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Ophthalmology Science Dec 2021To determine the safety, efficacy, and tolerability of combinations of pilocarpine (Pilo) and oxymetazoline (Oxy) ocular drops dosed once daily and identify the optimal...
PURPOSE
To determine the safety, efficacy, and tolerability of combinations of pilocarpine (Pilo) and oxymetazoline (Oxy) ocular drops dosed once daily and identify the optimal concentration of each for the pharmacologic treatment of presbyopia.
DESIGN
Two concurrent Phase 2, multicenter, double-masked, randomized, vehicle-controlled studies, 1 short-term and 1 extended study.
PARTICIPANTS
Emmetropic individuals affected by presbyopia and in good general health.
METHODS
Uncorrected near visual acuity (UNVA) was measured throughout both studies with various concentrations and combinations of Pilo (0%, 0.5% 1.0%, and 1.5%) and Oxy (0%, 0.0125%, 0.05%, and 0.125%). For safety, uncorrected distance visual acuity (UDVA) was measured, treatment-emergent adverse events (TEAEs) were recorded, and a temporal/supraorbital headache assessment was completed.
MAIN OUTCOME MEASURES
The primary efficacy end point was mean change from baseline in UNVA.
RESULTS
In the short-term study, Pilo was shown to produce a significant dose response in the average increase of letters ( < 0.001), whereas Oxy did not have a significant impact ( 0.4797). The addition or increase in concentration of Oxy did not reduce incidence or severity of headaches when compared with Pilo alone. Efficacy results from the extended study supported the results from the short-term study. As early as 15 minutes postadministration, a dose response could be seen, with peak effect at 1 hour. Peak improvement increased from day 1 to day 14 and was maintained up to day 28. The most common TEAE was headache. There was no clinically significant reduction in UDVA. A polynomial regression model was developed and determined that the optimal concentration range of Pilo is between 1.16% and 1.32%.
CONCLUSIONS
On the basis of the results of the 2 Phase 2 studies, AGN-190584, a reading drop containing an optimized concentration of pilocarpine HCl (1.25%) delivered using a proprietary formulation, was developed and is currently under investigation in Phase 3 studies.
PubMed: 36246939
DOI: 10.1016/j.xops.2021.100065 -
Clinical Ophthalmology (Auckland, N.Z.) 2021Oxymetazoline 0.1% is a novel ophthalmic agent for the treatment of acquired blepharoptosis in adults that has been shown to improve upper eyelid elevation and superior...
PURPOSE
Oxymetazoline 0.1% is a novel ophthalmic agent for the treatment of acquired blepharoptosis in adults that has been shown to improve upper eyelid elevation and superior visual field deficits. This analysis characterized the rapid onset of upper eyelid elevation with once-daily oxymetazoline 0.1% and durability of this effect over 42 days.
MATERIALS AND METHODS
Pooling data from two prospective, randomized, placebo-controlled, phase 3 studies, change in marginal reflex distance 1 (MRD-1) was evaluated at a range of post-instillation time points on treatment days 1, 14, and 42. Onset of effect was assessed beginning at 5 minutes post-administration (one study) and through 6 hours at the first two visits (both studies). Overall, 203 subjects received oxymetazoline 0.1% and 101 received vehicle.
RESULTS
Oxymetazoline 0.1% demonstrated a rapid onset of action on all days evaluated. Mean changes from baseline 5 and 15 minutes post-oxymetazoline 0.1% instillation on day 1 were 0.59 ± 0.72 mm and 0.93 ± 0.81 mm, respectively (vs 0.20 ± 0.57 mm and 0.32 ± 0.64 mm with vehicle; both p<0.001). On day 14, mean changes from baseline 5 and 15 minutes post-oxymetazoline 0.1% instillation were 0.77 ± 0.85 mm and 1.11 ± 0.92 mm, respectively (vs 0.42 ± 0.78 mm and 0.41 ± 0.83 mm with vehicle; both p<0.05). This effect was also observed immediately post-instillation on day 42, where mean increases 5 and 15 minutes post-oxymetazoline 0.1% instillation were 0.86 ± 0.85 mm and 1.04 ± 0.91 mm, respectively (vs 0.42 ± 0.80 mm and 0.47 ± 0.93 mm with vehicle; both p<0.005). Significant improvements vs vehicle (p<0.001) were also observed at 2-6 hours on days 1 and 14. At all time points, the proportion of subjects showing a positive response to treatment (>0% MRD-1 increase) was >15% greater in the oxymetazoline 0.1% group (range 16.6-36.1% more responders vs vehicle), with the largest differences observed 2 and 6 hours post-instillation.
