Nearly half a century has passed since the demonstration that cannabis and its chief psychoactive component Δ9-THC lowers intraocular pressure (IOP). Elevated IOP remains the chief hallmark and therapeutic target for glaucoma, a condition that places millions at risk of blindness. It is likely that Δ9-THC exerts much of its IOP-lowering effects via the activation of CB1 cannabinoid receptors. However, the initial promise of CB1 as a target for treating glaucoma has not thus far translated into a credible therapeutic strategy. We have recently shown that blocking monoacylglycerol lipase (MAGL), an enzyme that breaks the endocannabinoid 2-arachidonoyl glycerol (2-AG), substantially lowers IOP. Another strategy is to develop cannabinoid CB1 receptor agonists that are optimized for topical application to the eye. Recently we have reported on a controlled-deactivation approach where the “soft” drug concept of enzymatic deactivation was combined with a “depot effect” that is commonly observed with Δ9-THC and other lipophilic cannabinoids. This approach allowed us to develop novel cannabinoids with a predictable duration of action and is particularly attractive for the design of CB1 activators for ophthalmic use with limited or no psychoactive effects. We have tested a novel class of compounds using a combination of electrophysiology in autaptic hippocampal neurons, a well-characterized model of endogenous cannabinoid signaling, and measurements of IOP in a mouse model. We now report that AM7410 is a reasonably potent and efficacious agonist at CB1 in neurons and that it substantially (30%) lowers IOP for as long as 5 h after a single topical treatment. This effect is absent in CB1 knockout mice. Our results indicate that the direct targeting of CB1 receptors with controlled-deactivation ligands is a viable approach to lower IOP in a murine model and merits further study in other model systems.

Background and Hypothesis:  Component loosening and instability are the leading causes of revision total hip arthroplasty (THA). The purpose of this study was to compare patient-reported outcomes after revision THA based on failure etiology. We hypothesized that outcomes would differ based on reason for revision. Project Methods: 187 consecutive revision THAs performed between 2010 and 2017 were retrospectively reviewed. Prospectively collected preoperative and minimum one-year Hip Disability and Osteoarthritis Outcome Score/HOOS Jr., UCLA Activity Level, WOMAC Index, and patient satisfaction were assessed based on failure etiology.  Demographic variables and covariates were accounted for including sex, age, BMI, ASA classification, heart disease, lumbar spine pathology, narcotic use, fibromyalgia, depression, and autoimmune arthritis.   Results: Latest UCLA activity level did not differ based on failure etiology (p=0.381). However, the degree of improvement in activity level was higher (p= 0.04) in patients revised for loosening, instability, and infection compared to ALTR and polyethylene wear. HOOS Jr (p=0.949) and WOMAC total (p=0.147) scores did not differ based on failure etiology at latest follow-up, although patients revised for loosening had greater WOMAC improvement compared to all other groups except polyethylene wear (p=0.016). Satisfaction did not vary based on failure etiology (p=0.365), and demographic and covariates were unrelated to outcomes (p[Symbol]0.165).    Conclusion and Potential Impact: We observed that patient-reported outcomes following revision THA vary based on revision reason and activity level improvement is mitigated patients revised for ALTR and poly wear.  These findings may help surgeons and patients alike set expectations for recovery following revision THA.