Intraocular Pressure Lowering Activity Research Articles

Impact of mucoadhesive agent inclusion on the intraocular pressure lowering profile of Δ9-tetrahydrocannabinol-valine-hemisuccinate loaded nanoemulsions in New Zealand white rabbits

The current study aimed to determine the effect of inclusion of a mucoadhesive agent on the intensity and duration of intraocular pressure (IOP) lowering activity of Δ9-tetrahydrocannabinol-valine-hemisuccinate (THC-VHS) loaded in a nanoemulsion (THC-VHS-NE) formulation. THC-VHS-NE formulation with Carbopol®940NF added as a mucoadhesive agent (THC-VHS-NEC) was prepared using hot-homogenization followed by probe sonication and characterized. A comparative evaluation of the IOP lowering activity of THC-VHS-NEC, THC-VHS-NE, THC-NEC, and commercial latanoprost ophthalmic solution, was undertaken in normotensive New Zealand white rabbits. The effect of pH, surfactant concentration, and autoclave process on the IOP lowering activity of THC-VHS-NEC was also studied. The formulation demonstrated desired viscosity, physicochemical properties, and autoclave process stability. The THC-VHS-NEC formulation showed a significant (p < 0.05) improvement in the duration of IOP lowering activity, compared to THC-NEC and THC-VHS-NE. Moreover, in this model, THC-VHS-NEC was more effective than commercially available latanoprost ophthalmic formulation, in terms of both duration and intensity of IOP lowering. A change in formulation pH, surfactant concentration, or sterilization process did not impact the IOP lowering activity of THC-VHS-NEC. Overall, inclusion of a mucoadhesive agent in THC-VHS-NE formulation, significantly increased the duration of activity, and could lead to a once- or twice- a day dosing regimen.

Effect of surfactant concentration and sterilization process on intraocular pressure-lowering activity of Δ9-tetrahydrocannabinol-valine-hemisuccinate (NB1111) nanoemulsions.

The use of Δ9-tetrahydrocannabinol (THC) and Δ9-tetrahydrocannabinol-valine-hemisuccinate (THC-VHS; NB1111) has recently been investigated in the management of intraocular pressure (IOP). The current study was undertaken to develop an optimized THC-VHS-loaded nanoemulsion formulation (NE; THC-VHS-NE) that could improve the drug load and duration of activity. THC-VHS-NE formulation was prepared by homogenization followed by ultrasonication. Sesame oil, Tween®80, and Poloxamer®188 were used as the oil, surfactant, and cosurfactant, respectively. Stability of the optimized THC-VHS-NE formulation was observed at 4°C. The IOP lowering effect of the lead formulations, commercial timolol, and latanoprost ophthalmic solutions, as well as an emulsion in Tocrisolve™ (THC-VHS-TOC), was studied in New Zealand White rabbits following topical administration. The effect of surfactant concentration and sterilization process on IOP-lowering activity was also studied. THC-VHS-NE formulations (0.5, 1.0, and 2.0% w/v) showed dose dependent duration of action. The 1.0%w/v THC-VHS-NE formulation was selected for further evaluation because of its desirable physical and chemical characteristics. THC-VHS-NE formulation prepared with 2% w/v Tween®80 exhibited a higher drop in IOP than the 0.75 and 4.0% w/v of Tween®80 containing formulations. The IOP-lowering duration was, however, similar for the formulations with 0.75 and 2.0% Tween®80, while that with 4.0% Tween®80 was shorter. THC-VHS-NE formulation produced a greater drop in IOP (p<0.05) and a longer duration of activity compared to THC-VHS-TOC, latanoprost, and timolol. The formulation could be sterilized by filtration without impacting product attributes. Overall, the optimized THC-VHS-NE formulation demonstrated a significantly better IOP reduction profile in the test model compared to the commercial ophthalmic solutions evaluated.

