Clinical pharmacokinetics of atropine oral gel formulation in healthy volunteers.

Sialorrhea or drooling is a common problem in children and adults with neurodevelopmental disorders. It can negatively impact the quality of life due to its physical and psychological manifestations. Providers commonly prescribe atropine eye drops for topical administration to the oral mucosa, as an off-label treatment to manage sialorrhea. However, the off-label use of atropine eye drops can be associated with medication and dosing errors and systemic side effects. To address these limitations of treatment, we developed a mucoadhesive topical oral gel formulation of atropine as an alternative route to off-label administration of atropine eye drops. In this clinical pharmacokinetic (PK) study, we evaluated the safety and PK of atropine gel (0.01% w/w) formulation after single-dose administration to the oral mucosa in 10 healthy volunteers. The PK data showed that after topical administration to the oral mucosa, atropine followed a two-compartment PK profile. The maximum plasma concentration and area under the curve extrapolated to infinite time were 0.14 ng/mL and 0.74 h·ng·mL-1 , respectively. The absorption rate constant calculated by the compartmental analysis was 0.4 h-1 . Safety parameters, such as heart rate, blood pressure, and oxygen saturation, did not significantly change before and after administration of the gel formulation, and no adverse events were observed in all participants who received atropine gel. These data indicate that atropine gel formulation has a satisfactory PK profile, is well-tolerated at the dose studied, and can be further considered for clinical development as a drug product to treat sialorrhea.

Efficacy and Safety of CSF-1 (0.4% Pilocarpine Hydrochloride) in Presbyopia: Pooled Results of the NEAR Phase 3 Randomized, Clinical Trials.

PURPOSE: This study was undertaken to evaluate the safety and efficacy of CSF-1 (0.4% pilocarpine hydrochloride ophthalmic solution) for use in individuals with presbyopia. METHODS: Two Phase 3 multicenter, randomized, double-masked, vehicle-controlled, parallel-group clinical trials were conducted in 35 private ophthalmology clinics in the United States from October 2020 to February 2022. Key inclusion criteria were the following: (1) age 45-64 years, (2) distance-corrected near visual acuity (DCNVA) at 40 cm ≥0.40 and ≤0.90 logarithm of the minimum angle of resolution (logMAR, approximately 20/50-20/160 Snellen) in at least 1 eye, (3) manifest refraction (MR) between -4.50 and +2.00 diopter (D) sphere in each eye with ≤2.00D difference between eyes, (4) <2.00D of cylinder MR in each eye, (5) ≤0.04 logMAR (20/20-2 or better) corrected distance visual acuity (CDVA) at 4 m in each eye. Key exclusion criteria were the following: (1) >0.14 logMAR (7 letters) improvement in post-vehicle treatment in monocular DCNVA in either eye at visit 1, (2) introcular pressure (IOP) <9 or >22 mm Hg, (3) average dark-adapted pupillometry <3.5 mm in either eye, (4) prior refractive surgery or intraocular lens (IOL) implantation. Participants applied CSF-1 or vehicle twice per day for 2 weeks. Efficacy and safety assessments were performed at several times on days 1, 8, and 15. Response was defined as ≥3-line gain in DCNVA without loss of ≥1-line in CDVA in the study eye under mesopic room lighting conditions. The primary efficacy endpoint was measured 1 hour post-dose 1 on day 8. Key secondary endpoints were 2 hours post-dose 1, and 1 and 2 hours post-dose 2, also on day 8. Safety endpoints were ocular and non-ocular treatment-related adverse events (TRAE), conjunctival redness, drop comfort, slit-lamp biomicroscopy, intraocular pressure, indirect fundoscopy, and CDVA at 4 m. FINDINGS: Six hundred thirteen participants were randomized to CSF-1 (n = 309) or vehicle (n = 304). Participants were predominantly White (80.8%) and female (62.0%), with mean age (standard deviation) of 54.7 (4.8). CSF-1 met the primary and key secondary endpoints. At the primary endpoint, 40.1% of the CSF-1 group achieved response versus 19.1% of the vehicle group (P < 0.0001). The percentage of responders was significantly greater in CSF-1 compared with vehicle at all tested times. Changes from baseline in all safety endpoints were comparable between groups. Most adverse events (AEs) were mild and transient. Neither serious nor severe AEs were reported with CSF-1. IMPLICATIONS: CSF-1, a low-dose pilocarpine ophthalmic solution, demonstrated superiority to vehicle in improving near vision in individuals with presbyopia without compromising distance vision. CSF-1 demonstrated a favorable safety profile. CLINICALTRIALS: gov identifier: NCT04599933 (NEAR-1), NCT04599972 (NEAR-2).

