic manifestations of LINCL and the relationship with neurological function has not been previously described. METHODS: Patients underwent ophthalmic evaluations, including anterior segment and dilated exams, optical coherence tomography, fluorescein and indocyanine green angiography. Patients were also assessed with the LINCL Neurological Severity Scale. Ophthalmic findings were categorized into one of five severity scores, and the association of the extent of ocular disease with neurological function was assessed. RESULTS: Fifty eyes of 25 patients were included. The mean age at the time of exam was 4.9 years (range 2.5 to 8.1). The mean ophthalmic severity score was 2.6 (range 1 to 5). The mean neurological severity score was 6.1 (range 2 to 11). Significantly more severe ophthalmic manifestations were observed among older patients (p<0.005) and patients with more severe neurological findings (p<0.03). A direct correlation was found between the Ophthalmic Severity Scale and the Weill Cornell Neurological Scale (p<0.002). A direct association was also found between age and the ophthalmic manifestations (p<0.0002), with older children having more severe ophthalmic manifestations. CONCLUSIONS: Ophthalmic manifestations of LINCL correlate closely with the degree of neurological function and the age of the patient. The newly established LINCL Ophthalmic Scale may serve as an objective marker of LINCL severity and disease progression, and may be valuable in the evaluation of novel therapeutic strategies for LINCL, including gene therapy.


Subject(s)
Eye Diseases/etiology , Eye Diseases/pathology , Eye Diseases/physiopathology , Neuronal Ceroid-Lipofuscinoses/complications , Neuronal Ceroid-Lipofuscinoses/pathology , Neuronal Ceroid-Lipofuscinoses/physiopathology , Adolescent , Adult , Age Factors , Aged , Aged, 80 and over , Aminopeptidases/genetics , Dipeptidyl-Peptidases and Tripeptidyl-Peptidases/genetics , Eye Diseases/genetics , Female , Humans , Male , Middle Aged , Mutation , Neuronal Ceroid-Lipofuscinoses/genetics , Serine Proteases/genetics , Severity of Illness Index , Tripeptidyl-Peptidase 1
3.
J Pediatr Ophthalmol Strabismus ; 50(5): 282-8, 2013.
Article in English | MEDLINE | ID: mdl-23739460

ABSTRACT

PURPOSE: To describe the utility of using ultra-widefield digital fundus photography and ultra-widefield fluorescein angiography (UWFA) in the pediatric patient population to evaluate peripheral retinal pathology and to manage Coats' disease and familial exudative vitreoretinopathy (FEVR). METHODS: Retrospective review of pediatric retinal patients with FEVR or Coats' disease who underwent ultra-widefield fundus photography and UWFA. RESULTS: Eight patients were included in this case series. Five patients had the clinical diagnosis of FEVR, and two eyes of two patients with FEVR received UWFA-guided laser photocoagulation. Three patients were diagnosed as having Coats' disease and received UWFA-guided laser photocoagulation. CONCLUSIONS: Ultra-widefield fundus photography and UWFA can be used successfully as an outpatient procedure in the pediatric patient population without the necessity of examination under anesthesia and can aid the physician in the documentation and evaluation of peripheral retinal pathology. UWFA can also assist in directing laser photocoagulation in the treatment of pediatric retinal diseases.


Subject(s)
Fluorescein Angiography , Laser Coagulation , Osteoporosis/diagnosis , Retinal Telangiectasis/diagnosis , Vitreoretinopathy, Proliferative/diagnosis , Adolescent , Child , Diagnostic Imaging , Familial Exudative Vitreoretinopathies , Humans , Male , Osteoporosis/physiopathology , Osteoporosis/surgery , Photography , Retinal Telangiectasis/physiopathology , Retinal Telangiectasis/surgery , Retrospective Studies , Tomography, Optical Coherence , Visual Acuity/physiology , Vitreoretinopathy, Proliferative/physiopathology , Vitreoretinopathy, Proliferative/surgery
4.
Bioorg Med Chem Lett ; 23(10): 3059-63, 2013 May 15.
Article in English | MEDLINE | ID: mdl-23566514

ABSTRACT

The synthesis and biological evaluation of novel Tie-2 kinase inhibitors are presented. Based on the pyrrolopyrimidine chemotype, several new series are described, including the benzimidazole series by linking a benzimidazole to the C5-position of the 4-amino-pyrrolopyrimidine core and the ketophenyl series synthesized by incorporating a ketophenyl group to the C5-position. Medicinal chemistry efforts led to potent Tie-2 inhibitors. Compound 15, a ketophenyl pyrrolopyrimidine urea analog with improved physicochemical properties, demonstrated favorable in vitro attributes as well as dose responsive and robust oral tumor growth inhibition in animal models.


Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Drug Discovery , Neoplasms/drug therapy , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Pyrroles/pharmacology , Receptor, TIE-2/antagonists & inhibitors , Animals , Antineoplastic Agents/administration & dosage , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Humans , Male , Molecular Structure , Neoplasms/enzymology , Neoplasms/pathology , Protein Kinase Inhibitors/administration & dosage , Pyrimidines/chemical synthesis , Pyrimidines/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry , Rats , Rats, Sprague-Dawley , Receptor, TIE-2/metabolism , Structure-Activity Relationship , Xenograft Model Antitumor Assays
5.
Br J Ophthalmol ; 96(5): 694-8, 2012 May.
Article in English | MEDLINE | ID: mdl-22423055

ABSTRACT

PURPOSE: To determine the relationship between retinal ischaemia and the presence of macular oedema (DMO) in patients with diabetic retinopathy (DR) using ultra-widefield fluorescein angiography (UWFA) imaging. METHODS: A retrospective review of 122 eyes of 70 treatment-naïve diabetic patients who underwent diagnostic UWFA using the Optos 200Tx imaging system. Two independent, masked graders quantified the area of retinal ischaemia. Based on clinical examination and optical coherence tomography (OCT), each patient was given a binary classification as either having DMO or no DMO. McNemar's test (with Yates' correction as indicated) and a two-sample test of proportions were used to determine the relationship between DMO and ischaemia for binary and proportional data, respectively. Linear and logistic models were constructed using generalised estimating equations to test relationships between independent variables, covariates and outcomes while controlling for inter-eye correlation, age, gender, haemoglobin A1c, mean arterial pressure and dependence on insulin. RESULTS: Seventy-six eyes (62%) exhibited areas of retinal ischaemia. There was a significant direct correlation between DMO and peripheral retinal ischaemia as seen on UWFA (p<0.001). In addition, patients with retinal ischaemia had 3.75 times increased odds of having DMO compared with those without retinal ischaemia (CI 1.26 to 11.13, p<0.02). CONCLUSION: Retinal ischaemia is significantly correlated with DMO in treatment-naïve patients with DR. UWFA is a useful tool for detecting peripheral retinal ischaemia, which may have direct implications in the diagnosis, follow-up and treatment such as targeted peripheral photocoagulation.


Subject(s)
Diabetic Retinopathy/physiopathology , Fluorescein Angiography , Ischemia/physiopathology , Macular Edema/physiopathology , Retinal Vessels/physiopathology , Adolescent , Adult , Aged , Aged, 80 and over , Diabetic Retinopathy/diagnosis , Female , Humans , Ischemia/diagnosis , Macular Edema/diagnosis , Male , Middle Aged , Retrospective Studies , Tomography, Optical Coherence , Young Adult
6.
Retina ; 32(4): 785-91, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22080911

ABSTRACT

PURPOSE: To evaluate patients with diabetic retinopathy using ultra-wide-field fluorescein angiography and to compare the visualized retinal pathology with that seen on an overly of conventional 7 standard field (7SF) imaging. METHODS: Two hundred and eighteen eyes of 118 diabetic patients who underwent diagnostic fluorescein angiography using the Optos Optomap Panoramic 200A imaging system were included. The visualized area of the retina, retinal nonperfusion, retinal neovascularization, and panretinal photocoagulation were quantified by two independent masked graders. The respective areas identified on the ultra-wide-field fluorescein angiography image were compared with an overly of a modified 7SF image as outlined in the Early Treatment Diabetic Retinopathy Study. RESULTS: Ultra-wide-field fluorescein angiograms imaging, on average, demonstrated 3.2 times more total retinal surface area than 7SF. When compared with 7SF, ultra-wide-field fluorescein angiography showed 3.9 times more nonperfusion (P < 0.001), 1.9 times more neovascularization (P = 0.036), and 3.8 times more panretinal photocoagulation (P < 0.001). In 22 eyes (10%), ultra-wide-field fluorescein angiography demonstrated retinal pathology (including nonperfusion and neovascularization) not evident in an 7SF overly. CONCLUSION: Compared with conventional 7SF imaging, ultra-wide-field fluorescein angiography reveals significantly more retinal vascular pathology in patients with diabetic retinopathy. Improved retinal visualization may alter the classification of diabetic retinopathy and may therefore influence follow-up and treatment of these patients.


