Search

: ObjectiveTo compare the safety and intraocular pressure (IOP)-lowering efficacy of once-daily travoprost (0.0015% and 0.004%) to twice-daily timolol 0.5%.: DesignProspective, 6-month, randomized, controlled, multicenter, double-masked, phase III study.: ParticipantsSix hundred five patients with open-angle glaucoma or ocular hypertension.: MethodsPatients with an 8 am IOP between 24 to 36 mmHg in at least one eye (the same eye) at two eligibility visits received either travoprost 0.0015%, travoprost 0.004% (dosed every day), or timolol 0.5% (dosed twice daily).: Main outcome measuresMean IOP at 8 am, 10 am, and 4 pm in the patient’s eye with the higher baseline IOP.: ResultsThe mean IOP was significantly lower for both concentrations of travoprost compared with timolol. Travoprost was statistically superior to timolol at 9 of 13 visits, with differences in IOP reductions ranging from 0.9 to 1.8 mmHg (0.0015%) and 10 of 13 visits with differences in IOP reductions from 0.9 to 2.4 mmHg (0.004%). Mean IOP changes from baseline ranged from −6.0 to −7.5 mmHg (0.0015%), −6.5 to −8.0 mmHg (0.004%), and −5.2 to −7.0 mmHg for timolol. Hyperemia was experienced at rates of 29.2% (59 of 202) for travoprost 0.0015%, 42.8% (86 of 201) for travoprost 0.004%, and 8.9% (18 of 202) for timolol. Iris pigmentation changes were observed in 1.0% (2 of 200) of patients receiving travoprost 0.004% with no changes noted in the travoprost 0.0015% group or the timolol group. A decrease in pulse and systolic blood pressure was observed in the timolol group. There were no other clinically relevant or statistically significant changes from baseline in ocular signs or laboratory values, and no serious, related, unexpected adverse events were reported for any group.: ConclusionsTravoprost (0.0015% and 0.004%), dosed once daily in the evening, is statistically superior or equal to timolol 0.5% dosed twice daily at all treatment visits during this 6-month study. IOP reductions of up to 2.0 mmHg greater than timolol were found in the travoprost 0.004% pooled data group. Travoprost is safe and well tolerated in patients with open-angle glaucoma or ocular hypertension. [Copyright &y& Elsevier]

Abstract: Since 1991, more than 50% of pediatric transplant recipients have received a living donor (LD) kidney, and ≈ 85% of these allografts were one‐haploidentical parental kidneys. Short‐term (1 yr) and long‐term (5 yr) graft survival of LD kidneys are 10% and 15% better, respectively, than that of cadaver donor (CD) kidneys. Because of these results, children are frequently not placed on a cadaver waiting list until the possibility of a LD is excluded – a process that may take up to 1 yr. The hypothesis for this study was that the graft outcome of a six‐antigen‐matched CD kidney is superior to that of a one‐haploidentical LD kidney, and that children are at a disadvantage by not being placed on a CD list whilst waiting for a LD. The database of the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) for 11 yrs (1987–98), was reviewed to identify children who were recipients of a six‐antigen‐matched CD kidney (primary and repeat transplants), and those who were recipients of a one‐haploidentical LD kidney (primary and repeat transplants). Using standard statistical methods, the morbidity, rejection episodes, post‐transplant hospitalizations, renal function, long‐ and short‐term graft survival, and half‐life of primary recipients were compared in the two groups. Unlike adult patients, only 2.7% (87/3313) of CD recipients in the pediatric age range received a six‐antigen‐matched kidney, and the annual accrual rate over 11 yrs was never higher than 4%. Comparison of 57 primary six‐antigen‐CD kidneys (PCD) with 2472 primary LD (PLD) kidneys revealed that morbidity, rejection rates, and ratios were identical in the two groups. Renal function and subsequent hospitalizations were also identical in the two groups. Five‐year graft survival of the PCD group was 90% compared with 80% for the PLD group, and the half‐life of the PCD group was 25 ± 12.9 yrs compared with 19.6 ± 1.3 yrs. Our data suggest that the six‐antigen‐matched CD kidney may have less graft loss as a result of chronic rejection and would therefore confer a better long‐term outcome. Based on these findings we recommend that all children, whilst waiting for a LD work‐up, be listed with the United Network for Organ Sharing (UNOS) registry for a CD kidney. [ABSTRACT FROM AUTHOR]

