Emerging therapies for dry eye disease.

INTRODUCTION: Dry Eye Disease (DED) is defined as a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film, and a vicious cycle of inflammation on the ocular surface. Despite its high prevalence and standing as one of the most common eye conditions seen by practitioners, the current treatment options available to patients have not proven adequate. AREAS COVERED: This review will discuss the burden of DED, its pathophysiology, as well as emerging therapies. These therapies include immunosuppressants, immunomodulators, anti-inflammatory drugs, and corticosteroids. The mechanisms of these drugs will be discussed, as well as their phase of development and results from recent clinical trials. The literature search was performed using PubMed, Cochrane Library, Web of Science, ClinicalTrials.gov, and the Springer AdisInsight database. EXPERT OPINION: The optimal therapy for DED is associated with improved bioavailability, minimal ocular side effects, and effective dosing. The ideal treatment has not yet been established, but this paper outlines a number of promising therapies. Continued development of therapies targeting the inflammation cascade, as well as the establishment of objective markers to quantify DED severity, are important aspects in the progression of treatment.

Postrenal transplant infection: What is the effect of specific immunosuppressant agents?

BACKGROUND: Immunosuppression is a known risk for post-transplant infections. Little data exist on the risk contributions of specific agents for various infections. METHODS: A triply robust propensity score-adjusted analysis was performed in a renal transplant cohort between February 2006 and January 2014. The study was performed to identify the incidence and the risk factors for developing a post-transplant infection. After initial bivariate analysis, a triply robust propensity score-adjusted multivariate logistic regression was performed. RESULTS: The mean age of the 717 renal transplant recipients was 50.0 ± 13.3 years, with the majority being male (61.6%) and 349 (48.7%) experiencing at least 1 post-transplant infection. Neither race, graft type, nor insurance status was associated with an increased incidence or risk of infection. In a fully adjusted regression model, the immunosuppressants mycophenolic acid mofetil (OR 0.38, 95% CI 0.21-0.71; P < .001) and alemtuzumab (OR 0.40, 95% CI 0.19-0.85; P = .020) were protective. CONCLUSION: Alemtuzumab and mycophenolic acid mofetil as immunosuppressant agents in a multiagent protocol appear to decrease the incidence of infection. Cytomegalovirus antigenemia was the greatest risk for infection and mycophenolic acid mofetil possessed the greatest protective effect on viral infections.

Racial Disparity in Renal Transplantation: Alemtuzumab the Great Equalizer?

OBJECTIVES: Racial disparity as a barrier to successful outcomes in renal transplants for African Americans has been well described. Numerous unsuccessful attempts have been made to identify specific immunologic and socioeconomic factors. The objective of our study was to determine whether alemtuzumab (AL) induction abolishes this discrepancy and improves allograft survival in African American recipients. METHODS: A retrospective chart review of consecutive adult renal transplants was conducted between 2006 and 2014. Kaplan-Meier analysis and hazard ratios were calculated for the African Americans (AA) and white groups. Multiple linear regressions were performed to assess independent variables (race, retransplant, sex, donor type, induction agent) on allograft survival. RESULTS: A significant difference in allograft survival was identified between whites (n = 272) and AA (n = 445), with AA experiencing more graft losses (18.2% vs 12.1%, P = 0.0351). Induction with AL improved outcomes in all transplant recipients. Multiple linear regression identified that the strongest predictor of allograft failure was induction without AL (P < 0.0001). The data for a subset analysis matched for follow-up length demonstrated that whites compared with AA (n = 157, 67 whites and 90 AA) had lower rates of allograft failure in the absence of AL induction (14.9% vs 44.4%, P = 0.0156, hazard ratio = 2.077). In contrast, AL induction (n = 275, 105 whites and 170 AA) eliminated the racial disparity in allograft failure (5.7% vs 9.4%, P = 0.8248, hazard ratio = 1.504). CONCLUSIONS: This is the first study to describe the effects of AL induction therapy on AA renal transplant recipients beyond the first posttransplant year. Our early results suggest that AL induction therapy abolishes the disparity in renal allograft failure.

Generics: are all immunosuppression agents created equally?

BACKGROUND: The Affordable Care Act initiated innumerable cost-containment measures, including promoting generic conversion from brand medications and directing the Food and Drug Administration to decrease requirements for generic approvals. Despite this mandate, few data existed on generic conversion of immunosuppressant medications with narrow therapeutic troughs. METHODS: A retrospective analysis of our initial experience with generic tacrolimus (n = 39) was performed using a control cohort from our renal transplant database. A rejection and cost analysis was performed using a consecutive 2-year prior cohort (n = 159) as a control to determine the effect of generic conversion on tacrolimus a narrow therapeutic index immunosuppressant medication. RESULTS: During the first year after transplantation, the generic group had a greater drug variability (20% ± change in trough levels) that required more dosage adjustments (5.42 vs 3.59 drug dosage changes; P = .038) to obtain a stable dose, required increased number of intravenous magnesium infusions (4.95 vs 1.68 infusions; P = .001), and incurred a greater incidence of rejection (23.1% vs 10.2%; P = .024). A yearly institutional cost was evaluated against a negotiated $18,000/yearly central pharmacy cost savings compared with a $652,862 institutional cost to treat unanticipated rejections. CONCLUSION: Programmatic conversion from brand to generic tacrolimus resulted in increased drug variability, a greater incidence of magnesium wasting, and more episodes of rejection, leading to increases in institutional costs of care. This government-driven attempt at cost containment may be applicable to noncritical medications such as antibiotics and antihypertensives, but this policy should be reconsidered for narrow therapeutic index medications, such as tacrolimus and other immunosuppressant medications.

Role of the lens capsule on the mechanical accommodative response in a lens stretcher.

PURPOSE: To determine whether changes in elastic properties of the lens capsule ex vivo with age contribute to the forces necessary for accommodation. METHODS: Postmortem human (n = 22; age average: 41 +/- 17 years; range: 6-7) and cynomolgus monkey (n = 19; age average: 7.7 +/- 1.8 years, range: 4.2-10) tissues including the lens, capsule, zonules, ciliary body, and sclera were mounted in an optomechanical lens-stretching system. Starting at 0 load, the sclera was symmetrically stretched to 2 mm in 0.25-mm steps at a speed of 0.1 mm x s(-1). The load and lens diameter were measured at each step. The lens contents were removed through a mini-capsulorhexis. The stretching cycles were repeated on the empty capsular bag. The forces necessary to stretch the natural lens and empty bag were quantified as a function of age and compared. RESULTS: The force needed to stretch the empty lens capsule was independent of age (human, 2.6-34.9 g/mm [25.2-342.7 mN/mm]; monkey, 8.2-21.3 g/mm [80.3-208.6 mN/mm]). The ratio of the force necessary to stretch the empty lens capsule to the force necessary to stretch the natural lens decreased with age in the human and monkey lenses (P = 0.003, P = 0.72, respectively). CONCLUSIONS: The mechanical properties of the empty lens capsule assessed ex vivo in a lens stretcher remain constant with age, suggesting that the changes in elasticity of the lens capsule do not play a significant role in presbyopia. In young eyes, the lens capsule determines the force necessary to stretch the whole lens. The age-related increase in force needed to stretch the lens is due to changes in the lens contents.