Subject(s)
Diabetic Retinopathy/diagnosis , Fluorescein Angiography/methods , Ophthalmoscopy/methods , Aged , Diabetic Retinopathy/classification , Female , Humans , Male , Middle Aged , Retrospective Studies
7.
Bioorg Med Chem Lett ; 21(5): 1429-33, 2011 Mar 01.
Article in English | MEDLINE | ID: mdl-21295469

ABSTRACT

The synthesis and structure-activity relationships for a novel series of 6-amino-4-(pyrimidin-4-yl)pyridones derived from a high throughput screening hit are discussed. Optimization of lead matter afforded compounds with good potency, selectivity and central nervous system (CNS) exposure.


Subject(s)
Glycogen Synthase Kinases/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Pyridones/chemical synthesis , Central Nervous System/drug effects , Crystallography, X-Ray , Humans , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/pharmacology , Pyridones/chemistry , Pyridones/pharmacology , Structure-Activity Relationship
8.
Ophthalmic Plast Reconstr Surg ; 27(4): e92-4, 2011.
Article in English | MEDLINE | ID: mdl-20940657

ABSTRACT

A 46-year-old woman presented after blunt facial trauma for evaluation of bilateral orbital floor fractures, which were confirmed by clinical and radiographic examination. In addition, findings of right traumatic mydriasis and left traumatic ptosis were seen. On close investigation, miosis was noted on the side of the traumatic ptosis. Therefore, a workup for Horner syndrome was obtained, including neuro-ophthalmic consultation and magnetic resonance angiography of the neck. The magnetic resonance angiography showed an internal carotid pseudoaneurysm, an uncommon but potentially fatal complication of blunt carotid injury. The authors describe an interesting case where a life-threatening diagnosis was nearly masked by more common, benign pathology.


Subject(s)
Blepharoptosis/pathology , Carotid Artery Injuries/diagnosis , Carotid Artery, Internal/pathology , Facial Injuries/pathology , Horner Syndrome/diagnosis , Mydriasis/pathology , Wounds, Nonpenetrating/pathology , Diagnostic Techniques, Ophthalmological , Eye Injuries/pathology , Female , Humans , Magnetic Resonance Angiography , Middle Aged , Orbital Fractures/pathology , Tomography, X-Ray Computed
9.
Cornea ; 30(4): 481-5, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21045666

ABSTRACT

PURPOSE: To describe a case of Lisch dystrophy; review the clinical, histopathologic, and electron microscopic features of this entity; and discuss a novel treatment approach using photorefractive keratectomy (PRK) and mitomycin C (MMC). METHODS: A 45-year-old man with a feathery, comet-shaped, right-sided, corneal lesion was treated with excimer laser PRK and 20 seconds of MMC. The uninvolved fellow eye underwent traditional PRK without the use of MMC. Epithelial scrapings were sent for histopathologic analysis. RESULTS: Histopathologic analysis showed vacuolated cells in the epithelial layer. Electron microscopy revealed empty intracytoplasmic vacuoles, electron-dense whorled inclusions, and reduced tonofilaments. Surface ablation and MMC was successful in treating the initial lesion, with only minimal recurrence noted in the affected eye. Surprisingly, a new asymptomatic lesion was noted in the unaffected eye but dissipated over time. CONCLUSIONS: Although the whorled inclusions represent a novel finding, the overall clinical and microscopic analysis was consistent with Lisch dystrophy. Surface ablation with MMC should be considered as a treatment option for this disease.


Subject(s)
Alkylating Agents/therapeutic use , Corneal Dystrophies, Hereditary/drug therapy , Corneal Dystrophies, Hereditary/surgery , Lasers, Excimer/therapeutic use , Mitomycin/therapeutic use , Photorefractive Keratectomy , Combined Modality Therapy , Corneal Dystrophies, Hereditary/pathology , Humans , Male , Microscopy, Confocal , Middle Aged , Visual Acuity
10.
J Med Chem ; 52(6): 1731-43, 2009 Mar 26.
Article in English | MEDLINE | ID: mdl-19239259

ABSTRACT

As exemplified by the lead compound 2, octahydrophenanthrene-2,7-diol analogues exhibit the profile of a pathway-selective or "dissociated" agonist of the glucocorticoid receptor (GR), retaining the potent activity that glucocorticoids have for transrepression (as measured by inhibition of IL-1 induced MMP-13 expression) but showing an attenuated capacity for transactivation (as measured in an MMTV luciferase reporter assay). With the guidance of a homology model of the GR ligand binding domain, structural modifications to 2 were carried out that were successful in replacing the allyl and propynyl side chains with groups likely to be more chemically stable and less likely to produce toxic metabolites. Key to success was the introduction of an additional hydroxyl group onto the tricyclic carbon framework of the series.


