Brinzolamide/timolol fixed combination: a new ocular suspension for the treatment of open-angle glaucoma and ocular hypertension

For the treatment of open-angle glaucoma, the most frequent cause of irreversible visual loss, fixed combinations of different topical intraocular pressure (IOP) lowering molecules have gained an important role in recent years. The use of fixed combinations reduces the number of daily instillations, which promotes adherence to the prescribed medication and diminishes the exposition of the ocular surface to preservatives. The fixed combination of brinzolamide and timolol was recently approved by the European Medicines Agency (EMEA) and is now available in several countries in Europe. It contains two molecules widely used to treat glaucoma: timolol 0.5% (5 mg/ml) and brinzolamide 1% (10 mg/ml) in ophthalmic suspension formulation. This fixed combination is approved for twice-daily instillation to reduce elevated IOP in open-angle glaucoma and ocular hypertension. The brinzolamide/timolol fixed combination provides an approximately 30 – 33% IOP reduction from the untreated baseline IOP of 25 – 27 mmHg; thus, it is more potent than either of its ingredients alone. It is similarly effective but better tolerated than the dorzolamide/timolol fixed combination, which consists of molecules from the same pharmacological classes. The brinzolamide/timolol fixed combination can be used by itself as a separate therapy, but owing to the additivity of its ingredients to IOP-lowering drugs belonging to other classes, it may also be administered adjunctive to other IOP-reducing molecules, most importantly topical prostaglandin analogues. The ocular and systemic tolerance of the brinzolamide/ timolol fixed combination was reported favorable in Phase III studies, but no long-term clinical experience with this preparation is available at present.     

Brimonidine tartrate for the treatment of glaucoma

Introduction: Brimonidine tartrate is a commonly used eyedrop for short- and long-term lowering of intraocular pressure. Its use has been popularized due to its effects on aqueous suppression and uveoscleral outflow, as well as the suggestion of neuroprotection. Although available with alternative preservative vehicles, brimonidine is associated with high rates of local allergy and is contraindicated in breastfeeding women, neonates, young children, and the elderly due to risk of central nervous system depression. Other topical agents with differing advantages have challenged brimonidine’s role in the treatment algorithm of ocular hypertension and glaucoma.

Areas covered: The authors review the development of topical alpha-adrenergic agonists, with particular attention to the currently available formulations of brimonidine tartrate. Its mechanism of action, pharmacodynamics and safety, and clinical efficacy are analyzed.

Expert opinion: Despite clinical familiarity with brimonidine after two decades of use, agents that offer daily dosing, nocturnal effect, and more favorable ocular and systemic side effect profiles have ultimately led to brimonidine’s adjunctive use in patients with elevated intraocular pressure or high- or low-tension glaucomas. Still, brimonidine may be advantageous in patients undergoing laser trabeculoplasty or iridotomy, in certain forms of glaucoma, or in pregnant individuals prior to the last trimester, underscoring its clinical importance.     

Sustained release of brimonidine from BRI@SR@TPU implant for treatment of glaucoma

Glaucoma is the leading cause of irreversible vision loss worldwide, and reduction of intraocular pressure (IOP) is the only factor that can be interfered to delay disease progression. As the first line and preferred method to treat glaucoma, eye drops have many shortcomings, such as low bioavailability, poor patient compliance, and unsustainable therapeutic effect. In this study, a highly efficient brimonidine (BRI) silicone rubber implant (BRI@SR@TPU implant) has been designed, prepared, characterized, and administrated for sustained relief of IOP to treat glaucoma. The in vitro BRI release from BRI@SR@TPU implants shows a sustainable release profile for up to 35 d, with decreased burst release and increased immediate drug concentration. The carrier materials are not cytotoxic to human corneal epithelial cells and conjunctival epithelial cells, and show good biocompatibility, which can be safely administrated into rabbit’s conjunctival sac. The BRI@SR@TPU implant sustainably released BRI and effectively reduced IOP for 18 d (72 times) compared to the commercial BRI eye drops (6 h). The BRI@SR@TPU implant is thus a promising noninvasive platform product for long-term IOP-reducing in patients with glaucoma and ocular hypertension.     

