Effect of methazolamide in patients with refractory uveitic macular edema / 国际眼科杂志(Guoji Yanke Zazhi)

AIM:To evaluate the efficacy and safety of methazolamide in treating refractory uveitic macular edema.METHODS: Retrospective self-controlled study was designed.A total of 15 patients (20 eyes) with refractory uveitic macular edema which used methazolamide as adjuvant therapy were enrolled in Shanghai First People`s Hospital from January 2015 to June 2016.The changes of central macular thickness (CMT) and best corrected visual acuity (BCVA) were observed at baseline and 2, 4, 8wk after treatment.We also focused on the incidence of complications and relapse.RESULTS: The CMT was 445.95±154.10μm, 338.83±138.34μm, 251.50±40.20μm, 244.90±35.68μm at baseline, 2, 4 and 8wk after treatment, respectively.The differences among them were statistically significant (F=15.467, P<0.05).The BCVA (log MAR) were 0.40±0.17, 0.28±0.21, 0.19±0.20, 0.18±0.21 at baseline, 2, 4 and 8wk respectively, with a significant difference among them (F=5.208, P<0.05).When the cumulative dose reached to 700mg and 1400mg, no one had methazolamide-related complications;and when it came to 2800mg, 5 patients (33%) had methazolamide-related complication.After the withdrawal of methazolamide 1wk, 1 and 3mo, 3 patients (20%), 5 patients (33%) and 8 patients (53%) relapsed, respectively.CONCLUSION: Methazolamide is beneficial in improving macular edema and vision in 4wk.When the cumulative dose is more than 1400mg, we need pay attention to the complications.After discontinuing methazolamide for 1wk, macular edema relapsed in some patients, and more than half of patients recurred after 3mo.So the patients should be followed closely in 3mo after withdrawal of methazolamide.

Effects of dorzolamide/timolol and tafluprost on intraocular pressure and pupil diameter in healthy dogs / Efeitos da dorzolamida/timolol e da tafluprosta sobre a pressão intraocular e o diâmetro pupilar em cães saudáveis

ABSTRACT: This study aimed to evaluate and compare the effects of the fixed combination of dorzolamide/timolol with those of tafluprost on intraocular pressure (IOP) and pupil diameter (PD) in healthy dogs (n=10). Two experiments were conducted with an interval of 30 days. In both, IOP and PD were assessed at 8, 11, 14, 17, and 20h. Parameters were evaluated during baseline, treatment period of four days, and one day of post-treatment. During treatment phase, IOP decreased by 0.74 (P<0.05), 1.88 (P<0.01), 2.94 (P<0.001), and 3.10mmHg (P<0.01), in dorzolamide/timolol-treated eyes; and by 1.50, 2.18, 2.14, and 2.18mmHg (P<0.001), in tafluprost-treated eyes. PD decreased by 0.24 (P<0.01), 0.32 (P<0.01), 0.49 (P<0.001), and 0.40mm (P<0.001), in dorzolamide/timolol treated eyes; and by 2.31, 2.55, 2.43, and 2.70mm (P<0.001), in tafluprost-treated eyes. Dorzolamide/timolol and tafluprost were able to decrease IOP and PD in healthy dogs. However, a cumulative effect of the fixed combination of dorzolamide/timolol was more effective in reducing IOP, than tafluprost. Comparisons between treatments showed that tafluprost was more effective in reducing PD throughout the treatment phase.

RESUMO: O estudo objetivou avaliar e comparar os efeitos da combinação fixa da dorzolamida/timolol com os da tafluprosta sobre a pressão intraocular (PIO) e o diâmetro pupilar (DP) em cães saudáveis (n=10). Dois experimentos com intervalo de 30 dias foram conduzidos. Em ambos, a PIO e o DP foram avaliados às 8, 11, 14, 17 e às 20h. Os parâmetros foram avaliados durante a fases basal, um período de tratamento de quatro dias, e um dia de pós-tratamento. Durante a fase de tratamento, a PIO dos olhos tratados com dorzolamida/timolol reduziram em 0.74 (P<0.05), 1.88 (P<0.01), 2.94 (P<0.001), e 3.10mmHg (P<0.01); e dos olhos tratados com tafluprosta em 1.50, 2.18, 2.14 e 2.18mmHg (P<0.001). O DP dos olhos tratados com dorzolamida/timolol reduziram em 0.24 (P<0.01), 0.32 (P<0.01), 0.49 (P<0.001) e 0.40mm (P<0.001); e dos olhos tratados com tafluprosta em 2.31, 2.55, 2.43 e 2.70mm (P<0.001). A dorzolamida/timol e a tafluprosta foram capazes de reduzir a PIO e o DP em cães saudáveis. Porém, efeito cumulativo do tratamento com dorzolamida/timolol foi observado, decorridos três dias de tratamento. Por essa razão, a dorzolamida/timolol foi mais efetiva que a tafluprosta na redução da PIO. Comparações entre os tratamentos demonstraram que a tafluprosta foi mais efetiva em reduzir o DP, durante toda a fase de tratamento.

