Effectiveness of Netarsudil versus Brimonidine in Eyes already Being Treated with Glaucoma Medications at a Single Academic Tertiary Care Practice: A Comparative Study

ABSTRACT: Background: Rho kinase inhibitors, such as netarsudil, are a relatively new class of medications recently introduced into the market for the treatment of glaucoma, the leading cause of irreversible blindness in the world. Previous clinical trials have studied netarsudil's efficacy when used as a first- or second-line agent but limited studies have investigated its effectiveness in the real world where it is more commonly used as a third, fourth, or fifth agent in combination with other topical medications. Equally important, prior studies have not compared its effectiveness to its peer medications in these settings. Objective: To compare intraocular pressure (IOP) lowering after initiation of netarsudil or brimonidine therapy in patients with glaucoma using >2 medications for IOP management. Methods: A chart review of 369 eyes from 279 patients followed at a single academic tertiary practice was performed with an institutional review board waiver of consent to compare IOP lowering after prescription of netarsudil (n = 176) versus brimonidine (n = 193) as a third, fourth, or fifth IOP-lowering agent. Patients were identified by querying the electronic medical record for those with a glaucoma-related diagnosis who were prescribed either medication. Five sequential IOP measurements were obtained to determine the mean change in IOP before and after treatment (ΔIOP = mean IOP4,5 – mean IOP1,2,3). A multilevel linear mixed-effects model assessed the influence of medication (independent variable) on ΔIOP (dependent variable). Additional independent variables of interest included the number of glaucoma medications at baseline, age, sex, glaucoma type and severity, race, and pretreatment IOP. Bootstrap analysis was performed to remove sampling bias and confirm mixed-effects model findings. Kaplan-Meier survival analysis evaluated the probability of requiring additional intervention within 3 years following the date of medication prescription. Results: The unadjusted mean (SD) ΔIOP for netarsudil and brimonidine was −2.20 (4.11) mm Hg and −2.21 (3.25) mm Hg, respectively (P = 0.484). The adjusted linear mixed-effects models and bootstrap analysis demonstrated that there was no statistical difference in IOP-lowering effectiveness between the medications. Netarsudil and brimonidine failed to adequately control IOP at similar rates with 42% and 47% probabilities of survival respectively by the 3-year follow-up (P = 0.520). Conclusions: When escalating pharmacologic therapy, the IOP-lowering effect of netarsudil appeared to be similar to that produced by brimonidine. (Curr Ther Res Clin Exp. 2023; 84:XXX–XXX

Orlistat treatment of unconjugated hyperbilirubinemia in Crigler-Najjar disease: A randomized controlled trial

Unconjugated hyperbilirubinemia in Crigler-Najjar (CN) disease is conventionally treated with phototherapy and phenobarbital. Orlistat treatment increases fecal fat excretion and decreases plasma unconjugated bifirubin (UCB) concentrations in Gunn rats, the animal model for CN disease. We determined in CN patients the effects of orlistat treatment on plasma UCB concentrations, and on fecal excretion of fat and UCB. A randomized, placebo-controlled, double-blind, cross-over trial was conducted in 16 patients, simultaneous with their regular treatment (phototherapy, n = 11, and/or phenobarbital, n = 6). Patients received orlistat or place bo, each for 4-6 wk. Compared with placebo, orlistat increased fecal fat excretion (+333%) and fecal UCB excretion (+43%). Orlistat treatment significantly decreased plasma UCB concentration (-9%). In 7 of 16 patients, the decrease in plasma UCB levels was clinically relevant (>10%, mean 21%). In patients with a clinically relevant response, plasma UCB concentrations during orlistat were strongly, negatively correlated with fecal fat excretion (r = -0.93). Clinically relevant response to orlistat treatment was not correlated with age, sex, CN type, BMI, or co-treatment with phototherapy or phenobarbital, but appeared correlated with a relatively lower dietary fat intake. In conclusion, orlistat treatment decreases plasma UCB concentrations, particularly in a subgroup of CN patients. Dietary fat intake may determine the responsiveness to orlistat treatment

Novel kinetic insights into treatment of unconjugated hyperbilirubinemia: Phototherapy and orlistat treatment in Gunn rats

Treatment with phototherapy or with the lipase inhibitor orlistat decreases plasma unconjugated bilirubin (UCB) concentrations in hyperbilirubinemic Gunn rats. We investigated the mechanism(s) underlying the effects of orlistat, phototherapy, and combined treatment, using steady-state 3H-UCB kinetics. After three weeks of treatment with orlistat (200 mg/ka chow), phototherapy (19 mu W/cm(2)/nm) or combined treatment, tracer H-3-UCB was administered IV to treated and untreated (control) Gunn rats. Plasma samples and feces were collected every 12h for 60h, and bile for 30 min at 60h. The following results were obtained: 1) each treatment decreased plasma bilirubin levels compared with controls: orlistat-19%, phototherapy-32%, combined treatment-53%; 2) plasma bilirubin concentrations were strongly, negatively correlated with fractional bilirubin turnover; 3) orlistat treatment induced net transmucosal excretion of UCB into the intestinal lumen, whereas phototherapy increased biliary UCB excretion rate; 4) all treatments profoundly increased the enterohepatic circulation of UCB derivatives, indicating enhanced metabolism by intestinal bacteria. In conclusion, orlistat and phototherapy lower plasma bilirubin concentrations in Gunn rats by increasing (net) intestinal influx of UCB, either by transmucosal excretion (orlistat), or increased biliary secretion (phototherapy). The mechanism of phototherapy and orlistat treatment involves increasing the availability of UCB in the intestinal lumen for fecal excretion and for metabolism by intestinal bacteria

Combined Treatment Strategies for Unconjugated Hyperbilirubinemia in Gunn Rats

We recently demonstrated that acceleration of the gastrointestinal transit by polyethylene glycol (PEG) treats unconjugated hyperbilirubinemia in jaundiced Gunn rats. It is unclear whether acceleration of gastrointestinal transit also (partly) underlies the therapeutic effects of established hypobilirubinemic treatments or whether PEG cotreatment might enhance these effects. We treated Gunn rats with phototherapy (17 mu W/cm(2)/nm), orlistat (200 mg/kg chow), ursodeoxycholate (5 g/kg chow), or calcium phosphate (CaP) (20 g/kg chow) either as single treatment or in combination with PEG. Three weeks of phototherapy, orlistat, ursodeoxycholic acid, or CaP treatment decreased plasma unconjugated bilirubin (UCB) levels by 47, 27, 28, and 45%, respectively (each p <0.001), without a significant impact on gastrointestinal transit time. PEG cotreatment accelerated the gastrointestinal transit in all treatment groups, which resulted in an additive hypobilirubinemic effect of -20% and -26% (final plasma UCB -67 and -53%, respectively) in phototherapy- and orlistat-treated animals. PEG cotreatment did not enhance the hypobilirubinemic effect of ursodeoxycholic acid or CaP. We conclude that phototherapy, orlistat, ursodoxycholic acid, and CaP do not exert their hypobilirubinemic effect via acceleration of the gastrointestinal transit. PEG cotreatment enhanced the hypobilirubinemic effects of phototherapy and of orlistat treatment. Current results support a clinical trial to evaluate PEG cotreatment during phototherapy. (Pediatr Res 70: 560-565, 2011