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.

Subcellular distribution of the 1,4-dihydropyridine receptor in rabbit skeletal muscle in situ: an immunofluorescence and immunocolloidal gold-labeling study.

The subcellular distribution of the 1,4-dihydropyridine receptor was determined in rabbit skeletal muscle in situ by immunofluorescence and immunoelectron microscopy. Longitudinal and transverse cryosections (5-8 microns) of rabbit gracilis muscle were labeled with monoclonal antibodies specific against either the alpha 1-subunit (170,000-D polypeptide) or the beta-subunit (52,000-D polypeptide) of the 1,4-dihydropyridine receptor by immunofluorescence labeling. In longitudinal sections, specific labeling was present only near the interface between the A- and I-band regions of the sarcomeres. In transverse sections, specific labeling showed a hexagonal staining pattern within each myofiber however, the relative staining intensity of the type II (fast) fibers was judged to be three- to fourfold higher than that of the type I (slow) fibers. Specific immunofluorescence labeling of the sarcolemma was not observed in either longitudinal or transverse sections. These results are consistent with the idea that the alpha 1-subunit and the beta-subunit of the purified 1,4-dihydropyridine receptor are densely distributed in the transverse tubular membrane. Immunoelectron microscopical localization with a monoclonal antibody to the alpha 1-subunit of the 1,4-dihydropyridine receptor showed that the 1,4-dihydropyridine receptor is densely distributed in the transverse tubular membrane. Approximately half of these were distributed in close proximity to the junctional region between the transverse tubules and the terminal cisternae. Specific labeling was also present in discrete foci in the subsarcolemmal region of the myofibers. The size and the nonrandom distribution of these foci in the subsarcolemmal region support the possibility that they correspond to invaginations from the sarcolemma called caveolae. In conclusion, our results demonstrate that the 1,4-dihydropyridine receptor in skeletal muscle is localized to the transverse tubular membrane and discrete foci in the subsarcolemmal region, possibly caveolae but absent from the lateral portion of the sarcolemma.

Sequence and expression of mRNAs encoding the alpha 1 and alpha 2 subunits of a DHP-sensitive calcium channel.

Complementary DNAs were isolated and used to deduce the primary structures of the alpha 1 and alpha 2 subunits of the dihydropyridine-sensitive, voltage-dependent calcium channel from rabbit skeletal muscle. The alpha 1 subunit, which contains putative binding sites for calcium antagonists, is a hydrophobic protein with a sequence that is consistent with multiple transmembrane domains and shows structural and sequence homology with other voltage-dependent ion channels. In contrast, the alpha 2 subunit is a hydrophilic protein without homology to other known protein sequences. Nucleic acid hybridization studies suggest that the alpha 1 and alpha 2 subunit mRNAs are expressed differentially in a tissue-specific manner and that there is a family of genes encoding additional calcium channel subtypes.

32,000-Dalton subunit of the 1,4-dihydropyridine receptor.

Polyclonal antibodies to the 32,000-Da polypeptide of the 1,4-dihydropyridine receptor of the voltage-dependent Ca2+ channel have been produced and used to characterize the association of the 32,000-Da polypeptide (gamma subunit) with other subunits of the dihydropyridine receptor. The 32,000-Da polypeptide was found to copurify with alpha 1 and alpha 2 subunits at each step of the purification of the dihydropyridine receptor. Monoclonal antibodies against the alpha 1 and beta subunits immunoprecipitate the digitonin-solubilized dihydropyridine receptor as a multisubunit complex that includes the 32,000-Da polypeptide. Polyclonal antibodies generated against both the nonreduced and reduced forms of the alpha 2 subunit and the gamma subunit have been used to show that the 32,000-Da polypeptide is not a proteolytic fragment of a larger component of the dihydropyridine receptor and not disulfide linked to the alpha 2 subunit. Our results demonstrate that the 32,000-Da polypeptide (gamma subunit) is an integral and distinct component of the dihydropyridine receptor.

Isolated pedunculated congenital corneal dermoid.

PURPOSE: To investigate a case of isolated pedunculated congenital corneal dermoid. METHODS: Case report. RESULTS: In a 14-day-old infant, the pedunculated portion of the dermoid was removed and confirmed by histopathologic examination. No surgical complication or recurrence was encountered, and the patient is waiting for a rotational autokeratoplasty. CONCLUSIONS: Prompt treatment of such an unusual tumor is important to allow for visual rehabilitation and development.

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.

Traumatic partial unfolding of laser in situ keratomileusis flap with severe epithelial ingrowth.

We report an unusual flap-related complication that occurred 11 months after uneventful laser in situ keratomileusis (LASIK) performed in the eye of a 50-year-old woman. She developed partial infolding of the LASIK flap in her left eye after blunt trauma. The initial diagnosis was partial flap loss and 4 weeks later, infolding of the flap was diagnosed after severe epithelial ingrowth. Surgical repositioning of the flap resulted in a best corrected visual acuity of 20/20. Clinical features that assist in the diagnosis of this unusual complication and guidelines for its management are described.

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.