CONCLUSION
Oxymetazoline 0.1% provided rapid and sustained upper eyelid elevation. Together with data demonstrating superior visual field improvement and a favorable safety profile, this analysis supports oxymetazoline 0.1% as an effective non-surgical treatment for acquired ptosis.
PubMed: 34211263
DOI: 10.2147/OPTH.S306155 -
Cureus Sep 2022Introduction In the current otorhinolaryngology practice, technology has always been an essential part. Therefore, diagnostic nasal endoscopy (DNE) has become a vital...
Introduction In the current otorhinolaryngology practice, technology has always been an essential part. Therefore, diagnostic nasal endoscopy (DNE) has become a vital examination in today's practice. In order to visualize the nasal cavity in a systematic manner without any discomfort to both patient and doctor, the nose should be well anesthetized and decongested. Objective The study is to compare and evaluate the efficacy of 4% lignocaine-oxymetazoline cotton pledget packing versus topical sprays in the preparation of nasal cavities for DNE. Methodology The prospective, randomized, double-blind study was conducted among 246 patients and was divided into two groups. In the first group, the nose was packed with cotton pledgets containing 4% lignocaine-oxymetazoline and another group with 4% lignocaine-oxymetazoline spray. Following DNE, patients and surgeons were questioned on a pre-formed questionnaire to evaluate their experience during the procedure. Results It was observed that the time taken for the pre-endoscopic preparation of the packing group was more than the spray group. A total of 91.9% of the spray group had pain during the pre-endoscopic preparation and more burning and tingling sensation than in the nasal pack (75.6%). A total of 69.9% of the patients among the spray group participants compared to 32.5% of the packing group patients experienced more throat discomfort. In addition, 12% of the packing group had mucosal bleeding during the preparation. A total of 32.5% of the spray group experienced severe pain when compared to 12.2% of the packing group during the endoscopic procedure. Most of the participants from both groups had difficulty visualizing the superior turbinate and sphenoethmoidal recess during the procedure. There was a significant difference seen between both the groups with respect to pain during the pre-endoscopic procedure (p=0.0005), burning/tingling sensation (p<0.0001), throat pain (<0.0001), mucosal bleed (p=0.0003), pain during the procedure (p=0.0001), and discomfort after the procedure (p<0.0001). Conclusion Both methods of nasal preparation have merits and demerits in terms of discomfort, pain, and visualization of structures. Still, the packing of the nasal cavity with cotton pledgets is better when compared to spraying with 4% lignocaine-oxymetazoline. However, 4% lignocaine-oxymetazoline spray can be used during an emergency situation and with sensitive patients.
PubMed: 36299946
DOI: 10.7759/cureus.29436 -
The Laryngoscope Dec 2019Oxymetazoline is an α-adrenergic agonist that is commonly used as a topical hemostatic agent in the operating room during ear, nose, and throat surgery. There are... (Clinical Trial)
Clinical Trial
OBJECTIVES/HYPOTHESIS
Oxymetazoline is an α-adrenergic agonist that is commonly used as a topical hemostatic agent in the operating room during ear, nose, and throat surgery. There are limited data on oxymetazoline pharmacokinetics in children who undergo general anesthesia. We assessed the hemodynamic effects and systemic absorption of topically applied oxymetazoline in children undergoing various nasal procedures.
STUDY DESIGN
Prospective trial.
