Weeks Of Once-daily Treatment Research Articles

The effect of spironolactone versus eplerenone on blood pressure targets in resistant hypertension patients

Abstract Objective to evaluate different effects on blood pressure (BP) control in two treatment options spironolactone (SPIR) versus eplerenone (EPL) as an add-on therapy in resistant hypertensive (RAH) patients. Design and methods: We studied 208 patients with true RAH confirmed by the office and ambulatory BP monitoring (ABPM) despite the use of 3 antihypertensive medications including a calcium channel blocker, a blocker of the renin-angiotensin system, and a thiazide diuretic with maximally tolerated doses for at least 3 months. Patients were randomized into 2 groups throughout 12 weeks of once-daily treatment with SPIR (25–50 mg) or EPL (25-50 mg) in addition to their baseline triple-combination and then rotated with drugs. BP was measured in the office and by ABPM. Changes in laboratory tests were also studied. The predictive values of plasma aldosterone, active renin concentration (ARC), aldosterone-renin ratio (ARR), and serum potassium were analyzed to determine the antihypertensive response. Results There were no significant differences in the reduction of average office BP, average systolic 24-h, daytime, and nighttime BP by SPIR and EPL. SPIR reduced average diastolic 24-h BP by 7.3 mm Hg, diastolic daytime BP by 7.2 mm Hg, and diastolic nighttime BP by 7.5 mm Hg compared with a reduction of 5.6 mm Hg (P = 0.01), 5.6 mm Hg (P = 0.03) and 4.2 mm Hg (P = 0.0001) with EPL, respectively. Overall, 40.7 % RAH patients achieved targets of clinical BP and 24-h ABPM levels on SPIR and 33.3 % on EPL (Р = 0.002). After 12 weeks of treatment mean plasma potassium concentrations increased by 7.1 (P = 0.0001) on SPIR and by 5.0 % (Р = 0.0001) on EPL, but eGFR did not significantly change on the two drugs. Plasma aldosterone (β = 0.498, Р = 0.02) and ARC (β= -0.374, Р = 0.04) were predictors of the BP-lowering effect of SPIR and plasma aldosterone (β = 0.453, Р = 0.04) was a predictor of reduction BP for EPL in multivariate modeling. Breast pain or tenderness, changes in sex drive, and irregular menstrual cycles or spotting were more often by SPIR than by EPL (5.2 % vs 1.9 %, respectively, P = 0.04). Conclusions The greater antihypertensive effect of SPIR is related to aldosterone status, ARS level in resistant hypertension. EPL may be recommended for RAH patients who have high serum potassium levels that cannot tolerate spironolactone and for people with systolic resistant hypertension.

Clindamycin Phosphate 1.2%/Adapalene 0.15%/Benzoyl Peroxide 3.1% Gel for Male and Female Acne: Phase 3 Analysis.

Clindamycin phosphate 1.2%/adapalene 0.15%/benzoyl peroxide 3.1% gel (CAB) is the only fixed-dose triple-combination treatment approved for acne. This post hoc analysis assessed the impact of sex on efficacy and safety/tolerability of CAB. In two multicenter, double-blind, phase 3 studies (NCT04214639 and NCT04214652), participants aged ≥9 years with moderate-to-severe acne were randomized (2:1) to 12 weeks of once-daily treatment with CAB or vehicle gel. Pooled data were analyzed by sex. Assessments included treatment success (≥2-grade reduction from baseline in Evaluator’s Global Severity Score and a score of 0 [clear] or 1 [almost clear]), inflammatory/noninflammatory lesion counts, Acne-Specific Quality of Life (Acne-QoL) questionnaire, treatment-emergent adverse events (TEAEs), and cutaneous safety/tolerability. At week 12, treatment success rates were significantly greater with CAB versus vehicle irrespective of sex (females: 53.7% vs 23.0%; males: 43.1% vs 24.6%; P<0.05, both). CAB-treated female and male participants both experienced greater reductions from baseline versus vehicle in inflammatory (females: 77.7% vs 57.9%; males: 77.5% vs 57.1%; P<0.001, both) and noninflammatory lesions (females: 72.5% vs 45.6%; males: 72.3% vs 49.6%; P<0.001, both). Acne-QoL improvements from baseline to week 12 were significantly greater with CAB than vehicle. No significant differences in any efficacy measures between CAB-treated males and females were observed. Most TEAEs were of mild-to-moderate severity; no sex-based trends for safety/tolerability were observed. CAB demonstrated comparable efficacy, quality-of-life improvements, and safety in female and male participants with moderate-to-severe acne. As the first fixed-dose, triple-combination topical formulation, CAB represents an important new treatment for acne. J Drugs Dermatol. 2024;23(10):873-881. doi:10.36849/JDD.8484.