Abstract: We define delayed graft function (DGF) as the need for dialysis during the first post‐transplant week. We analyzed 5272 transplants, of which 2486 were of living donor (LD) and 2786 were of cadaver donor (CD) origin. Twelve per cent (620/5272) of all patients developed DGF. Donor specific rates were 5.6% for LD and 19.1% for CD patients. Factors predictive of DGF in CD patients were: African‐American race (25%), prolonged cold ischemia (24%), absence of T‐cell induction antibody therapy and absence of HLA‐DR matching. The relative risk (RR) for graft failure due to DGF was 6.02 (p < 0.001) in LD patients and 2.58 (p < 0.001) for CD recipients. Two‐year graft survival (GS) in LD patients without DGF was 89.6%, compared to 41.6% for those with DGF (p < 0.001); in CD patients it was 80.2% and 49.5%, respectively (p < 0.001). Censoring for primary non‐function, GS for LD patients with a functioning graft at 30 d post‐transplant and no DGF was 91.5%, compared to 70.1% for those with DGF (p < 0.001); GS for CD patients was 83.8% and 68.7%, respectively (p < 0.001). However, when patients whose grafts had failed during the first year were censored no differences in GS were noted between patients with and without DGF for either LD or CD recipients. To determine whether DGF acts as an independent risk factor for graft failure, patients were segregated into four groups: rejection with DGF; rejection without DGF; DGF without rejection; and no DGF, no rejection. When these groups were compared DGF emerged as an independent risk factor for graft failure. This large study reviewing pediatric renal transplantation over 10 yr clearly delineates the role of DGF as a major risk factor for graft failure. [ABSTRACT FROM AUTHOR]

Purpose: The safety and intraocular pressure (IOP)-lowering efficacy of brimonidine tartrate 0.15% preserved with polyquaternium-1 were evaluated and compared with brimonidine tartrate 0.15% preserved with chlorine dioxide in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). Design: Randomized, double-masked, parallel group, multicenter equivalence study. Participants: Eight hundred forty-two patients randomized to the study treatments. Methods: Patients with OAG or OHT and with qualifying IOP (22–36 mmHg at 8 am on 2 eligibility visits after an appropriate washout period from previous treatment) were assigned randomly to either brimonidine tartrate 0.15% preserved with polyquaternium-1 (brimonidine PQ) or brimonidine tartrate 0.15% preserved with chlorine dioxide (brimonidine P) dosed 3 times daily and were followed up for 6 months. Approximately one half of the study sites continued to follow up their patients for an additional 6 months to obtain longer-term safety data. Results: Brimonidine PQ produced statistically significant and clinically relevant reductions from baseline ranging from 4.3 to 6.5 mmHg, which were statistically and clinically equivalent to brimonidine P at all 18 visit days and times. No safety concerns were identified based on an assessment of ocular and cardiovascular parameters. Patient discontinuations resulting from adverse events were similar for both groups and most of these were a result of signs or symptoms of ocular allergic reaction. Conclusions: Brimonidine PQ is equivalent in IOP-lowering efficacy and safety to brimonidine P. [Copyright &y& Elsevier]