Pharmacokinetics and intraocular pressure–lowering activity of TAK-639, a novel C-type natriuretic peptide analog, in rabbit, dog, and monkey

TAK-639 is a topical, 9–amino acid, synthetic, C-type natriuretic peptide analog in development for the treatment of primary open-angle glaucoma and ocular hypertension. This study investigated the impact of TAK-639 on intraocular pressure (IOP), the levels of TAK-639 in aqueous humor, and the pharmacokinetic/pharmacodynamic relationship of TAK-639 following topical ocular administration to normotensive female Dutch belted rabbits, beagle dogs, and cynomolgus monkeys. In the IOP studies, rabbits (n = 6/group) and dogs (n = 8/group) received a single topical ocular dose of TAK-639 0.03%, 0.1%, 0.3%, or 0.6% in the right eye and vehicle in the left eye; monkeys (n = 8/group) received TAK-639 0.1%, 0.3%, 0.6%, 0.9%, or 1.2% in the right eye only. IOP was measured pre dose and at various time points from 0.5 to 24 h post dose for rabbits, and 1–48 h post dose for dogs and monkeys. To assess exposure in aqueous humor, another set of animals received a single ocular dose of TAK-639 0.03%, 0.1%, 0.3%, or 0.6% (rabbits, n = 20/group; dogs, n = 14/group) or TAK-639 0.3%, 0.6%, or 1.2% (monkeys, n = 10/group) in both eyes. Aqueous humor and plasma were collected at the same post dose time points at which IOP was measured. Aqueous humor and plasma TAK-639 concentrations were measured by liquid chromatography–mass spectrometry, and pharmacokinetic parameters were estimated with non-compartmental analysis. Topical ocular administration of TAK-639 resulted in a dose-dependent decrease in IOP, with maximum mean decreases in IOP ranging from −8.90% to −34.4% in the rabbit, from −16.5% to −26.4% in the dog, and from −3.43% to −13.5% in the monkey. The duration of the IOP-lowering effect was 12 h in the rabbit and monkey and 48 h in the dog. TAK-639 exposure in aqueous humor (both maximum concentration and area under the curve) was also dose dependent, with maximum concentration ranging from 0.152 to 93.6 ng/mL (0.03% and 0.6% doses, respectively) in rabbits, 0.490–13.8 ng/mL (0.03% and 0.3% doses, respectively) in dogs, and 1.16–18.1 ng/mL (0.3% and 1.2% doses, respectively) in monkeys. The pharmacokinetic/pharmacodynamic profile, when fitted to an inhibitory sigmoidal model, demonstrated that TAK-639 exposure in aqueous humor correlated well with IOP reduction in these species. The TAK-639 exposure in aqueous humor at half maximal IOP reduction (EC50) was lower in monkey and dog than in rabbit (0.2 and 0.4 vs. 2.0 ng/mL, respectively). In plasma, quantifiable concentrations of TAK-639 were low and detectable predominantly at early time points. In conclusion, in rabbit, dog, and monkey, a single topical ocular drop of TAK-639 had a significant IOP-lowering effect that correlated well with increases in TAK-639 levels in aqueous humor and resulted in minimal systemic exposure of TAK-639.

Intraocular pressure-lowering effects of imidazo[1,2-a]- and pyrimido[1,2-a]benzimidazole compounds in rats with dexamethasone-induced ocular hypertension

Ocular hypertension is believed to be involved in the etiology of primary open-angle glaucoma. Although many pharmaceutical agents have been shown to be effective for the reduction of intraocular pressure (IOP), a significant opportunity to improve glaucoma treatments remains. Thus, the aims of the present study were: (1) to evaluate the IOP-lowering effect of four compounds RU-551, RU-555, RU-839 (pyrimido[1,2-a]benzimidazole), and RU-615 (imidazo[1,2-a]benzimidazole) on steroid-induced ocular hypertension in rats after single drop and chronic applications; and (2) to test in silico and in vitro conventional rho-associated kinase (ROCK) inhibitory activity of the selected compound. This study demonstrated that RU-551, RU-555, RU-839, and RU-615 significantly reduced IOP in Sprague Dawley rats with dexamethasone (DEXA) induced ocular hypertension after single drop administration (0.1%), however RU-615 showed the best IOP lowering effect as indicated by maximum IOP reduction of 22.32% from baseline. Repeated dose topical application of RU-615 caused sustained reduction of IOP from baseline throughout the 3 weeks of treatment with maximum IOP reduction of 30.31% on day 15. This study also showed that the steroid-induced increase in IOP is associated with increased retinal oxidative stress and significant retinal ganglion cells (RGCs) loss. Prolonged treatment with RU-615 over 3 weeks results in normalization of IOP in DEXA-treated rats with partial restoration of retinal antioxidant status (catalase, glutathione and superoxide dismutase) and subsequent protective effect against RGC loss. Thus, IOP lowering activity of RU-615 together with antioxidant properties might be the factors that contribute to prevention of further RGC loss. In vitro part of this study explored the ROCK inhibitory activity of RU-615 using dexamethasone-treated human trabecular meshwork cells as a possible mechanism of action of its IOP lowering activity. However, this study didn’t show conventional ROCK inhibition by RU-615 which was later confirmed by in silico consensus prediction. Therefore, in the future studies it is important to identify the upstream target receptors for RU-615 and then delineate the involved intracellular signalling pathways which are likely to be other than ROCK inhibition.