Symptomatic Netarsudil-Induced Verticillata.

This case report discusses a diagnosis of bilateral corneal verticillata in a woman aged 80 years who was using netarsudil eye drops for the treatment of primary open-angle glaucoma.

Efficacy and safety of platelet-rich plasma and autologous-serum eye drops for dry eye in primary Sjögren's syndrome: a randomized trial.

We compared the efficacy and safety of autologous-serum (AS) and platelet-rich plasma (PRP) eye drops for dry eye (DE) treatment in primary Sjögren's syndrome (SS). This prospective, randomized, double-blinded clinical study included patients diagnosed with primary SS DE. Thirty-eight participants were randomly assigned to the AS or PRP groups. Corneal and conjunctival staining scores, Schirmer I test, tear film break-up time (TBUT), and ocular surface disease index (OSDI) scores were evaluated at 4 and 12 weeks. Conjunctival impression cytology (CIC) metaplasia grade and goblet cell density grade at 12 weeks were compared with those at baseline. Corneal and conjunctival staining scores and TBUT significantly improved at 4 and 12 weeks in both groups (all p < 0.005). No significant difference between the AS and PRP groups was observed at 4 and 12 weeks. The Schirmer I values, OSDI scores, CIC metaplasia grade, and goblet cell density grade did not significantly change at 4 and 12 weeks in either group. Both AS and PRP eye drops are effective for primary SS DE without a significant difference. Considering that the preparation time of PRP is shorter than that of AS, PRP can be a good alternative treatment for primary SS DE.

Steroid-induced glaucoma: an avoidable cause of irreversible blindness.

A man in his 70s on regular follow-up with an ophthalmologist for 10 years presented with blurry vision in his right eye for 4 days. He was diagnosed with elevated intraocular pressure (IOP) bilaterally 18 months earlier and treated with antiglaucoma eye-drops. On direct questioning, he admitted to using fixed combination tobramycin 0.3%/dexamethasone 0.1% eye-drops frequently to relieve ocular redness and discomfort in both eyes for 3.5 years without his ophthalmologist's knowledge. Examination disclosed markedly elevated IOP, advanced optic disc cupping and tunnel vision due to steroid-induced glaucoma bilaterally. After cessation of the eye-drops and 2 weeks of antiglaucoma therapy, his IOP returned to normal and his visual field remained stable for 4 years.Our case highlights the danger of habitual self-treatment of prescription medications containing corticosteroids and the importance of taking a detailed medication history in the diagnosis and management of steroid-induced glaucoma.

Efficacy and Safety of the Melanocortin Pan-Agonist PL9643 in a Phase 2 Study of Patients with Dry Eye Disease.

Purpose: The melanocortin receptor pan-agonist PL9643, a potential therapy for ocular diseases, was investigated in a phase 2, 12-week study in patients with dry eye disease (DED). Methods: This was a placebo-controlled study evaluating efficacy and safety of thrice-daily PL9643. Placebo (vehicle) was similar to tears. Primary endpoints were intra-patient changes in inferior corneal fluorescein staining and ocular discomfort after 12 weeks. Secondary endpoints were changes in additional DED signs or symptoms. Multiple secondary endpoints were not adjusted for multiplicity. Patients with moderate or severe DED were analyzed in addition to the overall intent-to-treat (ITT) population. Results: In the ITT population (n = 160) the PL9643 group did not demonstrate significant treatment difference versus placebo at week 12/day 85 for the primary endpoints (P > 0.05). In patients with moderate or severe DED (n = 53), PL9643 treatment demonstrated either nominally significant (P < 0.05) or trending (P < 0.1) improvement over placebo in mean change from baseline at week 12/day 85 in several sign endpoints, including fluorescein staining in inferior, superior, corneal sum, and total sum regions; Lissamine Green staining in temporal, nasal, conjunctival sum, and total sum regions; and tear film breakup time. Conjunctival redness also showed (nonsignificant) improvement at week 12/day 85. There were no drug-related adverse events (AEs) and no drug-related discontinuations. Conclusions: PL9643 showed no significant efficacy for the ITT population; however, efficacy results across several signs and symptoms in the subpopulation of moderate to severe DED patients, the low number of ocular AEs, and no tolerability issues suggest that PL9643 shows promise as a therapeutic for DED. Clinical Trial Registration number: NCT04268069.