Triple-Combination Clindamycin Phosphate 1.2%/Adapalene 0.15%/Benzoyl Peroxide 3.1% Gel for Acne in Adult and Pediatric Participants.

Topical clindamycin phosphate 1.2%/adapalene 0.15%/benzoyl peroxide 3.1% gel (CAB) is the first fixed-dose triple-combination approved for the treatment of acne. This post hoc analysis investigated the efficacy and safety of CAB in pediatric (<18 years) and adult (greater than or equal to 18 years) participants. In two multicenter, double-blind, phase 3 studies (NCT04214639 and NCT04214652), participants greater than or equal to 9 years of age with moderate-to-severe acne were randomized (2:1) to 12 weeks of once-daily treatment with CAB or vehicle gel. Pooled data were analyzed for pediatric and adult subpopulations. Assessments included treatment success (greater than or equal to 2-grade reduction from baseline in Evaluator's Global Severity Score and a score of 0 [clear] or 1 [almost clear], inflammatory/noninflammatory lesion counts, Acne-Specific Quality of Life (Acne-QoL) questionnaire, treatment-emergent adverse events (TEAEs), and cutaneous safety/tolerability. At week 12, treatment success rates for both pediatric and adult participants were significantly greater with CAB (52.7%; 45.9%) than with vehicle (24.0%; 23.5%; P<0.01, both). CAB-treated participants in both subgroups experienced greater reductions from baseline versus vehicle in inflammatory (pediatric: 78.6% vs 50.4%; adult: 76.6% vs 62.8%; P<0.001, both) and noninflammatory lesions (pediatric: 73.8% vs 41.1%; adult: 70.7% vs 52.2%; P<0.001, both). Acne-QoL improvements from baseline to week 12 were significantly greater with CAB than with a vehicle. Most TEAEs were of mild-to-moderate severity; no age-related trends for safety/tolerability were observed.  Conclusions: CAB gel demonstrated comparable efficacy, quality of life improvements, and safety in pediatric and adult participants with moderate-to-severe acne. As the first fixed-dose, triple-combination topical formulation, CAB represents an important new treatment option for patients with acne. J Drugs Dermatol. 2024;23(6):394-402.     doi:10.36849/JDD.8357.

Topical Treatments for Photoaged Skin.

Photoaging due to cumulative lifetime ultraviolet light exposure is the greatest contributing factor to facial aging. With the continued growth of the population of individuals aged ≥65 years and over, demand for safe and effective photoaging treatments will likely increase. This qualitative review provides an overview of efficacy and safety of over-the-counter (OTC) and prescription topical treatments for photoaging, including recent data from an investigator-initiated trial of the topical retinoid tazarotene. OTC and cosmeceutical products comprise the majority of treatment options for photoaging, although clinical data in support of their efficacy are generally lacking. Topical retinoids have been shown to increase collagen and elastic fibers and normalize melanocytes and keratinocytes, yielding improvements in wrinkling, texture, elasticity, and skin tone. Prescription topical retinoids (adapalene, tazarotene, tretinoin) are the most studied and efficacious treatments for photoaging, though their use is typically associated with adverse effects such as erythema, peeling, dryness, and burning/stinging in a concentration-dependent manner. In a 12-week, open-label study, lower-dose tazarotene 0.045% lotion led to significantly reduced signs and severity of photoaging vs baseline. Prescription topical retinoids are the most potent treatment option for photoaging, though their use may be limited by irritation concerns. Tazarotene 0.045% polymeric emulsion lotion has recently demonstrated significant photoaging improvements with 12 weeks of once-daily treatment, with a favorable safety and tolerability profile. Sadick N, Pannu S, Abidi Z, et al. Topical treatments for photoaged skin. J Drugs Dermatol. 2023;22(9):867-873. doi:10.36849/JDD.7753.

