Therapeutic inhibitors for the treatment of dry eye syndrome

Introduction: Dry eye disease (DED), defined as a multifactorial disease of tears and ocular surface, results in symptoms of discomfort, ocular irritation, visual disturbance and tear film instability. This syndrome is accompanied of ocular surface inflammation and it is produced by a deficient activity of the lacrimal functional unit. In addition, it is associated with systemic autoimmune diseases such as Sjögren´s Syndrome, rheumatoid arthritis, systemic lupus erythematosus and some drug administration. The treatment of dry eye disease is based on the typical signs and symptoms of dry eye, which are associated with hyperosmolarity, ocular surface inflammation, discomfort, visual disturbance, and tear film instability.

Areas covered: This review is focused on synthetic drugs currently used in clinical practice, from phase III development onwards to treat the ocular surface signs and symptoms of dry eye disease.

Expert opinion: The multifactorial disease and the lack of correlation between signs and symptoms imply that not all the pharmacological approaches will be successful for dry eye. The correct design of the clinical trials, with appropriate endpoints, and the type of dry eye under study are complicated but mandatory. The anti-inflammatory and secretagogues drugs are both the main compounds to currently treat the dry eye disease.     

Safety and efficacy of autologous serum eye drop for treatment of dry eyes in graft-versus-host disease

Purpose: To evaluate the treatment of autologous serum eye drops (ASED) on dry eyes in patients with graft-versus-host disease (GVHD).

Methods: A retrospective chart review of 35 patients with a history of ocular GVHD following hematopoietic stem cell transplantation that used ASED to alleviate dry eye symptoms was performed. Patients were categorized into three different groups. If patients had available ophthalmic data before and after starting treatment was group 1 (n?=?14), had available ophthalmic data after starting treatment in group 2 (n?=?10) and had available ophthalmic data before treatment or did not have any data after starting treatment in group 3 (n?=?11). Data were collected on patient’s age, gender, primary diagnosis, visual acuity and fluorescein corneal staining were collected on individual eyes in order to evaluate the efficacy of the ASED on alleviating dry eye-related signs and symptoms.

Results: No adverse ocular effect from the ASED was found in our series (except one fungal keratitis). All patients reported either improvement (55%) or stability (45%) in their ocular symptoms upon the use of ASED. In patients with available data before and after starting treatment, the corneal staining score improved by a median of 1 (p?=?0.003) and the LogMAR visual acuity had a non-significant improvement.

Conclusion: In our study, ASED used by patients with ocular GVHD were both safe and effective. ASED should be considered in patients with GVHD who suffer from dry eyes.     

Ciclosporin use in dry eye disease patients

Background: Dry eye disease is one of the most commonly encountered conditions in eye care, and inflammation is a frequent finding. Ciclosporin has long been used systemically to decrease the deleterious effects of inflammation. Ciclosporin is a calcineurin inhibitor that acts by primarily blocking the action of T cells, decreasing the release of pro-inflammatory cytokines, and preventing the apoptosis of goblet cells. Objective: This article reviews the clinical trials and safety profile of an ophthalmic preparation of ciclosporin in the treatment of dry eye. Results/conclusion: Clinical trials have demonstrated that ciclosporin minimizes the signs and symptoms of dry eye disease and is not associated with any significant systemic or ocular adverse reaction.     

立他司特：黏附因子抑制剂类干眼症新药

立他司特（Lifitegrast）是一种新的细胞间黏附因子的抑制剂,可以通过阻断细胞间黏附分子-1和整合素蛋白淋巴细胞功能相关抗原-1之间的结合起效。2016年7月,美国食品药品管理局（FDA）正式批准了5%立他司特滴眼剂（商品名Xiidra^TM）的申请。该药的临床试验主要包括针对干眼症患者的1个为期12周的II期临床试验和3个为期12周的III期临床试验,研究结果充分证明了该药的有效性和安全性。立他司特是FDA批准的第一个可以改善和治疗干眼症症状的新药,其他类似药物只有环孢素,在不久的将来其临床应用会更加广泛。     

Lifitegrast for the treatment of dry eye disease in adults

Introduction: Dry eye disease (DED) is a common ocular disorder that can have a substantial burden on quality of life and daily activities. Lifitegrast ophthalmic solution 5.0% is the first medication approved in the US for the treatment of the signs and symptoms of DED. The aim of this article is to summarize the preclinical and clinical data on lifitegrast and discuss how lifitegrast may fit into the current treatment landscape for DED.

Areas covered: A literature search of published preclinical and clinical data was conducted to review the chemistry, pharmacodynamics, pharmacokinetics, and clinical efficacy/safety of lifitegrast. The impact that lifitegrast may have on DED treatment practices is also discussed.

