Clinical Therapeutics

Published by Elsevier
Online ISSN: 0149-2918
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Article
Advances in the development of oral rehydration solutions (ORS) for the treatment of diarrheal disease depend on a knowledge of the disease process itself and of the factors that determine the movement of water and solutes across the gut. The formulation of ORS in current use is based on information derived from a number of different experimental approaches that attempt to take account of these factors. The fate of orally ingested solutions depends first on the processes of gastric emptying that control the rate of entry of fluid to the small intestine and second on the rates of absorption and secretion in the intestine. In the absence of a model that can reliably assess the effects of these two processes together, they are normally investigated separately. The methods of choice for measurement of gastric emptying are gamma scintigraphy and gastric aspiration. Multi-lumen perfusion techniques permit measurement of net flux in short segments of intestine. A promising new technique that takes account of both gastric emptying and intestinal transport involves measurement of accumulation in the circulation of isotopic tracers for water added to ingested solutions. The efficacy of new solutions must, however, ultimately be assessed in clinical trials on patients.
 
Article
The objective of this study was to directly compare the intraocular pressure (IOP)-lowering efficacy and safety of travoprost 0.004% eyedrops with the fixed combination of latanoprost 0.005%/timolol 0.5% eyedrops in patients with primary open-angle glaucoma or ocular hypertension. This was a randomized, double-masked, multicenter, parallel-group, active-controlled study. Adult subjects with open-angle glaucoma (with or without pseudoexfoliation or pigment dispersion component) or ocular hypertension were eligible to participate if their IOP was inadequately controlled with > or =4 weeks of beta-blocker monotherapy, as indicated by IOP of 22 to 36 mm Hg at 9 AM at screening. Patients were randomly assigned in a 1:1 ratio to receive placebo + travoprost or latanoprost/timolol + placebo. Patients in the travoprost group administered travoprost at 9 PM and placebo at 9 AM; patients in the latanoprost/timolol group administered latanoprost/timolol at 9 AM and placebo at 9 PM. IOP measurements were performed using Goldmann applanation tonometry at 9 AM and 5 PM at the week-2 and week-6 visits. Both volunteered and elicited reports of adverse events were collected; all patients who were randomized and received > or =1 dose of study drug were included in the safety analysis. One hundred ten patients were randomized, of whom 106 patients were evaluable (travoprost, n = 50; latanoprost/timolol, n = 56). There were no statistically significant differences at baseline between the treatment groups, based on age group, sex, race, iris color, or diagnosis. Mean IOP values were not statistically different between groups at baseline or during treatment. In the pooled results for 9 Am assessment at weeks 2 and 6, mean (SEM) IOP reductions for travoprost and latanoprost/timolol were 7.0 (0.5) and 6.4 (0.5) mm Hg, respectively (P = NS). Adverse events related to therapy were mild in nature, and there were no statistically significant differences between the 2 treatment groups. The most frequently experienced adverse events in the travoprost group were ocular hyperemia (9.3%), foreign body sensation (5.6%), abnormal vision (1.9%), allergic reaction (1.9%), conjunctivitis (1.9%), dacryocystitis (1.9%), eye discharge (1.9%), eye pruritus (1.9%), lid edema (1.9%), lid erythema (1.9%), and tearing (1.9%). In the latanoprost/timolol group, the most frequently experienced adverse events were cataract (1.8%), dry eyes (1.8%), eye pruritus (1.8%), foreign body sensation (1.8%), and ocular hyperemia (1.8%). Mean IOP changes from baseline for travoprost 0.004% and latanoprost 0.005%/timolol 0.5% fixed combination were not significantly different at follow-up in these patients. Both medications were well tolerated.
 
Article
Background: Primary open-angle glaucoma (POAG) is a chronic and progressive optic nerve and retinal nerve fiber layer neuropathy, with characteristic visual field damage. The intraocular pressure (IOP) is typically higher than the level considered statistically normal. Although there is no known cure, appropriate reduction of IOP with hypotensive drugs (eg, the topical prostaglandin analogue travoprost) delays the progression of POAG. Chemical-stability studies of travoprost performed by the manufacturer suggest that the stability of travoprost is maintained beyond the expiration date, which is 6 weeks after the laminated packaging has been opened. Objective: The goal of this study was to assess the efficacy and tolerability of travoprost 0.004% ophthalmic solution, 6 to 12 weeks after its expiration date, in patients with POAG. Methods: This randomized, controlled, investigator-blinded study was conducted at 2 centers in Brazil: the Ophthalmology Department, Federal University of Goiás, Goiânia, and the Ophthalmology Department, Santa Casa de Misericordia Hospital in São José do Rio Preto, Sao Paulo. Patients with POAG (in 1 or both eyes) were randomly assigned to receive travoprost, either from a bottle from which the laminated packaging had been removed and that had been stored at room light and temperature for 6 weeks (ie, after the expiration date; opened group), or from a bottle that had been sealed until first use by the patient (control group). Drug was to be administered, 1 drop in the lower conjunctival sac (in the affected eye[s]), QD between 7 pm and 9 pm, for 6 weeks. IOP was measured at study weeks 0 (baseline), 4, and 6. The 2 treatment groups were compared with regard to hypotensor effect and incidence of adverse events (AEs). Results: : Thirty-one patients completed the study (55 eyes; 28 right and 27 left eyes; 35 eyes of women, 20 eyes of men). The mean (SD) ages of the opened and control groups were 61.8 (13.5) and 62.8 (14.1) years, respectively. Twenty-four patients were included in both treatment groups (ie, 1 eye per group). The baseline IOP was similar between the 2 treatment groups. There was a significant reduction in IOP in both groups at 4 and 6 weeks (both, P < 0.001 vs baseline). However, no significant differences in IOP were found between the 2 treatment groups at any time during the study. Conjunctive hyperemia and a burning sensation in the eye immediately after application were the only AEs reported; the incidence of these was similar between the 2 treatment groups. Conclusions: In this study of patients with POAG, IOPs and AEs were similar in eyes receiving 6 weeks of treatment with travoprost 0.004% ophthalmic solution, either from bottles from which the laminated packaging had been opened and that had been stored at room light and temperature for 6 weeks (ie, after the expiration date), or from bottles that had been sealed until first use by the patient. These results suggest that travoprost remains effective for at least 12 weeks after the laminated packaging has been opened.
 
Article
The objective of this study was to assess the hypotensive efficacy of timolol maleate 0.5%, brinzolamide 1%, or brimonidine tartrate 0.2% ophthalmic solution, administered in conjunction with travoprost 0.004%, in patients with primary open-angle laucoma (OAG) or ocular hypertension (OHT) whose intraocular pressure (IOP) did not meet the treatment target using travoprost 0.004% monotherapy. This was a randomized, comparative, investigator-masked study. Patients with OAG or OHT treated with travoprost 0.004% monotherapy were randomized to receive 1 of the 3 adjunctive therapies (timolol maleate 0.5%, brinzolamide 1%, or brimonidine tartrate 0.2%), 1 drop BID in each randomized eye, in addition to 1 drop QD of travoprost for a period of 4 weeks. IOP was measured on days 0 (travoprost 0.004%) and 28 (travoprost 0.004% and adjunctive treatment). Adverse events were monitored on days 0 and 28 by patient interview. Twenty-nine patients with OAG (46 eyes) and 3 patients with OHT (6 eyes), with a total of 52 eligible eyes, completed the study; 28 eyes were from male patients and 24 were from female patients. In addition to continuing travoprost treatment, 20 eyes received timolol, 16 eyes received brinzolamide, and 16 eyes were treated with brimonidine. There were no significant differences among the groups in the mean (SD) IOP at baseline on day 0 (19.0 [4.1], 17.2 [3.5], and 17.0 [3.1] mm Hg, respectively; P=NS). On day 28, the reduction in mean (SD) IOP in eyes treated with brimonidine tartrate 0.2% was significantly smaller (2.3 [1.8] mm Hg vs 3.9 [1.8] mm Hg [P=0.01]) and the mean (SD) percentage reduction in IOP was significantly smaller (13.4% [9.1%] vs 20.2% [7.5%] [P=0.01]) when compared with timolol maleate 0.5%, and likewise when compared with brinzolamide 1% (4.0 [2.1] mm Hg [P=0.02] and 22.7% [8.6%] [P=0.006], respectively). The group treated with brinzolamide was associated with a similar reduction in IOP to timolol (P=NS for both mean [SD] IOP and percentage reduction in IOP compared with timolol monotherapy). Barring the occasional conjunctival hyperemia, which was excluded as an adverse event for the purposes of this study, no adverse events were recorded. Brinzolamide 1% and timolol maleate 0.5% treatment were both associated with a significantly greater reduction in IOP compared with brimonidine 0.2% when administered as a nonfixed adjuvant to travoprost 0.004% in the treatment of patients with OAG and OHT whose IOP was inadequately controlled with travoprost monotherapy. All treatments were well tolerated.
 
Article
The aim of this study was to compare the tolerability and efficacy of once-daily travoprost 0.004% versus latanoprost 0.005% for 6 weeks followed by 6 weeks of once-daily travoprost 0.004% in decreasing intraocular pressure (IOP) in patients with open-angle glaucoma (OAG) or ocular hypertension (OH). This multicenter, randomized, doublemasked, active-controlled, parallel-group trial was conducted at 32 centers across Latin America. Patients aged > or =18 years with OAG or OH were randomly assigned to receive topical travoprost 0.004% or latanoprost 0.005% 1 drop QD (9 PM) for 6 weeks (masked phase). At 6 weeks, all patients were assigned to receive open-label travoprost 0.004% 1 drop QD (9 PM) for 6 additional weeks (open-label phase). Study visits were scheduled at weeks 1, 2, 4, 6, 8, and 12. At each study visit, IOP was measured at 5 PM (+/-1 hour; approximately 20 hours after study drug administration). IOP changes from baseline were combined (pooled) from the 1-, 2-, 4-, and 6-week data to provide a comparison between the 2 treatment groups. Ocular adverse events (AEs) were monitored using slit-lamp examination. A total of 302 patients were enrolled (travoprost group, 155 patients; latanoprost group, 147 patients). The mean (SD) age of the travoprost group was 61.9 (10.6) years; 60.6% were female; and 47.1% were white. The mean (SD) age of the latanoprost group was 60.5 (12.4) years; 62.6% were female; and 49.0% were white. Mean IOP values were not significantly different between the travoprost and latanoprost groups at baseline (24.7 vs 24.2 mm Hg) or 6 weeks; however, the between-group difference in reductions from baseline in pooled IOP during the masked phase of the study was statistically significant (-8.3 vs -7.5 mm Hg; P = 0.009). At weeks 6 and 12, mean lOP levels were 16.1 and 16.2 mm Hg, respectively, in the travoprost group and 16.4 and 16.1 mm Hg in the group that was switched from latanoprost to travoprost (all, P = NS). The most common ocular AEs that occurred with masked travoprost, latanoprost, and open-label travoprost were hyperemia (26.9%, 12.2%, and 5.3%, respectively), discomfort (3.2%, 3.4%, and 1.1%), and pruritus (4.5%, 2.0%, and 2.1%). In this population of patients with OAG or OH, 6-week treatment with travoprost 0.004% was associated with a significantly greater decrease from baseline in pooled IOP compared with latanoprost 0.005% 20 hours after administration. There were no significant differences between the 2 groups. Travoprost and latanoprost were well tolerated.
 
