dorzolamide and Disease-Models--Animal

X-linked retinoschisis is the leading cause of macular degeneration in males and leads to splitting within the inner retinal layers leading to visual deterioration. Many missense and protein truncating mutations have now been identified in the causative retinoschisis gene (RS1) which encodes a 224 amino acid secretory retinal protein, retinoschisin. Retinoschisin octamerisation is implicated in cell-cell interactions and cell adhesion perhaps by interacting with beta2 laminin. Mutations cause loss of retinoschisin function by one of the three mechanisms: by interfering with protein secretion, by preventing its octamerisation or by reducing function in the secreted octamerised protein. The development of retinoschisis mouse models have provided a model system that closely resembles the human disease. Recent reports of RS1 gene transfer to these models and the sustained restoration of some retinal function and morphology suggest gene replacement may be a possible future therapy for patients.

Topics: Adult; Age of Onset; Animals; Biopolymers; Cell Adhesion; Child; Child, Preschool; Chromosomes, Human, X; Diagnosis, Differential; Diagnostic Techniques, Ophthalmological; Disease Models, Animal; Disease Progression; Eye Proteins; Female; Genes, X-Linked; Genetic Carrier Screening; Genetic Counseling; Genetic Therapy; Humans; Infant; Macular Degeneration; Male; Mice; Phenotype; Prevalence; Protein Structure, Tertiary; Retinoschisis; Sulfonamides; Thiophenes

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

The combination of a β-adrenergic receptors (AR) blocker and a carbonic anhydrase (CA, EC 4.2.1.1) inhibitor in eye drops formulations is one of the most clinically used treatment for glaucoma. A novel approach consisting of single-molecule, multitargeted compounds for the treatment of glaucoma is proposed here by designing compounds which concomitantly interact with the β-adrenergic and CA targets. Most derivatives of the two series of benzenesulfonamides incorporating 2-hydroxypropylamine moieties reported here exhibited striking efficacy against the target hCA II and XII, whereas a subset of compounds also showed significant modulation of β

Topics: Adrenergic beta-Antagonists; Animals; Carbonic Anhydrase II; Carbonic Anhydrase Inhibitors; Crystallography, X-Ray; Disease Models, Animal; Drug Design; Drug Evaluation, Preclinical; Glaucoma; Humans; Intraocular Pressure; Male; Molecular Targeted Therapy; Rabbits; Receptors, Adrenergic, beta; Structure-Activity Relationship

To test the hypothesis that acute topical dorzolamide (DZ) decreases intraocular pressure (IOP) and increases retinal and choroidal blood flow in the DBA/2J mouse model of glaucoma.. Retinal and choroidal blood flow were measured in 4- and 9-month-old DBA/2J mice, and 4-month C57BL/6 (control) mice under isoflurane anesthesia using magnetic resonance imaging. Ocular blood flow was measured at baseline, and 1 and 2 hours after topical dorzolamide. Intraocular pressure was measured using a rebound tonometer in a subset of animals at the same time points.. Baseline IOP in the 4-month-old DBA/2J mice and C57BL/6 mice was not significantly different (P > 0.05), and IOP in both groups was less than in the 9-month-old DBA/2J mice (P < 0.05 for both). Compared to baseline, dorzolamide reduced IOP at 1 and 2 hours after dorzolamide in the 4- (P < 0.05) and 9-month-old (P < 0.01) DBA/2J mice, but not in the C57BL/6J mice (P > 0.05). Baseline retinal blood flow was lower in the 4-month and 9-month-old DBA/2J mice compared with the 4-month-old C57BL/6J mice (P < 0.05). Baseline choroidal blood flow in the 9-month-old DBA/2J mice was less than in the C57BL/6J mice (P < 0.05). Compared with baseline, both retinal and choroidal blood flow increased at 1-hour post-dorzolamide and remained elevated 2 hours later in the 9-month-old DBA/2J mice (P < 0.05).. Dorzolamide lowers IOP and raises retinal and choroidal blood flow in older DBA/2J mice, consistent with the study hypothesis.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Choroid; Disease Models, Animal; Glaucoma; Intraocular Pressure; Magnetic Resonance Imaging; Male; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Regional Blood Flow; Retina; Sulfonamides; Thiophenes; Treatment Outcome