科比根治疗开角型青光眼和高眼压症的疗效及安全性

目的：研究科比根治疗开角型青光眼和高眼压症的疗效及安全性。方法采用对照研究手段,将符合条件的患者随机分组进行科比根?（溴莫尼定和噻吗洛尔固定复合滴眼液）和非固定联合制剂治疗（0．2％酒石酸溴莫尼定滴眼液及0．5％噻吗洛尔滴眼液）比较。结果在5周的对比治疗后,分析疗效、治疗安全性,科比根?治疗效果与非固定联合制剂治疗效果接近,未出现新的与治疗有关不良事件,未观察到其他治疗安全性的明显差异。结论科比根治疗开角型青光眼和高眼压症的方法与非固定联合制剂的疗效和安全性相似。     

The evolving pharmacotherapeutic profile of brimonidine,an 2-adrenergic agonist,after four years of continuous use

Since its introduction in 1996, use of brimonidine tartrate 0.2% ophthalmic solution (Alphagan^®, Allergan), a highly selective ₂-adrenergic agonist, has become increasingly popular for the initial and long-term management of ocular hypertension and glaucoma. Recently, ongoing clinical comparison trials of up to three years in length have reported sustained intraocular pressure (IOP) lowering efficacy with brimonidine 0.2% b.i.d., which was comparable with timolol 0.5% (Timoptic^®; Merck & Co.), accompanied by a favourable tolerability and safety profile. Also, many post-market studies have demonstrated the utility of brimonidine 0.2% b.i.d. as mono- and adjunctive therapy. Furthermore, major inroads have been made in the study of other possible pharmacotherapeutic benefits of brimonidine treatment, namely the potential for neuroprotection. This review will present a brief developmental history and examine key pharmacotherapeutic characteristics of brimonidine, including its receptor selectivity, IOP-lowering mechanism of action and potential neuroprotective activities. Moreover, the literature on brimonidine’s efficacy and safety profiles in the treatment of ocular hypertension and glaucoma will be perused, and new four-year data from an ongoing double-masked clinical study comparing brimonidine tartrate 0.2% with timolol 0.5%, b.i.d will be introduced. Brimonidine 0.2% b.i.d. provided sustained IOP-lowering efficacy comparable to timolol 0.5% b.i.d., with no significant differences at trough or peak during year four of continuous use. Visual fields were well preserved in both treatment groups with 93% of brimonidine patients and 91% of timolol patients showing no change or improvement. Brimonidine continued to appear safe and well-tolerated, with no clinically significant effects on mean heart rate or blood pressure, and no serious drug-related adverse events (AEs). Two out of 36 brimonidine patients developed ocular allergy; both were resolved without sequelae. Overall post-market surveillance found no reports of unexpected or serious drug-related AEs. These long-term results, in conjunction with those reported in the literature, suggest that brimonidine 0.2% b.i.d. is a highly appropriate first- and second-line therapy for long-term management of glaucoma and ocular hypertension. Potential neuroprotective effects of brimonidine therapy, which might provide additional vision sparing benefit, although supported by compelling animal studies, await clinical verification.     

Glaucoma: a review of adjunctive therapy and new management strategies

Glaucoma is a major cause of vision loss throughout the world. Treatment for glaucoma consists of reducing intraocular pressure (IOP) to an acceptable target range to prevent further optic nerve damage. Typically, this involves the selection of a topical IOP-lowering agent. Five major classes of glaucoma medications are presently available for clinical use. These include α-adrenergic agonists, β-adrenergic antagonists (β-blockers), carbonic anhydrase inhibitors (CAIs), cholinergics and prostaglandin analogs (PGAs). Although β-blockers enjoyed great success as first-line glaucoma therapy for many years, recently the PGAs have gained favor as the initial treatment of choice for most patients. Although the PGAs offer robust IOP reduction as monotherapy, a significant number of patients will require an adjunctive agent for adequate IOP control. Recent studies have demonstrated that α-agonists, β-blockers and CAIs can be used safely and effectively as adjunctive therapy for patients being treated with a PGA. Comparison studies are beginning to appear in the literature to help determine which adjunctive agent is the most effective when used in combination with a PGA. Additional IOP-lowering efficacy with adjunctive therapy does have limitations, particularly with the addition of a third or fourth agent. For those patients on maximal tolerated medical therapy who still need additional IOP reduction, other available options include laser trabeculoplasty and filtration surgery.     

