Glaucoma, the leading cause of irreversible blindness worldwide, is a chronic and progressive optic neuropathy characterized by damage to the optic and retinal nerve fiber layers, which can lead to permanent loss of peripheral or central vision. Reduction of intraocular pressure (IOP) is the only known modifiable risk factor for preventing and treating glaucoma. Rho kinase (ROCK) inhibitors are a new class of glaucoma drugs with a novel mechanism of action and good safety profile. They exert neuroprotective effects, act on the trabecular tissue, increase the outflow of aqueous humor, and reduce intraocular pressure. However, they also cause local adverse reactions, including common conjunctival congestion and subconjunctival bleeding; however, most are self-limiting and temporary. Netarsudil (0.02%), a ROCK inhibitor, relaxes the trabecular meshwork, increases the outflow of aqueous humor, reduces scleral venous pressure, and directly decreases IOP. Conjunctival congestion can be reduced if netarsudil is administered at night. The combination of these medications is always more effective than the single drug. Ripasudil (0.4%), another ROCK inhibitor, also lowers IOP; however, conjunctival hyperemia is the most common adverse drug reaction. The purpose of this review is to summarize the effects and adverse reactions of ROCK inhibitors in the experimental trial stage and in clinical treatment in recent years, providing suggestions for future clinical drug use, and research and development to reduce the side effects of these drugs, maximize the potential for reducing IOP, and improve the therapeutic effect.
Key Summary Points
Rho kinase inhibitors are a new class of drugs that act directly on trabecular meshwork cells to lower intraocular pressure (IOP), which also has neuroprotection effects.
The current clinical and preclinical studies were summarized, showing promising results.
New drug delivery systems and drug combinations might reduce the side effect and improve the IOP-lowering effects.
Introduction
Glaucoma, one of the leading irreversible causes of blindness worldwide, is characterized by apoptotic loss of retinal ganglion cells, optic nerve atrophy, visual field defects, and vision loss. Estimates show that globally there will be over 100 million patients with glaucoma by 2040, with more than 80 million patients in China alone [1, 2]. Studies have shown that ocular hypertension is a key pathogenic factor in glaucoma neuropathy [1]. An increase in the outflow resistance of the aqueous humor caused by pathological changes in the trabecular meshwork (TM), which is in the critical path of aqueous humor outflow, is the main reason underlying ocular hypertension. TM is a lymphatic-like tissue composed of cells and extracellular matrix with sieve mesh function. Interactions between TM cells play a vital role in tissue function. Approximately 75% of the resistance to aqueous humor outflow is because of this structure, making it a crucial component in regulating intraocular pressure (IOP) (Fig. 1). Normally, TM cells exhibit smooth-muscle-like characteristics. Changes in extracellular matrix components and local regulatory factors are impaired when contractility increases, leading to an increase in the outflow resistance of the aqueous humor. This, in turn, results in elevated intraocular pressure. The inner side of the TM is in contact with the aqueous humor, and the posterior two-thirds of the outer side is connected to the Schlemm's canal (SC). The inner wall of the SC consists of a single layer of endothelial cells and the outer wall connects the 25–35 collecting ducts to the internal scleral vein (aqueous vein). The outflow of the aqueous humor is not evenly distributed in 360°, exhibiting pulsatile changes in segmental developing signals, with the strongest signal distributed on the nasal side [3, 4]. The mechanism via which this drainage feature is regulated in the TM remains unclear, which adds to the difficulty in choosing the location for minimally invasive glaucoma surgery. Investigating the molecular mechanisms and drug targets involved in IOP reduction is an important objective for researchers and clinicians. Sympathomimetics, prostaglandin derivatives, carbonic anhydrase inhibitors, and hypertonic drugs are the common drugs used for lowering IOP. They reduce IOP by increasing aqueous humor outflow and reducing aqueous humor production and eye content [5]. However, none of these medications acts on the key site of aqueous humor drainage. Rho kinase (ROCK) inhibitors, a new class of drugs that act directly on TM cells to lower IOP, were approved for clinical use in Japan in 2014. ROCK inhibitors affect a wide range of signaling pathways and exert specific effects on TM, showing considerable application prospects [6]. This article reviews the progress in basic and clinical research on ROCK inhibitors as glaucoma therapeutics.