A new series of dithiocarbamates (DTCs) was prepared from primary/secondary amines incorporating amino/hydroxyl-alkyl, mono- and bicyclic aliphatic ring systems based on the quinuclidine, piperidine, hydroxy-/carboxy-/amino-substituted piperidine, morpholine and piperazine scaffolds, and carbon disulfide. The compounds were investigated for the inhibition of four mammalian α-carbonic anhydrases (CAs, EC 4.2.1.1) of pharmacologic relevance, that is, the human (h) hCA I, II, IX and XII, drug targets for antiglaucoma (hCA II and XII) or antitumor (hCA IX/XII) agents. The compounds were moderate or inefficient hCA I inhibitors (off-target isoform for both applications), efficiently inhibited hCA II, whereas some of them were low nanomolar/subnanomolar hCA IX/XII inhibitors. One DTC showed excellent intraocular pressure (IOP) lowering properties in an animal model of glaucoma, with a two times better efficiency compared to the clinically used sulfonamide dorzolamide.

Topics: Animals; Antihypertensive Agents; Carbon Disulfide; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Disease Models, Animal; Glaucoma; Humans; Intraocular Pressure; Male; Molecular Docking Simulation; Morpholines; Piperazines; Piperidines; Quinuclidines; Rabbits; Structure-Activity Relationship; Substrate Specificity; Sulfonamides; Thiocarbamates; Thiophenes

Two new sulfonamides incorporating arylsulfonylureido moieties were complexed with gamma cyclodextrin (γ-CD), hydroxypropyl-gamma cyclodextrin (HPγ-CD), hydroxypropyl-beta cyclodextrin (HPβ-CD) and hydroxyethyl-beta cyclodextrin (HEβ-CD) in order to obtain drug formulations with effective topical intraocular pressure (IOP) lowering effects, in an animal model of glaucoma. The HPγ-CD was the best solubilizing agent for the two sulfonamides and its complexes were characterized in detail and administered to rabbits with eye hypertension of 45-50 mmHg. The peak IOP lowering was observed after 1h post-administration and was of 36-37 mmHg. A low IOP pressure (of around-35 mmHg) was then maintained for the next 24h post-administration, which has not been observed before with any IOP lowering drug.

Topics: Administration, Topical; Animals; Benzenesulfonamides; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Chemistry, Pharmaceutical; Cyclodextrins; Disease Models, Animal; Glaucoma; Humans; Intraocular Pressure; Male; Rabbits; Solubility; Sulfonamides

Steroid-induced ocular hypertension (SIOH) is associated with topical and systemic use of steroids. However, SIOH-associated anterior and posterior segment morphological changes in rats have not been described widely. Here we describe the pattern of intraocular pressure (IOP) changes, quantitative assessment of trabecular meshwork (TM) and retinal morphological changes and changes in retinal redox status in response to chronic dexamethasone treatment in rats. We also evaluated the responsiveness of steroid-pretreated rat eyes to 5 different classes of antiglaucoma drugs that act by different mechanisms. Up to 80% of dexamethasone treated animals achieved significant and sustained IOP elevation. TM thickness was significantly increased and number of TM cells was significantly reduced in SIOH rats compared to the vehicle-treated rats. Quantitative assessment of retinal morphology showed significantly reduced thickness of ganglion cell layer (GCL) and inner retina (IR) in SIOH rats compared to vehicle-treated rats. Estimation of retinal antioxidants including catalase, superoxide dismutase and glutathione showed significantly increased retinal oxidative stress in SIOH animals. Furthermore, steroid-treated eyes showed significant IOP lowering in response to treatment with 5 different drug classes. This indicated the ability of SIOH eyes to respond to drugs acting by different mechanisms. In conclusion, SIOH was associated with significant morphological changes in TM and retina and retinal redox status. Additionally, SIOH eyes also showed IOP lowering in response to drugs that act by different mechanisms of action. Hence, SIOH rats appear to be an inexpensive and noninvasive model for studying the experimental antiglaucoma drugs for IOP lowering and neuroprotective effects.

