Oral N-acetylcysteine improves cone function in retinitis pigmentosa patients in phase I trial.

BACKGROUNDIn retinitis pigmentosa (RP), rod photoreceptors degenerate from 1 of many mutations, after which cones are compromised by oxidative stress. N-acetylcysteine (NAC) reduces oxidative damage and increases cone function/survival in RP models. We tested the safety, tolerability, and visual function effects of oral NAC in RP patients.METHODSSubjects (n = 10 per cohort) received 600 mg (cohort 1), 1200 mg (cohort 2), or 1800 mg (cohort 3) NAC bid for 12 weeks and then tid for 12 weeks. Best-corrected visual acuity (BCVA), macular sensitivity, ellipsoid zone (EZ) width, and aqueous NAC were measured. Linear mixed-effects models were used to estimate the rates of changes during the treatment period.RESULTSThere were 9 drug-related gastrointestinal adverse events that resolved spontaneously or with dose reduction (maximum tolerated dose 1800 mg bid). During the 24-week treatment period, mean BCVA significantly improved at 0.4 (95% CI: 0.2-0.6, P < 0.001), 0.5 (95% CI: 0.3-0.7, P < 0.001), and 0.2 (95% CI: 0.02-0.4, P = 0.03) letters/month in cohorts 1, 2, and 3, respectively. There was no significant improvement in mean sensitivity over time in cohorts 1 and 2, but there was in cohort 3 (0.15 dB/month, 95% CI: 0.04-0.26). There was no significant change in mean EZ width in any cohort.CONCLUSIONOral NAC is safe and well tolerated in patients with moderately advanced RP and may improve suboptimally functioning macular cones. A randomized, placebo-controlled trial is needed to determine if oral NAC can provide long-term stabilization and/or improvement in visual function in patients with RP.TRIAL REGISTRATIONNCT03063021.FUNDINGMr. and Mrs. Robert Wallace, Mr. and Mrs. Jonathan Wallace, Rami and Eitan Armon, Marc Sumerlin, Cassandra Hanley, and Nacuity Pharmaceuticals, Inc.

Quantitation of free and total N-acetylcysteine amide and its metabolite N-acetylcysteine in human plasma using derivatization and electrospray LC-MS/MS.

Studies of N-acetylcysteine amide (NACA) in nonclinical models have demonstrated various antioxidant, anti-apoptotic, anti-inflammatory and neuroprotective effects, and it is currently being developed as a treatment for retinitis pigmentosa. Sensitive LC-MS/MS methods were developed and validated to quantitate reduced and total NACA and its major metabolite, N-acetylcysteine (NAC), in human plasma to support clinical studies involving NACA. To trap and stabilize reduced NACA and NAC at the time of collection, whole blood was immediately treated with 2-chloro-1-methylpyridinium iodide (CMPI) to convert free thiols to 1-methylpyridinyl thioether derivatives. Plasma was harvested and frozen until samples were assayed using protein precipitation and an LC-MS/MS separation based on hydrophilic-interaction chromatography (HILIC). To process NACA and NAC present as disulfides, an intermediate portion of the extract was further subjected to reduction with tris(2-carboxyethyl) phosphine; the released thiols were then reacted with CMPI, extracted, and analyzed as before, to measure total thiols. The method for NACA and NAC, whether free/reduced or total, covered a range from 50 ng/mL to 50 µg/mL in human plasma and required a single 25 µL plasma sample. Up to 180 samples could be assayed in a single session. The inter-run mean bias and precision (%CV) were within ±5% for the free thiol method and within ±8.5% for the total thiol method. Benchtop, freeze/thaw, and long-term stability were evaluated and acceptable. The NAC/NACA method applied to a clinical study demonstrated incurred sample reproducibility of 95.5% for NAC and 99.1% for NACA.

Effect of ciprofloxacin/dexamethasone versus ciprofloxacin/hydrocortisone on lipopolysaccharide-induced experimental otitis media.

