Fenofibrate subcellular distribution as a rationale for the intracranial delivery through biodegradable carrier.

Fenofibrate, a well-known normolipidemic drug, has been shown to exert strong anticancer effects against tumors of neuroectodermal origin including glioblastoma. Although some pharmacokinetic studies were performed in the past, data are still needed about the detailed subcellular and tissue distribution of fenofibrate (FF) and its active metabolite, fenofibric acid (FA), especially in respect to the treatment of intracranial tumors. We used high performance liquid chromatography (HPLC) to elucidate the intracellular, tissue and body fluid distribution of FF and FA after oral administration of the drug to mice bearing intracranial glioblastoma. Following the treatment, FF was quickly cleaved to FA by blood esterases and FA was detected in the blood, urine, liver, kidney, spleen and lungs. We have also detected small amounts of FA in the brains of two out of six mice, but not in the brain tumor tissue. The lack of FF and FA in the intracranial tumors prompted us to develop a new method for intracranial delivery of FF. We have prepared and tested in vitro biodegradable poly-lactic-co-glycolic acid (PLGA) polymer wafers containing FF, which could ultimately be inserted into the brain cavity following resection of the brain tumor. HPLC-based analysis demonstrated a slow and constant diffusion of FF from the wafer, and the released FF abolished clonogenic growth of glioblastoma cells. On the intracellular level, FF and FA were both present in the cytosolic fraction. Surprisingly, we also detected FF, but not FA in the cell membrane fraction. Electron paramagnetic resonance spectroscopy applied to spin-labeled phospholipid model-membranes revealed broadening of lipid phase transitions and decrease of membrane polarity induced by fenofibrate. Our results indicate that the membrane-bound FF could contribute to its exceptional anticancer potential in comparison to other lipid-lowering drugs, and advocate for intracranial delivery of FF in the combined pharmacotherapy against glioblastoma.

A comparison of the polypropylene plate Ahmed glaucoma valve to the silicone plate Ahmed glaucoma flexible valve.

PURPOSE: To compare surgical outcomes following implantation of the polypropylene plate Ahmed glaucoma valve (AGV) (S-2) and the newer silicone plate AGV (FP-7) with minimum 12 months follow-up in patients with intractable glaucoma. DESIGN: Retrospective chart review of 25 eyes of 22 patients who underwent FP-7 and 26 eyes of 22 patients who underwent S-2 AGV implantation by a single surgeon. Main outcome measures included surgical outcomes in terms of intraocular pressure (IOP) control, hypertensive phase, and postoperative complications. RESULTS: There were no significant differences in diagnoses, pre-and postoperative IOP, pre- and postoperative visual acuities at all time points, and in the number of pre- and postoperative medications between the groups. Significant IOP reductions occurred after FP-7 implantation (29.6 +/- 13.1 to 12.1 +/- 3.4, p < 0.001) and S-2 implantation (31.4 +/- 11.7 to 16.1 +/- 5.7, p < 0.001). The FP-7 group had a statistically lower IOP compared to the S-2 group at 6 (p<0.05), 9 (p<0.01), and 12 months (p<0.01). There was no significant difference in the hypertensive phase between the two groups (p=0.41). CONCLUSIONS: FP-7 model silicone plate AGV resulted in lower IOP compared to the older S-2 polypropylene plate AGV at 1 year. This may suggest that the plate material may influence clinical outcome.

Aqueous shunts for glaucoma.