Rho, first discovered in 1985, consists of a 200–300 amino acid-long signaling peptide that is activated when combined with guanosine diphosphate (GDP). Rho-associated protein kinases (ROCK) are a group of 160-kDa serine/threonine protein kinases. Activated Rho binds to and activates ROCK, which phosphorylates downstream intracellular substrates (Fig. 2). Classical substrates include myosin light chain (MLC), myosin phosphatase substrate 1 (MYPT1), kinase C-potentiated phosphatase inhibitor 17 (CP1-17), LIM kinase (LIMK), calmodulin (CaM), ezrin, radixin, and moesin. Binding of ROCK to these substrates may regulate myoglobin/actin contraction, cell morphology, stiffness, adhesion, and matrix synthesis (Fig. 3). The two subtypes, ROCK1 and ROCK2, are highly homologous, but differ in tissue distribution and function. ROCK1 is mainly expressed in non-neural tissues, such as the heart, lung, and skeletal muscle, whereas ROCK2 is mainly expressed in the brain. Both subtypes were expressed in the eyeball, but not in the lens. ROCK inhibitors developed for the Rho/ROCK pathway have been extensively studied in ophthalmology, and their biological effects are mainly reflected in the following aspects.
Fig. 2
Activation of Rho kinase (ROCK). RhoA is regulated by various cytokines, and can shuttle between the inactive and active states. ROCK is the primary effector of GTP-RhoA. The catalytic center is exposed, and ROCK is activated when the GTP-RhoA binds to the Rho-binding domain in ROCK. GAP GTPase activating protein, GET guanine nucleotide exchange factor, GDI guanine nucleotide dissociation inhibitor, RhoA Ras homolog family member A, GDP guanosine diphosphate, GTP Guanosine-5'-triphosphate
Fig. 3
RhoA/ROCK signaling pathway. Guanine nucleotide exchange factors (GEFs) are regulated and activated by various membrane receptors, which then induce activation of the Rho protein from GDP-RhoA to GTP-RhoA, which subsequently activates ROCK. The active ROCK phosphorylates the substrates and induces different cellular responses. Inhibition of active ROCK mainly causes three pathophysiological changes: an increase in aqueous humor outflow, neuroprotection, and inhibition of scar formation. MLC myosin light chain, MYPT1 myosin phosphatase target 1, CPI-17 kinase C-potentiated phosphatase inhibitor 17, RhoA Ras homolog family member A, IOP intraocular pressure, TM trabecular meshwork, RGC retinal ganglion cell, ROCK Rho kinase
×
×
Targeting the Trabecular Meshwork
Studies have shown that ROCK inhibitors can act on the trabecular tissue to increase the outflow of the aqueous humor and reduce IOP [7]. The main mechanism involves direct inhibition of MLC phosphorylation or increase in the level of MLC dephosphorylation, thus reducing the diastolic pressure and resistance of trabecular cells and increasing the outflow of aqueous solutions [8, 9]. ROCK inhibitors also increase the number of stress fibers and reduce local adhesion of trabecular cells, leading to an increase in the outflow of aqueous humor and a decrease in IOP [10, 11]. Trabecular reticulum cells derived from neural crest cells share some properties with corneal endothelial cells, decrease in number with age, and are considered nonrenewable [12]. They also exert a phagocytic effect on the extracellular detritus. The progression of pathological glaucoma is promoted when the number of trabecular reticulum cells reduces significantly, resulting in dysfunction coupled with a decreased phagocytic effect [13]. Studies have shown that the ROCK inhibitor, Y27632, can increase the number of trabecular reticulum cells and promote phagocytosis, thereby improving the function of the trabecular reticulum during long-term lowering of IOP [14].
Effects of Neuroprotection
(1)
Improvement of local blood flow: under normal conditions, the blood flow in the optic papilla and retina is regulated by autoregulatory mechanisms. Hemodynamic changes caused by frequent vasoconstriction are the main causes of glaucomatous optic neuropathy [15]. Application of a ROCK inhibitor may increase myogenic vascular tone via endothelin 1, thereby improving optic nerve head perfusion and subsequently reducing retinal ganglion cell (RGC) loss [16, 17].