OBJECTIVES: The purpose of this study is to compare the effect of topical ciprofloxacin/dexamethasone versus topical ciprofloxacin/hydrocortisone on the outcome of lipopolysaccharide (LPS)­induced otitis media with effusion in chinchillas. STUDY DESIGN: A randomized experimental animal study. SETTING: Jerry L. Pettis Veteran's Medical Center. SUBJECTS AND METHODS: Otitis media with effusion was induced in 5 groups of chinchillas, 6 per group, by injecting 0.3 mL (1 mg/mL) of Salmonella enteric LPS into the superior bullae of each chinchilla with a venting needle in place. Each group was treated with 0.2 mL of test substance at ­2, 24, 48, and 72 hours relative to the 0-hour LPS induction. Group 1 was treated with vehicle control. Groups 2 to 5 received 0.3% ciprofloxacin with either 0.1% dexamethasone (group 2), 1% dexamethasone (group 3), 0.1% hydrocortisone (group 4), or 1% hydrocortisone (group 5). The outcome of each treatment was measured by the amount of middle ear effusion present and mucosal thickness at 120 hours posttreatment. RESULTS: Ciprofloxacin/dexamethasone 1% significantly (P = .0150) reduced middle ear effusion compared with control. Ciprofloxacin/dexamethasone 1% significantly reduced the mucosal thickness when compared with vehicle control (P = .0005), ciprofloxacin/dexamethasone 0.1% (P = .0240), and ciprofloxacin/hydrocortisone 0.1% (P = 1.00). Results also showed a dose-response effect between the ciprofloxacin/dexamethasone concentrations. CONCLUSIONS: This study demonstrated that treatment with a combination of topical ciprofloxacin and corticosteroid decreased the middle ear effusion when compared with the control group and that ciprofloxacin/dexamethasone suspension reduced the severity of LPS-induced experimental otitis media more than ciprofloxacin/hydrocortisone did.

Effect of topical glucocorticoid treatment in chinchilla model of lipopolysaccharide induced otitis media with effusion.

OBJECTIVE: To compare the efficacy of topical treatment with three glucocorticoids in lipopolysaccharide induced otitis media with effusion (OME). METHODS: Chinchillas were divided into seven treatment groups consisting of vehicle and three glucocorticoids: dexamethasone sodium phosphate (DSP), fluticasone propionate (FP), and hydrocortisone, each at concentrations of 0.1% and 1.0%. LPS (300 µg) was injected into the superior bullae of chinchillas to induce OME. Animals were treated with test substances at -2, 24, and 48 h relative to LPS inoculation. After 96 h, chinchillas were euthanized, samples of middle ear effusion (MEE) were collected, and temporal bones were removed for histopathological examination. Reduction of OME was evaluated by measuring MEE volume and thickness of mucosal lining for each bulla. RESULTS: One percent treatment of FP significantly reduced MEE. One percent treatment of DSP and HC significantly reduced the mucosal thickness (MT), DSP (15.0 µM) more than HC (30.8 µM). Treatment with 0.1% glucocorticoids did not lead to any significant reduction. CONCLUSIONS: Clearance of otitis media with effusion seems to be a class effect among glucocorticoids. DSP was the best in reducing MT. It is important to evaluate treatment with various glucocorticoids in order to discover alternative drugs for OME.

Olopatadine nasal spray for the treatment of seasonal allergic rhinitis in patients aged 6 years and older.

IMPORTANCE OF THE FIELD: Allergic rhinitis is an IgE-mediated condition that produces inflammation of the mucosa of the nose, paranasal sinuses and, frequently, of the ocular conjunctiva. Allergic rhinitis causes a significant disease burden in terms of quality of life, lost productivity and medical treatment costs. One of the newest treatments approved by the FDA is Patanase (olopatadine hydrochloride) Nasal Spray, 665 microg/spray (OLO). Olopatadine is an antihistamine with selective H(1)-receptor antagonist activity. AREAS COVERED IN THIS REVIEW: This review details the basic and clinical research on the olopatadine molecule and OLO nasal spray from 1996 to the present day. WHAT THE READER WILL GAIN: The reader will gain a better understanding of the pharmacology of OLO nasal spray, the clinical trial data that have established the efficacy of OLO nasal spray and the overall role of OLO nasal spray in the management of allergic rhinitis. TAKE HOME MESSAGE: Olopatadine nasal spray is one of the newest treatments approved by the FDA for the management of allergic rhinitis. OLO has a rapid onset of action, efficacy comparable to intranasal steroid sprays and is approved for seasonal allergic rhinitis in patients aged > or = 6 years.

Olopatadine nasal spray for the treatment of allergic rhinitis.