Article
Both tazarotene (a retinoid prodrug) and calcipotriene (a synthetic analog of vitamin D3) are effective in the treatment of plaque psoriasis, but no reports in the literature directly compare the efficacy and tolerability of these 2 drugs. Tazarotene is commonly used in conjunction with a topical corticosteroid. In this study, tazarotene was used with mometasone furoate (a synthetic corticosteroid), and the 2-drug regimen was compared with calcipotriene monotherapy. This study was conducted to compare the efficacy and tolerability of tazarotene 0.1% gel once daily plus mometasone furoate 0.1% cream once daily with those of calcipotriene 0.005% ointment twice daily in the treatment of plaque psoriasis. In this multicenter, investigator-blinded, parallel-group study, adult patients with chronic, stable plaque psoriasis affecting 5% to 20% of their body surface area were randomly allocated to receive up to 8 weeks of treatment with either tazarotene 0.1% gel once daily (in the evening) plus mometasone furoate 0.1% cream once daily (in the morning) or calcipotriene 0.005% ointment twice daily. Patients were assessed at baseline and at weeks 2, 4, and 8 of treatment. Patients who demonstrated complete clearance of plaque psoriasis after 2 or 4 weeks of treatment and those whose psoriasis had improved > or = 50% after 8 weeks of treatment entered a 12-week posttreatment follow-up phase during which they applied only moisturizer. Patients were reassessed after 4, 8, and 12 weeks of posttreatment follow-up. Physician-rated measures of efficacy included global improvement, plaque elevation, scaling, erythema, and percentage of body surface area involvement. Patient-rated assessments included efficacy of study treatment compared with previous therapies, comfort of treated skin, outlook for long-term control of psoriasis, and overall impression of treatment. Of 120 patients with moderate to severe psoriasis enrolled from 3 centers, 106 (88%) completed the study. No significant differences in baseline clinical variables were observed between the 2 groups. Twenty-seven patients (45%) in the tazarotene plus cortico-steroid group achieved marked improvement (> or = 75% global improvement) after 2 weeks of treatment compared with 15 patients (26%) in the calcipotriene group (P < or = 0.05). Between-group comparisons of the percentage of patients achieving complete or almost complete clearance (> or = 90% global improvement) did not reach statistical significance at any time point. When compared with the calcipotriene regimen, the tazarotene plus corticosteroid regimen resulted in significantly greater efficacy on trunk lesions in reducing plaque elevation (at the end of treatment and at week 4 of the posttreatment phase, P < or = 0.05), scaling (week 4 of treatment and week 4 of the posttreatment phase, P < or = 0.05), erythema (week 4 of treatment and at the end of treatment, P < or = 0.05), and percentage of body surface area involvement (weeks 2 and 4 of treatment, P < or = 0.01). In addition, the tazarotene plus corticosteroid regimen was significantly more effective in reducing the percentage of body surface area involvement in upper limb lesions (weeks 2 [P < or = 0.05] and 4 [P < or = 0.01] of treatment). Forty-two of 55 patients (76%) in the tazarotene plus corticosteroid group rated their medication as more or much more effective than previous therapies compared with 30 of 52 patients (58%) in the calcipotriene group (P < or = 0.05). Although adverse events (burning, pruritus, irritation, and erythema) occurred in a significantly greater proportion of patients who received tazarotene plus corticosteroid than in those who received calcipotriene (P < or = 0.05), 47 of 55 patients (85%) in both groups rated the comfort of their treated skin as "somewhat comfortable" or better and both groups had similar discontinuation rates due to treatment-related adverse events (3% and 5%, respectively). CONCL
 
Article
Emedastine difumarate 0.05% ophthalmic solution and ketotifen fumarate 0.025% ophthalmic solution are 2 topical antiallergic agents available in the United States and other countries. Emedastine is indicated for the temporary relief of the signs and symptoms of allergic conjunctivitis. Ketotifen is indicated for the temporary relief of ocular itching caused by allergic conjunctivitis. The purpose of this study was to compare the efficacy of these agents in the temporary relief of ocular itching due to allergic conjunctivitis. The 2 agents were compared with each other and with placebo (artificial tears) using the conjunctival allergen challenge (CAC) model. This was a single-center, randomized, double-masked, placebo-controlled study. At visit 1, CAC was performed on eligible subjects to identify the dose required to elicit a positive allergic reaction. Subjects returned after 7 days for visit 2 to confirm the allergen dose. On day 14 (+/-3) of the study, enrolled subjects were randomized to 1 of 3 treatment groups: emedastine in I eye and placebo in the other, ketotifen in 1 eye and placebo in the other, or emedastine in 1 eye and ketotifen in the other. In 25 subjects, bilateral CAC was performed 5 minutes after study medication instillation. In a second group of 20 subjects, CAC was performed 15 minutes after medication instillation. Itching was graded according to a standardized 5-point scale (0 = none to 4 = severe itching) at 3, 5, and 10 minutes postchallenge. Differences in efficacy scores between treatments and versus placebo were compared using 2-sample t tests of equal variance. A total of 45 patients (mean age, 41.2 years) received treatment: 16 received emedastine in 1 eye and ketotifen in the other; 14 received emedastine in 1 eye and placebo in the other; and 15 received ketotifen in 1 eye and placebo in the other. Both emedastine and ketotifen significantly inhibited itching (P < 0.05) compared with placebo at all time points after the 5- and 15-minute CAC. Mean raw scores for the active treatments were not statistically different. The mean itching efficacy scores were also not statistically different between active treatments. No adverse events were reported in this study. The results of this study suggest that emedastine and ketotifen are not significantly different with respect to anti-itching efficacy in the CAC model of acute allergic conjunctivitis.
 
Article
Topical antiallergic agents, such as antihistamines and mast-cell stabilizers, are the main therapeutic options for seasonal allergic conjunctivitis (SAC). Ketotifen fumarate and olopatadine HCl have dual action that offers a combination of these 2 mechanisms. Although clinical studies comparing the efficacy of these 2 drugs have shown that both were effective in the treatment of SAC, the results were contradictory and did not include the effects of these drugs on inflammatory markers. The aims of this study were to compare the clinical efficacy of topical ketotifen and olopatadine eye drops and to determine the effects of these 2 drugs on the expression of cell adhesion molecules (CAMs) and inflammatory markers in conjunctival surface cells in patients with SAC. This 30-day, randomized, double-masked, artificial tear substitute (ATS)-controlled clinical trial was conducted at the Department of Ophthalmology, Karadeniz Technical University, School of Medicine, Trabzon, Turkey. Patients with SAC were included in the study and randomly assigned to 1 of 3 groups: topical ketotifen fumarate 0.025% ophthalmic solution, topical olopatadine HCl 0.1% ophthalmic solution, or ATS (control group). All drugs were administered 2 drops per eye BID for 30 days. At the beginning of the study (day 0; baseline), on day 15, and on day 30, clinical scores (itching, tearing, redness, eyelid, swelling, and chemosis) and conjunctival impression cytology specimens were obtained. The percentages of cells expressing intercellular adhesion molecule 1, vascular CAM-1, human leukocyte antigen-DR, and beta1-integrin (CD29) from conjunctival impression cytology specimens were determined using flow cytometry. Patients were questioned about adverse events (AEs) at each visit. Ocular discomfort on installation of the drugs was recorded as an AE. Thirty-nine patients (20 men, 19 women; age range, 18-61 years) with SAC were included. Twelve patients received ketotifen; 13, olopatadine; and 14, ATS. In both active-treatment groups, the improvements of clinical scores (tearing and itching) were more pronounced compared with those in the ATS group, although the day-30 difference in tearing score between the olopatadine and ATS groups was not statistically significant. No significant within-group or between-group differences in mean scores for redness, chemosis, or eyelid swelling were found. The expression rates of CAMs and inflammatory markers in conjunctival surface cells were significantly more reduced with ketotifen and olopatadine compared with ATS. However, clinical and flow cytometric parameters were improved with ATS at 15 and 30 days compared with baseline. No AEs were observed during the study period. In this short-term study in a selected, small study population with SAC, ketotifen and olopatadine diminished the expression of CAMs and inflammatory markers on the conjunctival surface cells effectively. Both active treatments were more efficacious compared with ATS and were well tolerated.
 
Article
The purpose of this study was to compare the relative efficacy and clinical performance of olopatadine hydrochloride 0.1% ophthalmic solution and ketotifen fumarate 0.025% ophthalmic solution in the conjunctival antigen challenge model. This was a prospective, randomized, double-masked, contralaterally controlled, single-center, antigen challenge study. Of the 53 subjects screened, 32 were enrolled and completed the study. The study comprised 3 visits. Primary efficacy variables were ocular itching (assessed at visits 2 and 3) and subject satisfaction (assessed at visit 3). Tolerability variables were slit-lamp findings (all visits), visual acuity (all visits), ocular comfort after drug instillation (visit 3), and adverse events (visits 2 and 3). At visit 1, the antigen concentration that elicited a positive ocular allergic response was determined, and this concentration was confirmed at visit 2. Subjects graded itching on a 5-point scale at 3, 5, and 10 minutes postchallenge. The scores from this visit were used as baseline scores and compared with scores from visit 3 to determine drug efficacy. At visit 3, subjects were randomly assigned to 2 treatment groups. Group A received 1 drop of olopatadine in the right eye and I drop of ketotifen in the left eye. Group B received 1 drop of olopatadine in the left eye and 1 drop of ketotifen in the right eye. Following drug instillation, the subjects assessed the comfort level in each eye. Twelve hours after instillation, subjects were challenged with the antigen concentration that elicited a positive response at the previous visits. Itching was subjectively graded at 3, 5, and 10 minutes postchallenge. Subjects were asked to choose which therapy they were more satisfied with. Twelve hours after administration, efficacy scores for olopatadine were significantly higher than those for ketotifen at 3 and 5 minutes postchallenge (1.84 and 1.75 vs 1.25 and 1.34; P < 0.05). Olopatadine-treated eyes were rated significantly more comfortable than those treated with ketotifen immediately after drug instillation (1.25 vs 2.09; P < 0.05) and 12 hours later, as measured by patient ratings of ocular comfort. Of the 22 subjects who had a preference, 16 (73%) were more satisfied with olopatadine than with ketotifen. Olopatadine is more effective than ketotifen in reducing the itching associated with allergic conjunctivitis in the antigen challenge model. Olopatadine caused less ocular discomfort than ketotifen and was preferred by approximately 3 times as many patients as was ketotifen.
 
Article
Ketotifen fumarate 0.025% ophthalmic solution is an antiallergic treatment currently available in the United States. It is indicated for the temporary prevention of ocular itching due to allergic conjunctivitis. The purpose of this study was to determine the relative efficacy of ketotifen when applied topically to the eye, compared with placebo, in the treatment of nasal signs and symptoms of allergic rhinoconjunctivitis as induced by the conjunctival allergen challenge (CAC) model. This was a randomized, double-blind, parallel-group, single-center clinical study using the CAC model. Patients aged > or = 18 years, able to follow the study instructions, willing to avoid disallowed medications, and having a history of rhinoconjunctivitis and a positive skin test were eligible. At visit 1, the dose of allergen necessary to achieve a qualifying reaction was determined using bilateral ocular instillation of allergen to eligible patients. At visit 2, the allergen dose determined at visit 1 was confirmed, and all patients attaining a qualifying nasal reaction continued in the study. At visit 3, each patient was randomized to receive 1 drop of ketotifen bilaterally in the eyes or 1 drop of placebo bilaterally. Fifteen minutes after instillation of the study medication, bilateral CAC was performed. Patients rated nasal symptoms (sneezing, rhinorrhea and postnasal drip, nasal pruritus, palatal pruritus, and nasal congestion) on standardized scales at 10, 20, and 30 minutes after CAC. Thirty-two patients (16 men, 16 women; mean age, 45 years [range, 28-70 years]) were randomized to treatment and completed the study. Nineteen patients received ketotifen and 13 received placebo. Nasal symptom scores in ketotifen-treated patients were statistically and clinically significantly fewer than in those treated with placebo at all time points (mean baseline corrected total nasal score: 10 minutes, P = 0.010; 20 minutes, P = 0.025; 30 minutes, P = 0.006). In this study, topical ketotifen fumarate 0.025% ophthalmic solution, when dosed ocularly, offered protecdon against the nasal signs and symptoms of acute allergic rhinoconjunctival reaction as induced by the CAC model.
 
Article
Because the majority of migraineurs are young women in their peak reproductive years, it is important to understand the possible effects on the pharmacokinetics of both medications when sumatriptan is coadministered with an oral contraceptive (OC). The primary objective of this study was to assess the effect of multiple dosing of the OC norethindrone 1 mg/ethinyl estradiol 0.035 mg (NE/EE) on the single-dose pharmacokinetics of sumatriptan in healthy volunteers. Secondary objectives were to determine the effect of a single dose of sumatriptan on the multiple-dose pharmacokinetics of NE and EE, and to assess the safety and tolerability of the combination. This was an open-label, 1-sequence, crossover study in healthy women who had been receiving NE/EE for at least 3 months. Subjects received 1 cycle of NE/EE, consisting of 21 days of OC and 7 days of placebo. They also received a single dose of sumatriptan 50 mg on the last day of the OC or placebo regimen. Blood samples for the determination of plasma sumatriptan concentrations were collected on days 21 and 28, and blood samples for the determination of plasma NE and EE concentrations were collected on days 20 and 21. Treatments were compared by analysis of variance. Equivalence between treatments was to be concluded if the 90% Cl for the ratio of reference to test means for log(e)-transformed parameters (area under the plasma concentration-time curve [AUCI and maximum measured plasma concentration [C(max)]) for each analyte fell within the interval 0.80 to 1.25. Twenty-six women (mean age, 29.8 years; age range, 18-44 years; weight range, 52-82 kg) participated in the study. The 90% CI for the ratio of reference to test means for the AUC extrapolated to infinity (AUC(infinity)) of sumatriptan was 1.11 to 1.22, and the 90% CIs for the AUC over the dosing interval at steady state (AUC(tau)) of NE and EE were 0.96 to 1.00 and 0.91 to 0.97, respectively. The 90% CIs for the ratio of reference to test means for the C(max) of sumatriptan, NE, and EE were a respective 1.05 to 1.30, 0.76 to 0.88, and 0.88 to 1.04. Study treatments were well tolerated. Adverse events were mild or moderate, and there were no clinically significant changes in vital signs or laboratory values. The extent of absorption (AUC) of sumatriptan, NE, and EE was similar after oral administration of sumatriptan and NE/EE, both alone and in combination. Thus, in the opinion of the study investigators, there were no clinically relevant changes in the AUC of any of the medications when sumatriptan and NE/EE were administered concomitantly compared with administration alone. The results of this study suggest that dose adjustment is not necessary when sumatriptan is administered concomitantly with NE/EE in healthy premenopausal women.
 