(2)
Alleviation of cytotoxicity and ganglion cell injury: A previous study has indicated that Rho A levels increase in the optic heads of glaucomatous eyes. Therefore, Rho might be involved in glaucomatous neuropathy [18]. Rho kinase inhibitors protect ganglion cells against neurotoxic injury induced by N-methyl-d-aspartate and ischemic reperfusion injury in rats [15].
(3)
RGC survival and optic nerve axonal regeneration: in a rodent optic nerve crush injury model, RGC survival and optic nerve axonal regeneration were significantly higher in the presence of a ROCK inhibitor (SNJ-1656, ripasudil, or AR-13324) than the placebo [15, 19]. Clinical trials are still required to determine whether these agents exert neuroprotective effects in addition to their IOP-lowering effects.
Wound Healing and Scar Formation
Scar formation, marked by activation of the wound-healing process and the resultant subconjunctival fibrosis at the surgical site, is the primary factor contributing to the failure of glaucoma surgery. Ripasudil may decrease the activation of human conjunctival fibroblasts by inhibiting fibroblast-to-myofibroblast differentiation [20]. ROCK inhibitors possess the therapeutic possibility of reducing scar formation after glaucoma filtration surgery by inhibiting the transdifferentiation of fibroblasts into myofibroblasts and extracellular matrix deposition via decrease in TGF-β signaling [20‐22].
Anzeige
ROCK Inhibitors in Clinical Use for Glaucoma Therapy
Currently, medication to reduce IOP is the initial therapy for preventing glaucoma progression and optic nerve injury [1]. Drugs used in patients with glaucoma may increase the outflow of the uveal sclera or reduce aqueous humor production; for example, prostaglandin analogs and alpha agonists increase the outflow, and beta-receptor blockers, carbonic anhydrase inhibitors, and alpha agonists reduce aqueous humor production. However, these first-line drugs do not directly target trabecular meshwork. ROCK inhibitors, a novel class of drugs, can target the trabecular meshwork, the key position of aqueous humor outflow resistance, and reduce IOP. The results of the clinical trials of only four ROCK inhibitors are available: SNJ-1656 (Y-39983), AR-12286, ripasudil (K-115), and netarsudil (AR-13324). All these agents were mixed with ROCK1 and ROCK2 inhibitors. Ripasudil and netarsudil are the only drugs currently approved for treating glaucoma. Netarsudil is used in the USA, and ripasudil is used in Japan and China (Fig. 4).
Fig. 4
Number of papers in the past 5 years
×
Netarsudil (AR-13324)
Rhopressa® (netarsudil ophthalmic solution) 0.02% is indicated for the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension. As a new ophthalmic drug, netarsudil eye solution (0.02%) can be applied topically once a day [23]. This drug is an effective inhibitor of ROCK and a noradrenaline transporter that may relax the trabecular meshwork, increase the outflow of aqueous humor, reduce scleral venous pressure, and directly decrease IOP. The three pathways that affect aqueous humor dynamics appear to be unique combinations of mechanisms that reduce IOP. In the pooled phase III trial, 0.02% netarsudil once daily (n = 694) decreased the IOP from a mean baseline of 21.9–23.7 mmHg to 17.5–19.5 mmHg; furthermore, the efficacy of IOP reduction was stable regardless of the different subgroups of baseline IOP [24]. The results suggested that 0.02% netarsudil once daily was not inferior to 0.5% timolol twice daily in the treatment of open-angle glaucoma or ocular hypertension [24]. A recent Cochrane review indicate that the hypotensive effect of single netarsudil may be higher than latanoprost and slightly lower than timolol. Drug combinations may further reduce IOP compared with monotherapy[25]. Netarsudil is primarily used as an adjunct treatment for glaucoma in the United States. However, the effect of lowering IOP decreased as the number of adjunctive medications increased. Thus, the selection of drugs is associated with more complexity and variability than it appears.