Olopatadine hydrochloride nasal spray (Patanase Nasal Spray, Alcon Laboratories, TX, USA) was approved by the US FDA in 2008, and is indicated for the relief of symptoms of seasonal allergic rhinitis (SAR), also referred to as allergic rhinosinusitis. Olopatadine is an antihistamine with selective H1-receptor antagonist activity. Clinical trials of olopatadine nasal spray have demonstrated safety and efficacy in the treatment of SAR patients. With an onset of action of 30 min, olopatadine nasal spray has also been shown to improve quality of life, ability to perform work and the conduct of usual activities in SAR patients.

Safety and efficacy of olopatadine hydrochloride nasal spray 0.6% in pediatric subjects with allergic rhinitis.

Olopatadine (OLO) nasal spray 0.6% is indicated for treatment of seasonal allergic rhinitis (SAR) in subjects > or = 12 years of age. This study was designed to present the results of two studies that evaluated the efficacy, safety, and pharmacokinetics (PK) of OLO in children with allergic rhinitis (AR). These were multicenter, double-blind, randomized, parallel-group studies in subjects 6 to <12 years of age (study 1) and 2 to <6 years of age (study 2) with SAR (study 1) or AR (study 2). In study 1, nasal and ocular symptoms were scored for efficacy, and study 2 included PK analyses. In both studies, subjects were evaluated based on physical/nasal examinations and adverse events (AEs). Overall, 1188 subjects (study 1) and 132 subjects (study 2) were randomized, respectively. OLO (1 or 2 sprays/nostril, b.i.d.) was superior to vehicle in the percent decrease in reflective total nasal symptom scores (p < or = 0.0120). OLO 1 spray/nostril b.i.d. was also superior to vehicle in the percent decreases in reflective total ocular symptom scores (p < or = 0.0084), change from baseline in Pediatric Rhinoconjunctivitis Quality-of-Life Questionnaire scores (p < or = 0.0377), Caregiver Treatment Satisfaction Questionnaire scores (p < or = 0.0450), and proportions of subjects reporting improvements in Subject Global Assessments (p = 0.0035). The most frequently reported treatment-related events in the OLO group were bad/bitter taste and epistaxis. In subjects 6 to <12 years of age, OLO was superior to vehicle in the treatment of SAR. In subjects 2 to <12 years of age, OLO had an overall low rate of AEs and low systemic exposure.

Review of inactive ingredients in antibiotic ear drops.

The authors review the relevant chemical and biological characteristics of inactive ingredients in antibiotic ear drop drug products. Although many of the older aminoglycoside-containing otic products are still used today, only some fluoroquinolone-containing ear drops, approved in the last decade, have been proven safe and effective according to current rigorous scientific standards, including ototoxicity testing of the formulations. Preservatives, antioxidants, surfactants, buffers, suspending and emulsifying agents, osmotic agents, viscosity modifiers, solvents, and penetration enhancers are reviewed with regard to their functional role in formulations, as well as their potential for ototoxicity.

Stability improvement of a liquid enzyme product.

The shelf-life of a previously developed two-part liquid-liquid enzyme ceruminolytic product was improved maintaining the same final reconstituted composition and re-formulating the liquid enzyme portion as a drug granulate by a double wet granulation process. The critical steps for the preparation of the granulate were studied (mixing/granulating times and drying) determining the proteolytic activity, the residual ethanol, and the moisture content of the granulates. The original liquid-liquid formulation had been proven effective as a ceruminolytic agent, but only had stability of greater than 75% enzyme activity for up to 18 months and up to 1 day at room temperature after combining the two parts. The resulting improved product was proven to be stable for up to 24 months at 30 degrees C, and up to 3 days at room temperature after combining the two parts. Therefore, maintaining the enzyme in a granulated form until reconstitution afforded an improvement in stability compared with the original two-part liquid-liquid formulation.

Safety of ciprofloxacin and dexamethasone in the guinea pig middle ear.