Topics: Animals; Antihypertensive Agents; Brimonidine Tartrate; Catalase; Dexamethasone; Disease Models, Animal; Female; Glutathione; Intraocular Pressure; Latanoprost; Male; Ocular Hypertension; Oxidative Stress; Pilocarpine; Prostaglandins F, Synthetic; Quinoxalines; Rats, Sprague-Dawley; Retina; Sulfonamides; Superoxide Dismutase; Thiophenes; Timolol

Socially anxious cannabis users are influenced by cannabis expectancies and normative perceptions. The present study examines the influence of psychosocial factors on cannabis use vulnerability factors as the result of interactions between norms perceptions, social anxiety, and expectancies.. Participants were 149 (36.2% female) current cannabis users aged 18-36 (. Among cannabis users with perceptions of greater injunctive norms, social anxiety was associated with greater cannabis craving when tension reduction expectancies were greater. However, social anxiety was unrelated to cannabis craving when expectances were low. This suggests that cannabis craving among socially anxious adults was greatest when cannabis use was viewed as acceptable and expected to reduce tension, and highlights the importance of considering norms, expectancies, and social anxiety in understanding cannabis-related behaviors.. The A876P-substitution bridges in vitro and in vivo studies using J6/JFH1-based recombinants. We provide the first in vivo evidence that HVR1 protects cross-genotype conserved HCV neutralisation epitopes, which advocates the possibility of using HVR1-deleted viruses as vaccine antigens to boost broadly reactive protective nAb responses.. We conclude that the photo-processing of eVSGs leads to the production of PAHs with attached aliphatic sidegroups that are revealed by the 3.4. De 4,331 publicaciones encontradas, 16 estudios cumplieron con los criterios de inclusión. El 50 % (8/16) de los estudios revisados fueron realizados en países de Sur América, Centro América y del Caribe. El diseño de casos y controles fue el más frecuente. El anterior sistema de clasificación de casos (OMS-1997) fue utilizado en todos los estudios incluidos en esta revisión.. El estrés oxidativo-nitrosativo se encuentra presente en el curso de la infección por virus dengue, demostrado por los cambios en las concentraciones plasmáticas de óxido nítrico, antioxidantes y marcadores de lipoperoxidación y de oxidación de proteínas. Por último, parece existir una asociación entre la elevación de los niveles plasmáticos de los carbonilos proteicos y malondialdehído con la severidad del dengue.

Topics: Acid-Base Imbalance; Acidosis, Renal Tubular; Aged; Air Pollution, Indoor; Amino Acid Substitution; Animals; Animals, Newborn; Anti-Bacterial Agents; Antibodies, Neutralizing; Apoptosis; Blood Vessel Prosthesis; Blood Vessel Prosthesis Implantation; Bone Marrow Transplantation; Carbonic Anhydrase Inhibitors; Castleman Disease; Cat Diseases; Cats; Cell Proliferation; Cell- and Tissue-Based Therapy; Chemical and Drug Induced Liver Injury; Chemotaxis, Leukocyte; Clinical Trials as Topic; Coated Materials, Biocompatible; Diagnosis, Differential; Disease Models, Animal; Environmental Monitoring; Female; Gas Chromatography-Mass Spectrometry; Genotype; Granuloma, Foreign-Body; Heart Failure; Hepacivirus; Hepatitis C; Horse Diseases; Horses; Housing; Humans; Hypercalcemia; Hypokalemia; Immunophenotyping; In Vitro Techniques; Liver; Liver Function Tests; Lymphocytes; Macrophages; Male; Medicine, Chinese Traditional; Metabolomics; Mice; Mice, Inbred C57BL; Middle Aged; Models, Animal; Mutation; Myocardial Ischemia; Neovascularization, Physiologic; Neutrophil Infiltration; Ocular Hypertension; Ophthalmic Solutions; Parathyroid Hormone; Particulate Matter; Polyethylene Terephthalates; Prednisolone; Prospective Studies; Prosthesis Design; Prosthesis-Related Infections; Rats; Rats, Wistar; Reactive Oxygen Species; Rifampin; Saponins; Sepsis; Skin; Stem Cells; Stroke Volume; Sulfonamides; Texas; Thiophenes; Time Factors; Ventricular Dysfunction, Left; Ventricular Function, Left; Viral Hepatitis Vaccines; Viral Nonstructural Proteins; Viral Proteins; Vitamin D; Wound Healing

