Long-Term Intraocular Pressure-Lowering Effects and Adverse Events of Ripasudil in Patients with Glaucoma or Ocular Hypertension over 24 Months.

INTRODUCTION: Glaucoma is a leading cause of irreversible blindness and ripasudil was the first Rho kinase inhibitor approved as antiglaucoma medication. Here we present the final analysis of the ROCK-J study, a large-scale post-marketing surveillance study to evaluate the long-term safety and effectiveness of ripasudil in Japanese patients with glaucoma or ocular hypertension in a real-word clinical setting. METHODS: ROCK-J was a 24-month, prospective, open-label, observational study that included ripasudil-naïve patients with glaucoma or ocular hypertension who were initiating treatment with ripasudil according to the Japanese approved indication between June 1, 2015 and April 30, 2017. The primary safety endpoint was the incidence of adverse drug reactions (ADRs) (including blepharitis, plus assessment of its background factors); the primary efficacy endpoint was change in intraocular pressure (IOP) from baseline to 24 months. RESULTS: A total of 3374 Japanese patients with glaucoma or ocular hypertension were evaluated for safety and 3178 for effectiveness of ripasudil over a mean 524.5-day observational period. Overall, 853 (25.3%) patients experienced adverse drug reactions; the most common were blepharitis (8.6%), conjunctival hyperemia (8.5%), and conjunctivitis (6.3%). Multivariate analyses demonstrated that patients were more likely to experience the ADR blepharitis with ripasudil treatment if they were female (hazard ratio [HR] 1.307; p = 0.040), had comorbid or a previous history of blepharitis (HR 2.178; p = 0.001), or had a history of allergy to pollen (HR 1.645; p = 0.003) or medication (HR 2.276; p < 0.001). IOP decreased significantly from baseline with ripasudil; the least-squares mean ± standard error change in IOP from baseline to 24 months was - 2.6 ± 0.1 mmHg (p < 0.001). Significant IOP changes were seen in four types of glaucoma, namely primary open-angle glaucoma, normal-tension glaucoma, primary angle-closure glaucoma, and secondary glaucoma, and ocular hypertension. CONCLUSION: Ripasudil was safe and effective as an antiglaucoma medication with no new safety signals identified and significant reductions in IOP maintained over 24 months of treatment.

Correction to: Safety and efficacy of ripasudil in Japanese patients with glaucoma or ocular hypertension: 12-month interim analysis of ROCK-J, a post-marketing surveillance study.

An amendment to this paper has been published and can be accessed via the original article.

Safety and efficacy of ripasudil in Japanese patients with glaucoma or ocular hypertension: 12-month interim analysis of ROCK-J, a post-marketing surveillance study.

BACKGROUND: Ripasudil is approved in Japan for glaucoma or ocular hypertension (OH) when other treatments are ineffective or cannot be administered. Its long-term safety and efficacy are being examined in a post-marketing surveillance study; 12-month data are described here. METHODS: This prospective, open-label, observational study enrolled patients with glaucoma or OH who started ripasudil during routine care. The key safety outcome was the incidence of adverse drug reactions (ADRs), focusing on allergy and/or inflammation-related ADRs such as blepharitis (including allergic) or conjunctivitis (including allergic). The primary efficacy endpoint was least squares mean (LSM) ± standard error (SE) change in intraocular pressure (IOP) from baseline to 12 months in all patients and in diagnostic groups. Secondary endpoints were change in IOP in groups stratified by treatment initiation pattern, number of concomitant drugs, and baseline IOP. RESULTS: Overall, 3359 patients (48% male, mean age ± standard deviation [SD] 69.1 ± 12.7 years) were evaluated for safety and 3323 for efficacy. Diagnoses were primary open-angle glaucoma (43.9%), normal-tension glaucoma (36.6%), secondary glaucoma (8.7%), OH (4.2%), and primary closed-angle glaucoma (2.4%). Mean ± SD observation period was 300.1 ± 122.4 days; 1010 patients (30.1%) discontinued ripasudil by 12 months. ADRs occurred in 626 patients (18.6%); the most common were conjunctival hyperemia and blepharitis. Allergy and/or inflammation-related ADRs occurred in 388 patients (11.6%), most commonly blepharitis (5.6%) and conjunctivitis (4.2%). IOP decreased significantly from a mean ± SD 18.1 ± 6.1 mmHg at baseline; the LSM ± SE IOP change throughout 12 months of ripasudil treatment was - 2.6 ± 0.1 mmHg (- 14.0 ± 0.4%; p < 0.001). A significant decrease in IOP at 12 months was seen in all categories of baseline IOP (p < 0.001), and all types of glaucoma (p < 0.001), except neovascular glaucoma. Ripasudil was associated with a significant reduction in IOP at 12 months whether initiated as monotherapy or in combination with ≤4 concomitant glaucoma therapies (p < 0.001). CONCLUSIONS: Ripasudil was safe and effective in patients with glaucoma or OH during routine care. No new safety signals were identified, and significant reductions in IOP were maintained over 12 months.