Side effects Netarsudil is a novel drug that controls IOP with no obvious toxicity. Conjunctival congestion and subconjunctival hemorrhage are common side effects of netarsudil. However, most adverse effects were self-limiting and subsided with continued medication. Conjunctival congestion can be reduced if netarsudil is administered at night. Currently, contraindications for the use of this drug are not known, according to the manufacturer’s instructions. In two large randomized double-sided blind trials, researchers found that 0.02% netarsudil once daily was effective and well tolerated in patients with open-angle glaucoma [26]. The pooled results from phase III clinical trials suggested that conjunctival hyperemia (54.4%), corneal verticillata (20.9%), and conjunctival hemorrhage (17.2%) are the main side effects of using 0.02% netarsudil. Recent case reports have mentioned some experiences in exceptional circumstances, such as in children, patients undergoing corneal transplantation or corneal surgery, and in cases with lacrimal point stenosis [27‐29].
For glucocorticoid glaucoma Netarsudil may be particularly suitable for patients with normal blood pressure or steroid-induced glaucoma. Glucocorticoid glaucoma, also known as corticosteroid-induced glaucoma, refers to secondary glaucoma caused by the long-term use of ocular or systemic corticosteroids [30]. The incidence of corticosteroid-induced glaucoma has also increased with the increasing clinical use of glucocorticoids. The biological mechanism of steroid-induced glaucoma is the changes of cytoskeleton of TM cells by use of steroid. Our previous studies indicated that ROCK inhibitor can disrupt the stress fiber and cytoskeleton of TM [31‐33]. A previous study indicated that non-canonical Wnt signaling is a potential pathway via which ROCK is activated in steroid-induced glaucoma. Dexamethasone induces the formation of cross-linked actin meshwork in TM cells via the non-canonical Wnt receptor and ROR2/RhoA/ROCK signaling axis [30, 34]. This results in the obstruction of aqueous humor outflow and increase in IOP. Additionally, a clinical study showed netarsudil 0.02% ophthalmic solution can prevent corticosteroid-induced ocular hypertension [35]. However, there is a lack of clinical data for the use of ROCK inhibitor for other specific types of glaucoma. Netarsudil plays a key role in ROCK inhibition; therefore, it may be a viable treatment option for patients with corticosteroid-induced glaucoma. To assess whether prophylactic use of 0.02% netarsudil ophthalmic solution reduces the risk of IOP elevation associated with long-term use of topical corticosteroids administered to prevent corneal transplantation rejection, 120 patients were randomly assigned to receive 0.02% netarsudil once daily [35]. The results showed that IOP increased by 14% in the netarsudil group and by 21% in the placebo group. Thus, netarsudil did not show any significant clinical effect on the risk of hormone-induced IOP elevation after corneal transplantation compared with that of the placebo. However, the small sample size is a limitation of this study. Keratoplasty is associated with a relatively low risk of immunological rejection; therefore, steroid reduction is more efficient in decreasing the risk of steroid-associated ocular hypertension in patients who have undergone keratoplasty.
Drug combinations In a randomized trial involving 224 patients with open-angle glaucoma (OAG) or ocular hypertension (OHT), 0.02% netarsudil monotherapy was less effective than 0.005% latanoprost monotherapy and was associated with a higher risk of developing conjunctival hyperemia [36]. Therefore, a combination of netarsudil with latanoprost would be more beneficial than the monotherapy if netarsudil is considered the treatment choice for patients with glaucoma. According to the literature, application of a netarsudil/latanoprost fixed-dose combination once daily appears to be superior to netarsudil or latanoprost monotherapy for IOP reduction in patients with glaucoma [37]. These advantages of drug combinations emerged when monotherapy was found to be insufficient for some patients. Nonetheless, conjunctival hyperemia remains a major complication; however, serious adverse reactions were not observed in patients who received a netarsudil/latanoprost fixed-dose combination [37]. A fixed-dose combination of 0.02% netarsudil/0.005% latanoprost was well tolerated in the management of patients with glaucoma and demonstrated a significant and sustained reduction in IOP, even as a last-line therapy before incisional or laser surgery in patients on maximum glaucoma pharmacotherapy. This drug combination is a viable treatment option for glaucomatous eyes before surgical intervention [13, 14].
Summary of literature in the past 5 years
Retrieval method: AR-13324 [Title] OR netarsudil [Title] AND glaucoma [Title/Abstract].