A series of furazan and furoxan sulfonamides were prepared and studied for their ability to inhibit human carbonic anhydrase (CA, EC 4.2.1.1) isoforms hCA I, hCA II, hCA IX, and hCA XII. The simple methyl substituted products 3-5 were potent inhibitors. Differing structural modifications of these leads had differing effects on potency and selectivity. In particular, products in which the sulfonamide group is separated from the hetero ring by a phenylene bridge retained high potency only on the hCA XII isoform. The sulfonamides 3-5 exerted intraocular pressure (IOP) lowering effects in vivo in hypertensive rabbits more efficiently than dorzolamide. Some other products (39-42), although less effective in vitro hCA II/XII inhibitors, also effectively lowered IOP in two different animal models of glaucoma.

Topics: Acrylic Resins; Animals; Antineoplastic Agents; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Disease Models, Animal; Glaucoma; Humans; Male; Oxadiazoles; Protein Isoforms; Rabbits; Sulfonamides

To evaluate the effects of the activation of endogenous angiotensin-converting enzyme 2 (ACE2) using the compound diminazene aceturate (DIZE) in an experimental model of glaucoma in Wistar rats.. DIZE (1 mg/kg) was administered daily, either systemically or topically, and the IOP was measured weekly. To examine the role of the Mas receptor in the effects of DIZE, the Ang-(1-7) antagonist A-779 was co-administered. Drainage of the aqueous humor was evaluated by using scintigraphy. The analysis of ACE2 expression by immunohistochemistry and the counting of retinal ganglion cells (RGCs) were performed in histologic sections. Additionally, the nerve fiber structure was evaluated by transmission electron microscopy.. The systemic administration and topical administration (in the form of eye drops) of DIZE increased the ACE2 expression in the eyes and significantly decreased the IOP of glaucomatous rats without changing the blood pressure. Importantly, this IOP-lowering action of DIZE was similar to the effects of dorzolamide. The antiglaucomatous effects of DIZE were blocked by A-779. Histologic analysis revealed that the reduction in the number of RGCs and the increase in the expression of caspase-3 in the RGC layer in glaucomatous animals were prevented by DIZE. This compound also prevented alterations in the cytoplasm of axons in glaucomatous rats. In addition to these neuroprotective effects, DIZE facilitated the drainage of the aqueous humor.. Our results evidence the pathophysiologic relevance of the ocular ACE2/Ang-(1-7)/Mas axis of the renin-angiotensin system and, importantly, indicate that the activation of intrinsic ACE2 is a potential therapeutic strategy to treat glaucoma.

Topics: Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Antihypertensive Agents; Aqueous Humor; Blood Pressure; Caspase 3; Cell Count; Diminazene; Disease Models, Animal; Enzyme Activation; Fluorescent Antibody Technique, Indirect; Glaucoma; Immunoenzyme Techniques; Intraocular Pressure; Male; Nerve Fibers; Ophthalmic Solutions; Optic Nerve; Peptide Fragments; Peptidyl-Dipeptidase A; Radionuclide Imaging; Rats; Rats, Wistar; Renin-Angiotensin System; Retina; Retinal Ganglion Cells; Sulfonamides; Thiophenes; Tonometry, Ocular

Examination of the response of the retinal proteome to elevated intraocular pressure (IOP) and to the pharmacological normalization of IOP is crucial, in order to develop drugs with neuroptorective potential. We used a hereditary rat model of ocular hypertension to lower IOP with travaprost and dorzolamide applied topically on the eye surface, and examine changes of the retinal proteome. Our data demonstrate that elevated IOP causes alterations in the retinal protein profile, in particular in high-mobility-group-protein B1 (HMGB1), calmodulin, heat-shock-protein (HSP) 70 and carbonic anhydrase II expression. The changes of the retinal proteome by dorzolamide or travoprost are different and independent of the IOP lowering effect. This fact suggests that the eye drops exert a direct IOP-independent effect on retinal metabolism. Further investigations are required to elucidate the potential neuroprotective mechanisms signaled through changes of HMGB1, calmodulin, HSP70 and carbonic anhydrase II expression in glaucoma. The data may facilitate development of eye drops that exert neuroprotection through direct pharmacological effect.