Cystoid macular edema in a patient with Danon disease.

To report a patient with Danon retinopathy with cystoid macular edema treated with topical dorzolamide 2% eye drops and oral acetazolamide. A 37-year-old Caucasian man with Danon disease treated with topical and oral carbonic anhydrase inhibitors participated in the study. Examinations performed before and during treatment included visual acuity (VA), spectral-domain optical coherence tomography, and electroretinography. Following total 48 weeks of treatment, VA decreased from 20/30 OD, 20/200 OS, to 20/40 OD, CF OS. The mean central retinal thickness was unchanged from baseline 263 μm OD , 226 μm OS, after treatment 283 μm OD and 202 μm OS. In our case, carbonic anydrase inhibitors were not effective. However, a general recommendation cannot be given based on a single case.

The Effects of Topical Carbonic Anhydrase Inhibitors on Nitric Oxide Production in Trabecular Meshwork Cells

PURPOSE: To investigate and compare the effects of topical carbonic anhydrase inhibitors on the production and expression of nitric oxide in cultured human trabecular meshwork cells (HTMC). METHODS: Primarily cultured HTMC were exposed to 0, 10, and 100 microM dorzolamide and brinzolamide using serum-deprived media for 3 days. Production of nitric oxide was assessed with Griess assay. Expressions of eNOS mRNA were assessed with RT-PCR. RESULTS: Both dorzolamide and brinzolamide increased the production of nitric oxide eNOS activity (p < 0.05). Dorzolamide had a more potent effect than brinzolamide on the production of nitric oxide and the expression of eNOS mRNA. CONCLUSIONS: Topical carbonic anhydrase inhibitors increased the production of nitric oxide, which was accompanied by increased eNOS activity. Dorzolamide had a more potent effect than brinzolamide on the production of nitric oxide and expression of eNOS mRNA in HTMC. The increased production of nitric oxide by topical carbonic anhydrase inhibitors involves mechanisms other than carbonic anhydrase inhibition.

Malaria parasite carbonic anhydrase: inhibition of aromatic/heterocyclic sulfonamides and its therapeutic potential

Plasmodium falciparum (P. falciparum) is responsible for the majority of life-threatening cases of human malaria, causing 1.5-2.7 million annual deaths. The global emergence of drug-resistant malaria parasites necessitates identification and characterization of novel drug targets and their potential inhibitors. We identified the carbonic anhydrase (CA) genes in P. falciparum. The pfCA gene encodes anα-carbonic anhydrase, a Zn(2+)-metalloenzme, possessing catalytic properties distinct from that of the human host CA enzyme. The amino acid sequence of the pfCA enzyme is different from the analogous protozoan and human enzymes. A library of aromatic/heterocyclic sulfonamides possessing a large diversity of scaffolds were found to be very good inhibitors for the malarial enzyme at moderate-low micromolar and submicromolar inhibitions. The structure of the groups substituting the aromatic-ureido- or aromatic-azomethine fragment of the molecule and the length of the parent sulfonamide were critical parameters for the inhibitory properties of the sulfonamides. One derivative, that is, 4- (3, 4-dichlorophenylureido)thioureido-benzenesulfonamide (compound 10) was the most effective in vitro Plasmodium falciparum CA inhibitor, and was also the most effective antimalarial compound on the in vitro P. falciparum growth inhibition. The compound 10 was also effective in vivo antimalarial agent in mice infected with Plasmodium berghei, an animal model of drug testing for human malaria infection. It is therefore concluded that the sulphonamide inhibitors targeting the parasite CA may have potential for the development of novel therapies against human malaria.

Influence of topical carbonic anhydrase inhibitor on the expression of aquaporin-1 in rat cornea with neovascularization / 中华实验眼科杂志