Development and investigation of timolol maleate niosomal formulations for the treatment of glaucoma

The objective of the present study was to develop niosomal gels loaded with Timolol Maleate (TM), Non-selective beta-adrenergic receptor antagonist, for prolonged duration and improved bioavailability for glaucoma treatment. TM niosomes were prepared by film hydration method with various mixtures of different non-ionic surfactants including Span 20, 40, 60 and Tween 20, 40, along with cholesterol. The prepared vesicles were evaluated for entrapment efficiency, in vitro drug release, particle size, zeta potential and morphology by optical and transmission electron microscopy (TEM). The selected formulations were incorporated into Sodium carboxymethyl cellulose (CMC Na) and Carbopol 934 gels. Gel formulations were characterized for in vitro drug permeation and ex vivo drug permeation through bovine cornea. In addition, stability study, isotonicity test and in-vivo evaluation of the selected formulations were done. The results showed that, the niosomes formed were white and spherical in shape with uniform particle size. Formulations containing span 60 and that containing mixture of span 60 and tween 40 gave the highest entrapment efficiency (94.6% and 98.8%, respectively) and a sustained release of timolol maleate from the niosomes within 24 h (96% and 97.10%, respectively). The in vitro and ex vivo drug release studies showed that there was a slow and prolonged release of drug from niosomal gel formulations. Considering the in-vitro release, niosomal gel formulae GN5 and GN6 (containing CMC Na 3% w/w) were the best among the studied formulations. Draize test was carried out and the intra-ocular pressure lowering activity of prepared formulations were detected and compared with marketed Timogel. Formula containing 3% CMC Na showed relative bioavailability 1.6 times more than bioavailability of marketed Timogel.

Benzenesulfonamides Incorporating Flexible Triazole Moieties Are Highly Effective Carbonic Anhydrase Inhibitors: Synthesis and Kinetic, Crystallographic, Computational, and Intraocular Pressure Lowering Investigations.

Herein we report the synthesis of two series of benzenesulfonamide containing compounds that incorporate the phenyl-1,2,3-triazole moieties. We explored the insertion of appropriate linkers, such as ether, thioether, and amino type, into the inner section of the molecules with the intent to confer additional flexibility. All obtained compounds were screened in vitro as inhibitors of the physiologically relevant human (h) isoforms of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). Many of them were low nanomolar or subnanomolar hCA II, IX, and XII inhibitors, whereas they did not potently inhibit hCA I. Computational and X-ray crystallographic studies of the enzyme-inhibitor adducts helped us to rationalize the obtained results. Some of the sulfonamides reported here showed significant intraocular pressure lowering activity in an animal model of glaucoma.

Ocular Dorzolamide Nanoliposomes for Prolonged IOP Reduction: in-vitroand in-vivo Evaluation in Rabbits.