Article
Topical retinoids are considered first-line therapy in the treatment of acne vulgaris, yet can be associated with cutaneous irritation, including erythema, peeling, dryness, burning, and itching. Tretinoin gel microsphere (TGM) formulations were developed to minimize these effects. A lower-strength TGM formulation may be desirable to further reduce exposure to tretinoin. This study was conducted to assess the efficacy and safety profile of a lower-dose TGM (0.04%) formulation compared with TGM 0.1% for the treatment of mild to moderate acne vulgaris. In this multicenter, double-blind, parallel-group, Phase IV dose-ranging study, patients with facial acne were randomized to apply either TGM 0.04% or TGM 0.1% to the face each night for 12 weeks. Patients must have discontinued systemic retinoid treatment for at least 1 year before the study and were not to have used any topical retinoids, systemic antibiotics, nicotinamide, or systemic steroids for at least 1 month. All other topical medications applied to the face (including corticosteroids, antimicrobials, salicylic acid, and benzoyl peroxide) were to be discontinued at least 2 weeks before the study. End points were the acne lesion count (total, inflammatory, and noninflammatory lesions) and the investigators' and patients' assessments of improvement. Adverse events (including severity and relationship to treatment) and signs and symptoms of cutaneous irritation at the treatment site were monitored at each study visit. One hundred fifty-six patients (78 TGM 0.04%, 78 TGM 0.1%) were randomized and received treatment. Patients ranged in age from 12 to 41 years (mean, 18.4 years) and were predominantly white (n = 89 [57.1%]) and male (n = 80 [51.3%]). Both TGM 0.04% and TGM 0.1% were associated with a reduction from baseline in total, inflammatory, and noninflammatory lesions. The differences between groups in the change in lesion counts from baseline to weeks 2, 4, 8, and 12 were not statistically significant. However, there was a greater reduction in inflammatory lesions at week 2 for TGM 0.1% compared with TGM 0.04% (14.8% vs 6.0%, respectively; P < 0.047). Both treatment groups had similar improvements in the investigators' global evaluation and the patients' assessment of the response to treatment. Both TGM 0.04% and TGM 0.1% were well tolerated. The most common adverse events were skin-associated burning sensation (2.6% in the TGM 0.04% group and 7.7% in the TGM 0.1% group) and irritation (6.4% and 3.8%, respectively). In the TGM 0.04% group, significantly fewer patients experienced dryness of the treatment area during the early phase of treatment (P < 0.027). However, for other measures of cutaneous irritation (peeling, burning/stinging, and itching), either there were no statistically significant differences between treatment groups or, in the case of erythema, there was a significant difference in favor of TGM 0.1% (P = 0.035). Both TGM 0.04% and TGM 0.1% were associated with reductions in lesion counts in these patients with mild to moderate facial acne. Both concentrations were generally well tolerated. The results suggested an early (week 2) incremental benefit for the use of TGM 0.1% in the treatment of inflammatory lesions.
 
Article
The safety and efficacy of twice-daily applications of alclometasone dipropionate cream 0.05% were evaluated in 39 children with eczema during a three-week open study. Early-morning plasma cortisol levels were monitored at weekly intervals (visits 1, 2, and 3) for six children. For the remaining 33 children, levels were measured at visits 1 and 2 and two weeks later, at visit 4. Improvement in signs and symptoms of erythema, induration, and pruritus and a global response to therapy were determined weekly. Plasma cortisol levels remained within the acceptable normal range of 7 to 25 micrograms/100 ml throughout the study in all 39 children. At the conclusion of treatment, a favorable global response--complete clearing of monitored signs and symptoms--was observed in 28 (72%) children, and marked or moderate improvement was recorded for seven (18%) children.
 
Article
Olopatadine hydrochloride 0.1% ophthalmic solution and azelastine hydrochlofide 0.05% ophthalmic solution are 2 topical antiallergic agents indicated for the treatment of itching of the eye associated with allergic conjunctivitis. Olopatadine has recently received US Food and Drug Administration (FDA) approval for an expanded indication for the treatment of signs and symptoms of allergic conjunctivitis, including itching, tearing, eyelid swelling, redness, and chemosis. The purpose of this study was to compare the efficacy of olopatadine hydrochloride versus azelastine hydrochloride and placebo (artificial tears) in the conjunctival allergen challenge (CAC) model. This was a prospective, randomized, double-masked, contralaterally controlled, multicenter, allergen-challenge study. Itching was chosen as the primary efficacy variable since it is the only FDA-approved indication these 2 agents have in common. Subjects with a history of allergic conjunctivitis who responded to the CAC at screening visits 1 and 2 were randomized to 1 of 3 treatment groups: olopatadine in 1 eye and azelastine in the other eye; olopatadine in 1 eye and placebo in the other eye; or azelastine in 1 eye and placebo in the other eye. At the assessment visit (visit 3), subjects received masked study medication according to the randomization scheme. After 5 minutes, subjects were bilaterally challenged with the allergen concentration that had elicited a positive conjunctival allergic response at visits 1 and 2. Immediately after challenge, subjects gave itching assessments (scale, 0 = no itching to 4 = severe itching) every 30 seconds for a total period of 20 minutes. Mean itching scores for all eyes were compared by treatment. Mean itching scores at each time point were compared between treatments using 2 sample t tests. Results: Of the 180 subjects screened, 111 responded to the CAC at visits 1 and 2 and completed the study; 65% (72/111) of patients were female, 87% (97/111) were white, and 49% (54/111) had brown irides. The mean age was approximately 40 years. Seventy-three eyes were treated with olopatadine, 75 with azelastine, and 74 with placebo. A single dose of 1 of the 3 study medications per eye was well tolerated by all subjects. Both treatments were significantly more effective than placebo at reducing itching postchallenge. Olopatadine was significantly more effective than azelastine in reducing itching at 3.5 minutes through 20 minutes postchallenge (average mean unit difference of -0.31; P < 0.05) in the CAC model. In this population, olopatadine was significantly more effective than azelastine in the management of itching associated with allergic conjunctivitis in the CAC model.
 
Article
A double-blind, multicenter study was conducted to evaluate and compare the safety and efficacy of desoximetasone gel 0.05% and fluocinonide gel 0.05% in patients with scalp psoriasis. One hundred twenty-five patients were enrolled in this randomized, parallel-group trial. Responses based on clinical assessment in 123 patients showed that the desoximetasone gel formulation is a safe and effective treatment for psoriasis of the scalp. Although efficacy appears equivalent to that of fluocinonide gel 0.05% in treating psoriasis of the scalp, desoximetasone appears to be slightly better tolerated and better accepted cosmetically.
 
Article
Alclometasone dipropionate 0.05% and hydrocortisone 1.0% ointments were applied twice daily for three weeks to bilateral, paired eczematous lesions of children. Study ointments were assigned to left- and right-sided test sites in a randomized, double-blind manner. The potential of these preparations to induce clinically significant cutaneous atrophy was evaluated in 34 children by visual assessment of the test sites under magnification for telangiectasia. Efficacy was evaluated in 32 children by ratings of the severity of erythema, induration, and pruritus and global evaluations of eczema at the test sites. Safety and efficacy evaluations were performed prior to initial application of the study agents and after each week of treatment. Telangiectasia and other signs of cutaneous atrophy were not observed at any test site during the study, and treatment was well tolerated. Only one of the 34 children experienced an adverse effect: a mild, transient urticarial rash occurring with the application of both study ointments during the first week of the study. In general, the ointments were equally effective in relieving the children's signs and symptoms of eczema. After three weeks of therapy, improvement in the total score of ratings of the severity of signs and symptoms averaged 88% at alclometasone-treated sites and 86% at hydrocortisone-treated sites.
 
Article
When selecting treatment for allergic conjunctivitis, a primary concern is whether to choose local or systemic therapy. This study compared the efficacy of topical emedastine 0.05% ophthalmic solution with that of oral loratadine 10 mg and their combination in the conjunctival allergen challenge model of allergic conjunctivitis. This was a single-center, randomized, double-masked, placebo-controlled, parallel-group study. At visit 1, eligible subjects underwent conjunctival allergen challenge to identify the dose required to elicit a positive allergic reaction. After 7 days, subjects returned for visit 2, at which the allergen dose was confirmed. At visit 3, which took place 2 weeks later, subjects were randomized to receive either emedastine plus placebo capsules, loratadine plus placebo eyedrops, or both emedastine and loratadine. One hour after receiving study drug, subjects were challenged with allergen in both eyes. Allergic signs and symptoms were graded using standardized 5-point scales. The primary efficacy variables were itching and conjunctival hyperemia. Secondary efficacy variables were ciliary and episcleral hyperemia, chemosis, lid swelling, and tearing. Itching was graded subjectively at 3, 5, and 10 minutes after challenge. All other variables were assessed at 5, 10, and 20 minutes after challenge. Eighty subjects (mean age, 43.68 years) were randomized to receive study treatment. Forty subjects (20 men, 20 women) received emedastine plus placebo capsules, 20 (7 men, 13 women) received loratadine plus placebo eyedrops, and 20 (12 men, 8 women) received both active treatments. In the between-group efficacy comparison at visit 3, the difference in itching and hyperemia scores between emedastine and loratadine was statistically significant at all time points (all, P < 0.05). Efficacy scores for the combination of emedastine and loratadine were significantly better than those for loratadine alone at 2 of 3 time points for itching and all time points for hyperemia (P < 0.05). The combination was significantly better than emedastine alone at I of 3 time points for itching and 6 of 9 time points for hyperemia (P < 0.05). In this study, emedastine was more efficacious than loratadine for reducing the itching and redness associated with allergic conjunctivitis in the human conjunctival allergen challenge model.
 
Article
Keratoconjunctivitis sicca is a common eye condition characterized by itchiness, redness, and dryness due to a lack of tear production or abnormalities in the tear film. Cyclosporine works to increase the production of natural tears, which contain nutrients and proteins not found in artificial tears. The purpose of this report was to assess the association between self-reported compliance with topical cyclosporine 0.05% emulsion and the onset of effects of increased tear production in patients with dry eye. Practicing physicians were asked to identify patients for whom treatment with cyclosporine was appropriate and who were willing to participate in the study. Patients who agreed to participate were given medication samples and study materials. The participants were asked to respond to automated survey questions before they used cyclosporine and 30 and 60 days after initiating cyclosporine. Participants were asked how frequently they used the medication, how rapidly their symptoms were relieved, and whether they intended to continue using cyclosporine. Of the 5367 patients initially enrolled in the study, 3145 (59%) patients completed the baseline and 60-day follow-up surveys. The mean age of the participants was 60 years; 2677 (85%) of them were women, and 468 (15%) were men. Compliance with cyclosporine therapy was reported as follows: 2477 (79%) participants said they used cyclosporine twice daily as prescribed by their physicians, 468 (15%) reported missing some doses of cyclosporine, and 189 (6%) reported missing -50% or > or = 50% of the doses. The effects of increased tear production were reported to occur significantly sooner in participants who complied with cyclosporine treatment as prescribed than in those who did not comply with treatment (P < 0.01). Among those who complied with treatment, 1822 (73%) participants reported experiencing the effects of increased tear production in < 5 weeks compared with 468 (70%) participants who did not comply with treatment. Overall, the mean rate of satisfaction with cyclosporine was 7.5 on a scale from 0 (not at all satisfied) to 10 (very satisfied). Participants who reported using cyclosporine twice daily as prescribed gave satisfaction with cyclosporine a mean rating of 7.7 compared with 7.3 given by those who missed some doses and 5.3 from those who missed approximately 50% or > or = 50% of the doses (P < 0.01). An intention to continue using cyclosporine was reported by 2611 (83%) participants. The results of this study in participants using cyclosporine for dry eye in an actual-practice setting suggest an association between patient-reported compliance with medication and more rapid onset of the effects of increased tear production.
 