Ethical approval: This part is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
Anzeige
2018 (A total of six articles): review (3), phase III study (1), preclinical trial (1), small-sample clinical trial (1).
2019 (A total of nine articles): review (4), phase III study (3), preclinical trial (1), and non-inferiority clinical trials (1).
2020 (A total of 15 articles): review (1), phase II study (3), phase II study (3), case report (6), animal experiment (1), and cell experiment (1).
2021 (A total of 11 articles): review (1), retrospective cohort study (5), phase IV study (1), phase II study (2), case report (1), and animal experiment (1).
Anzeige
2022 (A total of 22 articles): meta-analyses of systematic reviews (2), retrospective cohort studies (10), and case reports (10).
In summary, the ROCK inhibitor netarsudil has emerged as a novel drug for glaucoma therapy in recent years. Cumulative reports have suggested that the application of netarsudil in glaucoma therapy is safe and effective. Recently, the number of case reports has increased, indicating that medical scientists have begun to focus on drug reactions in special cases.
Ripasudil (K-115)
Ripasudil/K-115 (GLANATEC, Kowa Co., Ltd., Aichi, Japan), a fluorinated analog of fasudil, is the world’s first small-molecule selective ROCK inhibitor [38, 39] that was approved in 2014 for the treatment of ocular hypertension and glaucoma. Ripasudil (0.4%) is administered twice daily for treating glaucoma in Japan [39]. The results of a phase II clinical trial indicated that compared with the placebo, ripasudil lowered IOP by an average of 2.0–4.4 mmHg 2 h after application in patients with glaucoma or OHT. In addition, the pharmacological effects were maintained for at least 7 h [39]. A 1-year clinical evaluation of ripasudil (0.4%) showed that the mean IOP reductions were 2.6 mmHg to 3.7 mmHg. In the patients with higher baseline IOP (over 21 mmHg), the IOP reduction would increase to 4.8 mmHg at the peak [39]. The results of a long-term large-scale post-marketing surveillance in Japan indicated that serious safety concerns or new safety signals were absent in glaucoma patients receiving ripasudil for over 12 months during routine clinical care, and that the subtype of glaucoma and the method of therapy initiation could be ignored [40]. This suggested that ripasudil is a promising drug for treating glaucoma.
Side effects Conjunctival hyperemia is the most common adverse drug reaction when ripasudil is applied to the eyes, probably because the smooth muscles in the blood vessels are relaxed by the ROCK inhibitor. In two phase III randomized clinical trials, when ripasudil was used in combination with first-line agents, the incidence of conjunctival hyperemia was observed in 68 of 104 patients (65.4%) in the ripasudil combined with timolol group, and in 57 of 102 patients (55.9%) in the ripasudil combined with latanoprost group [41]. Significant difference in the incidence of this side effect was not observed between ripasudil monotherapy and therapy using a combination of other agents [42]. However, in real-world clinical settings, the frequency of conjunctival hyperemia has always been underestimated. A 2-year prospective post-marketing surveillance study indicated that only 244 of 3058 patients (8%) experienced side effects after the application of ripasudil, and that only 4% had conjunctival hyperemia [43]. The incidences of other adverse drug reactions, such as allergic conjunctivitis, blepharitis, eye pruritus, and punctate keratitis, were not high [42, 44]. Although adverse drug reactions other than ocular reactions are mild and rare, reduced blood pressure, constipation, and headache should also be considered [45].
Anzeige
Glucocorticoid glaucoma Secondary glaucoma, unlike primary glaucoma, arises from various ocular or systemic dysfunctions that prevent the outflow of aqueous humor and induce an increase in IOP. Previous small-scale clinical studies have indicated that ripasudil is effective and safe for secondary glaucoma, including uveitic and exfoliation glaucoma [46, 47]. Recently, a retrospective multicenter large-scale clinical study of patients diagnosed with glucocorticoid glaucoma, uveitic glaucoma, and xanthination glaucoma demonstrated the favorable efficacy and safety of ripasudil in secondary glaucoma therapy [48]. The range of IOP reduction was possibly related to the baseline IOP levels. Dexamethasone-treated human TM cells were investigated in vitro as a model of steroid-induced glaucoma [49] and results suggested that ripasudil may inhibit dexamethasone-induced changes in physical properties, including the permeability, size, and stiffness of the extracellular matrix, and the expression of major extracellular matrix molecules. Further findings indicated that the roles of ROCK1 and ROCK2 in steroid-induced glaucomatous TM differed. The precise mechanisms underlying this phenomenon have to be elucidated in the future.
