Antiglaucoma Agents Research Articles

Managing Primary Open-angle Glaucoma – Ocular Tolerability, Compliance, Persistence and Patient Outcomes

Primary open-angle glaucoma (POAG) is a progressive optic neuropathy that, left untreated, can lead to irreversible damage to the optic nerve and permanent vision loss. To date, intraocular pressure (IOP) is the only modifiable risk factor for disease progression, and topical eye-drops are currently used as the leading non-surgical glaucoma therapy. Despite the efficacy of pharmacotherapy in lowering IOP, success is ultimately defined by patient compliance and patient persistence. Ocular tolerability is a crucial factor in patient compliance and persistence; non-adherence owing to adverse effects can lead to poor control of IOP and treatment failure. Prostaglandin analogues are currently the first-line antiglaucoma agents, with a good tolerability profile and a better IOP-lowering effect compared with β-blockers. Combination therapies have also shown greater efficacy in lowering IOP compared with the individual constituents, with fewer adverse effects. Treatment should be tailored to the individual patient, with a focus on ocular tolerability and its role in adherence, compliance and vision preservation.

Discovery of 13-oxa prostaglandin analogs as antiglaucoma agents: Synthesis and biological activity

FP-Class prostaglandin analogs have demonstrated utility for the treatment of glaucoma and ocular hypertension. A series of novel FP prostaglandin analogs was designed to optimize topical ocular activity and reduce ocular side-effects by replacing 13-carbon with oxygen. A facile synthesis was successfully developed for synthesis of the 13-oxa prostaglandins from the commercially available Corey aldehyde benzoate. Among the compounds synthesized, AL-16082 was the most potent prostaglandin FP agonist in vitro. In a prostaglandin FP receptor-linked second-messenger assay, phosphoinositide (PI) turnover, it exhibited a potency value (EC 50) of 1.9 nM (78% max. response relative to fluprostenol). The isopropyl ester of AL-16082, compound AL-16049, significantly lowered intraocular pressure (IOP) in the ocular hypertensive monkey eyes by 30%. In the study of acute ocular irritation response in New Zealand albino rabbits, AL-16049 produced lower incidence of hyperemia, swelling, and discharge than PGF 2α (1 μg), and a similar incidence of hyperemia, swelling, and discharge to latanoprost (1.8 μg). AL-16049 also produced no signs of ocular irritation or discomfort in the cat at the doses evaluated.

A case of melancholic depression induced by β‐blocker antiglaucoma agents

he most common medical treatments for glaucoma in Australia are prostaglandin analogues. However, β-blockers still comprise a substantial proportion of all prescriptions, either alone or in combination. Despite their topical administration, β-blockers are absorbed from the eye through the conjunctival epithelium, lacrimal channels, nasal mucosa and gastrointestinal tract into the systemic circulation. Although only small amounts are absorbed, concentrations may be sufficient to cause systemic β-adrenergic receptor-mediated effects, including slowing of heart rate, lowering of blood pressure and non-response to bronchodilators. Central effects such as depression have also been reported. The literature investigating a causal relationship between βblockers and depression is controversial. An evidence-based review concluded that depression was an uncommon side effect of treatment with β-blockers and usually occurred only in the presence of a pre-existing condition. 2 Randomised controlled studies of β-blockers in cardiovascular disease found the incidence of depressive symptoms was similar in β-blocker- and placebotreated groups. 3 However, a review of 24 case reports 4 showed a temporal relationship between the use of β-blockers and depression in more than half the cases. If there is a close temporal relationship between the commencement of a new treatment and the development of symptoms, the symptoms are considered likely to have been caused by the medication. In the initial case that we reported on this patient, 1 depressive symptoms began within days after the diagnosis of glaucoma and commencement of betaxolol treatment. The patient’s symptoms only fully remitted when the drug was stopped, providing further evidence of a causative relationship. The case we report here describes recurrence of depression after the introduction of another β-blocker, timolol, and again cessation of symptoms when treatment was stopped. The recurrence of the syndrome following a re-challenge further strengthens the argument for a causal relationship. (The travoprost component of the medication was unlikely to have been the cause of the depression.) It is possible that the onset of the disorder occurred coincidentally with the introduction of the medication (though such an event is unlikely to have occurred twice) or was caused by the underlying illness for which the new medication was prescribed. In the only study we could find of ophthalmological patients with depression with and without glaucoma, no association was shown between depression and glaucoma. 5 Glaucoma is mostly a disease of older people, a group prone to developing depressive illness. Depression is often dismissed in older people as a normal reaction to ageing, loss or chronic illness. However, it is treatable, with a very good prognosis. Older patients are frequently taking multiple medicines and may develop depressive symptoms as a side effect. The purpose of this case presentation is to emphasise that even a drug that is administered topically, such as antiglaucoma eye drops, is absorbed systemically and can potentially cause adverse effects elsewhere, including centrally. There are credible theoretical reasons why β-blockers may cause depression: the number of β 1 receptors is increased in the brains of suicide victims and chronically stressed animals, and antidepressants cause down-regulation of β 1 receptors. The fact that only a few patients develop depression after taking β-blockers may be due to genetic differences. It is possible that poor metabolisers of the enzyme cytochrome P450 2D6 will be exposed to higher systemic concentrations of β-blockers than those who are normal or fast metabolisers. 6,7 To our knowledge, there have been no

