Continuous treatment with odanacatib for up to 8 years in postmenopausal women with low bone mineral density: a phase 2 study.

UNLABELLED: The efficacy and safety of weekly oral odanacatib (ODN) 50 mg for up to 8 years were assessed in postmenopausal women with low bone mineral density (BMD). Treatment with ODN for up to 8 years resulted in continued or maintained increases in BMD at multiple sites and was well tolerated. INTRODUCTION: ODN is a selective inhibitor of cathepsin K. In a 2-year phase 2b study (3/10/25/50 mg ODN once weekly [QW] or placebo) and extensions (50 mg ODN QW or placebo), ODN treatment for 5 years progressively increased BMD and decreased bone resorption markers in postmenopausal women with low BMD ( ClinicalTrials.gov NCT00112437). METHODS: In this prespecified interim analysis at year 8 of an additional 5-year extension (years 6 to 10), patients (n = 117) received open-label ODN 50 mg QW plus weekly vitamin D3 (5600 IU) and calcium supplementation as needed. Primary end points were lumbar spine BMD and safety. Patients were grouped by ODN exposure duration. RESULTS: Mean (95 % confidence interval [CI]) lumbar spine BMD changes from baseline were 4.6 % (2.4, 6.7; 3-year continuous ODN exposure), 12.9 % (8.1, 17.7; 5 years), 12.8 % (10.0, 15.7; 6 years), and 14.8 % (11.0, 18.6; 8 years). Similar patterns of results were observed for BMD of trochanter, femoral neck, and total hip versus baseline. Geometric mean changes from baseline to year 8 for bone resorption markers were approximately -50 % (uNTx/Cr) and -45 % (sCTx), respectively (all groups); bone formation markers remained near baseline levels. No osteonecrosis of the jaw, delayed fracture union, or morphea-like skin reactions were reported. CONCLUSIONS: Treatment with ODN for up to 8 years resulted in gains in BMD at multiple sites. Bone resorption markers remained reduced, with no significant change observed in bone formation markers. Treatment with ODN for up to 8 years was well tolerated.

Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the Long-Term Odanacatib Fracture Trial.

SUMMARY: Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone resorption and increases bone mineral density, with only a transient decrease in bone formation. We describe the background, design and participant characteristics for the phase 3 registration trial. INTRODUCTION: Odanacatib (ODN) is a selective cathepsin K inhibitor being evaluated for the treatment of osteoporosis. In a phase 2 trial, ODN 50 mg once weekly reduced bone resorption while preserving bone formation and progressively increased BMD over 5 years. We describe the phase III Long-Term ODN Fracture Trial (LOFT), an event-driven, randomized, blinded placebo-controlled trial, with preplanned interim analyses to permit early termination if significant fracture risk reduction was demonstrated. An extension was planned, with participants remaining on their randomized treatment for up to 5 years, then transitioning to open-label ODN. METHODS: The three primary outcomes were radiologically determined vertebral, hip, and clinical non-vertebral fractures. Secondary end points included clinical vertebral fractures, BMD, bone turnover markers, and safety and tolerability, including bone histology. Participants were women, 65 years or older, with a BMD T-score≤-2.5 at the total hip (TH) or femoral neck (FN) or with a prior radiographic vertebral fracture and a T-score≤-1.5 at the TH or FN. They were randomized to ODN or placebo tablets. All received weekly vitamin D3 (5600 international units (IU)) and daily calcium supplements as needed to ensure a daily intake of approximately 1200 mg. RESULTS: Altogether, 16,713 participants were randomized at 387 centers. After a planned interim analysis, an independent data monitoring committee recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. Following the base study closeout, 8256 participants entered the study extension. CONCLUSIONS: This report details the background and study design of this fracture end point trial and describes the baseline characteristics of its participants.

Combined intravenous pulse methylprednisolone and oral cyclosporine A in the treatment of corneal graft rejection: 5-year experience.