Atropine Ophthalmic Solution to Reduce Myopia Progression in Pediatric Subjects: The Randomized, Double-Blind Multicenter Phase II APPLE Study.

PURPOSE: The purpose of this study was to assess the dose-response effects of low-dose atropine on myopia progression and safety in pediatric subjects with mild-to-moderate myopia. METHODS: This phase II, randomized, double-masked, placebo-controlled study compared the efficacy and safety of atropine 0.0025%, 0.005%, and 0.01% with placebo in 99 children, aged 6-11 years, with mild-to-moderate myopia. Subjects received 1 drop in each eye at bedtime. The primary efficacy endpoint was change in spherical equivalent (SE), while secondary endpoints included changes in axial length (AL) and near logMAR (logarithm of the minimum angle of resolution) visual acuity and adverse effects. RESULTS: The mean±SD changes in SE from baseline to 12 months in the placebo and atropine 0.0025%, 0.005%, and 0.01% groups were -0.55±0.471, -0.55±0.337, -0.33±0.473, and -0.39±0.519 D, respectively. The least squares mean differences (atropine-placebo) in the atropine 0.0025%, 0.005%, and 0.01% groups were 0.11 D ( P =0.246), 0.23 D ( P =0.009), and 0.25 D ( P =0.006), respectively. Compared with placebo, the mean change in AL was significantly greater for atropine 0.005% (-0.09 mm, P =0.012) and 0.01% (-0.10 mm, P =0.003). There were no significant changes in near visual acuity in any of the treatment groups. The most common ocular adverse events were pruritus and blurred vision, each occurring in 4 (5.5%) atropine-treated children. Changes in mean pupil size and amplitude of accommodation were minimal. CONCLUSIONS: Atropine doses of 0.005% and 0.01% effectively reduced myopia progression in children but no effect was noted with 0.0025%. All doses of atropine were safe and well tolerated.

Incidence of Adverse Events Induced by Atropine in Myopic Children: A Meta-Analysis.

A large number of studies have evaluated the efficacy of low-dose atropine in preventing or slowing myopic progression. However, it is challenging to evaluate the ocular safety from these studies. We aimed to evaluate the incidence of adverse events induced by atropine in children with myopia. We performed a systematic literature search in several databases for studies published until November 2022. The incidence of adverse events induced by atropine was pooled by a common-effect (fixed-effect) or random-effects model. Subgroup analyses were conducted according to drug doses, types of adverse events, and ethnicity. A total of 31 articles were ultimately included in the study. The overall incidence of adverse events for atropine was 5.9%, and the incidence of severe adverse events was 0.0%. The most commonly reported adverse events were photophobia (9.1%) and blurred near vision (2.9%). Other adverse events including eye irritation/discomfort, allergic reactions, headache, stye/chalazion, glare, and dizziness occurred in less than 1% of the patients. The incidence of atropine-induced adverse events varied depending on the drug doses. A lower dose of atropine was associated with a lower incidence of adverse events. There was no significant difference in the incidence of adverse events for low-dose atropine between Asian and White children. Our study suggests photophobia and blurred near vision are the most frequently reported adverse events induced by atropine. Low-dose atropine is safer than moderate- and high-dose atropine. Our study could provide a safe reference for ophthalmologists to prescribe atropine for myopic children.

Role of ripasudil as an adjunct treatment in the management of pseudoexfoliative glaucoma.

Purpose: Ripasudil is a class of drug which alters the trabecular meshwork to increase the aqueous outflow and has been shown to be effective in pseudoexfoliative glaucoma (PXF G). This study aimed at assessing the efficacy and safety profile of ripasudil as an adjunct treatment in patients with PXF G at maximal tolerated antiglaucoma medications. Methods: In this prospective, interventional study, 40 patients with PXF G were enrolled between May 2021 and Jan 2022. Ripasudil 0.4% was started as an adjunctive drug to the ongoing antiglaucoma medications. On follow-up visits at 1, 3, and 6 months, the visual acuity, intraocular pressure (IOP), anterior segment, and fundus findings were evaluated. The premedication and postmedication IOP values were compared by paired t-test, and a P-value <0.05 was considered statistically significant. Results: Average age at recruitment was 60.02 ± 8.74 years. Baseline premedication IOP was 25.375 ± 3.276 mmHg. IOP reduction at 6 months was found to be statistically significant in all patients, with the maximal response being 24.13%. Also, 87.5% (35/40) of patients reached target IOP or even lower IOP at the end of study. There was no statistically significant association between the PXF grade and IOP. However, the grade of inferior iridocorneal angle pigmentation was found to be higher in eyes with elevated IOP (P < 0.05). Only three patients developed conjunctival hyperemia as an adverse reaction, which was mild and transient. Conclusion: Ripasudil showed additional IOP-lowering effect with other antiglaucoma medications and exhibited no significant side effects.