Short-Term Effects of Topical Tafluprost on Retinal Blood Flow in Cats

The aim of this study was to determine the short-term effects of topical tafluprost, a novel prostaglandin F(2) derivative, on feline retinal circulation. Seventeen (17) adult cats were anesthetized with enflurane and mechanically ventilated. One (1) drop of tafluprost (0.0015%; n = 8), latanoprost (0.005%; n = 5), or control vehicle (n = 4) was instilled in 1 eye and the fellow eye was untreated. We measured the intraocular pressure (IOP), vessel diameter, and blood velocity simultaneously for 120 min in the large retinal arterioles and calculated the retinal blood flow (RBF) with a laser Doppler velocimetry system. Tafluprost 0.0015% significantly increased RBF (maximum change, 42.8 +/- 4.2% [mean +/- standard error of the mean; P < 0.01) and blood velocity (maximum change, 24.1 +/- 3.3%; P < 0.01) for 120 min after instillation; there was no significant change in vessel diameter. Latanoprost 0.005% significantly increased RBF (maximum change, 31.7 +/- 3.4%; P < 0.05); there was no significant change in vessel diameter and blood velocity. There were no significant differences in the IOP reduction among the three groups. We observed, for the first time, that topical tafluprost significantly increased RBF in cats, suggesting that dual-action tafluprost may be a beneficial antiglaucomatous agent for reducing IOP and increasing RBF.

Carbonic anhydrase inhibitors: The X-ray crystal structure of ethoxzolamide complexed to human isoform II reveals the importance of thr200 and gln92 for obtaining tight-binding inhibitors

Ethoxzolamide, an almost forgotten inhibitor of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1), is the only classical inhibitor whose structure in adduct with any isoform was not reported yet. We report here the inhibition data of this molecule with the 12 catalytically active mammalian isozymes (CA I-CA XIV) and the X-ray crystal structure with the cytosolic, ubiquitous isoform CA II. These data are presumably useful for the design of novel CA inhibitors, targeting various CA isozymes, considering that ethoxzolamide was already the lead molecule to obtain the second generation inhibitors, dorzolamide and brinzolamide, clinically used antiglaucoma agents with topical action, as well as various other investigational agents.

The Development of Topically Acting Carbonic Anhydrase Inhibitors as Antiglaucoma Agents

Inhibition of carbonic anhydrase (CA, EC 4.2.1.1) isoforms present in the eyes (CA I, II, IV and XII), with sulfonamides such as acetazolamide, methazolamide, ethoxzolamide and dichlorophenamide, is still widely used for the systemic treatment of glaucoma. The mechanism of action of these drugs consists in inhibition of CA isozymes present in ciliary processes of the eye, with the consequent reduction of bicarbonate and aqueous humour secretion, and of elevated intraocular pressure (IOP) characteristic of this disease. As isoforms CA II/IV/XII are present in many other tissues/organs, generally, systemic CAIs possess undesired side effects such as numbness and tingling of extremities; metallic taste; depression; fatigue; malaise; weight loss; decreased libido; gastrointestinal irritation; metabolic acidosis; renal calculi and transient myopia. For avoiding these side effects, recently, topically effective CAIs have been developed in the last 10 years, with two drugs available clinically: dorzolamide and brinzolamide. Both these drugs are applied topically as water solutions/suspensions, alone or in combination with other agents (beta-blockers, prostaglandin derivatives, etc) and produce a consistent and prolonged reduction of IOP. Furthermore, recent reports show both the systemically as well as topically acting sulfonamide CAIs to be effective in the treatment of macular edema, macular degeneration disease, or diabetic retinopathy, for which pharmacological treatment is unavailable up to now. Much research is in act in the search of more effective topically acting CAIs, free of the inconveniences and side effects of the presently available drugs. For achieving this goal, two recently reported strategy, the tail approach and its variant, the sugar-tail approach, were extensively applied for the synthesis of large numbers of derivatives possessing desired physico-chemical properties. Many such new sulfonamides showed promising antiglaucoma activity in animal models of the disease.