PURPOSE: To report the mid-term results of a treatment strategy using topical steroids, intravenous pulse methyl prednisolone and oral cyclosporine A (CSA) for the treatment of acute corneal graft rejection. METHODS: Noncomparative, interventional case series. Treatment of corneal graft rejection included 1% prednisolone eye drops, intravenous infusion of 500 mg methyl prednisolone, and oral CSA in two regimens--standard dose was 15 mg/kg/day for 2 days, 7.5 mg/kg/day for 2 days, then adjusted to maintain trough blood levels of 100-200 microg/l; low dose was 2 mg/kg/day with no loading dose. RESULTS: Outcome in 34 eyes of 34 patients (21 M;13 F) aged 60 +/- 17.7 years (range 9-83 years), who presented after an average duration of 6.6 +/- 6.3 days (range 0-30 days) following acute corneal graft rejection, are reported. Twenty-five patients received standard dose CSA while nine patients received the low dose regimen. Mean duration of treatment before reversal of graft rejection was 13.6 +/- 12.1 days (range 3-54 days). Treatment was successful in reversing the graft rejection in 32/34 (94%) eyes. Irreversible graft failure occurred in one eye in each group. During a mean follow-up period of 19.2 +/- 16.7 months (range 1-55 months), further episodes of graft rejection were seen in 1/32 (3%) eyes. Complications due to treatment included: duodenal ulcer in one patient that responded to medical treatment, and transient elevation in serum creatinine levels in three patients, which returned to normal after decrease in dosage or cessation of oral CSA. CONCLUSION: Our 5-year experience with the use of oral CSA in the treatment of acute corneal graft rejection has shown this treatment approach to be safe and effective in reversing the rejection process. This approach may also protect the graft from subsequent episodes of allograft rejection. A randomised controlled trial to further delineate the role of CSA in reversing acute graft rejection seems warranted.

Effect of preoperative keratometry on refractive outcomes after laser in situ keratomileusis.

PURPOSE: To evaluate the effect of preoperative keratometry on the refractive outcome after laser in situ keratomileusis (LASIK) for myopia. SETTING: University Eye Clinic, Prince of Wales Hospital, Hong Kong, China. METHODS: In this retrospective study, the records of patients who had LASIK for myopia greater than -6.0 diopters (D) using the Chiron Automated Corneal Shaper and the Schwind Keratome-F excimer laser were reviewed. RESULTS: Laser in situ keratomileusis was performed in 167 eyes of 103 patients (mean age 34.7 years +/- 7.5 [SD]). Preoperative myopic spherical equivalent (SE) refraction was -9.0 +/- 2.0 D (range -6.0 to -13.9 D). Three months after surgery, SE refraction was -0.04 +/- 1.1 D (range +2.3 to -3.3 D); uncorrected visual acuity > or = 20/40 was present in 91.8% of 110 eyes in which emmetropia was the postoperative goal. Mean preoperative keratometry was 43.9 +/- 1.5 D (range 40.3 to 48.1 D). When eyes were stratified by the degree of preoperative myopia in 1.0 D steps, a trend toward greater undercorrection was noted in eyes with preoperative keratometry < 43.5 D than in those with steeper keratometry (> 44.5 D) in all myopia groups except the -7.0 to -7.9 D group. This difference was statistically significant in eyes with a preoperative SE of -10.0 to -10.9 D and -11.0 to -11.9 D. CONCLUSIONS: Preoperative keratometry appeared to influence the refractive outcome after myopic LASIK. Eyes with flatter corneas tended to have greater undercorrection than eyes with similar myopia and steeper corneas. Validation of these findings in larger data sets using the methodology described may improve the predictability of current LASIK nomograms, particularly in eyes with high myopia.

Peribulbar anaesthesia with 1% ropivacaine and hyaluronidase 300 IU ml-1: comparison with 0.5% bupivacaine/2% lidocaine and hyaluronidase 50 IU ml-1.