Article
This study compared the clinical efficacy and safety of the combination agent mometasone furoate 0.1%-salicylic acid 5% ointment with those of the single agent fluocinonide 0.05% ointment, each applied twice daily for 21 days, in the treatment of patients with moderate to severe plaque psoriasis. Forty adult patients were included in this single-center, randomized, double-masked, intraindividual, bilateral-paired comparative trial. Two similar, bilaterally symmetrical target lesions on the trunk, arms, or legs of each patient were selected for treatment and evaluation. One lesion was treated with mometasone furoate 0.1%-salicylic acid 5% ointment, and the other was treated with fluocinonide 0.05% ointment, both twice daily for 21 days. Treatment was randomly assigned to the right or left side of the body. Signs of psoriasis (ie, erythema, induration, and scaling) and overall clinical response were evaluated and scored on days 4, 8, 15, and 22 and compared against baseline. Patients were asked to evaluate the treatments for efficacy and acceptability at each visit. The primary efficacy parameter was the mean percentage of improvement in total sign scores for the target lesions. Safety was evaluated based on clinical observation and patients' reports. Beginning with day 15, statistically significant differences favoring mometasone furoate 0.1%-salicylic acid 5% ointment over fluocinonide 0.05% ointment were seen in individual and total sign scores, as well as in overall global clinical response. On day 15, 20 patients expressed a preference for one treatment over the other, and 20 patients made no distinction between the two. Of those who expressed a preference, significantly more patients believed mometasone furoate 0.1%-salicylic acid 5% ointment to be better than fluocinonide 0.05% ointment. On day 22, of 25 patients who expressed a preference, significantly more patients thought mometasone furoate 0.1%-salicylic acid 5% ointment was better than fluocinonide 0.05% ointment. No adverse events were recorded for either treatment group. The combination mometasone furoate 0.1%-salicylic acid 5% ointment was significantly more efficacious than and equally as safe as fluocinonide 0.05% ointment in the management of patients with plaque psoriasis and was preferred by a greater number of patients.
 
Article
The use of topical corticosteroids has significantly enhanced the treatment of patients with dermatoses such as psoriasis and eczema. In particular, group I high-potency corticosteroids such as clobetasol propionate have proved safe and effective for limited-course treatment of inflammatory and pruritic manifestations of moderate-to-severe corticosteroid-responsive dermatoses. At the same time, much effort has gone into devising more effective strategies for addressing the dry skin conditions associated with various dermatologic disorders. An emollient added to a steroid, although not itself an active ingredient, can help restore the normal moisturizing process of the skin; this may be particularly important in soothing the discomfort of the dry skin conditions often encountered in moderate-to-severe dermatoses. In addition, the degree of epidermal hydration can affect the penetration of steroids into the skin. Therefore, successful outcomes in the treatment of patients with corticosteroid-responsive dermatoses may involve more than use of an effective topical steroid. This article examines a currently available cream formulation of 0.05% clobetasol propionate containing moisturizers--emollients, dimethicone, and a humectant--that may contribute to improved moisture content in treated skin. A review of recent studies shows that clobetasol propionate emollient cream is well tolerated and effective in courses of up to 4 weeks for the treatment of patients with psoriasis or atopic dermatitis.
 
Article
Mast cell stabilizers, such as the ocular antiallergic agent nedocromil sodium 2% ophthalmic solution, are not rapid acting and often require a loading period of > or =2 weeks for maximal efficacy. Olopatadine hydrochloride 0.1% ophthalmic solution is a member of a new class of topical antiallergic agents that have combined antihistaminic and mast cell-stabilizing properties. The purpose of this study was to compare the clinical efficacy and comfort of olopatadine with those of nedocromil in the conjunctival allergen challenge model. This was a single-center, 3-visit, randomized, double-masked, contralaterally controlled study. Seventy-five subjects with a history of allergic conjunctivitis were screened, and the 52 who responded to conjunctival allergen challenge at visits I and 2 were randomized by eye to receive olopatadine, nedocromil, or placebo (a "natural tears" lubricant eye drop). Because nedocromil may require a 2-week loading period for maximal efficacy, the eyes assigned to that agent received nedocromil for 14 days (between visits 2 and 3), whereas the eyes assigned to olopatadine or placebo received placebo during this period. Throughout the loading phase, subjects instilled 1 drop of the assigned masked medication in each eye twice daily. At the assessment visit (visit 3), subjects received I drop of masked olopatadine, nedocromil, or placebo in each eye and were asked to rate the comfort of each drop on a scale from 0 to 8. Fifteen minutes after instillation of medication, subjects were challenged with the allergen concentration that had elicited a positive conjunctival allergic response at the previous visits. Subjects then scored their itching on a scale from 0 to 4 at 3, 5, and 10 minutes after challenge. Mean itching scores for all eyes were compared by treatment. Paired t tests were performed on the mean itching and ocular comfort scores at each time point. At the end of the study, subjects were asked which treatment they preferred in terms of comfort and efficacy. Forty-nine subjects completed the study. Forty eyes received olopatadine, 36 received nedocromil, and 22 received placebo. Olopatadine was clinically and statistically superior to nedocromil at reducing itching in the conjunctival allergen challenge model (mean unit difference: -1.60 at 3 minutes, -1.68 at 5 minutes, -1.19 at 10 minutes; P < 0.001). One drop of olopatadine was more efficacious than 29 drops of nedocromil. Olopatadine-treated eyes were rated as being significantly more comfortable than nedocromil-treated eyes (0.73 vs 1.55; P = 0.034). Of the 14 subjects treated with olopatadine and nedocromil who stated a preference, 10 (71%) were more satisfied with olopatadine than with nedocromil. In the conjunctival allergen challenge model, olopatadine was more efficacious and comfortable than nedocromil in reducing the itching associated with allergic conjunctivitis.
 
Article
Olopatadine hydrochloride 0.1% ophthalmic solution and loteprednol etabonate 0.2% ophthalmic suspension are topical antiallergic agents indicated for treatment of the signs and symptoms of allergic conjunctivitis and seasonal allergic conjunctivitis (SAC), respectively. The purpose of this study was to compare the efficacy and tolerability of olopatadine, loteprednol, and placebo in inhibiting the early-phase allergic reaction (within 30 minutes) after conjunctival allergen challenge (CAC). This was a single-center, randomized, double-masked, parallel-controlled CAC study. It consisted of 3 visits, with CAC performed at visit 1, confirmation and randomization at visit 2, and evaluation of the treatments at visit 3. Subjects with a history of allergic conjunctivitis were randomized to receive olopatadine, loteprednol, or placebo in a 2:2:1 ratio. Because loteprednol requires a loading period to achieve maximum efficacy, subjects assigned to this treatment received loteprednol QID bilaterally for a 14-day period; the olopatadine and placebo groups received placebo QID bilaterally during this period. At the evaluation visit, subjects received 1 drop of the assigned treatment in each eye. Fifteen minutes later, they were challenged with allergen. Subjects evaluated itching at 3, 5, and 10 minutes after challenge using a standardized 5-point scale; the investigator evaluated redness at 10, 15, and 20 minutes after challenge. Intraocular pressure (IOP) was measured at baseline and after the 14-day loading period. Nonparametric analyses were performed on the change from visit 2 to visit 3 in mean itching and redness scores for each time point, and on the change in mean IOP from visit 1 to visit 3. Fifty subjects (86% white; 42% male, 58% female; age range, 21-71 years) were enrolled and completed the study (20 olopatadine, 20 loteprednol, 10 placebo). The allergens to which subjects reacted were ragweed pollen (40%), cat hair or dander (30%), grass pollen (24%), and tree pollen (6%). The difference in inhibition of itching and redness was clinically significant (> or =1 unit difference) and statistically significant (P < 0.05) in favor of olopatadine compared with loteprednol at all 3 time points. The loteprednol group had a statistically significant increase in IOP after 2 weeks of treatment (P < 0.001). In the population studied, olopatadine was more efficacious than loteprednol in reducing the acute signs and symptoms of SAC during the early phase of the ocular allergic reaction and appeared to be better tolerated.
 
Article
Background: The most common form of allergic ocular disease is seasonal allergic conjunctivitis, coinciding with the pollen season and generally associated with rhinitis. Symptoms of allergic conjunctivitis include ocular itching, hyperemia, tearing, mucus production, foreign body sensation, chemosis, and lid edema. Similarly, the primary symptoms of allergic rhinoconjunctivitis are nasal itching, irritation, sneezing, watery rhinorrhea, and congestion combined with ocular itching, tearing, and swelling. Objective: This study compared olopatadine 0.1% ophthalmic solution with placebo eyedrops (over-the-counter artificial tear product), instilled in the eye, with regard to the prevention and relief of the ocular and nasal symptoms of seasonal allergic conjunctivitis and rhinoconjunctivitis. Methods: This was a randomized, double-blind, parallel-group study, conducted at 7 US centers, to instill either olopatadine 0.1% ophthalmic solution or placebo eyedrops (artificial tears) in both eyes twice daily for 10 weeks. Patients were evaluated for efficacy (intent-to-treat) and safety. Only patients with proven grass pollen allergy (dermal and conjunctival allergen challenge tests) were selected; all patients were studied during the same period, historically shown to be grass season; and grass pollen counts were obtained. Results: A total of 131 patients (64 olopatadine; 67 placebo) were assessed for efficacy (intent-to-treat); 132 patients were assessed for safety. The mean (SD) age of participants was 38.53 (11.61) years (range, 18 to 87 years), and 58.0% were women (76/131), with no significant differences between groups for age or sex. In the olopatadine group, 1.6% of patients were black (1/64), compared with 14.9% of the placebo group (10/67) (P = 0.005). Mean scores of ocular itching and hyperemia were lower at all assessment times with olopatadine than placebo. The difference was statistically significant (P < 0.05) for itching on days 7, 14, 35, 63, and 70, and for hyperemia on days 14, 28, 42, and 63, after correction for multiplicity. Linear regression slopes predicting ocular itching and hyperemia from the pollen count were significantly lower (P < 0.003 and P < 0.035, respectively) with olopatadine than with placebo. Similar results were obtained for rhinorrhea, sneezing, and nasal itching (P < 0.006, P < 0.012, and P < 0.034, respectively). With placebo, the proportion of patients with frequent ocular itching and hyperemia increased as a function of pollen level; however, with olopatadine, the proportions remained low and virtually constant. Conclusion: In the population studied, olopatadine 0.1% ophthalmic solution controlled ocular and nasal symptoms of allergic conjunctivitis and rhinocojunctivitis and was well tolerated when administered twice daily for 10 weeks.
 
Article
Topical corticosteroids and keratolytics are both used widely in the management of patients with psoriasis. A combination of the two types of agents may provide enhanced relief. The purpose of this study was to compare the efficacy and safety of the combination ointment mometasone furoate 0.1% plus salicylic acid 5% with that of mometasone furoate 0.1% ointment in the treatment of moderate-to-severe psoriasis vulgaris. A total of 408 patients were enrolled in this controlled, randomized, double-masked, parallel-group, multicenter comparison. Patients applied either mometasone furoate-salicylic acid ointment or mometasone furoate ointment alone to target lesions twice daily for 21 days. Severity of erythema, induration, and scaling were scored at baseline and at days 4, 8, 15, and 22. An evaluation of overall change in disease status of all treated lesions was performed at each follow-up visit. Adverse events were also monitored and scored, including signs of skin atrophy. Beginning on day 8, the combination of mometasone furoate-salicylic acid was significantly more effective than mometasone furoate alone, as indicated by the mean percentage of improvement in total disease scores, mean total disease sign scores, and the individual score for scaling. Similarly, the combination was more effective beginning on day 15, as indicated by the global evaluation of overall clinical response and individual scores for erythema and induration. Both treatments were well tolerated. Mometasone furoate-salicylic acid ointment provides more effective treatment of moderate-to-severe psoriasis than does mometasone furoate ointment alone and is safe and well tolerated.
 