Novel free radical scavengers protect retinal cells and decrease elevated intraocular pressure in a rat ocular hypertension model

Glaucoma is a neurodegenerative disease with damage retinal cells (RC) often associated with elevated intraocular pressure (IOP). Novel free radical scavengers (FRS) with esterified ion chelator and reducing side groups on a methoxypolyethylene glycol backbone (MPs) were evaluated as anti–glaucoma agents capable of both IOP reduction and RC protection.The operated eye of surgical rat glaucoma model received topical MPs or amifostine, a clinical FRS (all agents 20 ml, 0.3 – 100 mM). IOP was measured via Goldmann tonometer. Slit lamp, confocal microscopy and chronic toxicity studies were performed on normal rats (10 or 87 mM MPs, 3x/day for 30 days). 14C MPs were used for pharmacokinetic studies. Intravitreal injection with NMDA (2μL, 10–40mM) to naïve rats induces RC ERG and histological losses in 2 weeks. This damage was challenged with co–administered intravitreal MPs (n=5–6).Topical MPs (3–100 mM), but not amifostine, decreased IOP up to 29.6 % for T1/2s of 1–2 hrs. MPs also caused no acute or chronic ocular/systemic toxicity. 14C topical MPs showed ocular penetration with elimination via urine. MPs also reduced NMDA induced RC loss and A and B waves decreases. In vitro isolated rat and bovine RC assays are currently evaluating the role of free radical generation, elevated intracellular calcium and mitochondrial depolarization in the MPs mechanism of action in vivo.Supported in part by CHRB and AHAF.

Drug Modification of Angiogenesis in a Rat Cornea Model

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.

Molecular Characterization of a Novel Type of Prostamide/Prostaglandin F Synthase, Belonging to the Thioredoxin-like Superfamily

Prostaglandin F (PGF) ethanolamide (prostamide F) synthase, which catalyzed the reduction of prostamide H(2) to prostamide F(2alpha), was found in mouse and swine brain. The enzyme was purified from swine brain, and its amino acid sequence was defined. The mouse enzyme consisted of a 603-bp open reading frame coding for a 201-amino acid polypeptide with a molecular weight of 21,669. The amino acid sequence placed the enzyme in the thioredoxin-like superfamily with Cys(44) being the active site. The enzyme expressed in Escherichia coli as well as the native enzyme catalyzed not only the reduction of prostamide H(2) to prostamide F(2alpha) but also that of PGH(2) to PGF(2alpha). The V(max) and K(m) values for prostamide H(2) were about 0.25 micromol/min.mg of protein and 7.6 microm, respectively, and those for PGH(2) were about 0.69 micromol/min.mg of protein and 6.9 microm, respectively. Neither PGE(2) nor PGD(2) served as a substrate for this synthase. Based on these data, we named the enzyme prostamide/PGF synthase. Although the enzyme showed a broad specificity for reductants, reduced thioredoxin preferentially served as a reducing equivalent donor for this enzyme. Moreover, Northern and Western blot analyses in addition to the prostamide F synthase activity showed that the enzyme was mainly distributed in the brain and spinal cord, and the immunohistochemical study in the spinal cord showed that the enzyme was found mainly in the cytosol. These results suggest that prostamide/PGF synthase may play an important functional role in the central nervous system.

Herpes Zoster Ophthalmicus Complicated by Hyphema, Glaucoma and External Ophthalmoplegia

Purpose: To report a patient with herpes zoster ophthalmicus in whom hyphema, glaucoma and external ophthalmoplegia occurred. Case summary: A 59-year-old male patient developed severe ocular pain and decreased visual acuity in his left eye 10 days ago. He had been diagnosed as herpes zoster ophthalmicus 14 days before and given antiviral agent. He could not percept light. His left eye showed hyphema, severe exudative iritis and elevated IOP. Lid drooping and complete external ophthalmoplegia were present in the left eye. Systemic corticosteroid with concomitant antiviral agents and antiglaucomatous agents was administered. Results: Light perception did not recover and phthisis bulbi developed in his left eye at 2 months after the onset of the skin lesion. The patient showed gradual improvement in movement of the lid and external ocular muscle.