BACKGROUND: Aqueous shunts are employed for intraocular pressure (IOP) control in primary and secondary glaucomas that fail medical, laser, and other surgical therapies. OBJECTIVES: This review compares aqueous shunts for IOP control and safety. SEARCH STRATEGY: We searched CENTRAL, MEDLINE, PubMed, EMBASE, NRR all in January 2006, LILACS to February 2004 and reference lists of included trials. SELECTION CRITERIA: We included all randomized and quasi-randomized trials in which one arm of the study involved shunts. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data for included studies and a third adjudicated discrepancies. We contacted investigators for missing information. We used fixed-effect models and summarized continuous outcomes using mean differences. MAIN RESULTS: We included fifteen trials with a total of 1153 participants with mixed diagnoses. Five studies reported details sufficient to verify the method of randomization but only two had adequate allocation concealment. Data collection and follow-up times were variable.Meta-analysis of two trials comparing Ahmed implant with trabeculectomy found trabeculectomy resulted in lower mean IOPs 11 to 13 months later (mean difference 3.81 mm Hg, 95% CI 1.94 to 5.69 mm Hg). Meta-analysis of two trials comparing double-plate Molteno implant with the Schocket shunt was not done due to substantial heterogeneity. One study comparing ridged with standard double-plate Molteno implants found no clinically significant differences in outcome. Two trials investigating the effectiveness of adjunctive mitomycin (MMC) with the Molteno and Ahmed implants found no evidence of benefit with MMC. Two trials that investigated surgical technique variations with the Ahmed found no benefit with partial tube ligation or excision of Tenon's capsule. One study concluded there were outcome advantages with a double versus a single-plate Molteno implant and one trial comparing the 350 mm(2) and 500 mm(2) Baerveldt shunts found no clinically significant advantage of the larger device but neither of these trials included all patients randomized. One study suggested improved clinical outcome when MMC was employed with a newly described shunt including ultrasound supporting the conclusion. One small study did not demonstrate an outcome advantage to systemic steroid use postoperatively with single-plate Molteno shunts. One study comparing endocyclophotocoagulation (ECP) with Ahmed implant in complicated glaucomas found no evidence of better IOP control with Ahmed implant over ECP. AUTHORS' CONCLUSIONS: Relatively few randomized trials have been published on aqueous shunts and methodology and data quality among them is poor. To date there is no evidence of superiority of one shunt over another.

Anatomic and histopathologic findings following a failed ahmed glaucoma valve device.

Ahmed glaucoma valve implant (AGV) is one of the more commonly used implants in difficult glaucomas. The histology of a functioning bleb following AGV implantation and its anatomic relationship to the optic nerve when placed in the superionasal quadrant has been described. We report the histology of a failed bleb and the anatomic relationship between the optic nerve and the AGV end-plate when placed 9 mm from the limbus in a patient with neovascular glaucoma.

Open-angle glaucoma secondary to blood clot in the Schlemm's canal following scleral buckle surgery and its treatment with tPA.

Obstruction of the episceral venous system can present with glaucoma. We present two patients who were referred to us for management of acute glaucoma with presumed episceral venous compression. The first patient had open-angle glaucoma with probable elevated episcleral venous pressure and blood in the Schlemm's canal, following a 360 degrees scleral buckle surgery. The second patient had open-angle glaucoma from delayed peribulbar hemorrhage following uncomplicated cataract surgery with blood in the Schlemm's canal. Both patients were successfully treated with intracameral injection with tissue plasminogen activator (tPA).

Penetrating keratoplasty and glaucoma.

Glaucoma remains the leading cause of blindness after penetrating keratoplasty. Post-keratoplasty glaucoma was originally described in 1969, and its management is still controversial. Recent developments in management include newer classes of drugs, surgical procedures, such as trabeculectomy with mitomycin-C, implantation of glaucoma drainage devices, and cyclodestructive procedures with Nd: YAG and diode lasers. However, the risk of graft failure continues to be high with all surgical procedures.

Comparison of different biomaterials for glaucoma drainage devices: part 2.

BACKGROUND: Inflammation associated with biomaterials may contribute to the failure of glaucoma drainage devices. OBJECTIVE: To compare the inflammatory reaction associated with the insertion of Krupin silicone, Molteno polypropylene, and Acrosof end plates in the subconjunctival space of rabbits. METHODS: Similar-sized glaucoma end plates made of 3 different biomaterials were sutured to the sclera in the superotemporal quadrant of the rabbit eye. Thirty eyes of 15 albino New Zealand rabbits were randomly assigned to the 3 groups. Conjunctival vascular hyperemia was graded in a masked fashion among the 3 groups. At the end of 3 weeks, the enucleated eyes were examined histologically and by scanning electron microscopy. RESULTS: Molteno polypropylene was associated with more inflammation both in clinical observations and based on histological grading. Silicone and Acrosof were associated with less intense inflammation. One polypropylene end plate was extruded on day 21. CONCLUSIONS: Polypropylene appears to be more inflammatory than silicone. Flexible biomaterials appear to be less inflammatory than rigid ones. CLINICAL RELEVANCE: Bleb failure following glaucoma drainage device implantation could be related to the biomaterial-associated inflammation. Choosing a biomaterial with the least inflammatory potential might enhance the success rate of the glaucoma drainage device. Arch Ophthalmol. 2000;118:1081-1084

Comparison of different biomaterials for glaucoma drainage devices.