Purpose: To compare 1-year safety and efficacy of anecortave acetate 15 mg with photodynamic therapy (PDT) with verteporfin in patients eligible for initial PDT treatment. Design: Prospective, masked, randomized, multicenter, parallel group, active control, noninferiority clinical trial. Participants: Five hundred thirty patients with predominantly classic subfoveal choroidal neovascularization secondary to age-related macular degeneration were randomized to treatment with either anecortave acetate 15 mg or PDT. Methods: In the anecortave acetate group, the drug was administered under the Tenon’s capsule as a periocular posterior juxtascleral depot (PJD) at the beginning of the study and at month 6. Before the first administration of anecortave acetate, patients in this treatment group received a sham PDT treatment, and sham PDT treatments were repeated every 3 months if there was evidence of leakage on fluorescein angiography (FA). Patients assigned to PDT received up to 4 PDT treatments at 3-month intervals, as needed based upon FA, and a sham PJD procedure at the beginning of the study and at month 6. Best-corrected visual acuity was determined at baseline and all follow-up visits. Safety data were regularly reviewed by an independent safety committee. Main Outcome Measure: Percent responders (patients losing <3 lines of vision) at month 12. Results: Percent responders in the anecortave acetate and PDT groups were 45% and 49%, respectively (not statistically different, P = 0.43). The confidence interval (CI) for the difference ranged from −13.2% favoring PDT to +5.6% favoring anecortave acetate. The month 12 clinical outcome for anecortave acetate was improved in patients for whom reflux was controlled and who were treated within the 6-month treatment window (57% vs. 49%; 95% CI, −4.3% favoring PDT to +21.7% favoring anecortave acetate). No serious adverse events related to the study drug were reported in either treatment group. Conclusions: The safety and efficacy outcomes in this study demonstrate that the benefits of anecortave acetate for the treatment of choroidal neovascularization outweigh the risks associated with either the drug or the PJD administration procedure. [Copyright &y& Elsevier]

The structure-activity studies that led to the identification of travoprost, a highly selective and potent FP prostaglandin analog, and AL-6598, a DP prostaglandin analog, are detailed. In both series, the 1-alcohol analogs are very effective and are thought to be acting as prodrugs for the biologically active carboxylic acids. The efficacy of amide prodrugs depends on the degree of substitution and the size of the substituents. Selected compounds are profiled in vitro and in vivo preclinically. Clinical studies show that travoprost 0.004% (isopropyl ester) provided intraocular pressure control superior to timolol 0.5% when used as monotherapy in patients with open-angle glaucoma or ocular hypertension. In clinical studies, AL-6598 0.01% provided a sustained intraocular pressure reduction with q.d. application; b.i.d. provided greater intraocular pressure control. The acute and, apparently, conjunctival hyperemia associated with topical ocular AL-6598 can be attenuated while maintaining intraocular pressure-lowering efficacy by formulating with brimonidine. [Copyright &y& Elsevier]

Purpose: To compare the IOP-lowering efficacy of the fixed combination of travoprost 0.004%/timolol 0.5% dosed once daily in the morning with the concomitant administration of travoprost 0.004% dosed once daily in the evening and timolol 0.5% dosed once daily in the morning., Methods: This was an analysis of pooled data from two similarly designed prospective, randomized, controlled clinical trials comparing the fixed combination and concomitant therapy., Results: Mean IOP ranged from 15.7 to 16.8 mmHg for the fixed combination group, and from 15.1 to 16.4 mmHg for the concomitant group. Mean IOP reductions were up to 9.0 mmHg in the fixed combination group, and up to 8.8 mmHg in the concomitant group. The differences in mean IOP change between treatment groups ranged from -0.2 to +0.9 mmHg across visits and time points. The safety profile was generally similar between groups. An exception was the incidence of ocular hyperemia, which was 13.7% with the fixed combination and 20.8% with concomitant therapy (p = 0.02)., Conclusion: The fixed combination of travoprost 0.004% and timolol 0.5% provides IOP-lowering efficacy that is similar to concomitant administration of travoprost 0.004% dosed once daily in the evening and timolol 0.5% dosed once daily in the morning.