Effect of antiglaucoma agents on postoperative intraocular pressure after cataract surgery with Viscoat

To compare the effectiveness of brinzolamide 1%, brimonidine 0.2%, acetazolamide 250 mg, intracameral acetylcholine, and timolol 0.5% in preventing intraocular pressure (IOP) peaks during the early period after phacoemulsification in which sodium chondroitin sulfate 4%-sodium hyaluronate 3% (Viscoat) was used as the ophthalmic viscosurgical device (OVD). Department of Ophthalmology, Baskent University Medical Faculty, Ankara, Turkey. This prospective randomized study comprised 185 eyes of 185 patients with uncomplicated cataract scheduled for phacoemulsification using Viscoat as the OVD. Patients were randomly assigned to 1 of 6 groups: postoperative application of topical brinzolamide 1%, brimonidine 0.2%, oral acetazolamide 250 mg, intracameral acetylcholine, timolol 0.5%, or no ocular hypotensive agent (control group). The IOP was measured at baseline (preoperatively) as well as 6 hours, 20 to 24 hours, and 1 week after surgery. The mean preoperative IOP values were not significantly different between the groups. Six hours and 20 to 24 hours postoperatively, the mean IOP was significantly lower in all groups receiving an ocular hypotensive agent than in the control group (P<.01). Six hours after surgery, the mean IOP significantly increased in all groups but was higher in the control group. At 20 to 24 hours, the mean IOP decreased significantly in all ocular hypotensive agent groups but remained significantly high in the control group. One week after surgery, there were no significant differences between the groups. Brinzolamide, brimonidine, acetazolamide, intracameral acetylcholine, and timolol had similar effects in reducing IOP increases after phacoemulsification performed using Viscoat.

The Effect of Ocular Hypotensive Agents on Macula

We evaluated the effect of long-term topical antiglaucoma drugs on the macula using the noninvasive macular visual field threshold test in 100 eyes of 75 patients with ocular hypertension or primary open-angle glaucoma. We found that topical antiglaucoma agents can alter macular sensitivity after long-term therapy and advise evaluation of the macula in glaucoma patients receiving antiglaucomatous agents.

Quantitative Structure Activity Relationship Studies of Sulfamide Derivatives as Carbonic Anhydrase Inhibitor: As Antiglaucoma Agents

Selective inhibition of ciliary process enzyme i.e. Carbonic Anhydrase-II is an excellent approach in reducing elevated intraocular pressure, thus treating glaucoma. Due to characteristic physicochemical properties of sulphonamide (Inhibition of Carbonic Anhydrase), they are clinically effective against glaucoma. But the non-specificity of sulphonamide derivatives to isozyme, leads to a range of side effects. Presently, the absence of comparative studies related to the binding of the sulphonamides as inhibitors to CA isozymes limits their use. In this paper we have represented "Three Dimensional Quantitative Structure Activity Relationship" study to characterize structural features of Sulfamide derivative [RR'NSO(2)NH(2)] as inhibitors, that are required for selective binding of carbonic anhydrase isozymes (CAI and CAII). In the analysis, stepwise multiple linear regression was performed using physiochemical parameters as independent variable and CA-I and CA-II inhibitory activity as dependent variable, respectively. The best multiparametric QSAR model obtained for CA-I inhibitory activity shows good statistical significance (r= 0.9714) and predictability (Q(2)=0.8921), involving the Electronic descriptors viz. Highest Occupied Molecular Orbital, Lowest Unoccupied Molecular Orbital and Steric descriptors viz. Principal moment of Inertia at X axis. Similarly, CA-II inhibitory activity also shows good statistical significance (r=0.9644) and predictability (Q(2)=0.8699) involving aforementioned descriptors. The predictive power of the model was successfully tested externally using a set of six compounds as test set for CA-I inhibitory activity and a set of seven compounds in case of CA-II inhibitory activity with good predictive squared correlation coefficient, r(2)(pred)=0.6016 and 0.7662, respectively. Overview of analysis favours substituents with high electronegativity and less bulk at R and R' positions of the parent nucleus, provides a basis to design new Sulfamide derivatives possessing potent and selective carbonic anhydrase-II inhibitory activity.