Article
Desquamative gingivitis (DG) is a clinical condition characterized by red, painful, glazed, and friable gingiva, which might be a manifestation of some autoimmune mucocutaneous diseases. The time from the development of initial signs of DG to diagnosis can vary from months to years. Based on a literature search, no data concerning patients with DG without signs of autoimmune disease were available. The aim of this trial was to compare the efficacy and tolerability of monotherapy with topical tacrolimus 0.1% in pectin ointment versus clobetasol propionate 0.5% ointment in adults affected by DG. This randomized, double-blind clinical trial was conducted at the Dipartimento di Medicina Clinica e Sperimentale, Universita di Verona, Verona, Italy. Patients aged > or =18 years were selected using the department's electronic medical records based on a clinical diagnosis of moderate to severe DG. After a 2-week washout period, patients were randomly assigned to receive 2 mL of tacrolimus 0.1% in pectin (equivalent to 0.2 mg of tacrolimus) or 2 mL of clobetasol propionate 0.5% ointment (equivalent to 1 mg of clobetasol) QD for 4 weeks. Evaluations were performed before treatment (baseline), after the treatment period (week 4), and at 2 follow-up visits at weeks 6 and 8. The signs of DG (ie, erythema [atrophy] and desquamation [erosions/ulceration]) were quantified by a blinded investigator using a calculated score based on their surface extension, using a drawing in which the areas of various zones of the mouth were indicated as a percentage of the whole oral mucosa. Severity of erythema and desquamation was rated on a 4-point scale (0 = absent; 1 = involvement of <5% of surface [mild]; 2 = 5%-15% [moderate]; and 3 = >15% [severe]). The primary end point was the number of patients who achieved remission (severity score of 0) in either sign; the secondary end point was the proportions of patients achieving improvement (severity score of 0 or 1) in either sign. Before and after treatment, we measured the serum concentrations of tacrolimus and its metabolites with an immunoenzymatic assay kit. Tolerability was assessed using hematology, biochemistry, urinalysis, measurements of systolic/diastolic blood pressure and heart rate, patient interview, and spontaneous reporting. A total of 24 patients (18 women, 6 men; all white of Italian origin; age range, 21-65 years; 12 patients per treatment group) were enrolled in the study. In the tacrolimus group, 11 (91.7%) patients achieved remission of erythema and/or desquamation at weeks 4 and 6; at week 8, these rates were 9 (75.0%) and 8 (66.7%), respectively; none of the patients in the clobetasol group achieved remission of either sign at any time point (all, P < 0.001). At weeks 4, 6, and 8, significantly greater proportions of patients treated with tacrolimus had improved erythema and desquamation compared with those treated with clobetasol (all, P < 0.001). At week 4, all patients had undetectable serum tacrolimus concentrations (<1.5 microg/L). Six (50.0%) patients in the tacrolimus group reported a mild oral burning sensation, and 6 (50.0%) patients in the clobetasol group reported mild mouth dryness. No other adverse events were reported. The results of this small study suggest that topical tacrolimus 0.1 % in pectin was more effective compared with clobetasol propionate 0.5% ointment in the treatment of DG. Both treatments were generally well tolerated in the population studied.
 
Article
This multicenter, double-masked, placebo-controlled, randomized study evaluated the efficacy, safety, tolerability, and cosmetic acceptability of hydrocortisone buteprate 0.1% cream in the treatment of patients with atopic dermatitis. One hundred ninety-four adults with clinically diagnosed atopic dermatitis were randomized to treatment with hydrocortisone buteprate 0.1% cream or placebo (the cream base of the medication) applied topically once daily for 14 days. Investigators assessed the severity of dermatitis signs on a four-point scale at baseline and on days 3, 7, and 14. Overall improvement was also assessed at each study visit using a seven-point scale. In addition, overall treatment efficacy, tolerability, and cosmetic acceptability of both treatments were evaluated at the last study visit. At each study visit, patients treated with hydrocortisone buteprate showed significant improvement in mean total lesion scores and overall improvement compared with those receiving placebo. Investigators and patients rated hydrocortisone buteprate significantly more effective and significantly more tolerable than placebo at the end of the treatment period. In general, most adverse effects were mild to moderate, with a burning sensation (4% of patients using placebo, 2% of patients using hydrocortisone buteprate) being the most commonly reported. Patients judged both hydrocortisone buteprate and placebo cosmetically acceptable for daily use.
 
Article
Seasonal allergic conjunctivitis (SAC) is caused by seasonal allergens and usually manifests as ocular itching and bulbar conjunctival injection (redness). Treatment options for SAC include corticosteroids and dual-acting antihistamine and mast-cell stabilizers. Our objective was to compare the efficacy and tolerability of loteprednol etabonate (LE), a C-20 ester-based corticosteroid, with those of olopatadine, a dual-acting antihistamine mast-cell stabilizer, in Chinese patients. This was a multicenter, randomized, investigator-masked, parallel group study. Patients with acute SAC experiencing grade 4 ocular itching and grade 2 or higher bulbar conjunctival injection received either LE suspension 0.2% QID at 4-hour intervals or olopatadine solution 0.1% BID at 6- to 8-hour intervals bilaterally for 15 days. Primary efficacy end points included the change from baseline (CFB) in ocular itching and bulbar conjunctival injection at day 15. The primary analysis tested the noninferiority of LE suspension 0.2% to olopatadine solution 0.1%. Tolerability outcomes included the incidence of adverse events (AEs), biomicroscopy findings, visual acuity, and intraocular pressure. A total of 300 patients were randomly assigned, and 293 were included in the per-protocol population (LE, n = 147; olopatadine, n = 146). Mean (SD) CFB at day 15 in the LE and olopatadine treatment groups, respectively, was -3.74 (0.47) and -3.28 (0.91) for ocular itching and -1.91 (0.52) and -1.71 (0.59) for bulbar conjunctival injection. The 95% CI for the differences in CFB in ocular itching (-0.59 to -0.27) and bulbar conjunctival injection (-0.27 to -0.08) was less than the prespecified noninferiority limit of 0.3. Treatment differences in CFB were significantly better with LE compared with olopatadine for both end points (P ≤ 0.0006). Ocular AEs were few and similar between treatment groups. There were no clinically significant biomicroscopy or visual acuity findings, and no patient experienced a clinically significant increase in intraocular pressure (≥10 mm Hg). Results of this investigator-masked study with Chinese patients suggest LE suspension 0.2% was noninferior to olopatadine solution 0.1% for the treatment of SAC. Both LE suspension 0.2% and olopatadine solution 0.1% were well tolerated. ClinicalTrials.gov identifier: NCT01435460.
 
Article
Treatments for allergic conjunctivitis have various mechanisms of action. Cromolyn sodium stabilizes conjunctival mast cells by preventing calcium influx across the cell membrane, whereas olopatadine hydrochloride is both an antihistamine and a mast cell stabilizer. This study compared the efficacy and tolerability of olopatadine and cromolyn in controlling the ocular signs and symptoms of seasonal allergic conjunctivitis. This was a multicenter, randomized, double-masked, parallel-group trial. One group instilled olopatadine 0.1% ophthalmic solution and placebo BID, and the other instilled cromolyn 2% ophthalmic solution QID, both for 6 weeks. The formulation of cromolyn used in this study is currently available only in Europe and Australia. The intent-to-treat efficacy and safety analyses included 185 patients, 91 in the olopatadine group and 94 in the cromolyn group. At 30 minutes after the first instillation, respective decreases of approximately 30% and approximately 20% were reported in self-rated ocular itching and redness with both treatments; by 4 hours, itching had decreased by approximately 38% in both groups. Differences between treatments were not statistically significant. At 4 hours, redness had decreased by approximately 38% and approximately 26% in the respective treatment groups. By day 42, both treatments had produced significant reductions from baseline in ocular signs and symptoms; however, the reductions in itching and redness were significantly greater with olopatadine compared with cromolyn (both variables, P < 0.05). The difference in physicians' impression of overall improvement on days 30 and 42 significantly favored olopatadine over cromolyn (both days, P < 0.05). Most patients (62.2%) had reacted positively to grass pollen at baseline. The regression slopes correlating itching and redness with pollen count were 5 times lower for olopatadine compared with cromolyn (P = 0.002 and P = 0.016, respectively), indicating that olopatadine's efficacy increased as the pollen count increased. Six weeks' instillation of olopatadine 0.19% ophthalmic solution BID had a significantly greater effect on the ocular signs and symptoms of allergic conjunctivitis compared with 6 weeks' instillation of cromolyn 2% ophthalmic solution QID. Both treatments were well tolerated by patients in all age groups; however, olopatadine appeared to have better local tolerability in children aged <11 years.
 
Article
Topical retinoids are one of the most effective classes of topical drugs used to treat acne vulgaris. The effects of the gel formulation of the topical retinoid tazarotene have been widely reported, but few data on the cream formulation are available. The primary aim of the 2 studies reported in this article was to determine the effects of tazarotene 0.1 % cream in patients with facial acne vulgaris. Two randomized, double-blind, parallel-group studies were performed. The first was conducted at 14 investigational sites across the United States, and the second took place at 15 sites, with 5 of these providing blood samples for analysis of tazarotenic acid. In both studies, patients aged > or =12 years with facial acne vulgaris were randomized to receive tazarotene or vehicle cream QD for 12 weeks. Lesion counts (noninflammatory, inflammatory, and total) and overall clinical and global assessments were made at weeks 0 (baseline), 4, 8, and 12. Adverse events (AEs) were monitored throughout the study In one of the studies, therapeutic drug monitoring was performed at weeks 4 and 8 in members of the study population who gave consent for blood withdrawal. Eight hundred forty-seven patients were enrolled in the 2 studies (430 males, 417 females; mean age,19 years; age range, 11-52 years [1 patient was entered into the study at age 11 years, in violation of the protocol]). At 12 weeks, the median percentage changes from baseline in all 3 lesion counts were significantly lower with tazarotene than with vehicle (all, P < 0.001), as were the overall clinical and global responses (both, P < 0.001). Treatment-related AEs whose incidence was higher with tazarotene than with vehicle included desquamation, dry skin, erythema, a burning sensation on the skin, and skin irritation (all, P < 0.001) and pruritus (P < 0.01); most (83%-98%) were mild or moderate. Systemic exposure to tazarotenic acid was limited (mean, <0.1 ng/mL) and did not increase with time. In these 2 studies in adolescent and adult patients with facial acne vulgaris, tazarotene 0.1%cream QD for 12 weeks was effective and well tolerated. Systemic exposure to tazarotenic acid was limited.
 
Article
The alpha-adrenergic agonist brimonidine and the carbonic anhydrase inhibitor dorzolamide have been studied both as monotherapy and in combination with beta-blockers in the treatment of glaucoma and ocular hypertension; however, a MEDLINE literature search failed to reveal any clinical studies directly comparing these 2 agents as adjunctive therapy. The purpose of this study was to compare the intraocular pressure (IOP)-lowering efficacy of brimonidine and dorzolamide as adjunctive therapy to beta-blockers in adult patients with glaucoma or ocular hypertension. In a prospective, investigator-masked, multicenter, parallel-design clinical trial, adult patients whose IOP was inadequately controlled with topical beta-blocker therapy were randomly assigned to receive brimonidine 0.2% twice daily or dorzolamide 2% 3 times daily as adjunctive therapy for 3 months. Efficacy was determined by the reduction in IOP from baseline. After 1 month of adjunctive treatment, patients who failed to meet a target 15% reduction in IOP at peak drug effect were crossed over to the other study medication. A total of 106 patients were treated. Approximately 70% (74/106) of the patients were white, and 61.3% (65/106) had a diagnosis of open-angle glaucoma. Mean baseline IOP (ie, with beta-blocker monotherapy) was comparable between treatment groups (approximately 21 mm Hg). After 1 month of adjunctive treatment, the mean daily IOP reduction was significantly greater with brimonidine (4.40 mm Hg, 20.4%) than with dorzolamide (3.0 mm Hg, 14.4%, P = 0.033). At peak drug effect at month 1, the mean IOP reduction was significantly greater in the brimonidine group (5.95 mm Hg, 27.6%) than in the dorzolamide group (4.11 mm Hg, 19.7%; P = 0.007). Significantly more patients treated with brimonidine (44/51, 86.3%) than with dorzolamide (29/47, 61.7%) achieved the target 15% reduction in IOP at month 1 (P = 0.005). At month 3, the mean daily IOP reduction and the mean IOP reduction at peak drug effect were not significantly different in the 2 treatment groups. The mean daily IOP reduction was 4.98 mm Hg in the brimonidine group and 3.15 mm Hg in the dorzolamide group (P = 0.092). At peak drug effect, the mean IOP reduction was 6.39 mm Hg with brimonidine and 4.06 mm Hg with dorzolamide. The incidence of adverse events leading to discontinuation was 9.3% (5/54) in the brimonidine group (depression, 2; allergic conjunctivitis, 1; dry mouth and tearing, 1; dermatitis, 1) and 9.8% (5/51) in the dorzolamide group (ocular burning and stinging, 2; ocular itch, 1; gastrointestinal complaints, 1; lack of tolerance for beta-blocker, 1), with no significant difference between groups. In this trial, brimonidine 0.2% twice daily produced greater mean decreases in IOP and was effective in more patients than dorzolamide 2% 3 times daily when used as adjunctive therapy to beta-blockers.
 
