Herpes simplex virus type 1 (HSV-1) is a large, enveloped, double-stranded DNA virus with a genome of approximately 150 kbp that encodes over 80 proteins, many of whose functions are still unknown (reviewed in reference 48). Productive HSV-1 infection occurs in a sequentially ordered cascade in which ␣ (immediate-early or IE) proteins precede the synthesis of ␤ (early or E) and ␥ (late or L) proteins (22,23). During the course of lytic infection, HSV-1 takes over the host cell, subjugating the cell's biomolecular synthesis machinery to serve its own reproduction. Cells react to viral infection by attempting to block viral replication, undergoing apoptosis, or by signaling neighboring cells to activate antiviral systems (reviewed in reference 31).The interplay between HSV-1 and its host involves numerous factors, and the virus employs several mechanisms to combat the many antiviral responses enacted by an infected cell. One of the most dramatic cellular responses to viral infection is the induction of apoptosis or programmed cell death. Apoptosis is characterized by cell shrinkage, membrane blebbing, redistribution of phosphatidylserine to the outer leaflet of the plasma membrane, fragmentation of nuclei (karyorrhexis), chromosomal DNA (pyknosis), and oligosomal DNA laddering (29,30,58). These structural modifications are a consequence of the activation of effector (executioner) caspases (cysteine aspartases), one of which is caspase 3, and the cleavage of poly(ADP-ribose) polymerase (PARP) and structural proteins (29,30,39,57,58). Apoptosis functions to limit virus spread by preventing viral replication, saving other cells from infection (34). HSV-1 has developed a mechanism to counteract this antiviral cell death process (3).The interaction of HSV-1 with its host cell results in the triggering of the apoptotic cell death program (2,4,33). During infection by wild-type HSV-1, caspase 3 is activated (4), the death factor DFF45 is completely cleaved (4), and phosphatidylserine is flipped from the inner to the outer membrane leaflet (25), indicating that replication-competent HSV-1 triggers the apoptosis death program and infected cells are actively in an apoptotic state. However, cells infected with wild-type HSV-1 do not show features of apoptosis, because infected cell proteins produced between 3 and 6 h postinfection (hpi), termed the apoptosis "prevention window" (4), prevent the process from killing the cells (4). Thus, human HEp-2 cells infected with either (i) viruses containing a deletion in the key viral regulators ICP4 or ICP27 or (ii) wild-type virus plus the addition of cycloheximide (CHX) at the time of infection, die by apoptosis (2,33,37). Although most recent efforts have focused on identifying viral gene products involved in apopto-* Corresponding author. Mailing address:

Bimatoprost SR demonstrated favorable efficacy and safety through 6 months. All dose strengths were comparable to topical bimatoprost in overall IOP reduction through week 16. A single administration controlled IOP in the majority of patients for up to 6 months.

on behalf of the ARTEMIS 1 Study GroupPurpose: To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of 10-and 15-mg bimatoprost implant in subjects with open-angle glaucoma (OAG) and ocular hypertension (OHT) after initial and repeated administrations.Design: Randomized, 20-month, multicenter, subject-and efficacy evaluator-masked, parallel-group, phase 3 clinical study.Participants: Adults with OAG or OHT in each eye, open iridocorneal angle inferiorly in the study eye, and study eye baseline IOP (hour 0; 8 AM) of 22e32 mmHg after washout.Methods: Study eyes received bimatoprost implant 10 mg (n ¼ 198) or 15 mg (n ¼ 198) on day 1 with readministration at weeks 16 and 32, or twice-daily topical timolol maleate 0.5% (n ¼ 198). Intraocular pressure was measured at hours 0 and 2 at each visit.Main Outcome Measures: Primary end points were IOP and change from baseline IOP through week 12. Safety measures included treatment-emergent adverse events (TEAEs) and corneal endothelial cell density (CECD).Results: Both dose strengths of bimatoprost implant were noninferior to timolol in IOP lowering after each administration. Mean diurnal IOP was 24.0, 24.2, and 23.9 mmHg at baseline and from 16.5e17.2, 16.5e17.0, and 17.1e17.5 mmHg through week 12 in the 10-mg implant, 15-mg implant, and timolol groups, respectively. The incidence of corneal and inflammatory TEAEs of interest (e.g., corneal endothelial cell loss, iritis) was higher with bimatoprost implant than timolol and highest with the 15-mg dose strength. Incidence of corneal TEAEs increased after repeated treatment; with 3 administrations at fixed 16-week intervals, incidence of !20% CECD loss was 10.2% (10-mg implant) and 21.8% (15-mg implant). Mean best-corrected visual acuity (BCVA) was stable; 3 implant-treated subjects with corneal TEAEs had >2-line BCVA loss at their last visit.Conclusions: Both dose strengths of bimatoprost implant met the primary end point of noninferiority to timolol through week 12. One year after 3 administrations, IOP was controlled in most subjects without additional treatment. The risk-benefit assessment favored the 10-mg implant over the 15-mg implant. Ongoing studies are evaluating other administration regimens to reduce the potential for CECD loss. The bimatoprost implant has potential to improve adherence and reduce treatment burden in glaucoma.

Objective The objective of this study was to evaluate the safety and intraocular pressure (IOP)-lowering effects over 24 months of biodegradable bimatoprost sustained-release implant (Bimatoprost SR) administration versus topical bimatoprost 0.03% in patients with open-angle glaucoma (OAG). Methods This was a phase I/II, prospective, 24-month, dose-ranging, paired-eye controlled clinical trial. At baseline following washout, adult patients with OAG (N = 75) received Bimatoprost SR (6, 10, 15, or 20 µg) intracamerally in the study eye; the fellow eye received topical bimatoprost 0.03% once daily. Rescue topical IOP-lowering medication or single repeat administration with implant was permitted. The primary endpoint was IOP change from baseline. Safety measures included adverse events (AEs).

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