Metabolically labile cannabinoid esters: A ‘soft drug’ approach for the development of cannabinoid-based therapeutic drugs

Biphenylic ester derivatives, designed by using a ‘soft-drug’ approach, proved to possess good binding properties toward cannabinoid CB 1 and CB 2 receptors and, at the same time, their metabolically labile ester portion would promote a rapid systemic inactivation. This may constitute a possible solution to the psychotropic side effects encountered when cannabinoids are therapeutically employed as local analgesic or antiglaucoma agents.

The Development of Topically Acting Carbonic Anhydrase Inhibitors as Antiglaucoma Agents

Carbonic anhydrase inhibitors (CAIs) such as acetazolamide, methazolamide, ethoxzolamide and dichlorophenamide were and still are widely used systemic antiglaucoma drugs. Their mechanism of action consists in inhibition of CA isozymes present in ciliary processes of the eye (such as CA II, IV and XII), with the consequent reduction of bicarbonate and aqueous humour secretion, and of elevated intraocular pressure (IOP) characteristic of this disease. Since CA II/IV/XII are present in many other tissues/organs, generally, systemic CAIs possess undesired side effects such as numbness and tingling of extremities; metallic taste; depression; fatigue; malaise; weight loss; decreased libido; gastrointestinal irritation; metabolic acidosis; renal calculi and transient myopia. In order to avoid these undesired side effects, recently, topically effective CAIs have been developed. Two drugs are available clinically: dorzolamide and brinzolamide. Both these drugs are applied topically as water solutions/suspensions, alone or in combination with other agents (such as beta-blockers, prostaglandin derivatives, etc) and produce a consistent and prolonged reduction of IOP. Furthermore, recent reports show both the systemically as well as topically acting sulfonamide CAIs to be effective in the treatment of macular oedema and other macular degeneration diseases, for which pharmacological treatment was unavailable up to now. Much research is in act in the search of even more effective topically acting CAIs, free of the inconveniences and side effects of the presently available drugs. For achieving this goal, a recently reported strategy, the tail approach, was extensively applied for the synthesis of large numbers of derivatives possessing various physico-chemical properties. Many such new sulfonamides showed promising antiglaucoma activity in animal models of the disease.

Therapeutic applications of the carbonic anhydrase inhibitors

Inhibitors of the zinc enzyme carbonic anhydrase (CA) targeting different isozymes among the 15 presently reported in humans have various therapeutic applications. These enzymes are efficient catalysts for the hydration of carbon dioxide to bicarbonate and protons, playing crucial physiological/pathological roles related to acid–base homeostasis, secretion of electrolytes, transport of ions, biosynthetic reactions and tumorigenesis. Many CA inhibitors have been reported as antiglaucoma, anticancer and antiobesity agents, or for the management of a variety of neurological disorders, including epilepsy and altitude disease. Furthermore, some CA isozymes appear to be valuable markers of tumor progression in a variety of tissues/organs. Various CAs present in pathogens such as Plasmodium falciparum, Helicobacter pylori, Mycobacterium tuberculosis, Candida albicans and Cryptococcus neoformans, have started to also be investigated recently as drug targets. Recent progress in all these areas, as well as in the characterization of new such enzymes isolated in many other organisms/tissues, in addition to their detailed catalytic/inhibition mechanisms, are reviewed herein, together with the therapeutic use of these enzyme inhibitors and drug-design studies for obtaining such new-generation derivatives with improved activity.

Carbonic anhydrase inhibitors: Binding of an antiglaucoma glycosyl-sulfanilamide derivative to human isoform II and its consequences for the drug design of enzyme inhibitors incorporating sugar moieties

N-(4-Sulfamoylphenyl)-α- d-glucopyranosylamine, a promising topical antiglaucoma agent, is a potent inhibitor of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1). The high resolution X-ray crystal structure of its adduct with the target isoform involved in glaucoma, CA II, is reported here. The sugar sulfanilamide derivative binds to the enzyme in a totally new manner as compared to other CA–inhibitor adducts investigated earlier. The sulfonamide anchor was coordinated to the active site metal ion, and the phenylene ring of the inhibitor filled the channel leading to the active site cavity. The glycosyl moiety responsible for the high water solubility of the compound was oriented towards a hydrophilic region of the active site, where no other inhibitors were observed to be bound up to now. A network of seven hydrogen bonds with four water molecules and the amino acid residues Pro201, Pro202 and Gln92 further stabilize the enzyme–inhibitor adduct. Topiramate, another sugar-based CA inhibitor, binds in a completely different manner to CA II as compared to the sulfonamide investigated here. These findings are useful for the design of potent, sugar-derived enzyme inhibitors.