Safety of Tazarotene 0.045% Lotion and Hyperpigmentation Improvements in Black Participants With Moderate-to-Severe Acne

Introduction: Post-inflammatory hyperpigmentation (PIH) that results from acne in patients with skin of color may be more distressing than the acne itself, and likely impacts patients with higher skin phototypes more greatly than those with lower skin phototypes. Topical retinoids, a mainstay of acne treatment, can also reduce hyperpigmentation. For example, significant PIH improvements with a cream formulation of the retinoid tazarotene (0.1%) were observed following 16 weeks of treatment in patients with acne. However, skin irritation and other skin reactions may limit use of some tazarotene gel and cream formulations. A hydrating, lower-dose tazarotene 0.045% lotion formulation utilizes polymeric emulsion technology to allow for more efficient delivery of tazarotene into dermal layers while reducing potential for skin irritation. This pooled, post hoc analysis evaluates safety of tazarotene 0.045% lotion and its effect on hyperpigmentation in Black individuals with acne.
 Methods: In two identical phase 3 randomized, double-blind, vehicle-controlled, studies (NCT03168321; NCT03168334), participants aged ≥9 years with moderate-to-severe acne (Evaluator's Global Severity Score of 3/4) were randomized (1:1) to once-daily tazarotene 0.045% or vehicle lotion for 12 weeks. Safety evaluations included adverse events (AEs) reports and investigator-assessed hyperpigmentation (4-point scale: 0 [none] to 3 [severe]). Post hoc analyses were based on participants’ self-identification of race, including ‘Black or African American’ (herein referred to as Black).
 Results: Of 1,614 participants randomized in the two phase 3 studies, 262 (16%) self-identified as Black. The safety population comprised 253 Black participants. The most common TEAEs with tazarotene 0.045% lotion were at the application site: pain (6.6%), exfoliation (5.0%), and dryness (3.3%). No Black participants reported application site irritation or dermatitis with tazarotene lotion. Hyperpigmentation rates in Black participants, which were high at baseline, decreased by week 12 with tazarotene treatment (40.5% to 31.4%) compared to vehicle (37.9% to 37.2%).
 Conclusions: Acne regimens that maximize efficacy while mitigating irritation is key to managing acne in patients with skin of color, given the higher pigmentary alteration risk in melanin-rich skin. Tazarotene 0.045% lotion was safe and well tolerated in Black participants, with no application-site irritation or dermatitis after 12 weeks of once-daily treatment. Tazarotene also led to improvements in hyperpigmentation, an inflammation-associated sequala of acne. As PIH can take longer than 12 weeks to resolve with treatment, additional improvements in hyperpigmentation may be expected with continued tazarotene 0.045% lotion use.
 Support: Ortho Dermatologics.

Once-Daily Valbenazine Is Effective for Tardive Dyskinesia in Elderly Patients (>=65 Years)