The low toxicity of ropivacaine makes it attractive for peribulbar anaesthesia. However, its motor-sparing properties are undesirable when akinesia is important. Hyaluronidase (300 IU ml-1) promotes the onset and quality of peribulbar blockade when used with other agents. We investigated the onset and quality of ocular akinesia in 80 patients randomized to receive 1% ropivacaine plus hyaluronidase 300 IU ml-1 (group 1), or bupivacaine 0.5%/Lidocaine 2% plus 50 IU ml-1 hyaluronidase (group 2). Ocular akinesia was scored from 0 (no movement) to 8 (full movement) every 2 min for 20 min. The groups showed no difference in the rate of onset or degree of akinesia achieved (analysis of variance with repeated measures; P = 0.34). Sixty per cent of patients in group 1 and 55% in group 2 achieved akinesia scores of < or = 4 by 6 min (chi 2 test; P = 0.5). We conclude that both peribulbar solutions produce equivalent onset and quality of ocular akinesia.

The association between cigarette smoking and ocular diseases.

OBJECTIVE: To review the effect of smoking on common ocular disorders. DATA SOURCES: Medline literature search, 1966 to 1999. STUDY SELECTION: The following key words were used: smoking; Graves' disease, age-related macular degeneration; glaucoma; cataract. DATA EXTRACTION: Epidemiological and experimental studies were reviewed. DATA SYNTHESIS: Cigarette smoking is an important risk factor for cardiovascular, respiratory, and malignant diseases. There is also a strong association between smoking and a number of common eye diseases, which include Graves' ophthalmopathy, age-related macular degeneration, glaucoma, and cataract. Despite the multifactorial aetiology of these ocular syndromes, smoking is an independent risk factor that has dose-response effects. It causes morphological and functional changes to the lens and retina due to its atherosclerotic and thrombotic effects on the ocular capillaries. Smoking also enhances the generation of free radicals and decreases the levels of antioxidants in the blood circulation, aqueous humour, and ocular tissue. Thus, the eyes are more at risk of having free-radical and oxidation attacks in smokers. CONCLUSION: Smoking, if continued, may perpetuate further ocular damage and lead to permanent blindness. Cessation of smoking and avoidance of passive smoking is advised to minimise the harmful effects of smoking on the eyes.

Efficacy and safety of the Ahmed glaucoma valve implant in Chinese eyes with complicated glaucoma.

AIMS: To evaluate the efficacy and safety of the Ahmed glaucoma valve implant in Chinese eyes with complicated glaucomas. METHODS: This retrospective study reviewed the final intraocular pressure, visual outcome, and incidence of complications in all patients with the Ahmed glaucoma valve implant performed at the Prince of Wales Hospital, Hong Kong, between June 1996 and November 1998. RESULTS: A total of 65 eyes from 60 patients were treated with the Ahmed glaucoma implant. At a mean follow up (SD, median) of 21.8 (9.2, 28. 0) months (range 6-37 months), the mean intraocular pressure was reduced from 37.0 (SD 12.1) mm Hg before the implant surgery to 16.1 (12.4) mm Hg at the last follow up after surgery. The success rate of intraocular pressure control of <22 mm Hg was achieved in 73.8% of operated eyes. Transient postoperative hypotony with shallow anterior chamber occurred in 10.8% of cases. The most common postoperative complication was the formation of encapsulated bleb (24.6%). CONCLUSIONS: The Ahmed glaucoma valve implant appears to be effective and relatively safe for treating complicated glaucomas in Chinese eyes. The success rate is comparable with those reported in non-Asian eyes. Formation of postoperative encapsulated bleb is, however, more commonly encountered.

Scleral fixation of a capsular tension ring for severe ectopia lentis.