Article
Brimonidine has been reported to decrease aqueous production and increase uveoscleral outflow; however, the hemodynamic effects of brimonidine are still under investigation. The purpose of this study was to report the acute and chronic effects of brimonidine 0.2% on intraocular pressure (IOP) and pulsatile ocular blood flow (pOBF) in patients with primary open-angle glaucoma (POAG). Nonsmoking patients aged 45 to 67 years with POAG and normal blood pressure, heart rate, body mass index, and hemorheologic parameters were enrolled in the study. Brimonidine 0.2% was self-administered twice daily for 180 days. IOP and pOBF were determined using Goldmann applanation tonometry and the Langham system. All measurements were taken at baseline and 4, 8, and 12 hours after treatment and were repeated on days 7, 15, 30, 60, 90, 120, 150, and 180 of treatment. Of the 18 eligible patients, 10 (6 men and 4 women) were enrolled (mean age, 51.5 +/- 4.39; range, 47-64 years). When measured 12 hours after instillation, mean IOP was significantly reduced by 21.5% (P < 0.001) compared with the baseline value. The greatest decrease in IOP (-23.5%) was observed at 8 hours. After 12 hours, a significant increase (P < 0.001) in pOBF was measured. A stable IOP reduction (P < 0.001 vs baseline), as well as an increase in pOBF (P = 0.015), was recorded at the subsequent time points. The pOBF increases ranged from 22.5% at day 30 to 9.2% at day 180 of treatment. No evidence of adverse events was found at any time point. In this sample of patients with open-angle glaucoma, brimonidine induced a rapid reduction in IOP that was significant even after 6 months. Moreover, an increase in pOBF was observed from the first day of treatment, and remained consistent throughout the study.
 
Article
Brimonidine tartrate 0.2%, a selective alpha2-adrenergic receptor agonist, and betaxolol 0.25% suspension, a cardioselective beta1-adrenergic receptor antagonist, are used in the treatment of elevated intraocular pressure (IOP). This study compared the clinical success and quality-of-life impact of 4 weeks of treatment with brimonidine 0.2% BID compared with those of 4 weeks of treatment with betaxolol 0.25% suspension BID in patients with elevated IOP. This was a multisite, double-masked, comparative clinical trial in patients with glaucoma or ocular hypertension. Patients were randomly assigned to receive either brimonidine or betaxolol BID. Morning IOP was measured at baseline and at weeks 1 and 4 using Goldmann applanation. Efficacy was determined by reduction in IOP from baseline. Patients experiencing a > or =20% reduction in IOP were considered to have a successful IOP-lowering response. The Glaucoma Disability Index questionnaire was administered at week 4 to assess quality-of-life factors and the incidence of adverse events. Ophthalmic examinations were conducted at each visit. One hundred fifty-nine patients were randomized to treatment and completed the study, 81 receiving brimonidine and 78 receiving betaxolol. The majority were white (77.4%) and female (61.6%), and had a diagnosis of open-angle glaucoma (56.0%). After 4 weeks of treatment, both brimonidine and betaxolol effectively lowered IOP from baseline (mean IOP reductions: brimonidine, 5.96 mm Hg; betaxolol, 5.07 mm Hg; P = NS). However, a significantly higher percentage of brimonidine patients (52/81 [64.2%]) than betaxolol patients (37/78 [47.4%]) had a > or =20% reduction in IOP (P = 0.033). No serious adverse events were reported with either study medication. On the quality-of-life assessments, more betaxolol patients reported hyperemia (P = 0.011), and the reported hyperemia was significantly more severe in betaxolol patients (P = 0.009). After 4 weeks of treatment, brimonidine 0.2% BID was clinically successful in significantly more patients and was better tolerated than 4 weeks of treatment with betaxolol 0.25% BID in this population.
 
Article
Evaluations of the comparative efficacy and safety of hydrocortisone valerate 0.2% ointment were made in six double-blind, multicenter trials involving a total of 485 patients, 209 with atopic dermatitis and 276 with plaque psoriasis. The vasoconstrictor activity of hydrocortisone valerate 0.2% ointment was also assessed in normal subjects. Hydrocortisone valerate 0.2% ointment displayed therapeutic effects within three days. In terms of global evaluations of efficacy, hydrocortisone valerate was more effective than vehicle and was comparable to other intermediate or moderate potency corticosteroid ointments. The vasoconstrictor activity of hydrocortisone valerate 0.2% ointment was greater than that of other moderate potency ointments.
 
Article
Previous studies have suggested that olopatadine hydrochloride ophthalmic solution 0.2% administered once daily is effective for up to 24 hours after instillation and is well tolerated in adults and children aged > or =3 years. The goal of this study was to evaluate the efficacy and safety profile of olopatadine 0.2% compared with placebo in patients with seasonal allergic conjunctivitis or rhinoconjunctivitis. This was a 10-week, randomized, placebo-controlled, double-masked environmental study conducted during the spring allergy season (April-August) of 2003. Patients assessed their ocular signs and symptoms in terms of frequency (whole-unit scale from 0 to 5) and severity (half-unit scale from 0 to 4), and grass pollen counts were obtained daily for each investigative site. Responder analyses were conducted by pollen level (frequency based) and pollen period (severity based) to evaluate the clinical significance of differences in ocular itching and redness between treatment groups. Two hundred sixty patients (137 females, 123 males) were enrolled in the study, including 28 children aged between 11 and 17 years; the overall population was 74% white, 11% black, 4% Hispanic, and 11% other. The frequency-based responder analyses of ocular itching and redness showed that when grass pollen counts were high (>20 gr/m(3) air), a respective 21% and 14% of patients in the olopatadine 0.2% group assessed the frequency of ocular itching and redness as >2, compared with 47% and 31% of patients in the placebo group (P < 0.001 for ocular itching; P < 0.003 for redness). The results of the severity-based responder analyses by peak pollen period were consistent with those of the frequency-based analyses. Compared with placebo, olopatadine 0.2% was associated with significant reductions in calculated mean scores for ocular itching and redness by pollen level and by pollen period. No patient was discontinued from the study because of a treatment-related adverse event, and no patient experienced a treatment-related serious adverse event. In the patients studied, olopatadine 0.2% appeared to be effective and well tolerated when administered once daily for the treatment of the ocular signs and symptoms of allergic conjunctivitis or rhinoconjunctivitis.
 
Article
Laryngoscopy and tracheal intubation (LTI) after induction of general anesthesia often cause hypertension and tachycardia. Labetalol and nicardipine have been used to prevent and treat acute cardiovascular responses to LTI. The goal of this study was to compare the preventive and therapeutic effects of labetalol 0.4 mg/kg IV and nicardipine 20 μg/kg IV on hypertensive responses to LTI during induction of general anesthesia. Patients undergoing general anesthesia were randomly allocated to 4 groups. In part I (prevention), 80 patients were randomized to receive either 0.4 mg/kg of labetalol (n = 40) or 20 μg/kg of nicardipine (n = 40) 4 minutes before LTI. In part II (treatment), patients were randomized to receive 0.4 mg/kg of labetalol (n = 40) or 20 μg/kg of nicardipine (n = 40) after LTI if hypertension occurred. The number of additional study drug doses required by patients with hypertension (parts I and II) and time to return to normotension (part II) were recorded. Mean arterial pressure and heart rate were monitored, and rate-pressure product was calculated. Adverse events were also monitored. A total of 130 patients (72 patients in part I and 58 patients in part II) were included in the analysis. In parts I and II, the number of patients who required additional doses of the study drug because of persistent hypertension was lower in the nicardipine groups than in the labetalol groups (P < 0.05). Mean arterial pressure was lower and heart rate was significantly higher over time in the nicardipine groups compared with the labetalol groups (P < 0.05) in parts I and II. In part II, time to return to normotension was shorter in the nicardipine treatment group than in the labetalol treatment group (61 [21] vs 130 [46] seconds; P = 0.01). No statistical differences were observed in the incidence of adverse events except for tachycardia in part I (2 cases in the labetalol prevention group vs 18 cases in the nicardipine prevention group; P = 0.01). Patients who received nicardipine were less likely to require additional doses for either the prevention or treatment of hypertensive responses to LTI and responded to the study drug more rapidly than patients who received labetalol for the treatment of hypertensive responses to LTI. However, labetalol was associated with a lower incidence of tachycardia and less of an increase in rate-pressure product when used for the prevention of hypertension during LTI.
 
Article
This multicenter, double-masked, randomized, parallel study compared the efficacy and safety profile of ketorolac tromethamine 0.5% ophthalmic solution with that of its vehicle in the maintenance of pupillary mydriasis during cataract surgery. A total of 176 adult patients scheduled to undergo unilateral extracapsular cataract extraction and posterior-chamber intraocular lens implantation received either ketorolac tromethamine 0.5% (n = 89) or vehicle (n = 87), starting 2 hours before surgery. One drop of study medication was instilled every 30 minutes for a total of 4 drops. No epinephrine was used in the intraoperative irrigating solution. Pupil diameter was measured with a caliper at 3 time points during surgery. To ensure participant safety, biomicroscopy, ophthalmoscopy, intraocular pressure, adverse events, and preoperative and postoperative visual acuity and refractive error were also monitored. The mean change in horizontal and vertical pupil diameter from the time of the first incision to after cortical irrigation and aspiration was significantly less with active ketorolac than with vehicle (P < or = 0.014). Consequently, mean pupil diameter after cortical irrigation and aspiration was significantly greater with ketorolac than with vehicle (P < or = 0.030). No significant between-group differences were observed in the change in pupil diameter between the end of surgery and postoperative administration of a miotic agent, safety variables, or occurrence of adverse events. In this study, ketorolac tromethamine 0.5% ophthalmic solution provided effective and well-tolerated inhibition of surgically induced miosis during cataract surgery.
 
Article
Effective ocular tissue concentrations and prolonged residence times of antibacterial agents are important in treating both acute and chronic diseases. Conjunctival biopsy allows the determination of specific tissue concentration data for topical ophthalmic agents. Drug concentration analysis at various time points following instillation allows interpretation of the residence time and a rationale for dosing frequency. This study compared the pharmacokinetic parameters of 2 currently available topical ocular antibiotics-azithromycin ophthalmic solution 1% and moxifloxacin ophthalmic solution 0.5%-in the conjunctiva of healthy volunteers after a single topical administration. This single-dose, randomized, open-label, active-controlled clinical trial was conducted at ORA Clinical Research and Development, North Andover, Massachusetts. Subjects were randomly assigned to receive a single dose of azithromycin or moxifloxacin and to undergo biopsy sampling at 30 minutes or 2, 12, or 24 hours after administration. Concentrations of azithromycin and moxifloxacin were determined using liquid chromatography tandem mass spectrometry. Adverse events (AEs) were assessed at all visits using visual acuity measurements, slit-lamp biomicroscopy, and direct questioning. Forty-eight subjects (mean age, 40.0 years; 48% female; 96% white, 2% black, and 2% Asian) underwent conjunctival biopsy. Mean (SD) concentrations of azithromycin in conjunctival tissue (lower limit of quantitation [LLOQ], 1 microg/g for 1-mg biopsy specimen) were 131 (89), 59 (19), 48 (24), and 32 (20) microg/g at 30 minutes and 2, 12, and 24 hours, respectively (median values, 117, 69, 46, and 30 microg/g). Mean concentrations concentrations of moxifloxacin in conjunctival tissue (LLOQ, 0.05 microg/g for 1-mg biopsy sample) were 1.92 (2.03), 3.77 (8.98), 0.02 (0.04), and 0.01 (0.02) microg/g at 30 minutes and 2, 12, and 24 hours, respectively (median values, 1.12, 0.12, <0.05, and <0.05 microg/g). Thirteen subjects (6 in the azithromycin group and 7 in the moxifloxacin group) experienced 20 AEs, 11 of which were considered possibly related to study treatment, and 15 of which were ocular (most commonly conjunctival hemorrhage). In this single-dose study of 2 currently available topical ocular antibiotics in healthy volunteers, therapeutic concentrations were achieved with both agents. Both treatments were well tolerated in the population studied. Clinical Trials Identification Number: NCT00564447.
 