Short- and long-term safety of glaucoma drugs

Glaucoma, a leading cause of blindness worldwide, is a chronic neurodegenerative disorder. Patients with glaucoma may require long-term administration of intraocular pressure (IOP)-lowering medications. These medications belong to several classes of molecules including β-adrenergic blockers, cholinergic agents, α-adrenergic agonists, carbonic anhydrase inhibitors and ocular hypotensive lipids. Most adverse effects associated with IOP-lowering medications are mild and ocular in nature; however, several of them are associated with systemic risks as well as serious ocular effects, especially following chronic use. The following review discusses the acute and long-term effects of commonly used IOP-lowering medications.     

国产与进口溴莫尼定滴眼液的多中心临床对照试验139例

目的:验证国产溴莫尼定滴眼液治疗原发性开角型青光眼和高眼压症的治疗价值。方法:对139例原发性开角型青光眼及高眼压症病人进行为期6 wk的多中心、随机、双盲、阳性对照研究,试验组滴用国产制剂,对照组滴用进口制剂,均早、晚各1次,于治疗前,治疗后2,4,6 wk,随访眼压的变化,并做眼部检查、视野检查,观察生命体征和不良反应。结果:试验组入选70例(70只眼),对照组入选69例(69只眼),完成试验的分别为60例(60只眼)和61例(61只眼)。6 wk后试验组眼压下降(1.0±s0.5)kPa,降眼压的有效率(眼压下降>10%)为98%;对照组下降(0.9±0.4)kPa,有效率为100%。2组比较差异无显著意义。部分病人出现眼烧灼感、眼刺痛、口干、疲劳等不适症状,除试验组2例病人因此中止试验外,其余均能良好耐受。结论:国产溴莫尼定滴眼液对于控制原发性开角型青光眼和高眼压症的眼压是有效和安全的,效果与进口制剂相当。     

他氟前列素治疗开角型青光眼和高眼压症的有效性及安全性评价

目的:综述他氟前列素滴眼液降低开角型青光眼和高眼压症患者眼内压的有效性及安全性评价。方法:使用"他氟前列素"、"开角型青光眼"、"高眼压症"、"有效性"、"安全性"作为检索词在PubMed数据库和中文数据库维普全文、电子期刊等对已发表的文献进行检索,检索2004年至2015年英文文献共52篇及中文文献多篇,包括多中心临床研究及药品信息资料,并对检索结果进行归纳性分析。结果:现有的研究已显示,他氟前列素是一种有效降低眼内压的药物。循证医学也发现他氟前列素安全有效,患者依从性良好。不含防腐剂他氟前列素的降眼压效果与含防腐剂的相同。结论:研究提示,他氟前列素每日1次滴眼可安全有效地降低开角型青光眼及高眼压症患者的眼内压。     

Guanfacine ER for the treatment of adolescent attention-deficit/hyperactivity disorder

Introduction: Guanfacine extended release (GXR) is an alpha 1A noradrenergic agonist that has been approved by the FDA for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD) as a monotherapy, and as an adjunctive therapy to stimulants for the treatment of ADHD in children and adolescents age 6 – 17.

Areas covered: PubMed, the Ovid Medline database, and the PsycInfo database were searched using the term ‘guanfacine'. Results were then limited to criteria such as English and human, from 1990 through December 2011. The resulting yield from the comprehensive literature search was 4391 articles. The titles and abstracts of all articles were reviewed. Studies were selected for full-text review based upon their place in the hierarchy of evidence (e.g., randomized controlled trials), relevance and quality of individual studies, and generalizability to clinical practice. The search was augmented by further search of article reference lists. A total of 15 articles were selected for full-text examination.