OBJECTIVES: To compare the inflammatory reaction associated with the insertion of silicone and polypropylene endplates and endplates made of a new biocompatible polymer, Vivathane, in the rabbit subconjunctival space. METHODS: Similar-sized endplates made of 3 different biomaterials were sutured to the sclera in the superotemporal quadrant of the rabbit eye. Thirty eyes of 15 albino New Zealand rabbits were randomly assigned to the 3 groups. Conjunctival vascular hyperemia was graded in a masked fashion among groups. At the end of 3 weeks, the enucleated eyes were examined histologically and using scanning electron microscopy. RESULTS: Polypropylene and Vivathane were associated with significantly more inflammation in clinical observations and based on histological grading. Silicone was associated with the least amount of inflammation. Three polypropylene and 1 Vivathane plate were extruded between the second and third week. CONCLUSIONS: Silicone is the most inert of the 3 materials tested. Inflammation associated with biomaterials may contribute to the failure of the glaucoma drainage devices. CLINICAL RELEVANCE: Bleb inflammation may be related to the biomaterial being used as the endplate. Endplates should be handled carefully during surgery to avoid creating rough spots.

A clinical study of the Ahmed glaucoma valve implant in advanced glaucoma.

OBJECTIVE: To assess clinical outcomes and establish the incidence and management of a hypertensive phase (HP) (defined as intraocular pressure [IOP] > 21 mmHg in the first 6 postoperative months) in patients with Ahmed glaucoma valve implant. DESIGN: Retrospective noncomparative case series. PARTICIPANTS: A total of 85 patients were included in the current study, including consecutive patients who had intractable glaucoma and underwent Ahmed valve implant insertion at the University Glaucoma Center, Tampa, Florida (DWR and WEL) and the Massachusetts Eye and Ear Infirmary (PAN) between January 1993 and June 1997. Only patients with a minimum of 6 months' follow-up were included. INTERVENTION: Ahmed glaucoma valve implant insertion to control intractable glaucoma was performed. MAIN OUTCOME MEASURES: Success was defined as IOP less than 22 mmHg and greater than 4 mmHg on the last two visits, a decrease of no more than two lines in the visual acuity and no additional surgical interventions to control IOP. RESULTS: The cumulative probability of success at 12 months was 77%. A total of 26 patients (30.6%) failed during the study period, and 70 patients (82%) exhibited HP. Hypertensive phase peaked at 1 month after the operation and stabilized at 6 months. There were 34 patients (48%) with HP who were controlled with additional medications: 14 (20%) with needling and 5-fluorouracil injections and 20 (28%) who needed secondary surgical intervention. There were 8 patients (9.4%) who exhibited hypotony (< 5 mmHg) on postoperative day 1 and 3 (3.5%) at 3 months. Visual acuity returned to baseline between 3 and 6 months after the operation. The major complications associated with the valve were hyphema in 14 cases (16.5%), suprachoroidal hemorrhage in 4 cases (4.7%), end-plate exposure in 10 cases (11.7%), tube exposure in 6 cases (7%), tube block in 4 cases (4.7%), loss of vision in 5 cases (5.8%), and corneal graft failure in 4 (30%) of 13 cases with clear grafts. CONCLUSIONS: The overall success rate is comparable to that of prior studies using different implants. The majority of the patients exhibit an HP that peaks at 1 month, with gradual stabilization over 6 months. One third of the patients needed secondary surgical intervention to control the HP. The incidence of postoperative hypotony and flat or shallow anterior chambers is very low after Ahmed glaucoma valve insertion.

Cystoid macular edema associated with latanoprost in aphakic and pseudophakic eyes.