Dorzolamide ophthalmic drop is one of the most common glaucoma medications but it has a short residence time in the eye. The aim of this study is to develop ocular dorzolamide HCl nanoliposomes (DRZ - nanoliposomes) and to evaluate their potential use for the treatment of ocular hypertension. Nanoliposomes were prepared using Reverse-phase evaporation vesicle (REV) and thin layer hydration (TLH) method with 7:3 and 7:4 molar ratios of phosphatidylcholine:cholesterol. The physicochemical properties of the formulations were investigated. Formulations with 7:4 lipid ratios were evaluated in terms of drug release, physical stability and ex-vivo permeation through the excised albino rabbit cornea. The rabbits in groups of 6 were treated with selected DRZ - nanoliposomes or dorzolamide solution or marketed dorzolamid preparation (Biosopt®) and intraocular pressure (IOP) was monitored. Formulations with 7:4 molar ratio entrapped greater amount of drug compared to those with 7:3 lipid components ratio. DRZ - nanoliposomes with 7:4 lipid ratio showed more transcorneal permeation than Dorzolamide solution (p<0.05); and the formulation prepared by TLH method exhibited higher permeability than that prepared by REV method (p<0.05). The selected DRZ - nanoliposomes showed greater IOP lowering activity and a more prolonged effect compared to dorzolamide solution and Biosopt®. DRZ - nanoliposomes prepared by TLH method with 7:4 ratios showed promising results as a candidate for the treatment of ocular hypertension.

A Novel Pilocarpine Microemulsion as an Ocular Delivery System: In Vitro and In Vivo Studies

Despite several disadvantages like a rapid wash out and dilution of the formulation leading to a low bioavailability, eye drops are the most commonly used dosage form for the ocular route. Due to their properties and numerous benefits, microemulsions are promising systems for topical drug delivery. The purpose of this work is to develop a suitable ocular microemulsion formulation with adequate physicochemical stability for enhancing the bioavailability of pilocarpine. Physicochemical characteristics of the microemulsion including the drug content, refractive index, conductivity, viscosity, intraocular pressure (IOP) and ocular tolerance were investigated. The ocular irritation test and the IOP lowering activity of the microemulsion were studied in New Zealand white rabbits. The developed formulation showed good physicochemical properties and a beneficial stability for six months. After microemulsion instillation into the rabbit eyes, the intraocular pressure was reduced significantly. The ocular irritation test used suggested that microemulsion formulation did not cause any significant allergies to the eye.

Formulation and evaluation of stimuli-sensitive hydrogels of timolol maleate and brimonidine tartrate for the treatment of glaucoma.

Background:Stimuli-sensitive hydrogels are hydrophilic, three-dimensional, polymeric network structure capable of imbibing large amounts of water or biological fluids on stimulation, such as pH, temperature, and ionic change. Owing to the drawback of conventional therapy for ocular delivery, and to provide additive effect on intraocular pressure (IOP) reduction, stimuli sensitive hydrogel membranes containing a combination of timolol maleate and brimonidine tartrate were formulated for the treatment of glaucoma.Materials and Methods:Stimuli-sensitive hydrogel were formulated by timolol maleate and brimonidine tartrate. Poly acrylic acid (carbopol C 934p) is used as a gelling agent, hydroxylpropyl methylcellulose as viscolizer, sodium chloride as tonicity agent. Bezalkonium chloride as preservative. White rabbits of both sexes, weighing between 2 and 3 kg were used for the study. Stirring of ingredients in pH 4 phosphate buffers at high speed was carried out.Result:Viscosity of the prepared hydrogels lies in the optimum range that is, 25-55 cps. Infrared spectroscopy studies show that there is no interaction between the drug and polymer. Drug released up to 90% at the end of 8 h. The hydrogel membranes were found to be sterile, nonirritant to the eye. Marketed formulation showed a decrease in IOP up to 14 mmHg at the end of 5 h and then elimination of drug, F2 and F6 maintain the sustained effect up to 12 h.Conclusion:Stimuli-sensitive hydrogels was successfully formulated and evaluated for rheological studies, drug release studies, drug interaction studies, sterility studies, ocular irritation studies, and in vivo studies. IOP lowering activity of the combination of timolol maleate and brimonidine tartrate in stimuli-sensitive hydrogel was better when compared with alone medication, which shows the additive effect of combination medication.