<h3>Introduction</h3> Valbenazine is a selective and potent vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of tardive dyskinesia (TD), a persistent and potentially disabling movement disorder associated with prolonged exposure to antipsychotics or other dopamine-receptor blocking agents (DRBAs). Valbenazine is the only approved TD medication with once-daily dosing and no requirements or cautions for dosing based on age. Older adults (≥55 years) have an increased risk for TD after a shorter duration of treatment with DRBAs, and previous analyses have shown that valbenazine is effective and well tolerated in this population (Sajatovic et al, Int J Geriatr Psychiatry 2020). The current presentation includes findings from the first analyses to evaluate the effects of an approved TD medication in an elderly population, using the more conventional age cutoff of ≥65 years. <h3>Methods</h3> Data from two long-term studies (KINECT 3-extension, KINECT 4) of participants receiving up to 48 weeks of once-daily treatment with valbenazine (40 mg or 80 mg) were pooled and analyzed by age (≥65 and <65 years). Analyses included mean change from baseline (CFB) to Week 48 in Abnormal Involuntary Movement Scale (AIMS) total score. AIMS response at Week 48 was also assessed as follows: clinically meaningful response (≥30% improvement from baseline); protocol-defined response (≥50% improvement from baseline). Additional analyses included response thresholds for Clinical Global Improvement-Tardive Dyskinesia (CGI-TD) and Patient Global Impression of Change (PGIC) as follows: rating of "minimally improved" or better (score ≤3) at Week 48 (CGI-TD≤3, PGIC≤3); rating of "much improved" or "very much improved" (score ≤2) at Week 48 (CGI-TD≤2, PGIC≤2). Treatment-emergent adverse events (TEAEs) were also monitored. <h3>Results</h3> Treatment outcomes were generally robust and comparable between the age subgroups. Pooled AIMS results indicated substantial improvements in TD movements were found in both age subgroups with valbenazine 40 mg (≥65 years, n=8; <65 years, n=46) and 80 mg (≥65 years, n=20; <65 years, n=105): mean CFB (≥65 years, -6.4 and -9.8 [for 40 and 80 mg, respectively]; <65 years, -5.5 and -8.3); clinically meaningful ≥30% response (≥65 years, 75% and 95%; <65 years, 61% and 80%); and protocol-defined ≥50% response (≥65 years, 75% and 85%; <65 years, 50% and 70%). CGI-TD and PGIC response rates indicated that clinician- and patient-reported global improvements were also substantial in both age subgroups: CGI-TD≤3 (≥65 years, 88% and 100% [for 40 and 80 mg, respectively]; <65 years, 89% and 97%); CGI-TD≤2 (≥65 years, 88% and 95%; <65 years, 62% and 83%); PGIC≤3 (≥65 years, 88% and 100%; <65 years, 89% and 94%); PGIC≤2 (≥65 years, 75% and 90%; <65 years, 77% and 80%). Analyses of TEAEs indicated no statistically significant differences between age subgroups for the incidence of any TEAEs (≥65 years, 73%; <65 years, 72%) or any serious TEAEs (≥65 years, 18%; <65 years, 17%). However, discontinuations due to TEAEs were significantly more common in elderly participants (≥65 years, 26%; <65 years, 13%; <i>P</i><0.05). <h3>Conclusions</h3> These analyses, which are the first to evaluate any approved TD medication in patients ≥65 years, indicate that long-term treatment with once-daily valbenazine is appropriate and beneficial for this age group. Elderly study participants had clinically meaningful and substantial improvements in TD that were comparable to (or better than) those in the younger cohort. These results may provide clinicians with important information about the management of TD in elderly patients. <h3>This research was funded by</h3> Neurocrine Biosciences, Inc.

Long-term inflammatory rosacea management with subantibiotic dose oral doxycycline 40 mg modified-release capsules once daily.

An important goal of effective rosacea treatment is to maximize the duration of remission. This was a two‐part study. Part 1 was a multicenter, open‐label, 12‐week study in which adults with moderate or severe inflammatory lesions (papules and pustules) of rosacea received subantibiotic dose oral doxycycline 40 mg modified release (SDD40) and topical metronidazole gel 1%. Part 2 was a multicenter, randomized, double‐blind, placebo‐controlled, 40‐week study in which successfully treated subjects received once‐daily SDD40 or placebo capsules. The primary objective was to assess relapse and efficacy during long‐term use of SDD40 versus placebo. Relapse was defined as a return to baseline investigator global assessment (IGA) or lesion count, or any other necessary change in treatment. Part 1 enrolled 235 subjects. Sixty‐five subjects in the SDD40 treatment group and 65 subjects in the placebo group met the definition of treatment success at week 12, and were included in the Part 2 analysis. At the end of Part 2, half as many subjects in the SDD40 group had relapsed compared to the placebo group (13.8% [n = 9] vs. 27.7% [n = 18], p < 0.05). Significant differences in the median change in inflammatory lesion counts were also observed (p < 0.05). Adverse events (AEs) were generally mild–moderate in severity, and most were not treatment‐related. Stinging/burning responded with more improvement in subjects treated with SDD40. After 52 weeks of once‐daily treatment, subantibiotic dose doxycycline significantly reduced the relapse rate and inflammatory lesion counts in subjects with moderate‐to‐severe inflammatory rosacea.