Background Researches showed that aquaporin-1 (AQP1) is closely associated with corneal neovescularization(CNV).Carbonic anhydrase inhibitor has the inhibitory effect on the AQP1 and further suppresses the CNV.However,the systemic adverse effect of Carbonic anhydrase inhibitor limit its clinical application.Therefore,the influence of topical carbonic anhydrase inhibitor on CNV is concerned.Objective Present study was to investigate the effects of topical carbonic anhydrase inhibitors on the expression of AQP1 in rat cornea after alkali burn and explore its role in corneal neovascularization (CNV).Methods The alkali-burn animal models were established in 60 eyes of 30 clean Sprague Dawley rats by putting the filter paper soaked 1 mol/L NaOH solution at the central cornea for 40 seconds.1％ Brinzolamide was topically administered in the 30 eyes of 15 models (Brinzolamide group),and the normal saline solution was used at the same way in other 30 eyes of 15 rats (model group).The 10 eyes of 5 normal Sprague Dawley received the eye drops of normal saline solution as the normal control group.The corneal burning degree was graded on the Mahoney ' s criteria in the third day,and Ee ' s method was used to score the opacification of cornea and the CNV area was analyzed in 3,5,7,10 days under the slit lamp microscope.The cornea tissue was obtained in the tenth day after burning for the observation of the pathology under the light microscope and the ultrastructure under the transmission electron microscope.The expressions of AQP1 and vascular endothelial growth factor(VEGF) in cornea tissue were detected using immunohistochemistry.The use of animals complied with the Statement of ARVO.Results No significant difference was seen in the scores of rat corneal alkali burn between the model group and brinzolamide group( t=0.97,P＞0.05 ).The scores of corneal edema and opacification and neovascular area were lower in brinzolamide group compared with model group ( t =2.18,P＜0.05 ;t =6.58,P＜0.01 ).The pathological and ultrastructural examinations showed less CNV and inflammatory cells in rat corneal tissue of the brinzolamide group in comparison with model group.The grey values of VEGF were 84.92±9.49 and 78.18± 11.41,and those of AQP1 were 88.01 ± 11.03 and 58.10 ± 12.14 in the model group and brinzolamidegroup respectively,showing statistically significant differences ( VEGF:t =2.48,P =0.02 ; AQPI:t =9.99,P =0.00 ).Conclusions 1％ Brinzolamide suppresses alkali burn-induced CNV by downregulating the expressions of AQP1 and VEGF in cornea in rat.

Homology modeling and QSAR analysis of 1,3,4-thiadiazole and 1,3,4-triazole derivatives as carbonic anhydrase inhibitors.

Carbonic anhydrase (CA) inhibitors are very interesting target for designing anticancer (hypoxic) and antiglaucoma drugs. In the present study, a 3D homology modeling of human carbonic anhydrase-IX (hCA-IX) isozyme, based upon the crystal structure of murine CA-XIVA (PDB CODE 1RJ5) was performed, as no experimental 3D structures are available. A homology model of hCA-IX was developed and validated. To explore the responsible physicochemical properties of 1,3,4-thiadiazole and 1,3,4-triazole derivatives for carbonic anhydrase inhibition, a quantitative structure activity relationship (QSAR) study was performed having hCA-II and hCA-IX inhibitory activity respectively. In hCA-II and hCA-IX inhibitory activities, four significant models with good correlations ( 0.945 & 0.926) were obtained; two models (models 1 and 3) were selected based on statistical criterion. The QSAR study revealed that in case of hCA-II, overall increase in size and volume of molecule, introduction of electropositive surfaces might increase the inhibitory activity, whereas in case of hCA-IX, decreasing the hydrophobicity and introduction of electron releasing substituents might increase the hCA-IX inhibitory activity.

A Study of Intraocular Pressure During Hemodialysis in CRF Patients

PURPOSE: Hemodialysis, a treatment for patients with severely compromised renal failure, is the elimination of osmotic active substances by diffusion. Some authors have reported that change in osmorality between the serum and the aquous humor during hemodialysis increased in intraocular pressure (IOP). We investigated the change of IOP and serum osmolarity during hemodialysis and the effect of oral carbonic anhydrase inhibitor (Diamox(R)), topical carbonic anhydrase inhibitor (Trusopt(R)) and oral hypertonic solution(glycerol). METHODS: In 45 CRF patients (90 eyes) without glaucoma, IOP, serum osmorality, pH, and HCO3- were measured during hemodialysis, and oral carbonic anhydrase inhibitor (Diamox(R)), topical carbonic anhydrase inhibitor (Trusopt(R)) and oral hypertonic solution (glycerol) werw administered if IOP rose by over 6mmHg during hemodialysis. After adminitration of the agents, we checked effect of preventing IOP elevation and metabolic change during hemodialysis. RESULTS: The intraocular pressure rose above 6 mmhg in 24 eyes (24.6%) during hemodialysis. Oral carbonic anhydrase inhibitor induced more severe metabolic acidosis than topical carbonic anhydrase inhibitor but topical carbonic anhydrase inhibitor was less effective in lowering IOP. CONCLUSIONS: Because of more effective lowering of IOP and rare complications of metabolic acidosis, hypertonic solution (glycerol) was effective and safe in neovascular glaucoma and in glaucoma patients with severely damaged optic nerve.

