SAFETY PROFILE OF OCRIPLASMIN FOR SYMPTOMATIC VITREOMACULAR ADHESION: A Comprehensive Analysis of Premarketing and Postmarketing Experiences.

PURPOSE: After the recent approval of ocriplasmin by the Food and Drug Administration, postmarketing safety concerns have been raised by the vitreoretinal community. The American Society of Retina Specialists Therapeutic Surveillance Committee was commissioned to monitor postmarketing drug-related and device-related adverse events. The purpose of this report is to analyze the postmarketing safety experience in the context of available premarketing safety data. METHODS: Periodic aggregate safety reports consisting of premarketing, or clinical trial, data (n = 999 injections) and postmarketing reports through July 16, 2013 (n = 4,387 injections), were retrospectively analyzed by the TSC. The aggregate data were analyzed to classify adverse events, and the postmarketing safety data for each event type were compared with the premarketing data. RESULTS: Eight categories of adverse events were identified. Acute reduction in visual acuity attributable to either worsening of macular pathology or development of subretinal fluid, electroretinogram changes, dyschromatopsia, retinal tears and detachments, lens subluxation or phacodonesis, impaired pupillary reflex, and retinal vessel findings were reported in both the premarketing and postmarketing experiences. Ellipsoid zone (inner segment/outer segment) findings were only reported in the postmarketing experience. Rates of postmarketing reports were lower than in the premarketing data. Adverse events were generally transient, and characteristics of these adverse events were generally similar between the premarketing and postmarketing experience. CONCLUSION: Postmarket analyses are limited by significant underreporting, and in the case of ocriplasmin as a first in-class drug, they may not have captured safety events that have only more recently been identified. Nonetheless, postmarket analyses can identify the scope of potential safety events based on real-world experiences. Ocriplasmin administration should be guided by an appropriate and informed risk-benefit discussion with the patient. Ongoing active postmarket surveillance by all practitioners will continue to be critical to better understand this safety profile.

Rate and timing of spontaneous resolution in a vitreomacular traction group: should the role of watchful waiting be re-evaluated as an alternative to ocriplasmin therapy?

INTRODUCTION: The incidence of spontaneous resolution of vitreomacular traction (VMT) is low in studies of Ocriplasmin that have had a limited follow-up. Previous studies did not look for morphological parameters in the natural history using spectral-domain ocular coherence tomography (SD-OCT) imaging. The purpose of this study was to investigate how often and when spontaneous VMT resolution occurs in candidates for Ocriplasmin therapy. METHODS: The study is a retrospective chart review of patients who would have high chances of a benefit by an Ocriplasmin injection, without epiretinal membrane or vitreomacular adhesion of 1500 µm or more on SD-OCT. Main outcome measures were the frequency of complete VMT resolution and the best corrected visual acuity seen in the natural history. RESULTS: Out of the 46 patients that were included after screening 889 SD-OCT images, 20 were found to exhibit spontaneous resolution during the follow-up period (median: 594 days, 95% CI 567 to 719 days), the majority after 6-12 months of observation (95% CI 266 to 617 days). The group with spontaneous VMT resolution and a mean improvement of one line in best corrected visual acuity included a few patients losing vision by macular hole formation. In the absence of resolution, patients lost on average one early treatment diabetic retinopathy study letter per year. Younger age was found to increase the chance of spontaneous resolution. CONCLUSIONS: A shorter follow-up might underestimate the incidence of spontaneous VMT resolution as the functional outcome of watchful waiting. The likelihood of resolution does not seem to decrease after 12 months.

Topical effectiveness of kiwifruit versus fibrinolysin ointment on removal of necrotic tissue of full-thickness burns in male rats.