Expert opinion: Due to the absence of positive evidence for the efficacy of GXR for monotherapy in adolescents, clinicians should be guarded in the use of GXR for monotherapy in adolescents with ADHD. The use of GXR has considerable promise as an adjunct to stimulants for other behavioral conditions associated with ADHD.     

Preservative-free versus preserved brimonidine %0.15 preparations in the treatment of glaucoma and ocular hypertension: short term evaluation of efficacy,safety, and potential advantages

Abstract

Purpose: To compare the efficacy, safety, and potential advantages of the preservative-free versus preserved brimonidine %0.15 preparations in patients with primer open-angle glaucoma (POAG) or ocular hypertension (OHT).

Methods: Forty-two eyes of the 21 treatment-naive patients with POAG or OHT were enrolled in this study. Eyes were randomly assigned to receive brimonidine-purite 0.15% or preservative-free brimonidine 0.15% two times daily. Efficacy of the two eye drops was assessed by measuring the intraocular pressure (IOP) at 9–10 am at baseline and week 4. Safety and potential advantages of the drops were evaluated at weeks 4 in terms of ocular symptoms and tear parameters. Ocular symptom values of the patients were evaluated with a scale of 0–4 (0?=?no discomfort and 4?=?severe discomfort).

Results: Both of the brimonidine tartrate formulations resulted in statistically similar IOP reduction (preserved formulation; ?5.2?mmHg [22.9% reduction] preservative-free formulation; ?5.7?mmHg [24.1% reduction], p?=?0.37). It was found that brimonidine tartrate formulations with and without topical preservatives did not produce a statistically significant difference in pain, stinging, and blurred vision at the upon instillation (p?>?0.05). However, the burning sensation was significantly higher in the preservative-free formulation at the first instillation compared to the preserved formulation (p?=?0.01). Also, there was no statistically significant difference between the two formulations in terms of symptoms (itching, burning, tearing, stinging, and photophobia) and tear parameters during the day (p?>?0.05).

Conclusions: Although topical preservative-free brimonidine tartrate treated eyes had a more burning sensation at the first drop, the two formulations were similar in terms of ocular tolerability in the short term period. Also, both formulations were found to reduce IOP at a similar rate.     

Efficacy,safety, and current applications of brimonidine

Background: The use of brimonidine to lower intraocular pressure has been the subject of considerable investigation. Variations of the initially approved drug including agents of a lower concentration (Alphagan^® P 0.15 and 0.1%, Allergan, Inc., Irvine, CA, USA) and a fixed-combination mating brimonidine with timolol (Combigan^®, Allergan) evolved the marketing and application of this therapy. Objective: We review available evidence regarding the efficacy and side effect profile of brimonidine as well as its role in glaucoma management. Results/conclusion: Brimonidine is an important component of topical glaucoma treatment that is most limited by local ocular intolerance.     

An evaluation of the fixed-combination of latanoprost and timolol for use in open-angle glaucoma and ocular hypertension

Glaucoma is one of the leading causes of irreversible blindness worldwide. Although there is no cure for this chronic disease, medical treatment is aimed at reducing levels of intraocular pressure (IOP) using ocular hypotensive agents. Very often, patients require more than one IOP-reducing drug, resulting in complex medication regimens that may be difficult to maintain and that can lead to non-compliance. A fixed-combination (FC) ophthalmic solution consisting of the prostaglandin, latanoprost (0.005%), and the β-blocker, timolol (0.5%), is now available. The primary mechanism of action of latanoprost is to increase uveoscleral outflow whereas timolol lowers IOP levels by decreasing the formation of aqueous humor in the ciliary epithelium. Due to the unique mechanism of action of latanoprost, once-daily dosing of one drop of FC latanoprost/timolol results in additional IOP reduction compared with either drug administered separately. FC latanoprost/timolol is well-tolerated and has a safety profile similar to that of its individual components. This combination drug provides a safe, effective and convenient alternative for the treatment of patients with elevated IOP levels uncontrolled with monotherapy.     