METHODS
Children ages 2 to 17 years undergoing functional endoscopic sinus surgery, turbinate resection, or adenoidectomy were enrolled. The surgeon placed oxymetazoline-soaked pledgets (1.5 mL of 0.05% solution) according to our usual clinical practice. Blood samples for oxymetazoline assay were drawn at 5, 10, 20, 45, 90, and 150 minutes, and hemodynamic data were recorded at 5-minute intervals. Data analysis included mixed-effects regression and population pharmacokinetic/pharmacodynamic modeling.
RESULTS
The analysis included 27 patients, age 7 ± 4 years, who received between 2 and 12 pledgets (3-18 mL) of oxymetazoline. Relative bioavailability compared to the spray formulation was 2.3 (95% confidence interval [CI]: 1.6-3.2), with slow absorption from the mucosal surface (absorption half-life 64 minutes; 95% CI: 44-90). Mean arterial pressure did not increase with oxymetazoline instillation at the observed oxymetazoline serum concentrations (0.04-7.6 μg/L).
CONCLUSIONS
Despite concerns regarding oxymetazoline administration to mucosal membranes, we found that hemodynamic changes were clinically negligible with our usual clinical use of pledgets soaked in oxymetazoline. Compared to data on oxymetazoline in spray formulation, bioavailability was increased twofold with pledgets, but systemic absorption was very slow, contributing to low serum concentrations and limited hemodynamic effects.
LEVEL OF EVIDENCE
1b. Laryngoscope, 129:2775-2781, 2019.
Topics: Administration, Intranasal; Adolescent; Adrenergic alpha-Agonists; Child; Child, Preschool; Female; Hemodynamics; Humans; Intraoperative Period; Male; Nasal Surgical Procedures; Nose Diseases; Oxymetazoline; Prospective Studies; Treatment Outcome
PubMed: 30786035
DOI: 10.1002/lary.27760 -
Structural insights into ligand recognition, activation, and signaling of the α adrenergic receptor.Science Advances Mar 2022The α adrenergic receptor (αAR) is a G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor that mediates important physiological functions in...
The α adrenergic receptor (αAR) is a G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor that mediates important physiological functions in response to the endogenous neurotransmitters norepinephrine and epinephrine, as well as numerous chemically distinct drugs. However, the molecular mechanisms of drug actions remain poorly understood. Here, we report the cryo-electron microscopy structures of the human αAR-GoA complex bound to norepinephrine and three imidazoline derivatives (brimonidine, dexmedetomidine, and oxymetazoline). Together with mutagenesis and functional data, these structures provide important insights into the molecular basis of ligand recognition, activation, and signaling at the αAR. Further structural analyses uncover different molecular determinants between αAR and βARs for recognition of norepinephrine and key regions that determine the G protein coupling selectivity. Overall, our studies provide a framework for understanding the signal transduction of the adrenergic system at the atomic level, which will facilitate rational structure-based discovery of safer and more effective medications for αAR.
Topics: Cryoelectron Microscopy; GTP-Binding Proteins; Humans; Ligands; Norepinephrine; Signal Transduction
PubMed: 35245122
DOI: 10.1126/sciadv.abj5347 -
Clinical Ophthalmology (Auckland, N.Z.) 2021An oxymetazoline 0.1% ophthalmic solution was recently approved for treatment of acquired blepharoptosis in adults. This study's objective was to evaluate the safety...
PURPOSE
An oxymetazoline 0.1% ophthalmic solution was recently approved for treatment of acquired blepharoptosis in adults. This study's objective was to evaluate the safety profile of oxymetazoline 0.1% when administered once daily for 14-84 days.
PATIENTS AND METHODS
Pooled analysis examined safety outcomes from four randomized, double-masked, placebo-controlled clinical trials conducted at 6, 16, 27, and 35 sites, respectively, in the United States. In total, 568 participants with acquired blepharoptosis were evaluated. Median age was 66 years and 74.8% of participants were female. Overall, 375 participants self-administered oxymetazoline 0.1% to both eyes once/day and 193 self-administered placebo (vehicle) daily. Treatment-emergent adverse event (TEAE) rates, severity, and causality were evaluated in the overall population and within participant subgroups defined based on age, race, and ethnicity. Vital signs and ophthalmic findings were evaluated at predefined study visits. Patient-reported treatment tolerability was recorded at study end.