Drug combinations Ripasudil (0.4%), timolol (0.5%), and latanoprost (0.005%) were administered to patients with primary open-angle glaucoma or ocular hypertension in a randomized controlled trial registered in Japan. The results revealed an additive IOP-lowering effect when a fixed-dose drug combination was applied. Mild conjunctival hyperemia was the most common side effect, which may resolve automatically prior to the next administration [41]. Another clinical trial indicated that the IOP-lowering effect of a ripasudil–brimonidine fixed-dose combination was superior to that of ripasudil or brimonidine alone [50]. In conclusion, ripasudil can be combined with other first-line drugs for treating glaucoma. Additional IOP reduction and absence of serious adverse reactions indicated that ripasudil can be used clinically.
Summary of literature in the past 5 years
Retrieval method: K-115 [Title] OR ripasudil [Title] AND glaucoma [Title/Abstract].
2018 (A total of six articles): retrospective observations (2); animal experiments on retinal vein occlusion and normal tension glaucoma (2); prospective, randomized, comparative studies (1); prospective, comparative studies on retinal vessel density (1).
2019 (A total of six articles): retrospective study (five articles about different subtypes of glaucoma; glaucoma with diabetic macular edema; prediction of the outcome of trabeculotomy; proportion of the incidence of blepharitis; evaluation of the offset of conjunctival hyperemia); post-marketing surveillance (1).
2020 (A total of ten articles): review (2); in vitro experiments (two articles about inflammatory injury of RPE cells and porcine model of pigmentary glaucoma); clinical observational studies (six articles on secondary glaucoma; efficacy and safety assessment; evaluation of conjunctival hyperemia; corneal endothelial cell morphology and density).
2021 (A total of eight articles): in vitro experiment (about the relaxation properties of isolated porcine retinal arterioles); case report (allergic contact dermatitis); clinical observational study (six articles, after suture trabeculotomy ab interno; comparison with selective laser trabeculoplasty; for endothelial protective effect; prediction of the therapeutic effect of SLT; pathophysiology of corneal endothelial cells; maximally tolerated medical therapy).
2022 (A total of six articles): animal experiment (new NO-donating ripasudil derivatives RNO-6); case report (honeycomb epithelial edema); clinical observation study (long-term safety and effectiveness in glaucoma; uncontrolled glaucoma; filtering bleb with trabeculectomy); phase III clinical trial (ripasudil–brimonidine fixed-dose combination).
In summary, ripasudil can be used clinically for the long term. The use of ripasudil for treating different subtypes of glaucoma, its long-term effects and adverse reactions, and maximum therapy tolerance, and the criteria for selecting target patients have been reported. Although ripasudil has been suggested as an effective monotherapy for uveitic glaucoma, most studies have indicated ripasudil as an adjuvant therapy to the first-line drugs for glaucoma [51]. So far, randomized controlled clinical trials of ripasudil monotherapy or existing standard therapy are lacking. These results suggest that ripasudil as an adjunct therapy is safe and effective in patients who require additional IOP reduction.
SNJ-1656 (Y-39983)
SNJ-1656 was the first Rho kinase inhibitor shown to lower IOP in a clinical trial. Animal experiments have shown that Y-39983 can improve trabecular reticulum contraction, promote the outflow of aqueous humor, and reduce IOP. The results of phase I and II clinical trials on SNJ-1656 have been reported previously [52]. In healthy subjects, SNJ-1656 steadily reduced IOP after a single dose. The main adverse reactions to long-term treatment include conjunctival congestion, blurred vision, photophobia, and dry eyes. These symptoms may disappear when the medication is discontinued [53]. A phase II trial showed that SNJ-1656 effectively reduced IOP in patients with open-angle glaucoma or ocular hypertension. The adverse reactions that need to be addressed include headache, abdominal pain, liver dysfunction, and conjunctivitis [54]. No new clinical trials of SNJ-1656 for glaucoma or ocular hypertension therapy have been published since 2015.