Probing influence of methodological variation on active loading of acetazolamide into nanoliposomes: Biophysical, in vitro, ex vivo, in vivo and rheological investigation

In the present work comparative evaluation of acetate and pH gradient techniques for effective drug loading in liposomes has been investigated. The acetazolamide (ACZ) loaded liposomes prepared by two methods were analyzed by vesicle size analysis, zeta potential, percent encapsulation efficiency, in vitro drug release studies and intraocular pressure lowering activity. ICH guidelines were followed for determining stability of the prepared liposomes. The superiority of acetate gradient method for active loading of acetazolamide has been established. The prepared acetate gradient positive liposomes showed extended hypotensive effect when compared to other liposomal formulations. Thus ACZ loaded liposomes prepared by acetate gradient technique may serve as promising ocular delivery system in the treatment of glaucoma. The current work emphasizes the fact that the techniques used for active drug loading into liposomes strongly influence the pharmaceutical performance of the final formulation.

Xanthates and Trithiocarbonates Strongly Inhibit Carbonic Anhydrases and Show Antiglaucoma Effects in Vivo

Dithiocarbamates (DTCs) were recently discovered as carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. A series of xanthates and a trithiocarbonate, structurally related to the DTCs, were prepared by reaction of alcohols/thiols with carbon disulfide in the presence of bases. These compounds were tested for the inhibition of four human (h) isoforms, hCA I, II, IX, and XII, involved in pathologies such as glaucoma (CA II and XII) or cancer (CA IX). Several low nanomolar xanthate/trithiocarbonate inhibitors targeting these CAs were detected. A docking study of some xanthates within the CA II active site showed that these compounds bind in a similar manner with the dithiocarbamates, coordinating monodentately to the Zn(II) ion from the enzyme active site. Several xanthates showed potent intraocular pressure lowering activity in two animal models of glaucoma via the topical administration. Xanthates and thioxanthates represent two novel, promising classes of CA inhibitors.

FORMULATION AND EVALUATION OF SOME SELECTED TIMOLOL MALEATE OPHTHALMIC PREPARATIONS

The purpose of this study was to prepare and evaluate certainTimolol maleate (TM) polymeric formulations including viscous solutions, hydrogels and in -situ gels aiming to improve its ocular bioavailability and decrease its side effects. In this study, Chitosan (CS), hydroxyehtylcellulose (HEC), hydroxypropylmethylcellulose (HPMC) and sodium carboxy - methylcellulose (NaCMC) were used to prepare TM viscous solutions and hydrogels. In -situ gels of Gelrite and Pluronic F-127 (Pl F-127) were prepared at different concentrations . Mucoadhesives namely CS or HEC were incorporated to Pl F127 to produce mucoadhesive/in- situ gel. The prepared formulations were evaluated for their in -vitro drug release, viscosity, gelation temperature and mucoadhesive force. The selected TM formulations were tested for their effect on intraocular pressure (IOP) and systemic side effects based on blood pressure (BP), heart rate (HR) and respiration rate (RR). The results revealed that, TM in situ-gels F25 (containing Pl F-127 20% and CS 1.5% w/w) and F31(containing Gelrite 0.6% w/w) showed reasonable in-vitro results, and a marked IOP lowering activity without systemic side effects compared to TM marketed eye drops.

Dithiocarbamates Strongly Inhibit Carbonic Anhydrases and Show Antiglaucoma Action in Vivo

A series of dithiocarbamates were prepared by reaction of primary/secondary amines with carbon disulfide in the presence of bases. These compounds were tested for the inhibition of four human (h) isoforms of the zinc enzyme carbonic anhydrase, CA (EC 4.2.1.1), hCA I, II, IX, and XII, involved in pathologies such as glaucoma (CA II and XII) or cancer (CA IX). Several low nanomolar inhibitors targeting these CAs were detected. The X-ray crystal structure of the hCA II adduct with morpholine dithiocarbamate evidenced the inhibition mechanism of these compounds, which coordinate to the metal ion through a sulfur atom from the dithiocarbamate zinc-binding function. Some dithiocarbamates showed an effective intraocular pressure lowering activity in an animal model of glucoma.