Expert opinion: The introduction of lifitegrast provides a potentially important additional option for eye care professionals treating DED. In clinical trials conducted in adults with DED, lifitegrast ophthalmic solution 5.0% improved both signs and symptoms of DED. Of note, in 2 phase 3 trials, symptom improvements were observed as early as 2 weeks, which may be explained by lifitegrast’s unique mechanism of action of blocking a specific signaling pathway in inflammation. Future research should include evaluation of whether lifitegrast can be used in combination with other DED treatments.     

The effect of antihypertensive therapy on dry eye disease

Context: There is a generalization that “antihypertensive (antiHT) therapy causes Dry Eye Syndrome”, which has been claimed for years however most of the publications are epidemiological studies. We performed a clinical study to investigate the effects of antiHT agents on tear function.

Objective: The aim of this article is to evaluate the effects of different classes of antiHT medications on tear osmolarity, ocular surface problems and dry eye symptoms.

Materials and methods: Prospective, non-randomized a clinical study. A total of 71 patients who would be initiated antiHT medication due to elevated systemic blood pressure were included in the study. Thirty of these patients were given antiHT drugs containing diuretic (diuretic +), and 41 of them were given diuretic-free drugs (diuretic ?). While the number of the patients medicated in the group that received Angiotensin Converting Enzyme inhibitors (ACE inh)/Angiotensin receptor blockers (ARB) (ACE/ARB +) was 29, the number of those medicated in the ACE/ARB-free group (ACE/ARB ?) was 42. Ocular surface disease index scores, tear osmolarity, Schirmer I test, tear film break-up time (TBUT), fluorescein (FL) and rose bengal corneal staining patterns of the patients were analyzed. The patients were examined through the repetition of all the tests in the 1st and the 3rd month.

Results: The participants (n?=?71) comprised 38 males and 33 females with a mean age of 51.8?±?10.4. When the first (0–1st month) and the third month (0–3rd months) control measurements between diuretics (+) and diuretics (?) groups before and after antiHT therapies were compared, a statistically significant difference was not found in any of the tests applied. When the 0–1st month measurements of ACE/ARB (+) and ACE/ARB (?) groups were compared, it was observed that staining with FL in ACE/ARB (+) group decreased in a statistically significant manner (p?=?0.035) and there was a significant increase in TBUT values (p?=?0.022).

Discussion and conclusion: The use of antiHT drugs containing diuretic had no adverse effect on the tear function tests, but using drugs that contain ACE/ARB could have a positive impact.     

Emerging therapies in allergic conjunctivitis and dry eye syndrome

Introduction: Inflammatory disorders of the anterior surface of the eye consist of a spectrum of disorders that range from ocular allergy, dry eye syndrome (DES), and various infections. They exhibit similar pathological profiles, but have divergent immune mechanisms with some overlap. A number of novel treatments are currently being studied that capitalize on the growing understanding of underlying immunopathophysiology.

Areas covered: The goal of this review is to examine the emerging pipeline for noninfectious inflammatory disorders of the anterior surface of the eye – primarily allergic conjunctivitis (AC) and DES – in light of the recent basic science discoveries that have fueled their development. Novel molecules for the treatment of AC and DES from clinicaltrials.gov as well as recently filed patents for new molecular entities were reviewed from PUBMED and OVID.

Expert opinion: Significant progress toward targeted treatments for AC and DES has become increasingly reliant on understanding the immunomodulatory and inflammatory mechanisms of the conjunctiva.     

Pharmacotherapy of dry eye

Introduction: Based on data from the largest studies of dry eye to date – the Women's Health Study (WHS) and the Physicians' Health Study (PHS) – and other studies, it has been estimated that about 3.23 million women and 1.68 million men, for a total of 4.91 million Americans aged ≥ 50 years, have dry eye. Tens of millions more have less severe symptoms and probably a more episodic manifestation of the disease that is notable only during contact with some adverse contributing factor(s), such as low humidity or contact lens wear. Dry eye disease is a common yet frequently under-recognized public health problem whose etiology and management challenge clinicians and researchers involved in this field.

Areas covered: Advances in the understanding of the disease have been made over the past 10 years in areas of epidemiology, pathogenesis, clinical manifestation, and possible therapy. Historical aspects and recent information in relation to the use of artificial tear substitutes and anti-inflammatory agents in dry eye disease, including topical cyclosporin and corticosteroids, autologous serum, tetracyclines and systemic immunosuppressants, are covered in this review. The reader will gain insight into the recent views on the pharmacological menu of treatments for dry eyes following the recommendations of the 2007 International Dry Eye Workshop.

Expert opinion: Dry eye is a visually disabling disease, the treatment of which needs tailoring according to the type and severity of dry eye disease.     