Contact Dermatitis to Ophthalmic Solutions: An Update.

Eyelid and periorbital dermatitis remains a distressing and recalcitrant disease. Contact dermatitis remains the most common cause of eyelid and periorbital dermatitis. Ophthalmic solutions used in the treatment of ophthalmic conditions can often be the cause. This article is an update of our previous study, summarizing the contact allergens involved and the new test concentrations reported to investigate through patch testing. New insights found during the review are also documented.

Efficacy and safety of atropine in myopic children: A meta-analysis of randomized controlled trials.

PURPOSE: To evaluate the safety and efficacy of atropine for childhood myopia and further explore the optimal concentration of atropine, so as to provide more reference for clinical application. METHODS: PubMed, Embase, Cochrane Library and ClinicalTrials.gov were comprehensively searched for randomized controlled trials (RCTs) up to October 14, 2021. The efficacy outcomes were progression of spherical equivalent (SE) and axial length (AL). The safety outcomes included accommodation amplitude, pupil size and adverse effects. The meta-analysis was performed using Review Manager 5.3. RESULTS: Eighteen RCTs involving 3002 eyes were included. The results showed that at 6-36 months of treatment, atropine was effective in slowing the progression of myopia in children. At 12 months, the WMD of SE and AL of low-dose atropine was 0.25 diopters (D) and 0.1 millimeter (mm), moderate-dose atropine was 0.44 D and 0.16mm, high-dose atropine was 1.21 D and 0.82mm, respectively, compared with the control group. Similarly, at 24 months, low-dose atropine was 0.22 D and 0.14mm, moderate-dose atropine was 0.60 D, high-dose atropine was 0.66 D and 0.24mm, respectively. Interestingly, we also found that there was no significant difference in the effects of low-dose atropine on accommodation amplitude and photopic pupil size compared with the control group, and the rate of photophobia, allergy, blurred vision and other side effects was similar between the low-dose atropine group and the control group. In addition, atropine appears to be more effective in myopic children in China than in other countries. CONCLUSIONS: Atropine in various concentrations can effectively slow myopia progression in children, and its effect is dose-dependent, while low-dose atropine (0.01% atropine) appears to be safer.

Effect of Low-Concentration Atropine Eyedrops vs Placebo on Myopia Incidence in Children: The LAMP2 Randomized Clinical Trial.

Importance: Early onset of myopia is associated with high myopia later in life, and myopia is irreversible once developed. Objective: To evaluate the efficacy of low-concentration atropine eyedrops at 0.05% and 0.01% concentration for delaying the onset of myopia. Design, Setting, and Participants: This randomized, placebo-controlled, double-masked trial conducted at the Chinese University of Hong Kong Eye Centre enrolled 474 nonmyopic children aged 4 through 9 years with cycloplegic spherical equivalent between +1.00 D to 0.00 D and astigmatism less than -1.00 D. The first recruited participant started treatment on July 11, 2017, and the last participant was enrolled on June 4, 2020; the date of the final follow-up session was June 4, 2022. Interventions: Participants were assigned at random to the 0.05% atropine (n = 160), 0.01% atropine (n = 159), and placebo (n = 155) groups and had eyedrops applied once nightly in both eyes over 2 years. Main Outcomes and Measures: The primary outcomes were the 2-year cumulative incidence rate of myopia (cycloplegic spherical equivalent of at least -0.50 D in either eye) and the percentage of participants with fast myopic shift (spherical equivalent myopic shift of at least 1.00 D). Results: Of the 474 randomized patients (mean age, 6.8 years; 50% female), 353 (74.5%) completed the trial. The 2-year cumulative incidence of myopia in the 0.05% atropine, 0.01% atropine, and placebo groups were 28.4% (33/116), 45.9% (56/122), and 53.0% (61/115), respectively, and the percentages of participants with fast myopic shift at 2 years were 25.0%, 45.1%, and 53.9%. Compared with the placebo group, the 0.05% atropine group had significantly lower 2-year cumulative myopia incidence (difference, 24.6% [95% CI, 12.0%-36.4%]) and percentage of patients with fast myopic shift (difference, 28.9% [95% CI, 16.5%-40.5%]). Compared with the 0.01% atropine group, the 0.05% atropine group had significantly lower 2-year cumulative myopia incidence (difference, 17.5% [95% CI, 5.2%-29.2%]) and percentage of patients with fast myopic shift (difference, 20.1% [95% CI, 8.0%-31.6%]). The 0.01% atropine and placebo groups were not significantly different in 2-year cumulative myopia incidence or percentage of patients with fast myopic shift. Photophobia was the most common adverse event and was reported by 12.9% of participants in the 0.05% atropine group, 18.9% in the 0.01% atropine group, and 12.2% in the placebo group in the second year. Conclusions and Relevance: Among children aged 4 to 9 years without myopia, nightly use of 0.05% atropine eyedrops compared with placebo resulted in a significantly lower incidence of myopia and lower percentage of participants with fast myopic shift at 2 years. There was no significant difference between 0.01% atropine and placebo. Further research is needed to replicate the findings, to understand whether this represents a delay or prevention of myopia, and to assess longer-term safety. Trial Registration: Chinese Clinical Trial Registry: ChiCTR-IPR-15006883.