Purpose: To compare the safety and efficacy of travoprost 0.004% without benzalkonium chloride (BAC) to that of the marketed formulation of travoprost 0.004% in patients with open-angle glaucoma or ocular hypertension., Methods: The study was a double-masked, randomized, parallel group, multicenter, noninferiority design. Adult patients with open-angle glaucoma or ocular hypertension with qualifying intraocular pressure (IOP) on 2 eligibility visits received either travoprost 0.004% with BAC (n=346), or travoprost 0.004% without BAC (n=344) dosed once-daily each evening. Patients were followed for a period of 3 months. IOP measurements at 8 AM, 10 AM, and 4 PM were taken at study visits on week 2, week 6, and month 3., Results: Mean IOP reductions, across all 9 study visits and times ranged from 7.3 to 8.5 mm Hg for travoprost 0.004% without BAC and from 7.4 to 8.4 mm Hg for travoprost 0.004% with BAC. Statistical equivalence was also demonstrated for the comparison of mean IOP changes; 95% confidence limits were within +/-0.8 mm Hg at 9 of 9 study visits and times in both the per protocol and intent-to-treat data sets. Adverse events and the number of patients discontinued owing to adverse events were similar for both treatment groups. Adverse events due to hyperemia occurred in 6.4% and 9.0% of patients treated with travoprost 0.004% without BAC and travoprost 0.004% with BAC, respectively., Conclusion: Travoprost 0.004% without BAC is equivalent to travoprost 0.004% with BAC in both safety and efficacy.

Purpose: To determine the least worsening of a visual field (VF) and the least number of confirming tests needed to identify progression of glaucomatous VF defects., Design: Cohort study of participants in a clinical trial., Participants: Seven hundred fifty-two eyes of 565 patients with advanced glaucoma., Methods: Visual field tests were quantified with the Advanced Glaucoma Intervention Study (AGIS) VF defect score and the Humphrey Field Analyzer mean deviation (MD). Follow-up was 8 to 13 years., Main Outcome Measures: Two measures based on the AGIS VF defect score: (1) sustained decrease of VF (SDVF), a worsening from baseline by 2 (alternatively, 3 or 4) or more units and sustained for 2 (alternatively, 3) consecutive 6-month visits and (2) after the occurrence of SDVF, the average percent of eyes with worsening by 2 (alternatively, 3 or 4) or more units from baseline. Two similar measures based on MD., Results: Based on the original AGIS criteria for SDVF (a worsening of 4 units in the AGIS score sustained during 3 consecutive 6-month visits), 31% of eyes had an SDVF. The percent of eyes with a sustained event increases by approximately 10% when either the minimum number of units of field loss or the minimum number of 6-month visits during which the loss is sustained decreases by 1. During 3 years of follow-up after a sustained event, a worsening of at least 2 units was found in 72% of eyes that had a 2-visit sustained event. The same worsening was found in 84% of eyes that had a 3-visit sustained event. Through the next 10 years after a sustained event, based on worsening of 2, 3, or 4 units at 2 or 3 consecutive tests, the loss reoccurred, on average, in >/=75% of study eyes. Results for MD are similar., Conclusions: In patients with advanced glaucoma, a single confirmatory test 6 months after a VF worsening indicates with at least 72% probability a persistent defect when the worsening is defined by at least 2 units of AGIS score or by at least 2 decibels of MD. When the number of confirmatory tests is increased from 1 to 2, the percentage of eyes that show a persistent defect increases from 72% to 84%.

Purpose: To evaluate clinical safety and efficacy of the angiostatic agent anecortave acetate for treatment of subfoveal choroidal neovascularization secondary to AMD., Methods: 128 patients were randomized to placebo treatment or one of three anecortave acetate doses. Study medication was administered as a posterior juxtascleral injection onto the posterior scleral surface. Best-corrected logMAR vision was obtained at baseline and follow-up visits. Fluorescein angiograms were evaluated for eligibility before enrollment and posttreatment., Results: Six months after a single treatment, visual acuity (mean change from baseline logMAR values) was significantly better (P = 0.003) after anecortave acetate 15 mg than placebo. More patients treated with anecortave acetate 15 mg than placebo maintained vision (88% versus 70%, P = 0.080), especially those with predominantly classic lesions (92% versus 65%, P = 0.021). Anecortave acetate 15 mg inhibited lesion growth significantly better than placebo (P = 0.001). Trends favoring the other doses over placebo were observed for vision preservation and lesion inhibition, but statistical significance was not achieved. The Independent Safety Committee overseeing this study identified no clinically relevant treatment-related changes., Conclusion: Anecortave acetate 15 mg is safe and effective for preserving or improving vision and for inhibiting lesion growth in patients with subfoveal AMD.