EFFECTS OF LONG-TERM VALBENAZINE IN KINECT 4: POST HOC RESPONSE AND SHIFT ANALYSES IN YOUNGER AND OLDER ADULTS WITH TARDIVE DYSKINESIA

Introduction Tardive dyskinesia (TD) is a persistent and potentially disabling movement disorder associated with prolonged antipsychotic exposure. Compared to younger patients, older patients have a higher risk of TD and may develop symptoms earlier during antipsychotic treatment. Valbenazine, a novel and highly selective vesicular monoamine transporter 2 (VMAT2) inhibitor, is approved to treat TD in adults of all ages, with no dose adjustment required for older patients. The long-term effects of valbenazine on TD were evaluated in KINECT 4 (NCT02405091), an open-label study in which participants received up to 48 weeks of once-daily treatment with valbenazine. Abnormal Involuntary Movement Scale (AIMS) data from this study were analyzed post hoc to evaluate treatment responses in older (≥55 to 85 years) and younger (18 to Methods KINECT 4 included participants who met the following criteria: ages 18 to 85 years; DSM-IV diagnosis of schizophrenia, schizoaffective disorder, or mood disorder; neuroleptic-induced TD for ≥3 months prior to screening; stable psychiatric status (Brief Psychiatric Rating Scale score Results Of 163 participants in the safety/efficacy population, 103 (63.2%) had an available AIMS assessment at Week 48. At Week 48, the percentages of patients who met the criteria for minimal response (≥10% AIMS total score improvement from baseline) or clinically meaningful (≥30% improvement) response were similar between the older and younger subgroups (≥55 years; Conclusions After 48 weeks of treatment with once-daily valbenazine, >95% of all KINECT 4 participants (older and younger) had a minimal AIMS total score response (≥10% improvement), >90% had a clinically meaningful response (≥30% improvement), and >80% had a robust response (≥50% improvement). Older patients seemed more likely than younger patients to achieve a maximal response, including 100% improvement, although these results may be limited by smaller sample sizes. Shift analyses based on AIMS item scores were supportive of AIMS total score responses. Together, the results presented in this post hoc analysis suggest that valbenazine is an appropriate long-term treatment for both older and younger adults with TD. This research was funded by: This study was sponsored by Neurocrine Biosciences, Inc.

Ledipasvir/sofosbuvir fixed‐dose combination tablet in Taiwanese patients with chronic genotype 1 hepatitis C virus

Pegylated-interferon-alpha plus ribavirin is the current standard-of-care regimen for treating chronic hepatitis C virus (HCV) infection in Taiwan; however, interferon-based regimens can be poorly tolerated. The interferon-free, two-drug, fixed-dose combination tablet ledipasvir/sofosbuvir is approved in Europe, the USA, and Japan for treating chronic genotype 1 HCV infection. Little is known about its efficacy/safety in Taiwanese patients. In this multicenter, open-label, phase 3b (NCT02021656) study, 85 Taiwanese patients (n = 42, treatment-naïve; n = 43, treatment-experienced) with chronic genotype 1 HCV infection (±compensated cirrhosis) received 12 weeks of ledipasvir/sofosbuvir fixed-dose combination tablet. The primary efficacy end point was the proportion of patients with sustained virologic response 12 weeks after treatment discontinuation (SVR12). Safety and pharmacokinetic data were collected. The overall SVR12 rate was 98% (83/85), with 100% (42/42) and 95% (41/43) of treatment-naïve and treatment-experienced patients, respectively, achieving SVR12. There were no on-treatment virologic failures. One patient relapsed after treatment discontinuation; one patient withdrew consent on day 2. The most common treatment-emergent adverse event (AE) was headache (14%, 12/85). There was one grade 3 AE (small cell lung cancer unrelated to ledipasvir/sofosbuvir), no grade 4 AEs, and four grade 3-4 laboratory abnormalities. Only the patient with small cell lung cancer prematurely discontinued treatment. Two patients reported three serious AEs; none was considered related to ledipasvir/sofosbuvir. Data from this phase 3b study suggest that 12 weeks of once-daily treatment with the interferon-free, ribavirin-free regimen ledipasvir/sofosbuvir is effective and well-tolerated in Taiwanese patients with chronic genotype 1 HCV infection, irrespective of treatment history.