RESULTS
TEAE incidence was similar among participants using oxymetazoline 0.1% (31.2%) or vehicle (30.6%). Nearly all TEAEs were mild-to-moderate, and most were not suspected of being treatment related. Serious TEAEs occurred in four participants receiving oxymetazoline 0.1% and one participant receiving vehicle. Nine and two participants in the oxymetazoline 0.1% and vehicle groups, respectively, discontinued due to a TEAE. Ocular TEAEs occurring in ≥2% of participants receiving oxymetazoline 0.1% were punctate keratitis, conjunctival hyperemia, dry eye, blurred vision, instillation site pain, and corneal vital dye staining, with none occurring in >3.5% of participants. TEAE rates were similar across subgroups based on age, race, and ethnicity. No clinically significant mean changes in vital signs or ophthalmologic findings occurred, and >98% of participants rated oxymetazoline 0.1% as causing no/mild discomfort.
CONCLUSION
Once-daily oxymetazoline 0.1% was safe and well tolerated in participants with acquired blepharoptosis when used for 14-84 days. Safety did not appear to differ based on age, race, or ethnicity.
PubMed: 34675472
DOI: 10.2147/OPTH.S322326 -
Pharmacology Research & Perspectives Oct 2022α2-adrenoceptors, (α2A, α2B and α2C-subtypes), are Gi-coupled receptors. Central activation of brain α2A and α2C-adrenoceptors is the main site for α2-agonist...
α2-adrenoceptors, (α2A, α2B and α2C-subtypes), are Gi-coupled receptors. Central activation of brain α2A and α2C-adrenoceptors is the main site for α2-agonist mediated clinical responses in hypertension, ADHD, muscle spasm and ITU management of sedation, reduction in opiate requirements, nausea and delirium. However, despite having the same Gi-potency in functional assays, some α2-agonists also stimulate Gs-responses whilst others do not. This was investigated. Agonist responses to 49 different α-agonists were studied (CRE-gene transcription, cAMP, ERK1/2-phosphorylation and binding affinity) in CHO cells stably expressing the human α2A, α2B or α2C-adrenoceptor, enabling ligand intrinsic efficacy to be determined (binding K /Gi-IC ). Ligands with high intrinsic efficacy (e.g., brimonidine and moxonidine at α2A) stimulated biphasic (Gi-Gs) concentration responses, however for ligands with low intrinsic efficacy (e.g., naphazoline), responses were monophasic (Gi-only). ERK1/2-phosphorylation responses appeared to be Gi-mediated. For Gs-mediated responses to be observed, both a system with high receptor reserve and high agonist intrinsic efficacy were required. From the Gi-mediated efficacy ratio, the degree of Gs-coupling could be predicted. The clinical relevance and precise receptor conformational changes that occur, given the structural diversity of compounds with high intrinsic efficacy, remains to be determined. Comparison with α1 and β1/β2-adrenoceptors demonstrated subclass affinity selectivity for some compounds (e.g., α2:dexmedetomidine, α1:A61603) whilst e.g., oxymetazoline had high affinity for both α2A and α1A-subtypes, compared to all others. Some compounds had subclass selectivity due to selective intrinsic efficacy (e.g., α2:brimonidine, α1:methoxamine/etilefrine). A detailed knowledge of these agonist characteristics is vital for improving computer-based deep-learning and drug design.
Topics: Animals; Brimonidine Tartrate; CHO Cells; Cricetinae; Cricetulus; Humans; Ligands
PubMed: 36101495
DOI: 10.1002/prp2.1003 -
JAMA Ophthalmology Nov 2020Treatment of acquired blepharoptosis (ptosis) is currently limited to surgical intervention.
IMPORTANCE
Treatment of acquired blepharoptosis (ptosis) is currently limited to surgical intervention.
OBJECTIVE
To examine the efficacy and safety of oxymetazoline hydrochloride, 0.1%, ophthalmic solution (oxymetazoline, 0.1%) in participants with acquired ptosis.