Topics: Animals; Calmodulin; Carbonic Anhydrase II; Cloprostenol; Disease Models, Animal; Glaucoma; HMGB1 Protein; HSP70 Heat-Shock Proteins; Intraocular Pressure; Ophthalmic Solutions; Peptide Mapping; Proteome; Proteomics; Rats; Retina; Sulfonamides; Thiophenes; Travoprost

Several aromatic/heterocyclic sulfonamide scaffolds have been used to synthesize compounds incorporating NO-donating moieties of the nitrate ester type, which have been investigated for the inhibition of five physiologically relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms: hCA I (offtarget), II, IV and XII (antiglaucoma targets) and IX (antitumor target). Some of the new compounds showed effective in vitro inhibition of the target isoforms involved in glaucoma, and the X-ray crystal structure of one of them revealed factors associated with the marked inhibitory activity. In an animal model of ocular hypertension, one of the new compounds was twice more effective than dorzolamide in reducing elevated intraocular pressure characteristic of this disease, anticipating their potential for the treatment of glaucoma.

Topics: Animals; Carbonic Anhydrase Inhibitors; Crystallography, X-Ray; Disease Models, Animal; Glaucoma; Humans; Models, Molecular; Molecular Structure; Nitric Oxide; Ocular Hypertension; Protein Isoforms; Rabbits; Sulfonamides; Thiophenes

A rapid, sensitive and selective method for the simultaneous quantification of carteolol and dorzolamide in rabbit aqueous humor (AH) and ciliary body (CB) has been developed and validated using reversed phase-high performance liquid chromatography (RP-HPLC) with isocratic elution coupled with atmospheric pressure chemical ionization mass spectrometry/mass spectrometry (APCI-MS/MS). The analytes and nadolol (used as internal standard, IS) were purified from AH by protein precipitation. The sample preparation from CB was based on a two steps extraction procedure at different pH, utilizing a liquid-liquid extraction with a mixture of ethyl acetate, toluene and isopropanol 50:40:10 (v/v) at pH 8, followed by a second extraction with ethyl acetate at pH 11. The combined organic extracts were then back extracted into 0.1% aqueous trifluoroacetic acid (TFA). The accuracy and precision values, calculated from three different sets of quality control samples analyzed in sestuplicate on three different days, were within the generally accepted criteria for analytical methods (<15%). The assay proved to be accurate and precise when applied to the in vivo study of carteolol and dorzolamide in rabbit AH and CB after single administration of an eye drops containing both drugs.

Topics: Animals; Antihypertensive Agents; Aqueous Humor; Carteolol; Chromatography, High Pressure Liquid; Ciliary Body; Disease Models, Animal; Humans; Male; Ocular Hypertension; Rabbits; Spectrometry, Mass, Electrospray Ionization; Sulfonamides; Thiophenes

The aim of this study was to examine intraocular pressure lowering, change of antiapoptotic molecules expression, and neuroretinal changes by a commercially available dorzolamide 2%/timolol 0.5% combination in a chronic ocular hypertension rat model. Chronic ocular hypertension was induced by three episcleral vein cauterizations. The expression of antiapoptotic molecules and the effect of dorzolamide 2%/timolol 0.5% combination in chronic ocular hypertensive retina were evaluated. Retinal ganglion cell (RGC) retrograde labeling and quantification with 4-di-10-ASP (DiA) and expression of glial fibrillary acidic protein (GFAP) were detected before and after the administration of dorzolamide 2%/timolol 0.5%. Treatment of ocular hypertensive eyes with dorzolamide 2%/timolol 0.5% significantly reduced, intraocular pressure when compared to the control eyes. Labeling of RGCs with DiA showed a significant decrease in RGC loss after the administration of dorzolamide 2%/timolol 0.5%. GFAP expression revealed a significant decrease in retinal damage after dorzolamide 2%/timolol 0.5% administration. However, dorzolamide 2%/timolol 0.5% did not affect Bcl-2 and Bcl-xL mRNA expression. In conclusion, dorzolamide 2%/timolol 0.5% may have neuroprotective potential in the animal model, which is not mediated by Bcl-2 or Bcl-xL. The mechanism of neuroprotection by dorzolamide 2%/timolol 0.5% in chronic glaucoma models requires further investigation.