PURPOSE: To describe four patients who developed cystoid macular edema shortly after onset of treatment with latanoprost. METHOD: Retrospective review of medical records of patients with open-angle glaucoma who developed cystoid macular edema shortly after starting latanoprost. RESULTS: The use of topical latanoprost was temporally related to the development of cystoid macular edema in four patients (six eyes; two aphakic eyes and four pseudophakic eyes). Cystoid macular edema resolved in all patients after latanoprost was discontinued. CONCLUSIONS: Cystoid macular edema is a potential complication of latanoprost therapy. Further observations are needed to determine if the risk of cystoid macular edema is limited to or greatest in patients who are pseudophakic or aphakic.

Comparison of mitomycin C trabeculectomy, glaucoma drainage device implantation, and laser neodymium:YAG cyclophotocoagulation in the management of intractable glaucoma after penetrating keratoplasty.

PURPOSE: This study aimed to compare the surgical outcomes of mitomycin C trabeculectomy glaucoma drainage device (GDD) surgery and laser neodymium:YAG (Nd:YAG) cyclophotocoagulation (CPC) in the management of intractable glaucoma after penetrating keratoplasty (PKP) in a retrospective study. DESIGN: Interventional case series. PARTICIPANTS/METHODS: The medical charts of consecutive patients who had pre-existing glaucoma or who developed glaucoma after PKP and underwent a surgical procedure to control the glaucoma at the University Eye Associates of Boston University Medical Center, New England Eye Center, and Massachusetts Eye and Ear Infirmary between January 1991 and July 1995 were reviewed. Follow-up ranged from 6 months to 4 years after the glaucoma procedure. A total of 38 patients were included consisting of 17 patients who underwent mitomycin C, 10 patients who underwent GDD surgery, and 11 patients who had CPC. INTERVENTION: Mitomycin C trabeculectomy, GDDs, or Nd:YAG CPC to control glaucoma after PKP was performed, MAIN OUTCOME MEASURES: Graft status, postoperative intraocular pressure (IOP), and visual acuity were the main outcome measures. RESULTS: There were no differences among the three groups with respect to the follow-up time after the corneal graft operation (P = 0.15) or after the glaucoma operation (P = 0.98). At the final follow-up, the average decrease in the IOP was 17 mmHg (P < 0.001) after mitomycin C, 15 mmHg (P = 0.003) after GDD surgery, and 14.4 mmHg (P = 0.001) after CPC. There were no differences in the proportion of patients who developed postoperative IOP above 20 mmHg (P = 0.50) and in the proportion who developed hypotony (P = 0.10) among the three groups. Two grafts failed after mitomycin C and one failed after CPC. Among the three procedures, there were no differences in the proportion of patients who experienced either an improvement (P = 0.14) or a decrease (P = 0.22) in the visual acuity by more than one line after the glaucoma procedure. One patient each in the GDD group and the CPC group lost light perception after the procedure. The risk of graft failure was almost three times higher for each additional PKP (odds ratio = 2.80, P = 0.02). CONCLUSIONS: No differences were found among the three glaucoma procedures with respect to controlling IOP and graft failure. There was a trend for patients treated with CPC to have a higher incidence of graft failure, glaucoma failure, hypotony, and visual loss by more than one line, although this was not statistically significant. The number of PKPs was associated with graft failure, independent of the surgical procedure.

Corneal melting and scleromalacia perforans in a patient with pyoderma gangrenosum and acute myeloid leukemia.

Postoperative endophthalmitis may present in an atypical fashion (absent or minimal anterior chamber reaction) in the presence of underlying immunosuppressive disorder. The authors describe an apparently healthy 58-year-old man who displayed endophthalmitis with minimal anterior chamber reaction following penetrating keratoplasty for granular corneal dystrophy with underlying acute myeloid leukemia. Scleromalacia perforans in association with pyoderma gangrenosum subsequently developed, leading to ciliary staphyloma and corneal melting. Pyoderma gangrenosum is an uncommon, idiopathic skin disease that may also have ocular manifestations.

Recurrent endophthalmitis after cataract surgery with a scleral-tunnel incision.