A 4-year-old boy with bilateral idiopathic and progressive ectopia lentis had phacoaspiration of the lens and capsular tension ring (CTR) insertion in his left eye. Postoperatively, lens capsule centration remained poor. Single-point scleral fixation of the CTR was performed and centration of the lens capsule achieved. In-the-capsule intraocular lens (IOL) implantation was tried, but excessive IOL manipulation sliced open the capsule at the equator. Anterior vitrectomy and scleral IOL fixation were required. A similar approach was adopted in the right eye with meticulous attention given to gentle maneuvers. The operation was uneventful, with good IOL centration. Three and 11 months after surgery in the right and left eye, respectively, best corrected visual acuity was 20/50 in both eyes. Scleral fixation of the CTR, accompanied by gentle IOL manipulation, is an option to improve IOL centration in patients with severe zonular deficiency.

Pathogenesis and management of laser in situ keratomileusis flap buttonhole.

PURPOSE: To describe the clinical features and outcomes in patients who had a flap buttonhole during laser in situ keratomileusis (LASIK) and propose an etiopathogenic mechanism for this complication. SETTING: University Eye Center, Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China. METHODS: Retrospective review of case records of 6 patients (6 eyes) who had a flap buttonhole during LASIK. RESULTS: The mean patient age was 38.2 years +/- 4.1 (SD) and the mean preoperative spherical equivalent (SE) refraction, -8.13 +/- 4.04 diopters (D). Mean keratometry was 44.20 +/- 1.30 D. Retreatment was performed after a mean interval of 9.2 +/- 3.2 months. Final postoperative SE refraction was -0.44 +/- 0.58 D after a mean follow-up of 59.0 +/- 5.3 weeks. No patient experienced loss of best spectacle-corrected visual acuity. CONCLUSIONS: Retreatment of eyes that have a flap buttonhole during LASIK is associated with good visual outcomes. Flap buttonholes can produce alterations in refraction, so retreatment is best performed after the refractive error has stabilized. Microkeratome malfunction may be responsible for the occurrence of a flap buttonhole during LASIK in eyes that do not have significant corneal steepening.

Latanoprost versus timolol gel to prevent ocular hypertension after phacoemulsification and intraocular lens implantation.

PURPOSE: To evaluate the efficacy of latanoprost and timolol gel in preventing ocular hypertension in the early period after phacoemulsification and posterior chamber intraocular lens (PC IOL) implantation. SETTING: Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, Hong Kong, China. METHODS: This prospective randomized double-masked clinical trial comprised patients with uncomplicated cataract having phacoemulsification with PC IOL implantation. They were randomly assigned to 1 of 3 groups: postoperative application of timolol 0.5% gel-forming solution (Timoptol-XE(R)) (Group 1), latanoprost 0.005% (Group 2), and control (Group 3). Intraocular pressure (IOP) was measured 2, 4, and 24 hours postoperatively. The anterior chamber was examined for the levels of cells and flare using slitlamp biomicroscopy. RESULTS: Group 1 had a significantly greater reduction in mean IOP 2, 4, and 24 hours after phacoemulsification and PC IOL implantation than Group 3 (P <.05). There were no significant differences between Groups 2 and 3 at any interval (P. 05). No excessive postoperative anterior chamber inflammation was observed in any group. CONCLUSIONS: A single dose of latanoprost given after phacoemulsification and PC IOL implantation did not produce a significant IOP-lowering effect when compared with a control group in the first 24 hours postoperatively. A single dose of timolol gel produced a significant postoperative IOP decrease as soon as 2 hours and up to 24 hours after surgery. Timolol gel and latanoprost are safe, but timolol is more effective than latanoprost in preventing postoperative ocular hypertension.

In situ tumbling of the AcrySof intraocular lens.

The small incision through which foldable acrylic intraocular lenses (IOLs) are implanted does not allow easy explantation of the lens in the event of intraoperative complications. Reversal of the IOL optic during insertion, although rare, can predispose to postoperative complications such as pupillary capture of the IOL, capsule bag distension syndrome, and refractive problems. Explanting the IOL can damage it, the cataract wound, or both. We describe a technique of in situ tumbling of the AcrySof IOL to correct reversed-optic implantation that preserves the integrity of the IOL and anterior segment structures.