Comparison of the Lipid-Lowering Effects of Pitavastatin 4 mg Versus Pravastatin 40 mg in Adults With Primary Hyperlipidemia or Mixed (Combined) Dyslipidemia: A Phase IV, Prospective, US, Multicenter, Randomized, Double-blind, Superiority Trial

PurposeResults from a Phase III, European, noninferiority trial in elderly (age ≥65 years) patients with primary hyperlipidemia or mixed (combined) dyslipidemia demonstrated significantly greater reductions in LDL-C for pitavastatin versus pravastatin across 3 pair-wise dose comparisons (1 mg vs 10 mg, 2 mg vs 20 mg, and 4 mg vs 40 mg, respectively). The present study investigated whether pitavastatin 4 mg is superior to pravastatin 40 mg in LDL-C reduction in adults (18–80 years old) with primary hyperlipidemia or mixed (combined) dyslipidemia. MethodsThis was a Phase IV, multicenter, randomized, double-blind, double-dummy, active-control superiority study conducted in the United States. Patients with baseline LDL-C levels of 130 to 220 mg/dL (inclusive) and triglyceride levels ≤400 mg/dL after a 6-week washout/dietary stabilization period were randomized to 12 weeks of once-daily treatment with either pitavastatin 4 mg or pravastatin 40 mg. FindingsA total of 328 subjects (164 per treatment arm) were randomized (mean age, 57.9 years [76% were aged <65 years]; 49.4% women; mean body mass index, 30.2 kg/m2) to treatment. The median percent change in LDL-C from baseline to the week 12 endpoint was –38.1% for pitavastatin 4 mg and –26.4% for pravastatin 40 mg; the difference in median percent change between treatments was –12.5% (P < 0.001). Differences between treatments in median percent reductions from baseline for apolipoprotein B, total cholesterol, and non–HDL-C were also significant in favor of pitavastatin (P < 0.001). Both treatments significantly (P < 0.001) increased HDL-C and decreased triglycerides, but the differences between treatments were not statistically significant. The overall rate of treatment-emergent adverse events was 47.6% (78 of 164) for pitavastatin and 44.5% (73 of 164) for pravastatin. Myalgia was reported by 3 patients (1.8%) in the pitavastatin group and by 4 patients (2.4%) in the pravastatin group. There were no reports of myositis or rhabdomyolysis. ImplicationsPitavastatin 4 mg demonstrated superior LDL-C reductions compared with pravastatin 40 mg after 12 weeks of therapy in adults with primary hyperlipidemia or mixed (combined) dyslipidemia. There were no new safety findings in the trial. Clinical Trials.gov identifier: NCT01256476.

Safety and efficacy of once-daily treatment with beclomethasone dipropionate nasal aerosol in subjects with perennial allergic rhinitis

Intranasal corticosteroids are recommended as first-line therapy for the treatment of the symptoms of persistent allergic rhinitis (AR). Since the phase-out of chlorofluorocarbon nasal aerosols, intranasal corticosteroids have been available only as aqueous nasal sprays. This study was designed to assess the efficacy, safety, and quality-of-life benefits of beclomethasone dipropionate (BDP) hydrofluoroalkane nasal aerosol in subjects with perennial AR (PAR). After a 7- to 21-day placebo run-in period, eligible subjects aged ≥12 years with PAR were randomized to 6 weeks of once-daily treatment with BDP nasal aerosol at 320 μg or placebo. Reflective and instantaneous total nasal symptom scores (rTNSS and iTNSS, respectively), Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) score, and physician-assessed total nasal symptom score were evaluated. The primary end point was change from baseline in average morning (A.M.) and evening (P.M.) subject-reported rTNSS over the 6-week treatment period. Safety and tolerability were also assessed. Treatment with BDP nasal aerosol showed significantly greater improvement in average A.M. and P.M. rTNSS compared with placebo (mean treatment difference, -0.84; 95% confidence interval, -1.2, -0.5; p < 0.001). Greater improvements in rTNSS were reported as early as day 1 and were maintained throughout the 6-week treatment period with the exception of day 2. Greater improvements were seen for all four individual nasal symptoms (nasal congestion, nasal itching, rhinorrhea, and sneezing) with BDP nasal aerosol compared with placebo. Similarly, significant improvements were seen in average A.M. and P.M. iTNSS (p < 0.001) and RQLQ score (p = 0.001) with BDP nasal aerosol compared with placebo. In addition, BDP nasal aerosol treatment was well tolerated, and its safety profile was comparable to that of placebo. This clinical study indicated that treatment with BDP nasal aerosol provides statistically significant and clinically meaningful nasal symptom relief accompanied by improved quality of life in subjects with PAR. Additionally, treatment with BDP nasal aerosol was well tolerated with a safety profile comparable to that of placebo. This study was part of the clinical trial NCT01134705 registered in www.ClinicalTrials.gov.