Subject(s)
Drug Discovery , Phenanthrenes/pharmacology , Receptors, Glucocorticoid/agonists , Chromatography, High Pressure Liquid , Crystallography, X-Ray , Mass Spectrometry , Models, Molecular , Phenanthrenes/chemistry
11.
Ophthalmic Plast Reconstr Surg ; 23(3): 242-3, 2007.
Article in English | MEDLINE | ID: mdl-17519671

ABSTRACT

A 90-year-old man reported a 1-year history of tearing and irritation in the left eye. Ophthalmic examination was significant for bloody mucopurulent material expressed from the left nasolacrimal duct. The patient underwent external dacryocystorhinostomy with excision of a soft-tissue mass. Initial histopathologic examination of the specimen revealed an atypical lymphoid infiltrate. Subsequent immunohistochemistry suggested that the mass was reactive lymphoid hyperplasia. Lymphoid hyperplasia should be considered in the differential diagnosis of bloody epiphora, in addition to primary malignancy of the nasolacrimal duct, hematologic abnormalities, coagulopathies, vascular tumors, and giant papillary conjunctivitis.


Subject(s)
Eye Hemorrhage/diagnosis , Lacrimal Apparatus Diseases/diagnosis , Nasolacrimal Duct/pathology , Pseudolymphoma/diagnosis , Aged, 80 and over , Dacryocystorhinostomy , Humans , Lacrimal Apparatus Diseases/surgery , Male , Pseudolymphoma/surgery
12.
Bioorg Med Chem Lett ; 16(13): 3444-8, 2006 Jul 01.
Article in English | MEDLINE | ID: mdl-16632359

ABSTRACT

The design, synthesis, and biological evaluation of potent inhibitors of the TrkA kinase is presented. A homology model is created to aid in the enhancement of potency and selectivity of isothiazole inhibitors found during a high-throughput screen. Three different syntheses are utilized to make diverse analogs within this series. Aminoheterocycles are found to be good urea surrogates, whereas bicyclic substituents on the C3 thio group were found to be extremely potent TrkA inhibitors in kinase and cell assays.


Subject(s)
Computer Simulation , Enzyme Inhibitors , Receptor, trkA/antagonists & inhibitors , Thiazoles , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Drug Design , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Models, Molecular , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/chemistry , Thiazoles/pharmacology
14.
Biochem Biophys Res Commun ; 307(2): 267-73, 2003 Jul 25.
Article in English | MEDLINE | ID: mdl-12859950

ABSTRACT

The discovery of small molecule kinase inhibitors for use as drugs is a promising approach for the treatment of cancer and other diseases, but the discovery of highly specific agents is challenging because over 850 kinases are expressed in mammalian cells. Systematic modification of the 4-anilino functionality of a selective quinazoline inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase can invert selectivity to favor inhibition of the highly homologous erbB2 tyrosine kinase. The selectivity pattern was demonstrated in assays of recombinant kinases and recapitulated in measures of kinase activity in intact cells. The most potent and selective erbB2 inhibitor of the analog series has anti-proliferative activity against an erbB2-overexpressing cell line that was lacking in the original EGFR-selective compound. Subtle changes to the molecular structure of ATP-competitive small molecule inhibitors of tyrosine kinases can yield dramatic changes in potency and selectivity. These results suggest that the discovery of highly selective small molecule inhibitors of very homologous kinases is achievable.


Subject(s)
Aniline Compounds/metabolism , Enzyme Inhibitors/metabolism , ErbB Receptors/antagonists & inhibitors , Quinazolines/metabolism , Receptor, ErbB-2/antagonists & inhibitors , Adenosine Triphosphate/metabolism , Aniline Compounds/chemistry , Aniline Compounds/pharmacology , Animals , Binding Sites , Cell Line , Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , ErbB Receptors/genetics , ErbB Receptors/metabolism , Humans , Models, Molecular , Molecular Structure , Phosphorylation , Protein Structure, Tertiary , Quinazolines/chemistry , Quinazolines/pharmacology , Receptor, ErbB-2/genetics , Receptor, ErbB-2/metabolism , Recombinant Fusion Proteins/chemistry , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/metabolism , Substrate Specificity
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