AR-12286
Animal studies and phase I and II clinical trials have shown that AR-12286 can increase the outflow of the aqueous humor and reduce IOP [15]. Although no serious adverse reactions were observed, the drug was abandoned for treating glaucoma by Aerie Pharmaceuticals in 2017 because of the short duration of reduced eye pressure. AR-12286 is a highly selective ROCK inhibitor developed by the same company that produced netarsudil (Aerie Pharmaceuticals Inc.). A recent study suggested that AR-12286 may lower steroid-induced ocular hypertension in mice that rely on steroid treatment [55].
Fasudil (HA-1077)
The results of an animal experiment indicated that HA-1077 may significantly reduce IOP in a rabbit ocular hypertension model by disrupting actin bundles in the trabecular reticulum [56]. In 2017, Pakravan et al. demonstrated that fasudil applied topically in four patients with end-stage primary open-angle glaucoma induced obvious IOP reduction and good tolerance [57]. Thus, fasudil can be considered a candidate agent for additional therapy in the future.
Potential Clinical Application of Other ROCK Inhibitors
Table 1 summarizes the potential clinical applications of other ROCK inhibitors. These molecules have been evaluated in human trials to obtain lasting IOP reduction and fewer adverse reactions; however, the number of such molecules that can be approved for clinical use remains unknown and research in this direction is evolving continuously. Alternatively, other significant beneficial effects may be observed, such as retinal neuroprotection, anti-scarring, and corneal endothelial protection.
Table 1
Overview of other ROCK inhibitors
Compound
Organization
Year introduced
Effects
Target
Current phase
Y-27632
C14H21N3O·2HCl
1997
IOP reduction; scarring inhibition
ROCK1/SMPP-1M/MLC
Preclinical
H-1152
C16H21N3O2S
1999
IOP reduction; smooth muscle actin expression; collagen gel contraction↓
The use of ROCK inhibitors has been approved for treating glaucoma. However, the high incidence of corneal congestion and possible subconjunctival bleeding, coupled with the need for frequent long-term use, have led to a reduction in patient compliance. After 3 years of use, approximately 20% of patients discontinue the drug. In addition, owing to local administration, corneal obstruction, and low drug permeability, approximately only 0.1–5% of the drug can penetrate the aqueous humor [58]. Therefore, pharmaceuticals have developed new delivery systems to overcome these problems. Mietzner et al. packed the ROCK inhibitor fasudil into poly (lactic-co-glycolic acid) (PLAG) microspheres, which can be delivered directly to aqueous ether via vitreous injection and can extend the drug release time to 45 days [59]. PLAG, as an advanced material, can encapsulate and control the release of large- and small-molecule drugs and has also been approved for vitreous injection by the FDA and the European Medicines Agency [60]. Coating a drug with PLAG may improve its bioavailability and reduce its side effects. Khallaf et al. focused on a new form of ophthalmic drops composed of a liposomal thermosensitive hydrogel loaded with a fasudil–phospholipid complex [61]. Compared to traditional eye drops, it can provide sustained release of the drug with higher therapeutic efficiency, is completely biodegradable and nontoxic, and may bypass several biological barriers. Nanotechnology is another novel and rapidly developing drug-delivery method. Nanoparticles ranging in size from 1 to 100 nm have the ability to bypass biological barriers and deliver the cargo drugs to the target site [62]. Thus, new drug-delivery systems must be developed continuously to change medication noncompliance in some patients with glaucoma.
Summary and Future Directions
As a new type of medication for glaucoma and ocular hypertension, ROCK inhibitors are being extensively studied worldwide from bench to bedside [6]. An interdisciplinary approach using evidence-based medicine and patient-centered care correlates with reduction in utilization of healthcare service and helps achieve better clinical outcomes. If patients use more than one eye drops, they should be instructed about the time interval between the administrations of each medication. A suitably closed nasolacrimal duct is a useful tool that may reduce the systemic absorption of drugs to reduce side effects, and increase the time of contact between drugs and the eyes. A trained nurse may perform initial screening to monitor disease progression and assist in the early-stage treatment of glaucoma. Medical students and residents can contribute significantly to patient education [63]. Collaboration and communication between these disciplines can achieve optimal patient outcomes [64].