A Six-Week, Randomized, Double-Blind, Placebo-Controlled, Multicenter Study to Evaluate Hypotensive Efficacy and Safety of 2%Dorzolamide vs Placebo Ophthalmic Solution

Two percent dorzolamide, a topical carbonic anhydrase inhibitor (CAI), was developed to reduce the side effects associated with systemic CAI such as fatigue, anorexia, dysesthesia, etc. and to effectively reduce the elevat-ed intraocular pressure(IOP). This study was designed to evaluate the effectiveness and safety of 2%dorzolamide in Korean patients with primary open-angle glaucoma or ocular hypertension. In this randomized, double-blind, placebo-controlled clinical study, 2%dorzolamide or placebo was given three times a day to the patients with primary open-angle glaucoma or ocular hypertension (22mmHg < or =IOP < or =30mmHg)to evaluate the hypotensive effect and safety of dorzolamide during the period of 6 weeks. After 1,3, and 6 weeks treatment, the mean percent decrease of IOP from baseline in the dorzolamide group (16.3 +/-8.9%,17.9 +/- 9.8%,and 18.2 +/-8 .7 %, respectively) was significantly larger (p<0.01)than that in the placebo group (7.5 +/- 6.8%, 8.5 +/-9.5%, 10.4 +/-10.4%, respectively). The decrease of IOP was also significant in each group(p<0.01)compared to the pre-treatment IOP. During the period of treatment, burning sensation was more frequent in the dorzolamide group (p<0.05). In conclusion,this study has shown that the topical application of 2% dorzolamide effectively reduces IOP without serious adverse effects in Korean patients with primary open-angle glaucoma or ocular hypertension.

The Effect of Short Term Use of Azopt in Normal Koreans

Azopt (brinzolamide ophthalmic suspension, 1%)is a carbonic anhydrase type II inhibitor,which reduces intraocular pressure by suppression of aque-ous humor production in ciliary process. It was developed as an agent which has little systemic side effect and was adjusted to physiologic ophthalmic environment. We observed the effect of intrao- cular pressure, pulsatile ocular blood flow and side effect to investigate the clinical effectiveness of Azopt in normal Azopt was instilled to 10 eyes of 10 volunteers and artificial tear was instilled to the other 10 eyes of 10 volunteers three times daily, respectively. We measured intraocular pressure by Goldman applanation tonometer at twohours, 8 hours, 1 day and 7 days after instillation. Pulsatile ocular blood flow, pupil diameter, blood pressure and pulse rate were also measured. Decrease of intraocular pressure after instillation of Azopt was statistically significant (p<0.05), compared with the pressure before instillation of Azopt and the decrease of pressure after instillation of artifical tear. No systemic side effect and ophthalmic discomfort was noted except for temporary visual blurring. Therefore we expect that Azopt will have a great effect on glaucoma patients in Korea who must be treated for long duration.

Ethanol-induced Back-Diffusion of H+ in Rat Stomach

Ethanol causes mucosal injury to the stomach and which accompanied by back-diffusion of H+. Using several drugs known to modify the gastric acid secretion and to provide cytoprotection the effect of back-diffusion of H+ by ethanol was examined. Following 48 hours of starvation rats were anesthetized with urethane, and their stomachs were filled with 4 ml of 20% ethanol solution containing 1.8 mM HCI (7.2 microEq/4 ml) every 15 min. H+ content of the collected perfusates was determined by back-titration to pH 6.0. The presence of ethanol in the stomach for 1 hour caused a loss of luminal H+ at a rate of 4.8 +/- 0.4 microEq/15 min. Pretreatment of rats with atropine (2 mg/Kg, i.v.), pirenzepine(2 mg/Kg. i.v.), cimetidine (10mg/Kg i.v.), cromolyn sodium (20mg/Kg/hr, i.v.) or domperidone (1 mg/kg. i.v.) did not affect the ethanol-induced H+ back-diffusion. Similarly, no effect was seen in rats treated with prostaglandin E2 (100 microgram/Kg i.v.) or indomethacin (5 mg/Kg, s.c). The addition of procaine (10(-5)~10(-3) M) or propranolol (10(-9)~10(-5) M) to the perfusate did not cause any changes in the ethanolinduced H+ back-diffusion. However, pretreatment of rats with acetazolamide (100 mg/Kg i.v.) or ethoxzolamide(50 mg/Kg/day, p.o. for 6 days), carbonic anhydrase inhibitors, markedly suppressed the ethanol-induced loss of luminal H+. Based on these results, it is suggested that ethanol-induced back-diffusion of H+ is mediated, at least in part, by the activity of carbonic anhydrase, and that cholinergic, histaminergic and dopaminergic mechanisms are not involved. Moreover, the implications of prostaglandins and membrane stability are not suggested.