Combination of available topical beta-blockers and antibiotic ointment for epidermal growth factor receptor tyrosine kinase inhibitor-induced paronychia and pseudopyogenic granulomas in Taiwan.

BACKGROUND: Painful paronychia and pseudopyogenic granuloma (PG) are common adverse drug reactions (ADRs) associated with the use of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) to treat non-small cell lung cancer (NSCLC). Multiple local management approaches have been tested with unsatisfactory results. We have introduced an occlusion therapy technique through which available topical drugs for longer than 2 years. METHODS: Based on the cancer registry and case management system of our hospital, from July 2019 to July 2020, we retrospectively enrolled patients with NSCLC who were treated with EGFR-TKIs and received applications of 0.5% timolol ophthalmic solution (TIMOPTOL XE 0.5%®) combined with a neomycin/tyrothricin ointment (Biomycin®) using the occlusion method to treat paronychia or PG. RESULTS: A total of 22 patients were enrolled, with a mean age of 66.5 years, most of whom were women (72.7%). Periungual lesion-related pain was reported by all patients, and periungual bleeding and PG were reported in 14% (3/22) and 64% (14/22) of patients, respectively. After the occlusion therapy application of timolol ophthalmic solution combined with neomycin/tyrothricin ointment twice daily, the overall response rate was 83.3%, including complete response in 18% (4/22) of cases and partial response in 68% (15/22) of cases. CONCLUSION: We presented an occlusion method using available topical beta-blockers and antibiotic ointment for EGFR-TKI-induced paronychia and PG in Taiwan. The result is favorable. Further randomized control trial is urgent to validate our findings.

Urinary excretion patterns and potential risks of beta-blocker ophthalmic drops in sports.

Beta-blockers have been prohibited by the World Anti-Doping Agency (WADA) in certain sports, but insufficient research data make it difficult to distinguish between therapeutic uses or misuses. This study aimed at investigating the urinary excretion pattern following beta-blocker ophthalmic drops and the potential risk of constituting an adverse analytical finding (AAF) in sports. Prescribed timolol and carteolol ophthalmic drops were used in healthy participants and glaucoma patients. The urine samples were then collected to investigate the urinary excretion pattern following acute and chronic administration of the above beta-blocker ophthalmic drops. The liquid chromatograph-tandem mass spectrometry method was applied for measuring urinary beta-blockers. Our results demonstrated that the levels of both urinary timolol and carteolol exceeded the minimum reporting levels (MRL) following acute and chronic administration. The highest levels of urinary timolol and carteolol observed in the present study were 255.7 and 923.8 ng/ml, respectively. Regarding the acute administration of timolol ophthalmic drop, 26.19 (11/42) of urine samples were detected with timolol higher than the MRL in timed and random sampling. In contrast, the acute administration of carteolol ophthalmic drops made the carteolol levels higher than the MRL among most urine samples. On the other hand, 36.36% (4/11) of urine samples were detected with beta-blockers higher than the MRL during the chronic administration of timolol and carteolol ophthalmic drops. In the context of receiving ophthalmic beta-blocker medications, the present study has highlighted the potential risk of constituting an AAF in specific sports and suggests strengthening athletes' awareness of therapeutic use exemptions.