OBJECTIVE: To investigate the ototoxic potential of ciprofloxacin hydrochloride, 0.3%, plus dexamethasone, 0.1%, after administration to the guinea pig middle ear. DESIGN: Fifty guinea pigs were randomly assigned to 4 test groups of 10 animals each and 2 control groups of 5 animals each. The 4 test groups were treated twice daily for 4 weeks with 10 muL of (1) ciprofloxacin hydrochloride, 0.3%, plus dexamethasone, 0.1%; (2) ciprofloxacin hydrochloride, 1.0%, plus dexamethasone, 0.3%; (3) ciprofloxacin hydrochloride, 0.3%, or (4) vehicle. The positive and negative control groups were treated with neomycin sulfate, 10%, or isotonic sodium chloride solution, respectively. SETTING: Academic research laboratory. INTERVENTIONS: Study animals were implanted with a drug delivery cannula to the middle ear, terminating in the round window niche for direct delivery to the round window membrane. MAIN OUTCOME MEASURES: Auditory brainstem responses were collected at baseline and following 2 and 4 weeks of dosing. At the termination of the study, inner ear tissues were evaluated microscopically. RESULTS: No biologically relevant hearing losses were observed after either 2 or 4 weeks of treatment with vehicle, ciprofloxacin alone, or combinations of ciprofloxacin plus dexamethasone. Examination of the organ of Corti revealed normal hair cell counts in all animals that received isotonic sodium chloride solution, vehicle, ciprofloxacin, or combinations of ciprofloxacin and dexamethasone. Conversely, the neomycin sulfate positive control group demonstrated a significant elevation in hearing threshold and profound hair cell loss (P <.001, P = .02, and P <.001 at 2, 8, and 16 kHz, respectively). CONCLUSION: The results of this preclinical study support the safety of ciprofloxacin hydrochloride, 0.3%, plus dexamethasone, 0.1%, for clinical use in the open middle ear cavity.

Differences in bacteriologic treatment failures in acute otitis externa between ciprofloxacin/dexamethasone and neomycin/polymyxin B/hydrocortisone: results of a combined analysis.

OBJECTIVE: To compare treatment failure rates for the two major acute otitis externa (AOE) pathogens, Pseudomonas aeruginosa and Staphylococcus aureus, by topical therapy with ciprofloxacin 0.3%/dexamethasone 0.1% (CDex) or neomycin 0.35%/polymyxin B 10,000 IU/mL/hydrocortisone 1% (Cort) based on clinical and microbiological failure in patients positive for these pathogens at baseline. RESEARCH DESIGN AND METHODS: A combined analysis was conducted from two similar, but non-identical clinical trials involving CDex vs. Cort. Outcomes of the combined efficacy analysis were treatment failure rates and antibiotic susceptibility values for P. aeruginosa and S. aureus. The raw data for the treatment failure rates from the two studies were combined to calculate the overall treatment failure rates of each treatment group. Chi-square tests of independence were conducted to assess differences in treatment failure rates between treatment groups. RESULTS: Of the 789 patients with culture-positive ears prior to the initiation of therapy, 61.0% (n = 481) were positive for P. aeruginosa and 8.9% (n = 70) were positive for S. aureus. While treatment failure rates for S. aureus were similar for the two therapies, CDex had a significantly lower treatment failure rate than Cort (5.1 vs. 13.0%; p = 0.0044) for P. aeruginosa. All of the persisting P. aeruginosa and S. aureus isolates were susceptible to fluoroquinolones and neomycin/polymyxin B. LIMITATIONS: The analysis strength is dependent on pooled data from similar studies. CONCLUSIONS: Ototopical ciprofloxacin 0.3%/dexamethasone 0.1% more effectively eradicates P. aeruginosa compared to Cort. Eradication of S. aureus by either drug was similar. These results favor CDex as a better first-line choice in the treatment of AOE compared to Cort.

Ciprofloxacin 0.3%/dexamethasone 0.1% sterile otic suspension for the topical treatment of ear infections: a review of the literature.

The objective of this article is to review the literature related to ciprofloxacin 0.3% and dexamethasone 0.1% sterile otic suspension. A systematic literature search utilizing Medline was conducted to identify peer-reviewed articles related to safety and efficacy. A total of 47 publications were identified and reviewed herein. The literature supports the use of antibiotic/antiiflammatory combination ear drops in the treatment of both acute otitis externa and acute otitis media in pediatric patients with tympanostomy tubes. Ciprofloxacin/dexamethasone has been demonstrated as safe and effective with regard to clinical cures and microbiological eradication of pathogens in either disease with low treatment failure rates. Additionally, the literature also provides clear evidence for the contribution of dexamethasone when added to ciprofloxacin for the topical treatment of ear infections.

A single topical agent is clinically equivalent to the combination of topical and oral antibiotic treatment for otitis externa.

