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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 -
Hospital Pharmacy Jul 2013This Hospital Pharmacy feature is extracted from Off-Label Drug Facts, a publication available from Wolters Kluwer Health. Off-Label Drug Facts is a...
This Hospital Pharmacy feature is extracted from Off-Label Drug Facts, a publication available from Wolters Kluwer Health. Off-Label Drug Facts is a practitioner-oriented resource for information about specific drug uses that are unapproved by the US Food and Drug Administration. This new guide to the literature enables the health care professional or clinician to quickly identify published studies on off-label uses and determine if a specific use is rational in a patient care scenario. References direct the reader to the full literature for more comprehensive information before patient care decisions are made. Direct questions or comments regarding Off-Label Drug Uses to [email protected].
PubMed: 24421520
DOI: 10.1310/hpj4807-558 -
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 -
The Journal of Pediatric Pharmacology... 2016The current study compared the amount of oxymetazoline delivered by various anesthesia providers when holding the bottle in the upright and inverted position....
OBJECTIVES
The current study compared the amount of oxymetazoline delivered by various anesthesia providers when holding the bottle in the upright and inverted position. Additionally, the amount delivered from a full bottle and a half-full bottle was also investigated.
METHODS
Using an analytical balance that was calibrated to zero, we evaluated the impact the position of the bottle and the volume of oxymetazoline in the bottle had on the amount being delivered by both anesthesia staff and trainees.
RESULTS
When using both filled and half-filled bottles, the amount delivered increased significantly when comparing the upright versus inverted position. With a full bottle, the amount delivered when the bottle was inverted increased almost 10-fold from 62 ± 80 to 606 ± 366 μL (p < 0.0001). Similarly, even with a half-filled bottle, the amount delivered increased in the inverted positions from 41 ± 48 to 645 ± 393 μL. Regardless of the scenario, we also noted significant variation from provider to provider.
CONCLUSIONS
Our results demonstrate that several factors may affect the amount of oxymetazoline delivered for metered dose bottles. Given the potential for severe end-organ effects with excessive dosage, alternative means of delivery are needed for its perioperative use.
PubMed: 27453703
DOI: 10.5863/1551-6776-21.3.247 -
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 -
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 -
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 -
Journal of the American Academy of... Jun 2018Limited treatments are available for persistent erythema of rosacea.
BACKGROUND
Limited treatments are available for persistent erythema of rosacea.
OBJECTIVE
To examine the long-term safety and efficacy of oxymetazoline cream 1.0% in patients with rosacea with moderate-to-severe persistent erythema.
METHODS
Patients applied oxymetazoline once daily for 52 weeks. Safety assessments included treatment-emergent adverse events (TEAEs), skin blanching, inflammatory lesion counts, telangiectasia, disease severity, and rebound effect. Efficacy was assessed by the Clinician Erythema Assessment and Subject Self-Assessment composite score at 3 and 6 hours after the dose on day 1 and at weeks 4, 26, and 52.
RESULTS
Among 440 patients, 8.2% reported treatment-related TEAEs; the most common were application-site dermatitis, paresthesia, pain, and pruritus. The rate of discontinuation due to adverse events (mostly application-site TEAEs) was 3.2%. No clinically meaningful changes were observed in skin blanching, inflammatory lesions, or telangiectasia. At week 52, 36.7%, and 43.4% of patients achieved a 2-grade or greater composite improvement from baseline in both Clinician Erythema Assessment and Subject Self-Assessment 3 and 6 hours after a dose, respectively. Less than 1% of patients experienced a rebound effect following treatment cessation.
LIMITATIONS
A vehicle-control group was not included.
CONCLUSION
This long-term study demonstrated sustained safety, tolerability, and efficacy of oxymetazoline for moderate-to-severe persistent erythema of rosacea.
Topics: Administration, Cutaneous; Adolescent; Adult; Dose-Response Relationship, Drug; Drug Administration Schedule; Erythema; Facial Dermatoses; Female; Humans; Male; Middle Aged; Oxymetazoline; Patient Reported Outcome Measures; Patient Safety; Prospective Studies; Rosacea; Severity of Illness Index; Skin Cream; Time Factors; Treatment Outcome; United States; Young Adult
PubMed: 29409914
DOI: 10.1016/j.jaad.2018.01.027 -
Journal of Advanced Pharmaceutical... 2022Metered-dose nasal sprays (MDNS) are the most widely used for treating rhinitis. Medicinal preparations in the pharmaceutical market vary in their characteristics. To...
Metered-dose nasal sprays (MDNS) are the most widely used for treating rhinitis. Medicinal preparations in the pharmaceutical market vary in their characteristics. To identify the most effective drug, it is necessary to compare the preparations regarding various parameters. The purpose of the research was to compare oxymetazoline MDNS of different brands regarding their dispersion qualities. To that end, nine oxymetazoline sprays available in the Russian market were chosen and analyzed considering their dynamic characteristics and the spraying dispersion composition. The research was conducted with the shadow photography method, the selection of which was justified by its simplicity, the possibilities for detecting the spray jet composition, the process of its formation in dynamics, and the possibility for measuring droplets of all forms. Momentary images of spray activation phases, as well as an averaged image of 100 shots of the spraying main phase, were obtained. According to a range of characteristics, such as spraying duration, a cone angle and cone structure, all the preparations were grouped into three categories. It was found out that the sprays from Group 2 had the best dynamic rates of dispersion, with Vicks Sinex having the best results. Regarding the distribution of particles of different size, the most optimal composition was found for the drugs from Group 2, particularly, Vicks Sinex and Afrin preparations. Hence, Vicks Sinex spraying regimen and microsprayer design were found the most effective for delivering the medicinal substance to the destination.
PubMed: 35223438
DOI: 10.4103/japtr.japtr_240_21 -
International Journal of Clinical and... 2015The object of the study is to experimentally investigate the possible systemic side effects of Oxymetazoline including its nasal spray which has been in use for a long...
OBJECTIVES
The object of the study is to experimentally investigate the possible systemic side effects of Oxymetazoline including its nasal spray which has been in use for a long time both by the physicians and patients. There is no study in the literature to address the damages of oxymetazoline on the end organ.
MATERIALS AND METHODS
The study conducted on 2 groups of rat. Group 1 (n = 8): Control; and Group 2 (n = 8): Oxymetazoline. During 4 week, the control group was applied with 2 drops of saline water on each nasal cavity 3 times a day and the other group was applied with 2 drops of oxymetazoline HCl 3 times a day. At the end of experiment, samples from mandible, parotid and tails of the rats were taken in 10% formalin for histopathological investigations.
RESULTS
In histopathological experiments, when compared with the control group, the oxymetazoline group showed significant increase in many of the histopathological parameters (ischemic changes: P = 0.0001; congestion: P = 0.0006; arterial thrombosis: P = Ns; PNL accumulations: P = 0.001; necrosis: P = 0.0001; and ulceration: P = 0.014). The results of histopathologic tests on the samples taken from mandible and parotid gland, in comparison with the control group, showed no significant increase (focal inflammation: P = Ns; and lymphocyte aggregation: P = Ns).
CONCLUSION
Due to the damage that the long-term use of nasal spray including oxymetazoline, it may cause injury on the end organ, which we revealed in our histopathological experiments. We believe that it's essential for the physicians to provide information on the side effects of the medicine to their patients who use for a long term.
PubMed: 25932218
DOI: No ID Found