Topically Effective Acetazolamide Eye-drop Solution in Man

Drug-cyclodextrin polymer co-complexes increase the solubility of lipophilic drugs in aqueous solutions, such as eye-drops, without affecting their lipophilicity. Also, the co-complexes are able enhance the ocular availability of the drug after topical administration. The anhydrase inhibitor acetazolamide was solubilized in an aqueous eye-drop formulation through formation of a co-complex with 2-hydroxypropyl-β-cyclodextrin and hydroxypropyl methylcellulose. The intraocular pressure (IOP)-lowering activity of a 1% (w/v) acetazolamide eye-drop solution was evaluated in nine ocular hypertensive patients. The patients were given the eye-drops three times a day for 28 days. Maximum IOP lowering activity was observed at 9 a m, 2 h after installation of the drops, with a mean IOP-lowering of 15.6 ± 8.9%. Through HP-β-CD-HPMC co-complex formation, it was possible to obtain a topically active aqueous acetazolamide eye-drop solution. In man, the 1% (w/v) acetazolamide eye-drop solution had less IOP-lowering activity than an aqueous 2% (w/v) dorzolamide eye-drop solution.

Carbonic anhydrase inhibitors: Design of thioureido sulfonamides with potent isozyme II and XII inhibitory properties and intraocular pressure lowering activity in a rabbit model of glaucoma

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 Is 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.

Update on topical carbonic anhydrase inhibitors.

Topical carbonic anhydrase inhibitors are a novel addition to the armamentarium of medical glaucoma treatment; dorzolamide has been available since 1995 and brinzolamide since 1998. They lower intraocular pressure by inhibiting carbonic anhydrase, a key enzyme for aqueous humor formation. Intraocular pressure-lowering activity of the substances appears to be the same and is similar to that of most other agents, but it does not reach the activity of the unselective beta-blocker timolol or the prostaglandin latanoprost. On concomitant treatment, additivity is reached with all other topical agents. A possible improvement of blood flow may offer an additional benefit, but its significance for the long-term outcome for human glaucoma remains to be shown. Side effects are mostly local. A more physiologic pH of brinzolamide appears to be advantageous.

Intraocular Pressure-Lowering Activity and In Vivo Disposition of Dipivalyl Terbutalone in Rabbits

The ocular hypotensive activity and in vivo disposition of dipivalyl terbutalone, a chemical delivery system for terbutaline, were investigated in the albino rabbit model. The dose–response relationship was assessed at drug concentrations ranging from 0.5 to 4% in normal saline. Intraocular pressure (IOP)-lowering activity of dipivalyl terbutalone was compared with epinephrine in equal concentrations. The in vivo disposition was investigated after topical administration of dipivalyl terbutalone at 4% dose level for which two metabolic products, terbutaline, and terbutalone, were monitored in different anterior segment tissues/fluid of albino rabbits, including corneal and iris–ciliary body homogenates and aqueous humor. The instillation of 0.5, 1, 2, and 4% solutions (1 drop of 50 μL) significantly decreased the IOP of normotensive rabbits in a dose-dependant manner. At the highest dose, the maximum reduction (5.6 ± 0.65 mm Hg) was observed at 3 h. In a comparative efficacy study, dipivalyl terbutalone was found to be more effective than epinephrine. In the in vivo distribution after the topical administration of dipivalyl terbutalone, terbutaline was found only in the iris–ciliary body, whereas terbutalone was found in all parts of the eye studied. This work suggests the potential use of dipivalyl terbutalone as an antiglaucoma agent, representing a new chemical delivery system for terbutaline.

Intraocular pressure-lowering activity of phenolic antioxidants in normotensive rabbits