Formation of necrotic tissues is a major issue affecting treatment of full-thickness burns. This study was designed to compare topical effectiveness of applying kiwifruit versus fibrinolysin on removal of necrotic tissue of burns. Ten adult male Wistar rats were randomly assigned to three groups. For group 1, the right-side wounds were treated with kiwifruit and the other side with fibrinolysin. For group 2, the wounds on the right side were treated with kiwifruit or fibrinolysin, and the left sides were kept as control group 2. All wounds in group 3 were considered as control group 1. The control wounds were left to heal naturally. In each group and for each wound, the time of debridement were noted. The results indicated that for the wounds where kiwifruit was applied, the average time for removal of dead tissue was 5.7 days, which is significantly shorter than the average 18.5 days it took for treatment with fibrinolysin (p = 0.02). However, there were no significant differences between control wounds 1 and 2. Findings of the present study can open new horizons and provide a new treatment modality for patients with deep burns.

Perioperative haemostatic management of Glanzmann thrombasthenia for abdominal surgery.

Glanzmann thrombasthenia is a rare congenital platelet disorder characterized by spontaneous mucocutaneous bleeding and severe bleeding complications during major surgery. This report centres on the perioperative haemostatic management of a patient with Glanzmann thrombasthenia undergoing elective major abdominal surgery. The treatment regimen was based mainly on recombinant activated factor VII, fibrinogen, and factor XIII, reducing platelet transfusion to a minimum. No red blood cell transfusions were needed perioperatively. For haemostatic monitoring, routine laboratory tests were sufficient.

Experimental evaluation of microplasmin - an alternative to vital dyes.

Complete separation of the vitreous from the retina is a major goal of vitrectomy. Mechanical vitrectomy, however, is not able to meet this need because remnants of the vitreous cortex are left behind at the retinal surface, resulting in incomplete posterior vitreous detachment (PVD). As incomplete PVD and an attached vitreous cortex are associated with the progression of common retinal diseases including diabetic retinopathy and maculopathy, central retinal vein occlusion, and proliferative vitreoretinopathy, induction of complete PVD is a major issue both in vitreoretinal surgery and in medical retina. This chapter focuses on one of the most promising current concepts of pharmacologic vitreolysis, i.e. microplasmin-assisted vitrectomy. Microplasmin (Thrombogenics Ltd., Dublin, Ireland) is a recombinant molecule consisting of the catalytic domain of human plasmin. It shares the same catalytic properties like human plasmin, but it is much more stable compared to plasmin. It has been shown previously that both plasmin and microplasmin are capable of inducing PVD. Herein, we report on the preclinical work regarding plasmin and microplasmin which led to the clinical investigation of microplasmin.

Plasmin induces local thrombolysis without causing hemorrhage: a comparison with tissue plasminogen activator in the rabbit.

The direct fibrinolytic enzyme, plasmin, was compared with tissue plasminogen activator (TPA) in rabbit models of local thrombolysis and fibrinolytic hemorrhage. Plasmin was produced by solid-phase urokinase activation of plasminogen and purified on benzamidine Sepharose. Applied as an intra-arterial infusion into the thrombosed abdominal aorta under conditions of unimpeded blood flow, plasmin (4 mg/kg) and TPA (2 mg/kg) achieved equivalent clot dissolution and flow restoration. Using the model of restricted blood flow into the thrombosed aorta, which limits local plasminogen supply, plasmin was superior to TPA in clot lysis and vascular reperfusion. Using similar dosages of plasmin (2 or 4 mg/kg) and TPA (1 or 2 mg/kg) in the earpuncture rebleed model. TPA induced rebleeding in a dose-dependent manner from prior puncture sites in 9 of 10 animals, while none of the 10 animals exposed to plasmin rebled from these sites. These results suggest that plasmin is an effective, unique thrombolytic agent, distinguished from the plasminogen activators in current usage by its striking safety profile.

Thrombolytic effect of nattokinase on a chemically induced thrombosis model in rat.