Topics: Animals; bcl-X Protein; Cell Survival; Disease Models, Animal; Drug Combinations; Glial Fibrillary Acidic Protein; Intraocular Pressure; Male; Ocular Hypertension; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Retinal Ganglion Cells; RNA, Messenger; Sulfonamides; Thiophenes; Timolol

To evaluate the influence of some widely used antiglaucoma agents on angiogenesis in a novel rat cornea model.. Angiogenesis was induced in 32 rats by slow-release polymer pellets containing basic fibroblast growth factor (bFGF) placed in a corneal micropocket. Angiogenesis was later measured and compared in groups of rats given one of four antiglaucoma drug therapies and one control group. The drugs were commercially available preparations of prostaglandins, beta-blockers, alpha-2 agonists, and carbonic anhydrase inhibitors given for 7 days in a manner similar to that used in humans. Growth was measured by calculating the maximum linear vessel growth divided by pellet-limbus distance.. Biomicroscopic observation disclosed that all tested animals showed an induction of neovascular reactions in their corneal stroma. The growth index results for the control, latanoprost, dorzolamide, brimonidine, and timolol malate groups were 1.65 +/- 0.16, 1.98 +/- 0.18, 1.85 +/- 0.19, 2.03 +/- 0.38, and 1.65 +/- 0.14, respectively, confirming the hypothesis that topically delivered antiglaucoma drugs modify the normal angiogenic response. Of them, the prostaglandins showed the most prominent angiogenic stimulatory effect (P = 0.03).. This modified micropocket assay of corneal angiogenesis in rats demonstrated the stimulatory effect of several widely used topically delivered antiglaucoma medications on the angiogenic process. The results indicate that the selection of drugs for treating different ophthalmic diseases should take into account their influence on angiogenic processes.

Topics: Animals; Antihypertensive Agents; Brimonidine Tartrate; Corneal Neovascularization; Corneal Stroma; Disease Models, Animal; Drug Implants; Fibroblast Growth Factor 2; Latanoprost; Prostaglandins F, Synthetic; Quinoxalines; Rats; Rats, Wistar; Sulfonamides; Thiophenes; Timolol

To study the effect of dorzolamide on the preretinal oxygen tension (RPO(2)) in retinal areas affected by experimental branch retinal vein occlusion (BRVO) in pigs.. Experimental BRVO was induced by diathermy close to the optic disc. RPO(2) was measured with an oxygen-sensitive electrode 0.5 mm above the BRVO-affected area, which was compared to the retinal areas not affected by BRVO. In one group of five pigs, RPO(2) was measured at baseline, 1 and 3 hours after BRVO, and after intravenous injection of 500 mg dorzolamide. In a second group of five pigs, RPO(2) was measured 1 week after the BRVO, both before and after intravenous injection of 500 mg dorzolamide.. The average baseline RPO(2) was 2.64 +/- 0.09 kPa (mean +/- SD). In the BRVO-affected areas, RPO(2) decreased significantly (by 0.67 +/- 0.29 and 0.94 +/- 0.13 kPa) at 1 hour and 3 hours after BRVO induction. In the non-BRVO areas RPO(2) increased significantly (by 0.51 +/- 0.14 kPa) 1 hour after BRVO induction, but subsequently decreased and reached baseline 3 hours after BRVO induction. One week after BRVO induction, RPO(2) was 0.67 +/- 0.29 kPa lower in affected areas when compared with the non-BRVO areas. In the BRVO-affected areas, dorzolamide increased RPO(2) significantly (by 0.36 +/- 0.21 kPa at 3 to 4 hours and by 0.67 +/- 0.40 kPa) 1 week after BRVO induction.. Retinal hypoxia induced by experimental BRVO remained significant 1 week after BRVO. Dorzolamide increased retinal oxygen tension in the BRVO-affected areas both at 4 hours and 1 week after experimental BRVO in pigs.