PURPOSE. The purpose of this study was to determine the intraocular pressure (IOP)-lowering activity of phenolic antioxidants injected intravenously into normotensive rabbits. Antioxidants belonging to the following classes were tested: cinnamic acids; flavonols; flavanols; anthocyanidins; isoflavones; and tannic acid. METHODS. Test compounds were dissolved in either water or oil/saline as vehicle and injected intravenously into normotensive rabbits. IOP was monitored hourly after injection and expressed as a percent relative to preinjection values. Controls were conducted using vehicle alone. IOP from each eye was averaged to provide one value per rabbit. Dose-response data beginning at 0.01 mg-2 mg doses were collected for compounds shown to be active at 1 mg. RESULTS. Epigallocatechin, epigallocatechin gallate and myricetin lowered IOP below control levels at doses of 1 mg. Tannic acid was the most active, lowering IOP more than 30% at doses of 200 µg. CONCLUSION. Only phenolic antioxidants containing a pyrogallol B-ring system and nonaromatic C-ring (epigallocatechin, epigallocatechin gallate and myricetin) or possible galloyl glucosides as found in tannic acid were active in lowering IOP, with tannic acid being the most active. Other antioxidants were not active in this system suggesting a more specific structural requirement for interacting with appropriate ocular systems. The protein or proteoglycan-binding properties of these molecules may also be important in this activity.

A Comparison of Dorzolamide and Timolol in Patients with Pseudoexfoliation and Glaucoma or Ocular Hypertension

The purpose of the study is to compare the efficacy and safety profile of 2.0% dorzolamide (three times daily) and 0.5% timolol (twice daily) for up to 6 months in patients with glaucoma or ocular hypertension associated with pseudoexfoliation. The additive effects of dorzolamide and timolol in patients requiring add-on therapy also was evaluated. This was a double-masked, randomized, parallel comparison study at 15 Scandinavian sites. One hundred eighty-four patients with pseudoexfoliation and either glaucoma or ocular hypertension who were 21 to 85 years of age were studied. The treatment groups were 2.0% dorzolamide three times daily and 0.5% timolol maleate twice daily. At 6 months, the mean percent reduction in intraocular pressure of 2% dorzolamide and 0.5% timolol was 24% and 29%, respectively, at morning peak and 21% and 23%, respectively, at afternoon trough. The additional intraocular pressure-lowering effect of adding 2.0% dorzolamide twice daily to patients receiving timolol was 14% and 15%, at peak and trough, respectively. There were no differences between treatment groups in the incidence of clinical adverse experiences, and dorzolamide was not associated with the systemic adverse effects typically ascribed to the use of oral carbonic anhydrase inhibitors. Two percent dorzolamide (three times daily) was effective and well tolerated in patients with glaucoma or ocular hypertension associated with pseudoexfoliation over the course of 6 months; 0.5% timolol (twice daily) had a greater level of intraocular pressure-lowering activity than did dorzolamide, although the difference between the two treatments became less pronounced during the study period. Finally, 2.0% dorzolamide (twice daily) produced additional lowering of intraocular pressure when given with 0.5% timolol (twice daily).

The preclinical pharmacology of dorzolamide hydrochloride, a topical carbonic anhydrase inhibitor.

Dorzolamide hydrochloride (S,S-5,6-dihydro-4H-4-ethylamino-6-methylthieno [2,3-b]thiopyran-2-sulfonamide-7,7-dioxide HCl; MK-507; L-671,152) is a water-soluble, potent inhibitor of human carbonic anhydrase isoenzymes II and IV in vitro, the respective IC50 values being 0.18 nM and 6.9 nM. In contrast, it was found to be a much weaker inhibitor of human carbonic anhydrase isoenzyme I (IC50 value of 600 nM). The topical administration of one 50 microliters drop of 0.5%, 1% and 2% solutions of dorzolamide maximally lowered the intraocular pressure (IOP) of glaucomatous monkeys by 22%, 30% and 37%, respectively. Good ocular hypotensive activity was also observed in ocular normotensive and hypertensive rabbits. Its site of action was within the eye, and the reductions in IOP in both species was achieved via decreased aqueous humor inflow. The duration of action of 2% dorzolamide was shorter than that of 0.5% timolol in glaucomatous monkeys. The IOP lowering activity of timolol in this paradigm was enhanced by the concomitant instillation of dorzolamide. Both acutely and repeatedly administered 2% dorzolamide did not decrease regional ocular blood flow in the rabbit, and the topical instillation of the drug had no adverse effects on the eye of rabbits, dogs and monkeys. Dorzolamide has been approved in a number of countries for use in patients with ocular hypertension or open-angle glaucoma.