双氯芬酸钠联合原花青素眼用剂型治疗干眼症的临床研究

目的研究原花青素(PC)眼用剂型联合双酚氯酸钠治疗干眼症疗效。方法 116例干眼症患者完全随机等分为4组,即对照组(0.9%氯化钠注射液)、单独使用PC滴眼液组、单独使用双氯芬酸钠组、PC滴眼液与双氯芬酸钠联合用药组。在用药前及用药后第5、10日,询问患者自觉症状。泪液分泌试验(ST)检查患者基础泪液分泌量、泪膜破裂时间(BUT)。结果与对照组比较,单独使用PC滴眼液及双氯芬酸钠均能有效缓解患者自觉症状,两者联合使用时,患者自觉症状缓解更明显;用药组均能延长BUT,且联合用药组延长效果更明显,差异有统计学意义(P<0.05);ST检测显示联合用药组患者变化更显著(P<0.05),单独使用组变化,但差异无统计学意义(P>0.05)。结论 PC滴眼液联合双氯芬酸钠对干眼症有较好的治疗效果。     

干眼病的眼表炎症机制研究进展

干眼病是常见的眼病之一,为多因素引起的泪液紊乱和眼表功能障碍。炎症反应环路在干眼病发病机制中起重要作用;多种免疫细胞和炎症因子参与干眼病的发病和进展过程;泪腺功能单位既是炎症的触发部位,又是炎症因子的效应器官。本文从眼部炎症改变、泪液中的炎症因子以及介导炎症反应的细胞等方面综述干眼病的眼表炎症机制研究进展。     

98例干眼症临床分析

目的 :分析干眼症的主要临床表现 ,探讨其诊断及治疗要点。方法 :对 98例干眼症患者进行回顾性临床分析 ,以干眼症的三项传统检查方法结果 (泪液分泌试验、泪膜破裂时间、角膜荧光染色 )为诊断标准。结果 :干眼症患者的“眼不适”明显 ,病因多因素 ,传统的三项检查法的阳性率较高。结论 :详细的病史资料、症状及传统的三项检查法是正确诊治干眼症的关键     

Lifitegrast clinical efficacy for treatment of signs and symptoms of dry eye disease across three randomized controlled trials

Objective: Report efficacy findings from three clinical trials (one phase 2 and two phase 3 [OPUS-1, OPUS-2]) of lifitegrast ophthalmic solution 5.0% for treatment of dry eye disease (DED).

Research design and methods: Three 84-day, randomized, double-masked, placebo-controlled trials. Adults (≥18 years) with DED were randomized (1:1) to lifitegrast 5.0% or matching placebo. Changes from baseline to day 84 in signs and symptoms of DED were analyzed.

Main outcome measures: Phase 2, pre-specified endpoint: inferior corneal staining score (ICSS; 0–4); OPUS-1, coprimary endpoints: ICSS and visual-related function subscale (0–4 scale); OPUS-2, coprimary endpoints: ICSS and eye dryness score (EDS, VAS; 0–100).

Results: Fifty-eight participants were randomized to lifitegrast 5.0% and 58 to placebo in the phase 2 trial; 293 to lifitegrast and 295 to placebo in OPUS-1; 358 to lifitegrast and 360 to placebo in OPUS-2. In participants with mild-to-moderate baseline DED symptomatology, lifitegrast improved ICSS versus placebo in the phase 2 study (treatment effect, 0.35; 95% CI, 0.05–0.65; p?=?0.0209) and OPUS-1 (effect, 0.24; 95% CI, 0.10–0.38; p?=?0.0007). Among more symptomatic participants (baseline EDS ≥40, recent artificial tear use), lifitegrast improved EDS versus placebo in a post hoc analysis of OPUS-1 (effect, 13.34; 95% CI, 2.35–24.33; nominal p?=?0.0178) and in OPUS-2 (effect, 12.61; 95% CI, 8.51–16.70; p?<?0.0001).

Limitations: Trials were conducted over 12 weeks; efficacy beyond this period was not assessed.

Conclusions: Across three trials, lifitegrast improved ICSS in participants with mild-to-moderate baseline symptomatology in two studies, and EDS in participants with moderate-to-severe baseline symptomatology in two studies. Based on the overall findings from these trials, lifitegrast shows promise as a new treatment option for signs and symptoms of DED.     

Emerging drugs for ophthalmic diseases

The ocular system is crucial to survival. It is subject to many of the same diseases found in other organ systems (e.g., diabetes) as well as diseases of ageing (e.g., macular degeneration) and other diseases (e.g., myopia). This review describes ocular diseases which are treatable, or potentially treatable, by pharmacological intervention (e.g., glaucoma, ocular infection, ocular allergy, ocular inflammation, dry eye and retinal pathology). Presented is a background of these diseases, the medical need for therapy, and current and potential new treatments.     