Topics: Animals; Carbonic Anhydrase Inhibitors; Disease Models, Animal; Fluorescein Angiography; Hypoxia; Injections, Intravenous; Ion-Selective Electrodes; Ischemia; Oxygen; Oxygen Consumption; Partial Pressure; Retina; Retinal Vein Occlusion; Sulfonamides; Swine; Thiophenes

A new series of thioureido-substituted sulfonamides were prepared by reacting 4-isothiocyanato- or 4-isothiocyanatoethyl-benzenesulfonamide with amines, hydrazines, or amino acids bearing moieties that can lead to an enhanced hydrosolubility, such as 2-dimethylamino-ethylamine, fluorine-containing aromatic amines/hydrazines, an aminodiol, heterocyclic polyamines (derivatives of morpholine and piperazine), 4-aminobenzoic acid, or natural amino acids (Gly, Cys, Asn, Arg, and Phe). The new compounds showed good inhibitory properties against three physiologically relevant carbonic anhydrase (CA, EC 4.2.1.1) isozymes, with K(I)s in the range of 24-324 nM against the cytosolic isoform CA I, of 6-185 nM against the other cytosolic isozyme CA II, and of 1.5-144 nM against the transmembrane isozyme CA XII. Some of the new derivatives were also very effective in reducing elevated intraocular pressure in hypertensive rabbits as a glaucoma animal model. Considering that this is the first study in which potent CA II/CA XII inhibitors are designed and investigated in vivo, it may be assumed that the target isozymes of the antiglaucoma sulfonamides are indeed the cytosolic CA II and the transmembrane CA XII.

Topics: Animals; Carbonic Anhydrase II; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Disease Models, Animal; Drug Design; Glaucoma; Intraocular Pressure; Rabbits; Structure-Activity Relationship; Sulfonamides

This study sought to elucidate the effects of timolol and dorzolamide on intraocular pressure (IOP) and retinal ganglion cell (RGC) death in an experimental model of glaucoma in rat.. Mild elevation of IOP was induced in rats by intracameral injection of India ink and subsequent laser trabecular photocoagulation. IOP was measured before the surgical procedures and weekly thereafter. Timolol (0.5%), timolol XE (0.5%), dorzolamide (1%), and artificial tears (vehicle) were topically applied daily. Retinal sections were prepared for histology to determine RGC number.. Timolol, timolol XE, and dorzolamide induced a significant reduction in IOP (p<0.05) and counteracted the reduction in RGC number that occurred in vehicle treated glaucomatous eyes (p<0.05). The coefficient of correlation between RGC number and IOP was significant in the dorzolamide treated group (r = -0.908, p<0.005), but not in other groups (p>0.05).. Both timolol formulation and dorzolamide reduced IOP and protected RGCs in a rat model of experimental glaucoma. It cannot be ruled out that timolol might protect RGCs by additional mechanisms other than simply lowering of IOP.

Topics: Animals; Antihypertensive Agents; Cell Count; Cell Survival; Cytoprotection; Disease Models, Animal; Glaucoma; Intraocular Pressure; Male; Ophthalmic Solutions; Rats; Rats, Wistar; Retinal Ganglion Cells; Sulfonamides; Thiophenes; Timolol

This study was designed to evaluate the effects of a dorzolamide-timolol combination or dorzolamide on retinal ganglion cell (RGC) density and intraocular pressure (IOP) in glaucomatous eyes of adult rats.. Glaucoma was induced in the right eye of adult Wistar rats by episcleral venous occlusion. One experimental group was administered dorzolamide 2%-timolol 0.5% combination eye drops, while the other experimental group was administered dorzolamide 2% eye drops. Control groups had surgery without drug administration. Drug application was initiated either 2 weeks before surgery (Group A), from the day of surgery (Group B), 2 weeks after surgery (Group C), or 4 weeks after surgery (Group D). RGCs were labeled by intratectal Fluorogold injections and counted from flat-mount preparations, and IOP was measured using Tonopen.. Both dorzolamide-timolol combination and dorzolamide, when applied topically, significantly reduced IOP and improved RGC densities in experimental eyes when compared to control eyes. Earlier initiation, as well as longer duration of drug application, resulted in higher RGC densities.. Topical application of a dorzolamide-timolol combination or dorzolamide saved RGCs to a significant extent and reduced IOP in glaucomatous rat eyes.