Influence of timolol,benzalkonium-preserved timolol,and benzalkonium-preserved brimonidine on oxidative stress biomarkers in the tear film

Abstract

Purpose

The objective of this study was to investigate the influence of topical preservative-free timolol, benzalkonium chloride(BAC)-preserved timolol, BAC-preserved timolol, and BAC-preserved brimonidine on total protein concentration, advanced oxidation protein products (AOPP) content, total sulfhydryl groups content, the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), as well as Total Oxidant Status (TOS), Total Antioxidant Response, and Oxidative Stress Index (OSI) in the tear film.     

Changing therapeutic paradigms in glaucoma management

Glaucoma is a family of diseases commonly characterised by progressive optic neuropathy with associated visual field deficits for which elevated intraocular pressure (IOP) is one of the primary risk factors. For more than a century the main goal of glaucoma management has been to eliminate the risk associated with elevated IOP. In recent years, accumulating evidence of pressure-independent causes of glaucomatous optic neuropathy has led to the recognition that lowering IOP alone may often be insufficient for the long-term preservation of visual function. An innovative therapeutic approach is now emerging to prevent progression of glaucomatous optic neuropathy and preserve vision, irrespective of disease aetiology: direct protection of the optic nerve. In addition to reducing the risk associated with elevated IOP, this neuroprotective approach will augment the overall goal of preserving the optic nerve through direct promotion of retinal ganglion cell (RGC) survival and/or prevention of RGC death. Although no currently available compounds have been clinically demonstrated to provide neuroprotective benefit in glaucoma, recent preclinical studies have shown that alpha-adrenergic agonists, such as brimonidine, provide neuroprotective benefits, as well as excellent IOP lowering efficacy. In addition, new agents with promising neuroprotective utility that are emerging from other studies are now being investigated for efficacy in glaucoma. The review discusses recently introduced compounds and new drugs in development with regard to their potential value in conventional and/or neuroprotective strategies for vision sparing in glaucoma.     

Patent Update: Antibacterial Patents Appearing in the Third Quarter of 1991

The sulfonamides constitute an important class of drugs, with several types of clinically used agents, possessing antibacterial, anticarbonic anhydrase (CA), diuretic, hypoglycaemic, anti-thyroid, protease inhibitory, anticancer and cyclooxygenase (COX) inhibitory activities, among others. A recently developed class of such pharmacological agents, incorporating primary sulfamoyl moieties in their molecule, is constituted by the COX-2 selective inhibitors, with at least two clinically used drugs, celecoxib and valdecoxib, discovered by Pharmacia Corp. It was recently shown that the sulfonamide COX-2-selective inhibitors (but not the methylsulfone ones, such as rofecoxib developed by Merck and Co.) also act as nanomolar inhibitors of CAs, some of which are strongly involved in tumorigenesis. In consequence, the potent anticancer effects of the sulfonamide COX-2-selective inhibitors and the much weaker effects of rofecoxib, reported ultimately by many researchers, may be explained by the contribution of CA inhibition to such processes in addition to COX-2 inhibition. In these two patents, Pharmacia Corp. claim the use of their sulfonamide COX-2 inhibitory compounds (celecoxib, valdecoxib and their many congeners), alone or in combination with classical sulfonamide CA inhibitors (acetazolamide, methazolamide, dichlorophenamide, dorzolamide, brinzolamide and their congeners, as well as structurally-related derivatives) for the treatment of CA-mediated disorders, including glaucoma and neoplasia. The patents do not contain any experimental evidence for the potential use of such compounds/combinations for the management of these pathologies, but are based on literature data from other laboratories.     