Ripasudil and netarsudil are currently available in the market. Studies suggested that the of IOP-lowering effect by ROCK inhibitor might be better than other first-line glaucoma medications [25]. In patients with poor IOP control after the long-term use of conventional glaucoma medication, ROCK inhibitors might achieve an additional effect.
However, clinical studies comparing the safety of these two ROCK inhibitors with other glaucoma medications are still lacking. The main side effects of netarsudil are conjunctival hyperemia, corneal verticillata, and conjunctival hemorrhage, while those of ripasudil are conjunctival hyperemia, blepharitis, and conjunctivitis. Most local adverse reactions are transient and self-limiting and can be tolerated under guidance. No serious systemic adverse reactions were reported. Compared with the results of previous clinical studies, analysis of a post-marketing surveillance study indicated that the use of ROCK inhibitors significantly reduced the incidence of adverse reactions [24, 37]. This also indicates that some minor clinical manifestations, such as conjunctival congestion, are often ignored or disappear by the time of examination. ROCK inhibitors are effective against almost all glaucoma subtypes. Therefore, they can be used in all patterns of treatment initiation (monotherapy, combination therapy, switching therapy, and add-on therapy). Currently, these two ROCK inhibitors are primarily used in combination with other first-line agents for glaucoma therapy to ensure adequate IOP-lowering effects. ROCK inhibitors are affected mainly by changes in the trabecular meshwork structure and the characteristics of endothelial cells of the Schlemm’s canal.
The use of ROCK inhibitors should be started in the early stages of glaucoma, as the effect of IOP lowering is affected by the trabecular meshwork status. Based on this view, ROCK inhibitors may be a better option for patients with steroid-induced ocular hypertension or uveitic glaucoma, as the rise in IOP is secondary to a sudden rise induced by steroids or inflammation, and as the normal physiological structure and function of the trabecular mesh are preserved. However, the advantages of ROCK inhibitor treatment in the early stages of glaucoma require further investigation. Clinical evidence regarding the efficacy and safety of other effects of ROCK inhibitors, such as neuroprotection, anti-scarring, and corneal endothelial healing, is negligible; therefore, they should be considered with caution.
In summary, ROCK inhibitors are a new class of topical IOP-lowering medication. More data from clinical trials and post-marketing studies are required to establish the best practices for the treatment of patients with glaucoma. To ensure patients’ compliance with this medication, other dosage forms of topical ROCK inhibitors with reduced side effects and increased drug permeability should be developed. ROCK inhibitors appear to be a promising candidate to our armamentarium if the associated transient but substantial side effects can be curtailed. Efforts to increase the specificity of ROCK inhibitors for target cells may not only minimize the side effects but may also enhance their efficiency, as well as lowering IOP and neuroprotective or vasoactive potential, maximizing their therapeutic effects.
Medical Writing/Editorial Assistance
The authors thank Editage Editing Service for editing the English text of a draft of this manuscript. The writing assistance was funded by the Key R&D and Promotion Projects of Henan Province No. 182102410099 and No. 182102310452.
Declarations
Conflict of Interest
The authors report no conflicts of interest.
Ethical Approval
This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.
Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
Fast ein Viertel der Personen mit mäßig dysplastischen Stimmlippenläsionen entwickelt einen Kehlkopftumor. Solche Personen benötigen daher eine besonders enge ärztliche Überwachung.
Bei Menschen mit Typ-2-Diabetes sind die Chancen, einen Myokardinfarkt zu überleben, in den letzten 15 Jahren deutlich gestiegen – nicht jedoch bei Betroffenen mit Typ 1.
Ob Patienten und Patientinnen mit neu diagnostiziertem Blasenkrebs ein Jahr später Bedauern über die Therapieentscheidung empfinden, wird einer Studie aus England zufolge von der Radikalität und dem Erfolg des Eingriffs beeinflusst.
„Kalte“ Tumoren werden heiß – CD28-kostimulatorische Antikörper sollen dies ermöglichen. Am besten könnten diese in Kombination mit BiTEs und Checkpointhemmern wirken. Erste klinische Studien laufen bereits.
Update Innere Medizin
Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.