DESIGN, SETTING, AND PARTICIPANTS
This pooled analysis of 2 randomized, double-masked, placebo-controlled, multicenter phase 3 clinical trials included participants 9 years and older with acquired ptosis and superior visual field deficit. The 2 studies were conducted across 16 and 27 sites in the United States. Patients were enrolled from May 2015 to April 2019. Analyses for the individual trials were initiated after database lock and completed on September 6, 2017, and May 16, 2019. Pooled analysis was completed on August 25, 2019.
INTERVENTIONS
Participants (randomized 2:1) received oxymetazoline, 0.1%, or vehicle, self-administered as a single drop per eye, once daily, for 42 days.
MAIN OUTCOMES AND MEASURES
The primary efficacy end point was change from baseline in the number of points seen on the Leicester Peripheral Field Test, a test to detect superior visual field deficits due to ptosis, on days 1 (6 hours after instillation) and 14 (2 hours after instillation). The secondary end point, change from baseline in marginal reflex distance 1, was assessed at the same time points.
RESULTS
In total, 304 participants were enrolled (mean [SD] age, 63.8 [13.8] years; 222 women [73%]). Overall, 97.5% (198 of 203) of participants receiving oxymetazoline, 0.1%, and 97.0% (98 of 101) of participants receiving vehicle completed the studies. Oxymetazoline, 0.1%, was associated with a significant increase in the mean (SD) number of points seen on the Leicester Peripheral Field Test vs vehicle (day 1: 5.9 [6.4] vs 1.8 [4.1]; mean difference, 4.07 [95% CI, 2.74-5.39]; P < .001; day 14: 7.1 [5.9] vs 2.4 [5.5]; mean difference, 4.74 [95% CI, 3.43-6.04]; P < .001). Oxymetazoline, 0.1%, also was associated with a significant increase in marginal reflex distance 1 from baseline (mean [SD]: day 1: 0.96 [0.89] mm vs 0.50 [0.81] mm; mean difference, 0.47 mm [95% CI, 0.27-0.67]; P < .001; day 14: 1.16 [0.87] mm vs 0.50 [0.80] mm; mean difference, 0.67 mm [95% CI, 0.46-0.88]; P < .001). Treatment-emergent adverse events (TEAEs) occurred in 31.0% (63 of 203) of participants receiving oxymetazoline, 0.1%, and 35.6% (36 of 101) of participants receiving vehicle. Among participants receiving oxymetazoline, 0.1%, with a TEAE, 81% (51 of 63) had a maximum TEAE intensity of mild, and 62% (39 of 63) had no TEAE suspected of being treatment related.
CONCLUSIONS AND RELEVANCE
Oxymetazoline, 0.1%, was associated with positive outcomes and was well tolerated in phase 3 trials after instillation at days 1 and 14, demonstrating its potential promise for the treatment of acquired ptosis, although further study is needed to elucidate the clinical relevance of these findings beyond 6 weeks.
Topics: Adolescent; Adrenergic alpha-Agonists; Adult; Aged; Aged, 80 and over; Blepharoptosis; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Male; Middle Aged; Ophthalmic Solutions; Oxymetazoline; Treatment Outcome; Visual Fields; Young Adult
PubMed: 33001144
DOI: 10.1001/jamaophthalmol.2020.3812 -
American Journal of Veterinary Research Feb 2020To examine the effects of imidazoline and nonimidazoline α-adrenergic agents on aggregation of feline platelets.
Effects of imidazoline and nonimidazoline α-adrenoceptor agonists and antagonists, including xylazine, medetomidine, dexmedetomidine, yohimbine, and atipamezole, on aggregation of feline platelets.
OBJECTIVE
To examine the effects of imidazoline and nonimidazoline α-adrenergic agents on aggregation of feline platelets.
SAMPLE
Blood samples from 12 healthy adult cats.
PROCEDURES
In 7 experiments, the effects of 23 imidazoline and nonimidazoline α-adrenoceptor agonists or antagonists on aggregation and antiaggregation of feline platelets were determined via a turbidimetric method. Collagen and ADP were used to initiate aggregation.