Central anticholinergic syndrome secondary to atropine eye drops: A case study.

Atropine eye drops are frequently used in the treatment of keratitis and during ophthalmic surgery. We described a rare complication of central anticholinergic syndrome secondary to atropine eye drops.

Dupilumab-Induced, Tralokinumab-Induced, and Belantamab Mafodotin-Induced Adverse Ocular Events-Incidence, Etiology, and Management.

ABSTRACT: Emerging monoclonal antibody therapies are assuming greater importance in the management of severe and refractory forms of immunity-driven and oncological disorders. However, some have been found to induce adverse ocular events (AOEs) leading to discontinuation of treatment or additional multidisciplinary management. We present the current knowledge concerning AOEs associated with 3 monoclonal antibody therapies: dupilumab, tralokinumab, and belantamab mafodotin. We examine the manifestations of their AOEs, proposed pathophysiological mechanisms, and current treatment recommendations. We identified and reviewed all studies for dupilumab, tralokinumab, and belantamab mafodotin using the keywords "dupilumab," "tralokinumab," "belantamab mafodotin," "conjunctivitis," and "keratopathy" from January 2016 to November 2021. Conjunctivitis was the most frequently reported AOE in patients with atopic dermatitis receiving dupilumab or tralokinumab. Mild cases were managed with warm compresses for associated meibomian gland dysfunction, artificial tears, and antihistamine/mast cell stabilizer eye drops. In more severe cases, additional anti-inflammatory therapy, with corticosteroid eye drops or ointments, or topical calcineurin inhibitors-such as tacrolimus or ciclosporin-were required. Patients with resistant or refractory multiple myeloma treated with belantamab mafodotin often developed keratopathy, which could necessitate contact lens fitting, or for cycles of belantamab mafodotin to be delayed.

A phase 2a, double-masked, randomized, vehicle-controlled trial of VVN001 in subjects with dry eye disease.

PURPOSE: Evaluate the initial ocular safety and tolerability and efficacy of VVN001 Ophthalmic Solution (VVN001), a small-molecule antagonist of lymphocyte function-associated antigen-1 (LFA-1), in subjects with dry eye disease (DED). METHODS: This was a multi-center, double-masked, randomized, dose-response, vehicle-controlled, parallel-group study conducted in 170 subjects with DED. Subjects were randomized to receive VVN001 (1% or 5%) or its vehicle, twice-daily in both eyes for 84 days. The primary outcome measure was inferior region corneal fluorescein staining (iCFS, 0-4 scale) at Day 84. Visual Analogue Scale eye dryness (VAS, 0-100 scale) was a secondary outcome. RESULTS: The primary and first secondary outcomes were not met. At Day 84 treatment effects in favor of VVN001 5% relative to its vehicle for iCFS were 0.29 units (p = 0.054), and for VAS were 3.18 units (p = 0.533). In other secondary outcomes, treatment effects in favor of VVN001 5% relative to its vehicle were seen in total CFS (1.61 units, 0-20 scale, p = 0.004) and Schirmer score (1.77 and 2.32 mm, p = 0.049 and p = 0.17 at Days 14 and 28 respectively). Adverse events of incidence 5% or greater in either active treatment group were instillation site pain (3/57, 5.3%), dysgeusia (3/56, 5.4%) and urinary tract infection (3/57, 5.3%). CONCLUSIONS: There were no major safety issues of note. Appropriately powered studies will be required with a priori selection of the efficacy endpoints to evaluate VVN001's therapeutic potential.

Life-threatening Vasospastic Angina Induced by Carteolol Eye Drops.

Vasospastic angina (VSA) can be worsened by oral nonselective beta-blockers. Ophthalmic carteolol eye drops are nonselective beta-blockers and effective against glaucoma and ocular hypertension. Systemic effects of ophthalmic beta-blockers on VSA have not yet been reported. We herein report a case of VSA that developed after a patient started carteolol eye drops for ocular hypertension. Even though benidipine, a calcium channel blocker, was started, a VSA attack with incessant non-sustained ventricular tachycardia occurred. Once the carteolol eyedrops were discontinued, the VSA resolved. This case demonstrates that carteolol eye drops can induce life-threatening VSA.