Objective

To determine the effect of 5% sodium chloride ophthalmic ointment (5% NaCl) on thickness and morphology of the normal canine cornea using ultrasonic pachymetry (USP), in vivo confocal microscopy (IVCM), and Fourier-domain optical coherence tomography (FD-OCT).

Methods

Five healthy laboratory Beagles received ophthalmic examinations including USP, IVCM, and FD-OCT prior to and at fixed intervals following treatment. The right and left eyes were treated with 5% NaCl and artificial tears ophthalmic ointment (AT), respectively, every 2 hours for 4 treatments/d (days 2-9), and then hourly for 7 treatments/d (day 10). Treatment groups were statistically compared using mixed-effects linear regression.

Results

Treatment with 5% NaCl resulted in a 12 μm decrease in corneal thickness from baseline (P < .001), while there was no significant difference in corneal thickness between values obtained at baseline and following treatment with AT (P = .82). Epithelial cell density significantly increased from baseline (530 ± 52 cells/mm² ) to 577 ± 43 and 567 ± 15 cells/mm² with 5% NaCl and AT, respectively (P = .003 and .005, respectively). However, keratocyte cell density in the anterior and posterior stroma and endothelial cell density did not significantly differ following treatment with 5% NaCl or AT ointment (P > .05).

Conclusions

Short-term topical treatment with 5% NaCl decreased corneal thickness in normal dogs with no observable changes in corneal morphology or signs of ocular toxicity.

Aims

The COLchicine Cardiovascular Outcomes Trial (COLCOT) demonstrated the benefits of targeting inflammation after myocardial infarction (MI). We aimed to determine whether time-to-treatment initiation (TTI) influences the beneficial impact of colchicine.

Methods and results

In COLCOT, patients were randomly assigned to receive colchicine or placebo within 30 days post-MI. Time-to-treatment initiation was defined as the length of time between the index MI and the initiation of study medication. The primary efficacy endpoint was a composite of cardiovascular death, resuscitated cardiac arrest, MI, stroke, or urgent hospitalization for angina requiring coronary revascularization. The relationship between endpoints and various TTI (<3, 4-7 and >8 days) was examined using multivariable Cox regression models. Amongst the 4661 patients included in this analysis, there were 1193, 720, and 2748 patients, respectively, in the three TTI strata. After a median follow-up of 22.7 months, there was a significant reduction in the incidence of the primary endpoint for patients in whom colchicine was initiated < Day 3 compared with placebo [hazard ratios (HR) = 0.52, 95% confidence intervals (CI) 0.32-0.84], in contrast to patients in whom colchicine was initiated between Days 4 and 7 (HR = 0.96, 95% CI 0.53-1.75) or > Day 8 (HR = 0.82, 95% CI 0.61-1.11). The beneficial effects of early initiation of colchicine were also demonstrated for urgent hospitalization for angina requiring revascularization (HR = 0.35), all coronary revascularization (HR = 0.63), and the composite of cardiovascular death, resuscitated cardiac arrest, MI, or stroke (HR = 0.55, all P < 0.05).

Conclusion

Patients benefit from early, in-hospital initiation of colchicine after MI.

Trial registration

COLCOT ClinicalTrials.gov number, NCT02551094.

Background

The randomized, placebo-controlled COLCOT (Colchicine Cardiovascular Outcomes Trial) has shown the benefits of colchicine 0.5 mg daily to lower the rate of ischemic cardiovascular events in patients with a recent myocardial infarction. Here, we conducted a post hoc pharmacogenomic study of COLCOT with the aim to identify genetic predictors of the efficacy and safety of treatment with colchicine.

Methods

There were 1522 participants of European ancestry from the COLCOT trial available for the pharmacogenomic study of COLCOT trial. The pharmacogenomic study's primary cardiovascular end point was defined as for the main trial, as time to first occurrence of cardiovascular death, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina requiring coronary revascularization. The safety end point was time to the first report of gastrointestinal events. Patients' DNA was genotyped using the Illumina Global Screening array followed by imputation. We performed a genome-wide association study in colchicine-treated patients.

Results

None of the genetic variants passed the genome-wide association study significance threshold for the primary cardiovascular end point conducted in 702 patients in the colchicine arm who were compliant to medication. The genome-wide association study for gastrointestinal events was conducted in all 767 patients in the colchicine arm and found 2 significant association signals, one with lead variant rs6916345 (hazard ratio, 1.89 [95% CI, 1.52-2.35], P=7.41×10^-9) in a locus which colocalizes with Crohn disease, and one with lead variant rs74795203 (hazard ratio, 2.51 [95% CI, 1.82-3.47]; P=2.70×10^-8), an intronic variant in gene SEPHS1. The interaction terms between the genetic variants and treatment with colchicine versus placebo were significant.

Conclusions

We found 2 genomic regions associated with gastrointestinal events in patients treated with colchicine. Those findings will benefit from replication to confirm that some patients may have genetic predispositions to lower tolerability of treatment with colchicine.