OBJECTIVE: To demonstrate clinical equivalence (statistical noninferiority) of topical ciprofloxacin and hydrocortisone (CHC, Cipro HC) and topical neomycin/polymyxin b/hydrocortisone (NPH, Cortisporin) with systemic amoxicillin (AMX, Amoxil), for treatment of acute otitis externa (AOE). DESIGN: Randomized, active-control, observer-blind, multicenter trial. PATIENTS: Altogether, 206 patients were enrolled (CHC, 106; NPH + AMX, 100). Patients were > or =1 year of age, had AOE >2 days with at least mild symptoms, and gave informed consent. All were evaluable for safety, and 151 were evaluable for efficacy. INTERVENTIONS: Ciprofloxacin and hydrocortisone 3 drops twice daily for 7 days (adults and children) or NPH 4 drops (adults) or 2 drops (children) with AMX 250 mg (adults and children) 3 times daily for 10 days, as directed in approved product labeling. MAIN OUTCOME MEASURES: The primary efficacy variable was response to therapy 7 days after treatment ended (test of cure). Secondary variables included time to end of pain, symptom scores (otalgia and tenderness) and microbiological eradication. Noninferiority was declared if the lower confidence limit around the measurement difference was above -10 (nearer zero). RESULTS: Response to therapy was higher for CHC (95.71% vs 89.83%) but was statistically noninferior (lower confidence limit, -4.98) to NPH + AMX. Median time to end of pain was 6 days for both groups. Noninferiority was declared for symptom scores at all measurement periods and for microbiological eradication. No serious adverse events related to treatment were reported. CONCLUSIONS: Ciprofloxacin and hydrocortisone is clinically equivalent to NPH + AMX for the treatment of AOE in adults and children. However, low systemic exposure, absence of ototoxicity, and less frequent dosing clearly favor Cipro HC.

Effect of topical ciprofloxacin/dexamethasone or dexamethasone alone on acute Streptococcus pneumoniae rhinosinusitis in mice.

OBJECTIVE: To test whether intranasal ciprofloxacin/dexamethasone or dexamethasone alone affects the course of acute bacterial rhinosinusitis in mice. STUDY DESIGN: We performed a randomized, double-blind, parallel, placebo-controlled study in mice. SUBJECTS AND METHODS: Three groups of 10 C57Bl/6 mice were infected with Streptococcus pneumoniae, and then 1 day later randomized to treatment with placebo, ciprofloxacin plus dexamethasone, or dexamethasone. The mice were killed 3 or 10 days after treatment was begun. RESULTS: The placebo-treated mice became infected and developed an inflammatory cell infiltration in their sinuses. None of the treatments significantly affected the course of the illness. CONCLUSION: The lack of topical, intranasal efficacy of ciprofloxacin and dexamethasone could be attributed to subpotent dosage, rapid nasal clearance, or inability of the drops to reach the site of infection. Treatment with dexamethasone neither improved nor worsened the bacterial infection.

Development of a liquid enzyme-based ceruminolytic product.

Various compositions for removal of human cerumen are marketed but they are not very effective. Therefore, a proteolytic enzyme-based ceruminolytic product was developed containing the enzyme, methyl trypsin, and sodium bicarbonate. Efficacy was optimized based on in vitro testing using both human and artificial cerumen preparations. Both qualitative (visual observation) and quantitative (spectrophotometric) assessments of ceruminolytic efficacy were employed. Optimal enzyme stability was observed for the aqueous formulation at pH 4, while greater ceruminolytic efficacy was observed at pH 8. The optimal concentration range of enzyme was 150-300 absorbance U/mL based on efficacy and stability considerations. An aqueous formulation containing both methyl trypsin and sodium bicarbonate was shown to be more effective than two commercial products, Murine Ear Wax Removal Drops and Cerumenex Ear Drops. A two-part packaging system was employed to provide adequate shelf-life. Long-term stability studies confirmed that the formulation maintained >75% enzyme stability for 24 months at 5 and 25 degrees C and after reconstitution at room temperature for up to 1 day.

Comparative study of sensory attributes of two antihistamine nasal sprays: olopatadine 0.6% and azelastine 0.1%.