Nattokinase is a new fibrinolytic enzyme which cleaves directly cross-linked fibrin in vitro. In this study, we investigated the thrombolytic effect of nattokinase on a thrombus in the common carotid artery of rat in which the endothelial cells of the vessel wall were injured by acetic acid. When a section of occluded vessel was stained for CD61 antigen by immunofluorescence utilizing a monoclonal antibody, the antigen was localized around the surface of the occluded blood vessels. This result suggests that the occlusive thrombosis was caused by platelet aggregation. In addition, thrombolysis with urokinase (UK; 50000 IU/kg, i.v.) or tissue plasminogen activator (tPA; 13300 IU/kg, i.v.) in our model was observed to restore the blood flow over a 60 min monitoring period. The results indicate that our chemically induced model is useful for screening and evaluating a thrombolytic agent. We evaluated the thrombolytic activity of nattokinase using this model and compared it with fibrino(geno)lytic enzyme, plasmin or elastase. On a molar basis, the recovery of the arterial blood flow with nattokinase, plasmin and elastase were 62.0 +/- 5.3%, 15.8 +/- 0.7% and 0%, respectively. The results indicate that the thrombolytic activity of nattokinase is stronger than that of plasmin or elastase in vivo.

Treatment of ligneous conjunctivitis.

A case of ligneous conjunctivitis, which presented in the acute form and converted to a mixed form after several months is described. Treatment with fibrinolysin was of value in reducing the reformation time of the membranes and in decreasing the viscosity of the serofibrinous discharge. The use of cryosurgery appeared to be of value in eliminating the membranes and granuloma and in markedly reducing the production and viscosity of the discharge.

Indications for and limitations of coronary thrombolysis.

Experimental studies in dogs with coronary thrombi induced by copper wire confirmed the optimal method of intracoronary thrombolysis, and showed that a high-dose, brief intravenous infusion of urokinase can lead to recanalization. The thrombolytic effects of intracoronary thrombolysin at a rate of 50 IU/kg over 10 minutes are similar to the effects of intracoronary urokinase at a rate 500 IU/kg over 20 minutes. Overall reperfusion rates of 83-86% have been achieved. These results indicate that the thrombolytic effect of thrombolysin is 20 times stronger than that of urokinase. The effect of a brief intravenous infusion of urokinase was less than that of intracoronary urokinase. The reperfusion rate in the same experimental model was 40%. Later, a clinical trial of intracoronary urokinase was performed in 47 patients with acute myocardial infarction who were admitted within 12 hours of the onset of symptoms. In 25 of 33 (75.8%) patients with complete occlusion, selective or ostial infusion of urokinase 500 IU/kg over 20 minutes was successful. When given intravenously, recanalization was achieved in 11 of 15 (73%) patients with complete occlusion who were admitted within 6 hours. Both reperfusion rates were similar except for dosage and the duration of infusion.

Proteolytic enzymes as adjuncts to antimicrobial prophylaxis of contaminated wounds.

When a tissue is injured, its vessels exhibit a marked increase in vascular permeability. Blood proteins, including fibrinogen, traverse the vessel walls and lead to the development of a surface coagulum. This inflammatory response continues until primary closure of the wound edges is accomplished. The thickness of the surface coagulum is roughly proportional to the time interval between wounding and closure. This coagulum encompasses the surface contaminants, preventing contact with either topical or systemic antibiotics. The presence of this surface coagulum limits the time in which antibiotic prophylaxis is effective. At three hours after injury, antimicrobial prophylaxis of contaminated wounds has no therapeutic value. Hydrolysis of the protein coagulum by proteolytic enzymes enhances the activity of the antibiotic in experimental wounds. The success of proteolytic enzymes as adjuncts to delayed antibiotic treatment can be correlated with the clot lysis activity of the enzymes in vitro. Travase, the most potent fibrinolytic enzyme, is the most effective adjunct to delayed antibiotic therapy of contaminated wounds. In contrast, the active enzymes found in Elase, which exhibit no significant clot lysis activity in vitro, do not potentiate the activity of antibiotics in wounds subjected to a delay in treatment. Travase prolongs the period of effective topical antibiotic action for at least eight hours in experimental contaminated wounds. The therapeutic merit of Travase is also apparent when the antibiotic is administered systemically. Travase shows promise as an adjunct to a variety of antibiotics that are effective against both gram-positive and gram-negative organisms. The results of these experimental studies support our belief that clinical studies support our belief that clinical studies should now be initiated to test the therapeutic value of Travase as an adjunct to antibiotics in heavily contaminated wounds subjected to an unavoidable delay in treatment.