RESULTS
Platelet aggregation was not induced by α-adrenoceptor agonists alone. Adrenaline and noradrenaline induced a dose-dependent potentiation of ADP- or collagen-induced aggregation. Oxymetazoline and xylometazoline also induced a small potentiation of ADP-stimulated aggregation, but other α-adrenoceptor agonists did not induce potentiation. The α-adrenoceptor antagonists and certain imidazoline α-adrenergic agents including phentolamine, yohimbine, atipamezole, clonidine, medetomidine, and dexmedetomidine inhibited adrenaline-potentiated aggregation induced by ADP or collagen in a dose-dependent manner. The imidazoline compound antazoline inhibited adrenaline-potentiated aggregation in a dose-dependent manner. Conversely, α-adrenoceptor antagonists and nonimidazoline α-adrenergic agents including xylazine and prazosin were ineffective or less effective for inhibiting adrenaline-potentiated aggregation. Moxonidine also was ineffective for inhibiting adrenaline-potentiated aggregation induced by collagen. Medetomidine and xylazine did not reverse the inhibitory effect of atipamezole and yohimbine on adrenaline-potentiated aggregation.
CONCLUSIONS AND CLINICAL RELEVANCE
Adrenaline-potentiated aggregation of feline platelets may be mediated by α-adrenoceptors, whereas imidazoline agents may inhibit in vitro platelet aggregation via imidazoline receptors. Imidazoline α-adrenergic agents may have clinical use for conditions in which there is platelet reactivity to adrenaline. Xylazine, medetomidine, and dexmedetomidine may be used clinically in cats with minimal concerns for adverse effects on platelet function.
Topics: Adrenergic alpha-Antagonists; Animals; Blood Platelets; Cats; Dexmedetomidine; Imidazoles; Imidazolines; Medetomidine; Xylazine; Yohimbine
PubMed: 31985287
DOI: 10.2460/ajvr.81.2.159 -
Lasers in Surgery and Medicine Jan 2020Oxymetazoline, an α-1A agonist, is approved by the United States Food and Drug Administration (FDA) for treatment of persistent facial erythema associated with rosacea...
BACKGROUND AND OBJECTIVE
Oxymetazoline, an α-1A agonist, is approved by the United States Food and Drug Administration (FDA) for treatment of persistent facial erythema associated with rosacea and induces vasoconstriction by interacting with α receptors. The objective of our study was to study the microvascular effects of oxymetazoline and pulsed dye laser (PDL).
MATERIALS AND METHODS
A dorsal window chamber was surgically installed on 20 mice. Each animal was assigned to one of four experimental groups: saline alone, oxymetazoline alone (10 μl applied once daily × 7 days), saline + PDL (saline applied 5 minutes before PDL irradiation [10 mm spot, 1.5 ms pulse duration, 7 J/cm delivered to epidermis]), or oxymetazoline + PDL (10 μl oxymetazoline applied 5 minutes before PDL and then once daily × 7 days). Brightfield and laser speckle imaging were performed for 7 days to monitor vascular architectural and functional changes.
RESULTS
We observed persistent blood flow in all of the saline-only and oxymetazoline-only experiments. A higher rate of vascular shutdown was observed with oxymetazoline + PDL (66.7%) compared with saline + PDL alone (16.7%). Oxymetazoline application increased venule diameter at 5 minutes post-application and decreased both arteriole and venule diameters at 60 minutes post-application.
CONCLUSION
The combination protocol of oxymetazoline + PDL induces persistent vascular shutdown observed 7 days after irradiation. This result may be associated with the acute vascular effects of oxymetazoline. Oxymetazoline + PDL should be evaluated as a treatment for cutaneous vascular disease, including rosacea and port wine birthmarks. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.
Topics: Adrenergic alpha-Agonists; Animals; Lasers, Dye; Low-Level Light Therapy; Mice; Mice, Inbred C3H; Microcirculation; Oxymetazoline; Skin
PubMed: 31758568
DOI: 10.1002/lsm.23186