Correction to: Safety and Efficacy of Ripasudil in Japanese Patients with Glaucoma or Ocular Hypertension: 3-month Interim Analysis of ROCK-J, a Post-Marketing Surveillance Study.

In the original publication values in the results section are incorrect. Errors were also identified in Fig. 5.

Safety and Efficacy of Ripasudil in Japanese Patients with Glaucoma or Ocular Hypertension: 3-month Interim Analysis of ROCK-J, a Post-Marketing Surveillance Study.

INTRODUCTION: To evaluate the safety and intraocular pressure (IOP)-lowering effects of a ripasudil 0.4% ophthalmic solution in Japanese patients with glaucoma and ocular hypertension (OH) as a post-marketing surveillance. METHODS: This was a 2-year prospective observational study in patients with glaucoma or OH who had not previously received ripasudil. Patients registered in the study using a central internet-based system from June 1, 2015 to April 30, 2017. Data on adverse drug reactions (ADRs) and IOP were collected and analysed from the first 3 months of ripasudil treatment. RESULTS: Of the 3058 patients in the safety analysis set, 3016 had IOP data and were included in the efficacy analysis. ADRs were seen in 244 (8.0%) of the 3058 patients. IOP decreased significantly in patients with primary open-angle glaucoma (- 2.9 ± 4.2 mmHg; p < 0.001), normal tension glaucoma (- 1.7 ± 2.4 mmHg; p < 0.001), primary angle-closure glaucoma (- 3.9 ± 5.3 mmHg; p < 0.001), and OH (- 3.8 ± 5.8 mmHg; p < 0.001). Significant IOP reduction was also noted in exfoliation glaucoma (- 3.0 ± 5.5 mmHg; p < 0.001), uveitis-associated glaucoma (- 4.7 ± 7.2 mmHg; p < 0.001) and steroid glaucoma (- 5.5 ± 6.0 mmHg; p < 0.001), but not for neovascular glaucoma (- 2.8 ± 12.1 mmHg; p = 0.669). CONCLUSION: Ripasudil was safe and effective in the treatment of glaucoma and OH in Japanese patients, with a low incidence of ADRs or treatment discontinuation, and reduced IOP after 3 months of treatment. FUNDING: Kowa Company, Ltd., Tokyo, Japan.

CXCR4-tropic, but not CCR5-tropic, human immunodeficiency virus infection is inhibited by the lipid raft-associated factors, acyclic retinoid analogs, and cholera toxin B subunit.

Development of an effective low-cost anti-acquired immunodeficiency syndrome (AIDS) drugs is needed for treatment of AIDS patients in developing countries. Host cell lipid raft microdomains, which are enriched with cholesterol, glycolipids, ceramide, and gangliosides, are important for human immunodeficiency virus type 1 (HIV-1) entry. Retinoid analogs have been shown to modulate ceramide levels in the cell membrane, while cholera toxin B subunit (CT-B) specifically binds to the ganglioside GM1. In this study, we found that the acyclic retinoid analogs geranylgeranoic acid (GGA) and NIK-333 as well as CT-B efficiently attenuate CXCR4-tropic, but not CCR5-tropic, HIV-1 vector infection. We also found that GGA and NIK-333 suppress CXCR4-tropic HIV-1 infection by attenuating CXCR4 expression. CT-B also attenuated CXCR4-tropic HIV-1 infection, but did not suppress CXCR4 expression. These results suggest a distinct role for lipid raft microdomains in CXCR4- and CCR5-tropic HIV-1 infections and illuminate novel agents for the development of AIDS therapy.

Dual induction of caspase 3- and transglutaminase-dependent apoptosis by acyclic retinoid in hepatocellular carcinoma cells.

BACKGROUND: Hepatocellular carcinoma has a high mortality rate due to its rate of recurrence. Acyclic retinoid prevents recurrence of hepatocellular carcinoma in patients after surgical removal of their primary tumors by inducing apoptosis in hepatocellular carcinoma cells, although the molecular mechanisms of action are not understood. METHODS: Human hepatocellular carcinoma cells in culture, as well as nude mice transplanted with hepatocellular carcinoma cells and rats given with N-diethylnitrosamine were treated with acyclic retinoid. Changes in activated caspase 3 and transglutaminase 2 (TG2) levels, Sp1 cross-linking and its activities, expression of epidermal growth factor receptor, and apoptotic levels were measured. RESULTS: Acyclic retinoid simultaneously stimulated the activation of caspase 3, and the expression, nuclear localization and crosslinking activity of TG2, resulting in crosslinking and inactivation of the transcription factor, Sp1, thereby reducing expression of epidermal growth factor receptor and cell death in three hepatocellular carcinoma cell lines. These effects were partially restored by a caspase inhibitor, transfection of antisense TG2, restoration of functional Sp1, or an excess of epidermal growth factor. Nuclear expression of TG2 and crosslinked Sp1, as also activated caspase 3 were found in both hepatocellular carcinoma cells transplanted into nude mice and cancerous regions within the liver in N-diethylnitrosamine-induced hepatocarcinogenesis model in rats, following treatment of animals with acyclic retinoid. CONCLUSIONS: Treatment with acyclic retinoid produces a dual activation of caspase 3 and TG2 induced apoptosis of hepatocellular carcinoma cells via modification and inactivation of Sp1, resulting in reduced expression of epidermal growth factor receptor.