Allergic rhinitis is a chronic, allergen-induced inflammatory reaction. Patients often differentiate intranasal treatments based on sensory attributes. The purpose of this study was to evaluate the sensory attributes of olopatadine HCl nasal spray 0.6% (OLO) relative to azelastine HCl nasal spray 0.1% (AZE). This was a multicenter, double-blind, randomized, crossover comparison of OLO versus AZE in adult, symptomatic patients with at least a 2-year history of allergic rhinitis. Patients received each of the treatments separately with a washout between exposures, evaluated their sensory perceptions immediately after and 45 minutes postdosing with each treatment, and evaluated their perceptions of the two medications after administering both therapies. The mean age of the 110 patients was 42.4 years; 67% were women. OLO was superior to AZE in overall aftertaste (60.6% versus 30.3%; p = 0.0005), patient preference (62.4% versus 33.9%; p = 0.0001), and likelihood of extended use (60.9% versus 34.5%; p = 0.0004). OLO was superior to AZE in perceptions of immediate taste (1.9 U versus 3.2 U, respectively; p < 0.0001). Perceptions of additional attributes after administration of both treatments were significant and favored OLO (p < or = 0.0036 for all variables). In these assessments, respectively, 54.1 and 32.1% of patients favored the taste and smell of OLO compared with 27.5 and 11.9% who favored AZE. Both treatments were well tolerated. The sensory attributes of OLO are superior to AZE in terms of immediate taste postdosing, overall aftertaste, overall patient preference, and likelihood of use. This outcome could lead to greater patient compliance and improved treatment effect.

Pharmacokinetics of CIPRODEX otic in pediatric and adolescent patients.

OBJECTIVE: Describe the pharmacokinetics of ciprofloxacin and dexamethasone after administration of CIPRODEX Otic Suspension (CIP/DEX) into the middle ears of children. DESIGN: Open-label, single-dose, pharmacokinetic studies, administering four drops of CIP/DEX instilled into each middle ear through the tympanostomy tubes immediately following tube placement. Blood was collected for 6h and analyzed for ciprofloxacin and dexamethasone concentrations using a validated liquid chromatography and tandem mass spectrometry (LC/MS/MS) method. SETTING: The study was conducted through a referral pediatric otolaryngology practice with actual surgical procedures performed in an ambulatory care center. PATIENTS: Twenty-five randomly selected patients, 1-14 years of age (mean age, 5 years), receiving tympanostomy tubes. RESULTS: Peak ciprofloxacin plasma levels were observed at about 1h, with a mean C(max) of 1.33+/-0.96 ng/mL (range <0.5-3.45 ng/mL) and an estimated half-life of 3.0+/-1.2h. Peak dexamethasone plasma levels were observed within 2h with a mean C(max) of 0.90+/-1.04 ng/mL (range <0.05-5.10 ng/mL) and an estimated half-life of 3.9+/-2.9h. CONCLUSION: These results demonstrated low systemic exposure of ciprofloxacin and dexamethasone following topical otic administration in pediatric patients.

Onset and duration of action of nasal sprays in seasonal allergic rhinitis patients: olopatadine hydrochloride versus mometasone furoate monohydrate.

Rapid relief of symptoms should be one of the primary goals of treatment for allergic rhinitis (AR). The onset and duration of action of olopatadine hydrochloride nasal spray, 665 mcg (OLO; Patanese), for seasonal AR (SAR) was evaluated in this study. This study was performed to determine the onset and duration of action of OLO compared with placebo spray, with mometasone furoate monohydrate, 50 mcg (MM; Nasonex), as a reference standard. This was a single center, single-dose, randomized, double-blinded parallel-group environmental exposure chamber study. Patients were primed at two 2-hour priming visits. Eligible patients were randomized to OLO, placebo spray, or MM, 2 sprays/nostril. Allergy symptoms (sneezing, runny, itchy, and stuffy nose) were rated by patients at 16 time points during 12 hours after dosing and patient satisfaction was assessed at 4 and 12 hours postdose. Safety was assessed by a review of adverse events, cardiovascular and nasal examination parameters. Four hundred twenty-five adult patients were randomized. OLO was superior to placebo spray in reducing total nasal symptoms (TNSS) within 30 minutes after dosing and maintained superiority for at least 12 hours (p < 0.05). The onset of MM was not observed until 150 minutes postdose and was smaller in magnitude compared with OLO. OLO was superior to both placebo spray (p < 0.0001) and MM (p < 0.05) in patient satisfaction. Treatment was well-tolerated with no safety concerns. OLO is superior to placebo spray and MM in reducing allergy symptoms; OLO has a rapid onset of action and a duration of effect of at least 12 hours.

Pooled analysis of two clinical trials comparing the clinical outcomes of topical ciprofloxacin/dexamethasone otic suspension and polymyxin B/neomycin/hydrocortisone otic suspension for the treatment of acute otitis externa in adults and children.