PURPOSE: To present a case of recurrent postoperative endophthalmitis with a scleral-tunnel abscess and adjacent microbial keratitis. METHODS: A 76-year-old woman with microbial keratitis and recurrent endophthalmitis after cataract surgery was referred to a tertiary care center for further management. The medical chart of the patient was reviewed. RESULTS: The patient was seen on the eighth postoperative day with endophthalmitis that responded to medical treatment. Initial vitreous cultures were negative. The endophthalmitis recurred after the medical treatment was discontinued. She subsequently developed microbial keratitis at 1 o'clock adjacent to the limbus. Cultures from the site of corneal abscess and vitreous grew coagulase-negative Staphylococcus. Gonioscopy revealed the presence of a scleral abscess, which responded to subconjunctival injection of vancomycin and an intense and prolonged course of topical antibiotics. CONCLUSION: A scleral abscess should be suspected in a patient with endophthalmitis or microbial keratitis or both after a scleral-tunnel incision for cataract surgery.

Corneal blood staining following autologous blood injection for hypotony maculopathy.

Hypotony is a common complication following trabeculectomy in which antimetabolites are used. Autologous blood injection is an accepted form of treatment for hypotony that occurs secondary to overfiltration; however, injection into the filtering bleb has been associated with a rise in intraocular pressure for some patients with chronic postoperative hypotony. The authors describe a patient in whom corneal blood staining with raised intraocular pressure and loss of vision occurred as a result of autologous blood injection.

Bleb infections: clinically different courses of "blebitis" and endophthalmitis.

BACKGROUND AND OBJECTIVES: To assess the differences in history, clinical course, and response between five cases of blebitis and three cases of endophthalmitis following mitomycin trabeculectomy. PATIENTS AND METHODS: The authors conducted a retrospective review of eight consecutive cases of bleb-related infection following successful mitomycin trabeculectomy. RESULTS: All patients with blebitis responded to treatment with return of visual acuity and intraocular pressure to preinfection levels. In the three cases of endophthalmitis, one patient underwent enucleation, one had a final visual acuity of counting fingers, and the third had a visual acuity of 20/60. CONCLUSIONS: Blebitis, a limited form of bleb-related infection with thin, cystic, leaky blebs, responds to intensive topical antibiotic treatment, returning visual acuity and IOP to preinfection levels. Bleb-related endophthalmitis causes a more virulent form of bleb-related infection that involves thin- or thick-walled blebs, with or without leakage, and poor visual prognosis despite immediate intensive topical, systemic, and intravitreal antibiotic administration combined with core vitrectomy.

Bleb infections: clinically different courses of "blebitis" and endophthalmitis.

1. Researchers have recently introduced the term "blebitis" to describe a limited form of bleb-related infection (with infection and inflammation limited to the bleb and the peri-bleb area, with or without anterior chamber involvement) in contrast to the more classic form of endophthalmitis. 2. Bleb-related endophthalmitis is the virulent form of bleb-related infection in which patients present with rapidly worsening visual acuity, redness, and pain with diffuse conjunctival congestion, opalescent blebs (with or without epithelial defects) with intense fibrin and/or hypopyon in the anterior chamber, and florid vitritis. 3. Blebitis and bleb-related endophthalmitis are two distinct bleb-related infections, each with different presentations, prognoses, and outcomes. It is important that clinicians recognize this and treat patients accordingly.

Transscleral flow of aqueous humor: an in vitro experiment.

BACKGROUND AND OBJECTIVE: The minimal scleral flap thickness to ensure transscleral flow following a trabeculectomy has never been determined. The present study was designed to determine, in vitro, the critical scleral flap thickness that allows transscleral flow. MATERIALS AND METHODS: The apparatus consisted of two horizontal glass chambers (A and B) connected to each other by a customized scleral disc holder. High-pressure chamber A (at 25 mm Hg) was filled with sodium pertechnetate (99mTc) labeled normal saline and low-pressure chamber B (at 5 mm Hg) with normal saline. Transscleral flow of labeled normal saline from high-pressure chamber A via varying thickness scleral discs to low-pressure chamber B was observed over 16 hours using a gamma camera. Computer analysis was performed on the obtained images. RESULTS: Transscleral flow of labeled saline was observed only with scleral discs 0.5 mm thick or less. CONCLUSIONS: If the findings hold true for the in vivo situation, aqueous humor may reach the subconjunctival space following trabeculectomy via the transscleral route, provided scleral flap thickness is less than 0.5 mm. In addition, normal uveoscleral aqueous outflow may occur across sclera less than 0.5 mm thick, e.g., posterior to extraocular muscle insertions.