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.

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.

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.

Combined surgery for severe eye trauma with extensive iridodialysis, posterior lens dislocation, and intractable glaucoma.

A 44-year-old woman sustained a severe left eye contusion from the explosion of a plastic bottle containing fermented orange juice. This resulted in extensive iridodialysis, posterior crystalline lens dislocation, and intractable glaucoma. Eleven days after the injury, combined surgery of trabeculectomy with mitomycin-C, pars plana vitrectomy, lens removal, iridodialysis repair, and scleral-fixated intraocular lens implantation under general anesthesia was performed. Intraocular pressure (IOP) was under control until 5 weeks postoperatively; glaucoma implant surgery was then performed. At the last follow-up 15 months after the combined surgery, best corrected visual acuity was 20/50 and IOP was 15 mm Hg without medication. Combined surgery can be considered a safe, effective option in the management of severe eye trauma in selected cases.

Short-term results of scleral intraocular lens fixation in children.

PURPOSE: To study the safety and efficacy of scleral intraocular lens (IOL) fixation in children. SETTING: A university practice. METHODS: This retrospective review evaluated the results and complications in 6 consecutive eyes of 3 children who had anterior vitrectomy, with or without lensectomy, and scleral IOL fixation to correct ectopia lentis or aphakia. RESULTS: At a mean follow-up of 17.3 months (range 13 to 21 months), all eyes had a stable and well-positioned posterior chamber IOL and good visual improvement. The only complication was asymptomatic pupillary capture of the IOL in 3 eyes. Reversal of the pupillary capture was achieved by pupil dilation with the patient in a supine position. CONCLUSIONS: The preliminary results of scleral IOL fixation in children are encouraging. The procedure's application in well-selected cases can be considered. However, its long-term safety and efficacy must be further assessed through studies with larger sample sizes and a longer follow-up.

Culture-negative ulcerative keratitis after laser in situ keratomileusis.

A 40-year old man, highly myopic in both eyes, had laser in situ keratomileusis (LASIK) in the left eye in November 1996. Corneal melting and ulceration and fine striae-like interface infiltrates were noticed 1 day postoperatively. There was no response to intensive topical antibiotics in the form of hourly ofloxacin 3% (Tarivid), and satellite lesions developed on day 4. Corneal scrapings for gram stain and culture were done twice. No bacterial or fungal organisms were identified. Intensive topical fortified vancomycin (50 mg/mL) was added, and the lesions resolved gradually over the ensuing 2 weeks. Eighteen months after LASIK, refraction was -1.50 - 0.75 x 105 in the left eye, and uncorrected visual acuity was 20/70, correctable to 20/25 with spectacles.

Management of severe flap wrinkling or dislodgment after laser in situ keratomileusis.

PURPOSE: To review the management and results of cases with severe flap wrinkling or dislodgment after laser in situ keratomileusis (LASIK). SETTING: University Eye Center, Department of Ophthalmology and Visual Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong. METHODS: Four patients with severe flap wrinkling or dislodgment after LASIK are described. Surgical repositioning of the flap was performed in all cases. Flap status, refractive changes, and final uncorrected and best corrected visual acuities were used to evaluate the outcome of flap repositioning. RESULTS: Flap repositioning required suturing in 2 patients, 1 of whom developed severe epithelial ingrowth with melting of the corneal flap and stromal bed and eventually required flap removal. The stromal inflammation resolved, and the corneal surface re-epithelialized after flap excision. In 2 other patients, wedge-shaped tissue excision (1.0 x 1.5 mm) from the superior portion of the corneal flap was necessary to allow better flap realignment. In 1 of these patients, the corneal flap was eventually converted to a free cap to correct residual wrinkling. At a mean follow-up of 15 months, the postoperative uncorrected visual acuity ranged from 20/20 to 20/60, and the best spectacle-corrected visual acuity (BSCVA) was 20/30 or better in all patients. In 1 patient, BSCVA decreased by 1 line. CONCLUSIONS: Flap dislodgment and wrinkling are serious postoperative complications of LASIK. Early recognition of these complications and prompt surgical management are crucial to achieve a successful surgical and visual outcome.

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.

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.

Inferior limbal-conjunctival autograft transplantation for recurrent pterygium.

PURPOSE: To study the safety and efficacy of inferior limbal-conjunctival autograft (LCAT) transplantation in the surgical management of recurrent pterygium. METHODS: Prospective non-comparative case series. Inferior limbal-conjunctival autografting was performed on 11 patients (11 eyes) with recurrent pterygium. Pterygium recurrence was considered a surgical failure. RESULTS: Recurrence of pterygium was noted in two (18.2%) eyes, after a mean follow up of 16.2 +/- 0.9 months (range: 10-19 months). Neither recurrence required further surgical treatment. Nonprogressive pseudopterygium formation was noted at the donor site in five (45.5%) eyes. CONCLUSION: Inferior LCAT appears to be a safe and effective option in the management of recurrent pterygium. In patients with suspected or proven glaucoma, this may be the procedure of choice, if mitomycin C is contraindicated.