Novel cubosome based system for ocular delivery of acetazolamide

Acetazolamide is the drug of choice for glaucoma treatment in an emergency. However, it is not available in any topical formulation and it is available only as systemic tablets. Despite its efficiency as a drug in decreasing intraocular pressure, it has negative systemic effects as renal toxicity and metabolic acidosis. Moreover, it suffers from poor aqueous solubility and low corneal permeability limiting its ocular bioavailability and its use topically. Cubosomes have enormous advantages as a drug delivery system, most importantly, high surface area, thermal stability, and ability to encapsulate hydrophobic, amhiphilic, and hydrophilic molecules. Herein, we have exploited the unique properties of cubosomes as a novel nano-delivery system for acetazolamide as eye drops dosage form for glaucoma treatment. Different acetazolamide-loaded cubosomes have been developed and evaluated. The best-optimized formulation (F5), was cubic shaped structure, with an average particle size of 359.5 ± 2.8 nm, surface charge −10.8 ± 3.2 mV, and 59.8% entrapment efficiency. Ex-vivo corneal permeation studies have revealed a 4-fold increase in acetazolamide permeability coefficient compared to that stated in the literature. F5 showed superior therapeutic efficacy represented by a 38.22% maximum decrease in intraocular pressure vs. 31.14 and 21.99% decrease for the commercial Azopt^® eye drops and Cidamex^® tablets, respectively. It also exhibited higher (AUC_0–10) compared to Azopt^® eye drops and Cidamex^® tablets by 2.3 and 3 times, respectively. F5 showed mean residence time 4.22 h vs. 2.36 and 2.62 h for Azopt^® and Cidamex^® with no eye irritation observed according to the modified Draize test. To the best of our knowledge, this is the first study for developing acetazolamide-loaded cubosomes as the topical delivery system for glaucoma treatment.     

Drug interaction considerations in the therapeutic use of carbonic anhydrase inhibitors

Introduction: Carbonic anhydrase inhibitors (CAIs) of the sulfonamide and sulfamate type are clinically used drugs as diuretics, antiglaucoma, antiepileptic, antiobesity and anti-high altitude disease agents. Anticancer agents based on CAIs are also in clinical development for the management of hypoxic, metastatic tumors. Acetazolamide, methazolamide, dichlorophenamide, dorzolamide and brinzolamide are mainly used as antiglaucoma drugs, sulthiame, topiramate and zonisamide as antiepileptic/antiobesity agents, celecoxib and polmacoxib are dual carbonic anhydrase/cycloxygenase inhibitors. Girentuximab, a monoclonal antibody and SLC-0111, a sulfonamide inhibitor, are in clinical trials as anticancer agents.

Areas covered: The drug interactions with many classes of pharmacological agents are reviewed. Some of these drugs, such as acetazolamide, topiramate and celecoxib show a large number of interactions with non-steroidal anti-inflammatory drugs (NSAIDs), diuretics, antiepileptics, immunosupressants, anticholinesterase drugs, β-blockers, anesthetics, oral contraceptives, anticancer agents, antifungals, anti-mycobacterials, lithium, metformin and clopidogrel.

Expert opinion: The multiple drug interactions in which CAIs are involved should be carefully considered when such drugs are used in combination with the drug classes mentioned above, as the risks of developing toxicity and serious side effects if the dosages are not adjusted are high. There are also synergistic effects between CAIs and some NSAIDs, anticancer agents and benzodiazepines for the management of cystoid macular edema, some tumor types and neuropathic pain, respectively.     

Novel therapies for glaucoma: a patent review 2007 – 2011

Introduction: Glaucoma affects a large number of people, and therapies for its management are based on the use of adrenergic agonist/antagonists, carbonic anhydrase (CA) inhibitors and prostaglandin (PG) analogs. However, no new drugs have been launched on the market, although some new drug classes, such as 5-hydroxy-tryptamine (5HT₂) agonists and rho kinase inhibitors entered into advanced clinical investigations.

Areas covered: The main classes of clinically used antiglaucoma drugs, as well as potential new targets (e.g., 5HT₂ agonist, rho kinase inhibitor, RNA interference), are reviewed. A patent literature review covering the period 2007 – 2011 is presented.

Expert opinion: Most of the patents deal with sulfonamide CA inhibitors incorporating nitric oxide donating moieties or with PG analogs based on the latanoprost scaffold. The PG analogs are the predominant patented compounds. Several new potential targets emerged (e.g., rho kinase inhibitors), but no such derivatives progressed to the clinic due to adverse effects. There is an urgent need of new antiglaucoma drugs/approaches to treat and diagnose this disease in the very near future.