Article
A new 0.5% fluorouracil cream has been developed that provides an alternative to the more highly concentrated topical formulations of fluorouracil that are currently available. This was a comparison of the tolerability and efficacy of the 0.5% and 5% fluorouracil creams in the treatment of actinic keratosis (AK). During this single-blind, randomized study, patients with > or =6 AK lesions were treated for 4 weeks with the 0.5% (once daily) and 5% (twice daily) fluorouracil creams applied to opposite sides of the face. After the end of treatment, patients were followed for an additional 4 weeks. Efficacy variables included absolute and percent reductions in AK lesions from baseline and total clearance of AK lesions. A questionnaire was used to evaluate patients' treatment preferences. Tolerability was evaluated through continuous monitoring of adverse events. Treatment with 0.5% fluorouracil cream reduced the number of AK lesions from 11.3 at baseline to 2.5 at the end of the 4-week follow-up phase, compared with a reduction from 10.3 to 4.2 lesions after treatment with 5% fluorouracil cream. The reduction was significantly greater with the 0.5% cream compared with the 5% cream (P = 0.044). The 0.5% cream was as effective as the 5% cream in terms of the percent reduction in AK lesions from baseline (67% and 47%, respectively) and in achieving total clearance of AK lesions (both treatments, approximately 43% of patients). Both treatments were associated with similar degrees of investigator-rated irritation; however, patients preferred the 0.5% cream because they felt it was more tolerable (P = 0.003), easier to apply, and had a once-daily application schedule. Although all patients experienced facial irritation in association with both creams, fewer patients treated with the 0.5% cream reported symptoms of facial irritation. In this study, 0.5% fluorouracil cream once daily was at least as effective as 5% fluorouracil cream twice daily in terms of the percent reduction in AK lesions and total clearance of AK lesions; it was more effective than the 5% cream in reducing the absolute number of AK lesions from baseline. Patients preferred the 0.5% cream to the 5% cream.
 
Article
Topical fluorouracil has proven efficacy in the treatment of actinic keratosis. The systemic absorption of various topical formulations of fluorouracil varies, however, and may be affected by the concentration and delivery system used. This study compared the flux and percutaneous absorption of 3H-labeled fluorouracil from three 0.5% fluorouracil formulations incorporated into a porous microsphere delivery system with those from a commercially available 5% fluorouracil formulation. Penetration of all formulations through the skin was sampled every 3 hours for 24 hours using full-thickness human cadaver skin samples mounted in a Bronaugh flow-through diffusion cell apparatus. Total absorption was defined as the sum of the amount of cumulative flux through the skin over 24 hours and the amount retained in the skin at 24 hours. The flux through the skin of the 5% fluorouracil formulation was 20 to 40 times greater (normalized, 2-4 times greater) than that of the 0.5% fluorouracil formulations. A higher percentage of absorbed fluorouracil was retained in the skin after 24 hours with the 0.5% formulations (86%-92%) than with the 5% formulation (54%). These findings suggest that the 0.5% formulations are associated with less flux through the skin than the 5% formulation and, therefore, potentially less systemic exposure.
 
Article
The aim of this study was to compare symptoms and anterior segment tolerability with short-term (3-day) administration of once-daily timolol hemihydrate 0.5%, timolol maleate in sorbate 0.5%, and generic timolol maleate gel-forming solution 0.5% in the treatment of glaucoma and/or ocular hypertension. In this prospective, randomized, double-masked, active-controlled, 3-period crossover pilot study, eligible patients had primary open-angle, pigment-dispersion, or exfoliation glaucoma, and/or ocular hypertension in > or = 1 eye; had a best corrected visual acuity of 1.0 or better in each eye, as measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity testing chart; were receiving 1 glaucoma medication; and had an untreated intraocular pressure (IOP) of < or = 28 mm Hg in both eyes after washout (if required) at visit 2 (day 0). Patients were assigned to receive, in randomized order, timolol hemihydrate 0.5%, timolol in sorbate 0.5%, or generic timolol gel-forming solution 0.5%, 1 drop each morning (approximately 8 am) in the qualified eye(s) (washout IOP < or = 28 mm Hg) for 3 days. Each treatment period was separated by a 7-day washout period. At all baseline and end-of-treatment study visits, patients completed a solicited symptom survey (used for the assessment of stinging or burning [grade 0 = none to 4 = severe] and blurred or dimmed vision [grade 0 = none to 4 = severe], among other parameters) and underwent ETDRS, Goldmann applanation tonometry, slit-lamp biomicroscopy, anterior segment staining (corneal, conjunctival nasal, and conjunctival temporal staining), conjunctival hyperemia assessment, measurement of tear breakup time, and Schirmer's testing with anesthesia. At end-of-treatment assessments, patients were questioned about adverse events. Thirty patients were enrolled (15 men, 15 women; mean [SD] age, 66.3 [8.9] years; white, 19 patients, black, 11; primary open-angle glaucoma, 17; ocular hypertension, 13). Mean (SD) stinging or burning grade was significantly greater with timolol in sorbate compared with timolol hemihydrate and timolol gel-forming solution (0.9 [0.9] vs 0.4 [0.6] and 0.2 [0.6], respectively; P < 0.001). The between-treatment differences on anterior segment staining, conjunctival hyperemia, tear breakup time, and Schirmer's testing with anesthesia were not significant, with the exception of the change from baseline in conjunctival nasal staining by count, which was significantly higher with timolol gel-forming solution compared with timolol hemihydrate and timolol in sorbate (3.1 [13.4] vs -2.9 [10.1] and -3.0 [8.0], respectively; P = 0.04). On the solicited symptom survey, timolol gel-forming solution was associated with a poorer mean score on blurred or dimmed vision compared with timolol hemihydrate and timolol in sorbate (0.3 [0.7] vs 0.1 [0.3] and 0.0 [0.2], respectively; P = 0.02). Mean best corrected ETDRS visual acuity immediately after instillation was significantly lower with timolol gel-forming solution compared with timolol hemihydrate and timolol in sorbate (49.6 [8.4] vs 53.0 [6.1] and 53.1 [6.7], respectively; P = 0.007). The mean 24-hour trough IOP did not differ significantly between the 3 treatments. In this pilot study that compared the symptoms and tolerability of once-daily timolol hemihydrate 0.5%, timolol in sorbate 0.5%, and timolol gel-forming solution 0.5% in these patients with glaucoma and/or ocular hypertension, short-term (3-day) administration of timolol in sorbate was associated with more stinging or burning compared with timolol hemihydrate and timolol gel-forming solution. Timolol gel-forming solution was associated with more postinstillation blurred or dimmed vision compared with timolol hemihydrate and timolol in sorbate.
 
Article
Based on the potential risks of post-menopausal hormone therapy (HT) found by the Women's Health Initiative, guidelines for HT now recommend use of the lowest effective dose and shortest treatment duration consistent with individual treatment goals. Current (2003) guidance established by the US Food and Drug Administration (FDA) recommends that clinical assessments of HT include women with more frequent and more intense vasomotor symptoms than previously studied. Therefore, this analysis was conducted to further assess the efficacy of a low-dose combination of norethindrone acetate and ethinyl estradiol (NA/EE) previously assessed in dose-ranging studies, while meeting conservative FDA trial design and analysis criteria. The aim of this post hoc analysis and overview was to present data on the efficacy and tolerability of a low-dose combination-NA/EE 0.5 mg/2.5 microg-in the treatment of postmenopausal symptoms, based on data from previously published studies of NA/EE. In addition, the effects of low-dose NA/EE on bone and endometrium are briefly reviewed. Data from 3 previously published randomized, placebo-controlled trials were analyzed using current FDA guidance for the assessment of HT in postmenopausal women. Studies 1 and 2 assessed the efficacy of NA/EE at various doses, including 0.5 mg/2.5 microg, in vasomotor symptom (hot-flush [HF]) relief over 16 and 12 weeks, respectively, using self-reporting of symptom frequency and intensity (scores: 0=none; 1=mild; 2=moderate; and 3=severe) in daily diaries. Study 3 assessed the effects of NA/EE at various doses, including 0.5 mg/2.5 microg, on bone and endometrium, using quantitative computed tomography of the lumbar spine at 12 and 24 months and endometrial biopsy at 6, 12, 18, and 24 months of treatment. In all 3 studies, women were asked to record vaginal bleeding and spotting in diaries. Any adverse events were recorded in diaries and/or at clinic visits. Physical and gynecologic examinations and standard clinical laboratory testing were conducted at baseline and at appropriate follow-up visits in all 3 studies. Studies 1, 2, and 3 enrolled 219, 266, and 1265 women, respectively. Overall, in studies 1 and 2, 91% of women were white, the mean age was approximately 52 years, and mean time since last menstrual period was approximately 24 months. In study 1, NA/EE 0.5 mg/2.5 microg was associated with significant reductions from baseline in mean weekly total HF frequency from week 4 (63.6%) through week 16 (73.7%) (all, P<0.05). In study 2, the frequency of moderate or severe HFs was decreased by 61.1% at week 4 (P<0.05) and by 82.2% at week 12 (P<0.001) with NA/EE 0.5 mg/2.5 microg, and the mean intensity score was significantly lower than that with placebo at weeks 8 and 12 (both, P=0.001). In study 3, cumulative amenorrhea rates were approximately 90% in the NA/EE 0.5-mg/2.5-microg and placebo groups at 12 months. Lumbar spine bone mineral density (BMD) was maintained at 24 months with NA/EE 0.5 mg/2.5 microg but was significantly decreased from baseline, by 7.4%, in the placebo group (P<0.001). Endometrial hyperplasia was not observed in the group receiving NA/EE 0.5 mg/2.5 microg over 24 months. The tolerability of NA/EE was similar to that of placebo. The most common adverse events experienced with NA/EE were headache (15.2%), abdominal pain (10.2%), and breast pain (9.0%). The results from this post hoc analysis and overview of 3 previously published studies suggest that NA/EE 0.5 mg/2.5 microg was associated with decreased frequency and intensity of vasomotor symptoms. This dose of NA/EE was also associated with maintenance of BMD over 24 months, a significant positive effect on BMD compared with placebo. Low-dose NA/EE was also associated with cumulative amenorrhea rates comparable to those of placebo and was not associated with endometrial hyperplasia. This dose was well tolerated, with rates of adverse events generally similar to those of placebo.
 
Article
We compared the efficacy of timolol maleate ophthalmic gel-forming solution 0.5% QD with that of levobunolol hydrochloride 0.5% BID, as measured by change in intraocular pressure (IOP), effect on heart rate, and ocular tolerability. The study had a positive-controlled, double-masked, randomized, multicenter, 12-week, two-period (6 weeks each), crossover design. One hundred fifty-two patients with open-angle glaucoma or ocular hypertension were randomized to receive either timolol maleate gel-forming solution QD or levobunolol BID for 6 weeks, followed by a crossover to the alternate treatment. IOP and heart rate were measured at morning trough and peak during weeks 3, 6, 9, and 12. Timolol maleate gel-forming solution QD was comparable to levobunolol BID in reducing IOP at peak and trough. Although the effects on peak heart rate were similar between the two medications, the effect on trough heart rate of timolol maleate gel-forming solution QD was significantly less than that of levobunolol BID (P = 0.001). The incidence of ocular burning and stinging was comparable between the two treatments. Patients experienced significantly more blurred vision when using timolol maleate gel-forming solution than when using levobunolol (P = 0.013). Overall, more patients experienced at least one adverse event when using timolol maleate gel-forming solution. Timolol maleate gel-forming solution QD is as efficacious in reducing IOP as levobunolol BID.
 