OBJECTIVE: This study aimed to compare the clinical outcome of patients receiving topical ciprofloxacin 0.3%/dexamethasone 0.1% (CD) otic suspension with that of those receiving polymyxin B/neomycin/ hydrocortisone (PNH) otic suspension for the treatment of acute otitis externa (AOE). METHODS: Data from 2 institutional review board-approved, multicenter, observer-masked, parallel-group, randomized, noninferiority clinical trials conducted at 76 institutions across the United States between April 1998 and July 1999 were pooled together for this analysis. Patients > or =1 year of age diagnosed with AOE were considered for inclusion in the studies. Patients with AOE >4 weeks' duration, a perforated tympanic membrane, chronic suppurative otitis media, or use of either antibiotics or steroids within the previous 7 days were excluded from the studies. Patients were randomly assigned to receive CD or PNH for 7 days. CD was administered as 3 drops in children and 4 drops in patients > or =12 years of age BID. PNH was administered as 3 drops in children and 4 drops in patients > or =12 years of age TID. The clinical investigators were blinded to treatment assignment. Due to the different dosing regimens, patients were not blinded, but they also were not directly informed of their treatment assignments. Otic inflammation, tenderness, edema, and discharge were clinically assessed on days 3, 8, and 18 of the studies. Otic inflammation and edema were evaluated using a 4-point scale (none = 0; mild = 1; moderate = 2; and severe = 3). Otic tenderness and discharge were rated on a binomial scale (absent = 0 and present = 1). The clinical assessments were aggregated into a 9-point composite clinical scale (range, 0-8) to compare baseline severity between groups. For the final outcomes assessment in this study, the aggregated clinical scores were dichotomized into cured (0) versus noncured (>0) and analyzed using a Kaplan-Meier survival technique. A log-rank test was used to compare the cure curves between treatment groups. Kaplan-Meier summary statistics provide the mean and median times to cure, and the mean times to cure for the 25th and 75th patient quartiles. Tolerability was assessed by monitoring patients for adverse events at each visit. RESULTS: Data from 1072 patients (1242 ears) were included in the analysis (CD, 537 patients; PNH, 535 patients). Baseline AOE severity and demographic characteristics were similar between the 2 treatment groups. The mean patient age was 21.7 and 22.0 years in the CD and PNH groups, respectively. Both groups were similar with respect to sex, with 50.7% and 53.5% females in the CD and PNH groups, respectively. The racial composition was predominately white (88.6% vs 84.9% in the CD and PNH groups, respectively). The log-rank test revealed a significant difference in the AOE cure curves between the CD and PNH groups (P = 0.038). The proportions cured in the AOE at-risk groups at the day-3, -8, and -18 assessments in the CD and PNH treatment groups were 0.14 and 0.10, 0.75 and 0.72, and 0.98 and 0.97, respectively. The Kaplan-Meier summary statistics indicated that the mean time to cure was 0.6 day less with CD compared with PNH (9.7 vs 10.3 days). Treatment-related adverse event rates were similar between the 2 groups and occurred in 3.8% of the patients. The most common adverse events included otic pruritus (2.1%), otic congestion (0.6%), otic debris (0.5%), otic pain (0.3%), superimposed ear infection (0.3%), and erythema (0.1%). CONCLUSION: These data from 2 previous studies suggest that time to cure was significantly less with CD compared with PNH in patients with AOE.

An assessment of the onset and duration of action of olopatadine nasal spray.

OBJECTIVE: Seasonal allergic rhinitis (SAR) is a highly prevalent disease. This study was conducted to evaluate the onset and duration of action of three concentrations of olopatadine nasal spray. METHODS: This was a randomized, double-blind, single-dose, placebo-controlled study, conducted in an environmental exposure chamber in patients with SAR. A total of 320 patients were exposed to ragweed allergen in the chamber and randomized to olopatadine nasal spray 0.2%, 0.4%, 0.6%, or placebo nasal spray. Symptoms (sneezing, runny, itchy, and stuffy nose) were self-assessed during a 12-hour study period. RESULTS: All concentrations of olopatadine nasal spray provided clinically meaningful reductions in total nasal symptom scores at 30 minutes compared to the placebo. Olopatadine nasal spray 0.6% was significantly more effective (P < 0.05) than placebo nasal spray at all time-points starting at 90 minutes post-dose and continuing over 12 hours. CONCLUSIONS: Olopatadine nasal spray 0.6% demonstrated a fast onset of action and maintained an effect for at least 12 hours after dosing.