Emerging drugs for conjunctivitis

Background: Conjunctivitis is a highly prevalent ocular condition with potential complications that include visual impairment. Infectious causes include bacterial, viral, parasitic and fungal etiologies, while noninfectious conjunctivitis is typically owing to allergy, tear film dysfunction or chemical trauma. Treatment requires frequent dosing and often lacks complete efficacy. Objective: The goal of this review is to investigate therapies for conjunctivitis that are undergoing clinical study and development. These data are presented in light of currently available treatment options to provide an understanding of the present and future direction of conjunctivitis management. Methods: The Pharmaprojects database was searched for conjunctivitis therapies currently in development around the world. Current treatment guidelines for infectious and noninfectious conjunctivitis were researched through PUBMED and OVID databases. Results: Several new compounds, including antimicrobial, antihistamine, anti-inflammatory and immunomodulating drugs, along with a novel thiazolidinedione, are currently undergoing investigation for their potential use in conjunctivitis management. These ophthalmic agents show promise in improving clinical outcomes for infectious and noninfectious conjunctivitis.     

准分子激光原位角膜磨镶术相关干眼的药物治疗进展

干眼是准分子激光原位角膜磨镶术(LASIK)后最常见的并发症之一。术前患者存在的眼表疾病和干眼状态是增加或加重术后干眼发生率的主要因素。本文综述LASIK术后干眼的药物治疗进展。     

Alpha-lipoic acid: A possible pharmacological agent for treating dry eye disease and retinopathy in diabetes

Alpha-lipoic acid (ALA) is a naturally occurring dithiol micronutrient which acts as a cofactor for mitochondrial enzyme activity. Due to its potential antioxidant activity, it is considered as “universal antioxidant”. Previous studies reported the pharmacological benefits of ALA such as glycaemic control, improved insulin sensitivity and alleviation of diabetic complications such as neuropathy and cardiovascular diseases. Dry eye disease and retinopathy are prevalent in diabetic patients. Experimental studies demonstrated the beneficial effects of ALA in dry eye and diabetic retinopathy. ALA can prevent the dry eye by down regulating the expression of matrix metalloproteinase-9 in the corneal epithelial cells and activating the antioxidant status of the ocular surface. Furthermore, its direct antioxidant effect can also prevent oxidative stress-induced corneal surface erosion and lachrymal gland damage. ALA prevents diabetic retinopathy through inhibition of O-linked β-N-acetylglucosamine transferase and nuclear factor-kappa B activity and alleviation of oxidative stress. It can activate the nuclear factor erythroid-2-related factor 2 and AMP-activated protein kinase in retinal ganglion cells. Clinical trials conducted in pre-retinopathic diabetic patients showed ALA with genistein and vitamins could protect the retinal cells and decline the inflammatory effect in diabetic patients. However, studies are scant to explore its beneficial effects in dry eye disease and diabetic retinopathy. Therefore, this review article discusses an update on the role of ALA in dry eye disease and diabetic retinopathy, two ocular diseases prevalent in diabetic patients.     

Emerging drugs for treatment of anemia of chronic kidney disease

Introduction: Erythropoiesis-stimulating agents (ESAs) prevent transfusions among anemic patients with chronic kidney disease (CKD). Clinical trials, meta-analyses, and guidelines identify arterial and venous thromboembolism as well as myocardial event risks with the traditional ESAs, erythropoietin (EPO), and darbepoietin. Side effects of anemia treatment, considering frequency and dosage of treatment as well as targeted hemoglobin levels when utilizing ESAs, greatly impact overall well-being and the quality of life. There is a need for less frequent but equally effective ESAs in this setting.

Areas covered: The three generations of ESAs used in CKD-associated anemia are described. Cost effectiveness of the utilization of these therapies, in addition to emerging therapies, is also presented. The few clinical and controlled trials only highlight the need for clarity in molecular biology surrounding the components that control EPO levels and utilization.

Expert opinion: Anemia associated with CKD is an important area for development of newer therapies which are potentially safer and more convenient to administer.     

异黄酮片治疗更年期女性干眼症的临床研究

目的 观察异黄酮对更年期女性干眼症的临床疗效.方法 收集本院2012年1月～2013年6月收治的更年期女性干眼症患者218例,随机分成采用常规治疗的对照组和采用异黄酮治疗的观察组,每组各109例,比较两组临床疗效.结果 观察组的总有效率为72.5％,显著高于对照组的49.5％（P＜0.05）;两组患者治疗前后体内血清雌激素的水平均未发生显著性变化（P＞0.05）;对照组和观察组的不良反应发生率分别为2.8％和1.8％,差异无统计学意义（P＞0.05）.结论 异黄酮治疗更年期女性干眼症临床效果显著,不良反应较少,值得临床推广应用.