Article
This study assessed the long-term effects of dorzolamide 2% BID added to timolol maleate 0.5% BID on intraocular pressure (IOP), retrobulbar blood flow, and the progression of visual field damage in patients with primary open-angle glaucoma. This was a prospective, 4-year, open-label intervention study. All consecutive patients with a clinical diagnosis of open-angle glaucoma in both eyes (mean defect greater than -6 dB) who presented for a regular check-up between January and July 2001 at the Instituto Galego de Oftalmoloxía were screened for study eligibility. All participants had been treated with timolol 0.5% BID in both eyes for at least 6 months before the screening visit. Dorzolamide 2% BID was added to timolol 0.5% BID in the eye with the larger visual field defect (study eye), whereas timolol 0.5% BID was continued in the eye with the smaller visual field defect (control eye). Variables evaluated at baseline and every 6 months for 48 months included retrobulbar hemodynamic parameters (using color Doppler imaging), progression of visual field damage, and IOP. Progression of visual field damage was defined according to modified Anderson criteria. Visual field progression-free survival rates for the study and control eyes were plotted using Kaplan-Meier analysis and were compared using a log-rank test. Forty-five patients met the inclusion criteria, of whom 5 were lost to follow-up. Thus, 80 eyes of 40 patients were included in the analysis. Patients' mean (SD) age was 68.0 (7.1) years; all patients were white and 21 (52.5%) were male. Mean baseline IOP was 19.18 (1.34) and 18.23 (1.64) mm Hg in the study and control eyes, respectively (P=0.006). The combination of dorzolamide and timolol was associated with significant increases from baseline in enddiastolic velocity in the ophthalmic and short posterior ciliary arteries (P<0.001) and significant decreases in the resistivity index in both arteries (P<0.001). Twenty-three of the 80 eyes (28.8%) had progression of visual field damage (7 study eyes and 16 control eyes). On Kaplan-Meier survival analysis, the risk of progression was significantly lower in the eye treated with dorzolamide and timolol compared with the eye treated with timolol alone (hazard ratio=0.41; 95% CI, 0.17 to 0.94; P=0.035). Mean changes in IOP from baseline to month 48 were -1.10 mm Hg in the dorzolamide and timolol group (95% CI, -1.73 to -0.51; P<0.001) and 1.27 mm Hg in the control group (95% CI, -2.74 to 1.72; P=NS). In this 4-year, open-label study in patients with primary open-angle glaucoma, dorzolamide 2% BID added to timolol 0.5% BID was associated with a significant reduction in IOP and significant increases in retrobulbar hemodynamic parameters in both the ophthalmic and short posterior ciliary arteries. Dorzolamide added to timolol may be effective in preventing progression of glaucomatous visual field damage.
 
Article
Systemic absorption of topical fluorouracil, although usually low, may vary as a result of the specific skin disease, product formulation, and other factors. The present study was conducted to determine the pharmacokinetic profile and tolerability of a new topical 0.5% fluorouracil cream formulation compared with that of a currently available topical formulation of 5% fluorouracil cream. This was an open-label, parallel-group study in which patients with actinic keratosis (AK) were randomized to treatment with either topical 0.5% fluorouracil once daily or topical 5% fluorouracil twice daily for up to 28 days. Twenty-one patients (all white; mean age, 64 years) participated in the study, 11 receiving topical 0.5% fluorouracil and 10 receiving topical 5% fluorouracil. Ten patients receiving 0.5% fluorouracil and 7 patients receiving 5% fluorouracil completed the 28-day study. Plasma concentrations of fluorouracil were detectable in 3 of 10 patients treated with 0.5% fluorouracil and 9 of 10 patients treated with 5% fluorouracil; fluorouracil was detected in the urine of 5 and 9 patients, respectively. Despite the one-tenth difference in drug concentration between formulations, the cumulative amount excreted in the urine of the 0.5% fluorouracil group was approximately one fortieth that of the 5% fluorouracil group. This difference may be a result of variations in vehicle formulations. At least 1 adverse event was reported by 4 of 11 patients in the 0.5% fluorouracil group and all 10 patients in the 5% fluorouracil group. The most common adverse event, facial irritation, was evident with both formulations but reached a plateau during treatment with 0.5% fluorouracil. All patients treated with 0.5% fluorouracil tolerated the full course of therapy, whereas 3 patients in the 5% fluorouracil group discontinued treatment early. No serious treatment-related adverse events were reported. These data suggest that 0.5% fluorouracil has minimal systemic absorption and is well tolerated in patients with AK.
 
Article
A multicenter, parallel-design, randomized, double-masked study was conducted to compare the efficacy and safety of 2% dorzolamide with those of 0.5% betaxolol in the treatment of elevated intraocular pressure (i.o.p). A total of 311 adults with ocular hypertension or open-angle glaucoma were randomly allocated to receive either 2% dorzolamide administered topically TID or 0.5% betaxolol administered topically BID plus placebo administered topically QD for 12 weeks. After the washout of previous ocular hypotensive drugs, patients with IOP > or = 23 mm Hg in at least one eye at 10 AM or 4 PM on study day 1 were randomly allocated to receive one of the study treatments. Throughout the study, IOP was measured 2 and 8 hours after instillation of study medication for the morning peak effect (hour 2) and afternoon trough effect (hour 8). After 12 weeks of therapy, the mean change in IOP was not significantly different between the dorzolamide and betaxolol treatment groups at hour 8 (-3.6 mm Hg in both groups) or hour 2 (-5.4 vs -5.3 mm Hg, respectively). The differences between treatments (and 95% CIs associated with these differences) in mean IOP changes from baseline were 0.02 mm Hg (-0.870 to 0.901) for hour 8 and -0.14 mm Hg (-0.959 to 0.685) for hour 2. The ocular adverse experience (AE) most frequently reported by patients was ocular burning and/or stinging, and the most frequently reported nonocular AEs were taste perversion, upper respiratory infection, and headache. Only the incidence of taste perversion was significantly different between treatment groups (14.6% for the dorzolamide group and 0.0% for the betaxolol group). Two percent of patients in each treatment group discontinued the study due to AEs. This study confirmed the similar IOP-lowering effect of 2% dorzolamide and 0.5% betaxolol. Both treatments were generally well tolerated, and their safety profiles were similar.
 
Article
Several fluorinated carboxyquinolones are used to treat ocular infectious disease. Levofloxacin, in particular, has demonstrated activity against both gram-negative and gram-positive bacteria. An open-label study was undertaken to assess the pharmacokinetics and ocular bioavailability of levofloxacin in human tears, and to determine the tear concentration of levofloxacin in healthy volunteers, following topical administration of a single-dose of 0.5% levofloxacin ophthalmic solution. Volunteers received 1 drop of 0.5% levofloxacin in each eye and were assigned sequentially to 1 of 5 groups for tear sampling. Tear samples were collected on Schirmer test strips at 9 predetermined time points ranging from 5 minutes to 24 hours after administration. Six tear samples were collected at each time point (1 eye each from 6 volunteers), except the 24-hour time point, at which 12 samples were collected (both eyes of 6 volunteers). No eye had > 1 tear sample taken during the study. Levofloxacin concentrations were measured using reverse-phase high-performance liquid chromatography. Thirty volunteers were enrolled, with 6 assigned to each of the 5 sampling groups. At 5 minutes after administration of a single topical dose of levofloxacin, the mean tear concentration was 49.19 +/- 26.73 microg/mL. The mean peak concentration of levofloxacin in the tear film, 221.06 +/- 256.68 microg/mL, was reached at 15 minutes after administration. At 4 hours after administration, the mean tear concentration of levofloxacin was 17.04 +/- 15.13 microg/mL. At 6 hours after administration, the mean concentration of levofloxacin was 6.57 +/- 5.26 microg/mL. At 24 hours after administration, levofloxacin concentrations > 2 microg/mL were measured in 2 of 6 (33%) subjects. Levofloxacin concentrations in the tear fluid after a single topical dose (1 drop) reached high levels quickly and remained above the minimum inhibitory concentration for most suspected ophthalmic pathogens (< or = 2 microg/mL) for at least 6 hours in most healthy volunteers, and for up to 24 hours in some volunteers.
 
Article
Etizolam is an anxiolytic drug with a pharmacologic profile similar to that of the classic benzodiazepines. Neurochemical research suggests that etizolam may have selectivity for the subpopulation of Y-aminobutyric acid type A receptors associated with anxiety (ie, alpha1, beta2, gamma2). This property, plus its characterization as a ligand with fewer of the adverse events typical of full agonists (impaired cognitive function, tolerance, and dependence), led to its selection for this study. The primary aim of this study was to test for the noninferiority of etizolam 0.5 mg BID versus placebo in affecting cognitive function in patients with mild to moderate anxiety disorder of recent onset (<1 month). Anxiety measures and tolerability were also assessed. Patients between the ages of 18 and 65 years were eligible for enrollment. This double-blind, placebo-controlled study was performed in 5 centers in Italy using a 2-treatment, 3-period crossover design. Patients were randomized to 3-week sequences of either etizolam-placebo-placebo or placebo-etizolam-etizolam. They were evaluated at 4 scheduled visits (screening and days 7, 14, and 21). Cognitive function was assessed using scores from the Wechsler Adult Intelligence Scale (WAIS) Digit Span test (total forward and backward scores and the time required to perform the test). Anxiety was measured using the Hamilton Anxiety Rating Scale (HAM-A) and the State-Trait Anxiety Inventory (STAI) for screening and to monitor adequacy of therapy. Blood pressure, heart rate, weight, and adverse events were also recorded. A total of 77 white patients were enrolled (mean age, 33.3 years [range, 22-60 years]; 62.3% female; mean weight, 65.2 kg). With a power of 0.80, the difference between the effects of etizolam and placebo on WAIS Digit Span performance was not significant for total score (0.102 [90% CI, -0.130 to 0.335]) or time required for completion (0.029 second [90% CI, -0.574 to 0.632]). Anxiety, as measured using the HAM-A and STAI instruments, did not differ significantly between groups. No significant differences were found between etizolam 0.5 mg BID and placebo for cardiovascular events, weight changes, or adverse events. Mild or moderate somnolence was reported by 7 of 77 patients (9.1% [3 patients while receiving etizolam and 4 patients while receiving etizolam and placebo]). No significant differences between etizolam 0.5 mg BID and placebo were found for cognitive function or anxiety measures in these patients with anxiety. Etizolam was well tolerated.
 
Article
Besifloxacin ophthalmic suspension 0.6% is a new topical fluoroquinolone for the treatment of bacterial conjunctivitis. Besifloxacin has potent in vitro activity against a broad spectrum of ocular pathogens, including drug-resistant strains. The primary objective of this study was to compare the clinical and microbiologic efficacy of besifloxacin ophthalmic suspension 0.6% with that of vehicle (the formulation without besifloxacin) in the treatment of bacterial conjunctivitis. This was a multicenter, prospective, randomized, double-masked, vehicle-controlled, parallel-group study in patients with acute bacterial conjunctivitis. Patients received either topical besifloxacin ophthalmic suspension or vehicle administered 3 times daily for 5 days. At study entry and on days 4 and 8 (visits 2 and 3), a clinical assessment of ocular signs and symptoms was performed in both eyes, as well as pinhole visual acuity testing, biomicroscopy, and culture of the infected eye(s). An ophthalmoscopic examination was performed at study entry and on day 8. The primary efficacy outcome measures were clinical resolution and eradication of the baseline bacterial infection on day 8 in culture-confirmed patients. The safety evaluation included adverse events, changes in visual acuity, and biomicroscopy and ophthalmoscopy findings in all patients who received at least 1 dose of active treatment or vehicle. The safety population consisted of 269 patients (mean [SD] age, 34.2 [22.3] years; 60.2% female; 82.5% white) with acute bacterial conjunctivitis. The culture-confirmed intent-to-treat population consisted of 118 patients (60 besifloxacin ophthalmic suspension, 58 vehicle). Significantly more patients receiving besifloxacin ophthalmic suspension than vehicle had clinical resolution of the baseline infection at visit 3 (44/60 [73.3%] vs 25/58 [43.1%], respectively; P < 0.001). Rates of bacterial eradication also were significantly greater with besifloxacin ophthalmic suspension compared with vehicle at visit 3 (53/60 [88.3%] vs35/58 [60.3%]; P < 0.001). The cumulative frequency of adverse events did not differ significantly between the 2 groups (69/137 [50.4%] and 70/132 [53.0%]). The most common ocular adverse events were eye pain (20/190 treated eyes [10.5%] and 13/188 [6.9%]), blurred vision (20/190 [10.5%] and 22/188 [11.7%]), and eye irritation (14/190 [7.4%] and 23/188 [12.2%]); these events were of mild or moderate severity. Changes in visual acuity and treatment-emergent events observed on biomicroscopy and direct ophthalmoscopy also were comparable between treatment groups. Besifloxacin ophthalmic suspension 0.6% given 3 times daily for 5 days was both efficacious and well tolerated compared with vehicle in the treatment of these patients with bacterial conjunctivitis. ClinicalTrials.gov Identifier: NCT00622908.
 
Top-cited authors
Ami J Claxton
  • DaVita Clinical Research
Joyce A Cramer
  • Yale University
Rajesh Balkrishnan
  • University of Virginia
Thomas Ray Einarson
  • University of Toronto
Kevin Farmer
  • University of Oklahoma Health Sciences Center