Topics: Animals; Antihypertensive Agents; Cell Count; Disease Models, Animal; Drug Combinations; Female; Glaucoma; Intraocular Pressure; Pilot Projects; Rats; Rats, Wistar; Retinal Ganglion Cells; Sulfonamides; Thiophenes; Time Factors; Timolol

Reaction of 26 aromatic/heterocyclic sulfonamides containing amino, imino, hydrazino, or hydroxyl groups with Boc-Gly, Boc-Sar, TrS-Crt, or Boc-Gly-Gly (Sar = sarcosine, N-Me-Gly; Crt = creatine, N-amidinosarcosine; TrS = tritylsulfenyl; Boc = tert-butoxycarbonyl) in the presence of carbodiimide derivatives afforded after removal of the protecting groups a series of water-soluble compounds (as salts of strong acids, such as hydrochloric, trifluoroacetic, or trifluoromethanesulfonic). The new derivatives were assayed as inhibitors of the zinc enzyme carbonic anhydrase (CA) and more precisely of three of its isozymes, CA I, II (cytosolic forms), and IV (membrane-bound form), involved in important physiological processes. Efficient inhibition was observed against all three isozymes and especially against CA II and IV (in the nanomolar range), the two isozymes known to play a critical role in aqueous humor secretion within the ciliary processes of the eye. Some of the best inhibitors synthesized were applied as 2% water solutions into the eye of normotensive or glaucomatous albino rabbits, when strong and long-lasting intraocular pressure (IOP) lowering was observed with many of them. Thus, the aminoacyl/dipeptidyl tail conferring water solubility to these sulfonamide CA inhibitors coupled with strong enzyme inhibitory properties and balanced lipid solubility seem to be the key factors for obtaining compounds with effective topical antiglaucoma activity.

Topics: Administration, Topical; Animals; Carbonic Anhydrase Inhibitors; Carbonic Anhydrases; Cell Membrane Permeability; Cornea; Delayed-Action Preparations; Dipeptides; Disease Models, Animal; Glaucoma; Humans; Intraocular Pressure; Isoenzymes; Models, Molecular; Rabbits; Solubility; Sulfonamides; Time Factors

The aim of this study was to set-up and validate the use of a radio-telemetry system in order to record IOP in chronic ocular hypertensive animals. The transmitter of a miniaturized radio-telemetry system was implanted in rabbits, and its catheter was tunnelled subcutaneously to the superior conjunctival sac and inserted into the midvitreous. Implantation was performed in chronic ocular hypertensive rabbits induced by an injection of alpha-chymotrypsin into the posterior chamber of the eye. The effects of 0.5% timolol maleate, 2% dorzolamide hydrochloride and 1% epinephrine were assessed and compared after topical administration in this model. Implanted radio-telemetric system into the vitreous allowed IOP measurement for more than 6 months. In this study, circadian IOP kinetic profiles were monitored in all animals over 24 h for 3 weeks. Timolol maleate was found significantly potent in reducing IOP, while changes depended on the nyctemeral period. Dorzolamide hydrochloride induced a very large IOP reduction and was found to be also well effective at night. We evidenced a biphasic time-dependent effect after topical epinephrine, with a long lasting IOP increase occurring after the administration. This change was found to be related to side effects resulting from a poor ocular tolerance of this drug in the rabbit, leading to either a complete eye closure or a higher blinking rate. By using our method, we confirmed the pressure pulses and undershoots occurring during blinking. Radio-telemetry in chronic glaucoma rabbits appears as a refined method to assess anti-glaucoma drug activity, 24 hours a day, for long-term periods in unrestrained animals, while also providing information on the ocular side effects of eye drops.

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Animals; Carbonic Anhydrase Inhibitors; Chymotrypsin; Circadian Rhythm; Disease Models, Animal; Epinephrine; Female; Glaucoma; Intraocular Pressure; Ophthalmic Solutions; Rabbits; Sulfonamides; Telemetry; Thiophenes; Timolol