Cellular and molecular effects of unoprostone as a BK channel activator

Effects of unoprostone isopropyl (unoprostone), a prostaglandin metabolite analog; latanoprost, a PGF 2α analog; and PGF 2α were examined in HCN-1A cells, a model system for studies of large conductance Ca 2+ activated K +(BK) channel activator-based neuroprotective agents. Unoprostone and latanoprost, both used as anti-glaucoma agents, have been suggested to act through FP receptors and have neuroprotective effects. Ion channel activation, plasma membrane polarization, [Ca 2+] i changes and protection against long-term irreversible glutamate-induced [Ca 2+] i increases were studied. Unoprostone activated iberiotoxin (IbTX)-sensitive BK channels in HCN-1A cells with an EC 50 of 0.6 ± 0.2 nM and had no effect on Cl − currents. Unoprostone caused IbTX-sensitive plasma membrane hyperpolarization that was insensitive to AL8810, an FP receptor antagonist. In contrast, latanoprost and PGF 2α activated a Cl − current sensitive to [Ca 2+] i chelation, tamoxifen and AL8810, and caused IbTX-insensitive, AL8810-sensitive membrane depolarization consistent with FP receptor-mediated Ca 2+ signaling Cl − current activation. Latanoprost and PGF 2α, but not unoprostone, increased [Ca 2+] i. Unoprostone, PGF 2α only partially, but not latanoprost protected HCN-1A cells against glutamate-induced Ca 2+ deregulation. These findings show that unoprostone has a distinctly different mechanism of action from latanoprost and PGF 2α. Whether unoprostone affects the BK channel directly or an unidentified signaling mechanism has not been determined.

Carbonic anhydrase inhibitors and activators and their use in therapy

Among the 16 different α-carbonic anhydrase (CA, EC 4.2.1.1) isoforms isolated in mammals, 13 possess catalytic activity for the reversible hydration of carbon dioxide to bicarbonate. Some of them are cytosolic (CA I, CA II, CA III, CA VII, CA XIII), others are membrane-bound (CA IV, CA IX, CA XII, CA XIV and CA XV); CA VA and CA VB are mitochondrial and CA VI is secreted in saliva and milk. Representatives of the β – δ-CA family are highly abundant in fungi, yeasts, plants, diatoms, bacteria and archaea. These enzymes are very efficient catalysts playing crucial physiological/pathological roles related to acid–base homeostasis, secretion of electrolytes, transport of ions, biosynthetic reactions and tumourigenesis. Many of the catalytically active CAs present in humans are targets for the drug design. CA inhibitors of the sulfonamide, sulfamate or sulfamide type show applications as antiglaucoma, antiepileptic, antiobesity or antitumour agents and they target different isoforms involved in such processes (CA II and XII for the antiglaucoma action; CA VII and II for the antiepileptic one; CA VA and VB for the antiobesity activity and CA IX and XII for the antitumour effects, respectively). Various CAs present in pathogenic organisms (such as Plasmodium falciparum, Helicobacter pylori, Mycobacterium tuberculosis, Candida albicans, Cryptococcus neoformans etc.) also started to be investigated recently as drug targets. Activation of mammalian CAs by various classes of activators intensively studied may ultimately lead to the design of pharmacologically useful derivatives for the enhancement of synaptic efficacy, which may represent a conceptually new approach for the treatment of depression, Alzheimer’s disease, ageing and other conditions in which spatial learning and memory therapy must be enhanced. Important progress has been achieved in the drug design of CA inhibitors and activators both by synthesising novel classes of such agents, in the search of compounds with selectivity for various isozymes and also by resolving the X-ray crystal structure of adducts of different CA isoforms with inhibitors/activators with pharmacological applications.

Anterior chamber depth and intraocular pressure following panretinal argon laser photocoagulation for diabetic retinopathy

Anterior chamber depth and intraocular pressure following panretinal argon laser photocoagulation for diabetic retinopathy