Minor infection encouraged by steroid administration during cardiac surgery.

The aim of this study was to investigate whether steroid administration would increase the risk of postoperative infection. Sixty adults who underwent elective cardiac surgery under cardiopulmonary bypass were prospectively randomized into two groups. Thirty-one patients received hydrocortisone (50 mg x kg(-1)) before and after cardiopulmonary bypass, the other 29 served as controls. Various hemodynamic and pulmonary measurements were obtained perioperatively, and the white blood cell counts and levels of C-reactive protein were checked up to the 14(th) postoperative day. Steroid administration did not have any favorable effects during the perioperative period. Re-administration of antibiotics was needed in 7 patients (22.6%) after the 7(th) postoperative day in the steroid group, and in 3 (10.3%) in the control group. The peak white cell counts and C-reactive protein levels after the 7(th) postoperative day were significantly higher in the steroid group. Steroid administration offered no clinical benefit to patients undergoing cardiac surgery with cardiopulmonary bypass, and it may encourage minor infections in the late postoperative period.

Prostaglandin E1 attenuates impairment of cellular immunity after cardiopulmonary bypass.

OBJECTIVE: It is well documented that cardiopulmonary bypass (CPB) severely impairs cellular immunity. The objective of this study was to investigate the effect of prostaglandin E1 (PGE1) on cellular immunity after CPB. METHODS: Patients who underwent elective cardiac surgery were randomly divided into the PGE1 group (n=12) and the control group (n=12). In the PGE1 group, PGE1 was administered at 20 ng/kg/min from just after the induction of anesthesia to the end of surgery. Peripheral blood mononuclear cells (PBMCs) were taken before anesthesia and on postoperative days 1, 3 and 7 (POD 1, POD 3 and POD 7). Proliferation responses of T cells to phytohemagglutinin (PHA) and pure protein derivative (PPD) antigen were measured as indicators of cellular immunity. RESULTS: PGE1 significantly attenuated the impairment of both PHA and PPD response after cardiac surgery on POD 1 (PHA response, 30 +/- 21% vs. 53 +/- 32%, control vs. PGE, p=0.048; PPD response, 18 +/- 21% vs. 39 +/- 27%, control vs. PGE, p=0.046). The reduced glutathione content of PBMCs in the control group was significantly decreased on POD 1. CONCLUSION: PGE1 attenuated the impairment of cellular immunity after cardiac surgery with CPB by reducing oxidative stress on PBMCs.

Long-term effectiveness of total arch replacement for type A aortic dissection.

BACKGROUND: With recent improvements in cerebral protection during aortic arch repair, total aortic arch replacement has become an accepted surgical method for acute type A aortic dissection involving the aortic arch. Our surgical strategy is to perform total arch replacement with a branched graft using antegrade selective cerebral perfusion for the patients with type A aortic dissection involving the aortic arch. The objective of this study is to evaluate the effectiveness of this strategy on late outcome. METHODS: From October 1988 to April 2003, 46 patients underwent total arch replacement for acute type A dissection involving the aortic arch. Operations were performed with hypothermic cardiopulmonary bypass, antegrade selective cerebral perfusion during the arch repair, and open distal anastomosis. RESULTS: Hospital mortality was 6.5% (3 patients), and permanent neurologic dysfunction was observed in 1 patient. During the follow-up period (mean, 5.4 years; range, 13 months to 15.6 years), 2 patients died, but the causes were not related to the aorta or aortic valve. Survival rates at 5 and 10 years postoperatively were 89.6% +/- 5.2% and 82.7% +/- 8.2%, respectively. Of the 41 survivors, 3 patients underwent successful reoperation for the distal thoracic aorta. Freedom from reoperation was 93.6% +/- 4.6% and 88.7% +/- 6.5% at 5 and 10 years, respectively. The residual false lumen in the thoracic aorta was frequently thrombosed (76.2%). CONCLUSIONS: Total arch replacement for acute type A dissection may decrease the risk of late complications related to the false lumen and lead to excellent long-term survival.