A Double-Blind, Placebo-Controlled, Crossover Trial Comparing the Effects of Amiloride and Hydrochlorothiazide on Glucose Tolerance in Patients With Essential Hypertension

Hypertension guidelines advise limiting the dose of thiazide diuretics and avoiding combination with β-blockade, because of increased risk of diabetes mellitus. We tested whether changes in the 2-hour oral glucose tolerance test could be detected after 4 weeks of treatment with a thiazide and could be avoided by switching to amiloride. Two double-blind, placebo-controlled, crossover studies were performed. In study 1 (41 patients), we found that changes in glucose during a 2-hour oral glucose tolerance test could be detected after 4 weeks of treatment with bendroflumethiazide. In study 2, 37 patients with essential hypertension received, in random order, 4 weeks of once-daily treatment with hydrochlorothiazide (HCTZ) 25 to 50 mg, nebivolol 5 to 10 mg, combination (HCTZ 25-50 mg+nebivolol 5-10 mg), amiloride (10-20 mg), and placebo. Each drug was force titrated at 2 weeks and separated by a 4-week placebo washout. At each visit, we recorded blood pressure and performed a 75-g oral glucose tolerance test. Primary outcome was the difference in glucose (over the 2 hours of the oral glucose tolerance test) between 0 and 4 weeks, when HCTZ and amiloride were compared by repeated-measures analysis. For similar blood pressure reductions, there were opposite changes in glucose between the 2 diuretics (P<0.0001). Nebivolol did not impair glucose tolerance, either alone or in combination. There was a negative correlation between Δpotassium and Δ2-hour glucose (r=-0.28; P<0.0001). In 2 crossover studies, 4 weeks of treatment with a thiazide diuretic impaired glucose tolerance. No impairment was seen with K(+)-sparing diuretic or β(1)-selective blockade. Substitution or addition of amiloride may be the solution to preventing thiazide-induced diabetes mellitus.

Treatment of seborrhoeic dermatitis of the scalp with a topical solution of urea, lactic acid, and propylene glycol (K301): results of two double‐blind, randomised, placebo‐controlled studies

Alternative treatments for seborrhoeic dermatitis are needed because of the increasing risk of anti-fungal resistance to existing therapies. To investigate the efficacy, safety and tolerability of topical scalp treatment with K301 solution. Two multi-centre, randomised, double-blind studies were conducted. Study I: 4 weeks of once-daily treatment with either one form of K301 (a or b) or placebo, followed by 4 weeks of maintenance treatment three times-per-week. Study II: 4 weeks of K301 (a) or placebo once-daily. Study I: 98 patients enrolled (K301a + b, n = 51; placebo, n = 47) and 83 completed; 201 entered Study II (K301a, n = 136; placebo, n = 65) and 195 completed. Erythema and desquamation sum score at 4 weeks, mean (SD) values were 2.4 (2.0) for K301a + b and 3.2 (2.2) for placebo in Study I (P = 0.025) and 2.5 (1.9) for K301a and 3.2 (1.8) for placebo in Study II (not significant). In both studies, 4-week desquamation scores were significantly improved for K301 vs. placebo (P < 0.05). Both studies showed significant improvements in symptomatic investigator and patient assessments for K301 over placebo after 4 weeks (P < 0.05). Treatment-related adverse events were generally mild and included some smarting or burning upon application. The K301 was well tolerated and associated with clinically meaningful improvements in seborrhoeic dermatitis endpoints.

The Efficacy and Safety of Valsartan in Obese and Non-Obese Pediatric Hypertensive Patients

This post hoc analysis assessed the efficacy and tolerability of valsartan for the treatment of hypertension in obese vs non-obese children and adolescents. After a 1-week antihypertensive washout period, 142 obese and 119 non-obese hypertensive children and adolescents aged 6 to 16 years were randomized to 2 weeks of once-daily treatment with valsartan 10 to 20 mg, 40 to 80 mg, or 80 to 160 mg, followed by re-randomization to either valsartan or placebo for an additional 2 weeks. Patients could continue to receive valsartan during an optional 52-week, open-label extension. Valsartan resulted in statistically significant (P<.05) and clinically relevant reductions in mean sitting blood pressure (BP), ranging from approximately 7/4 mm Hg (valsartan 10-20 mg) to 13/9 mm Hg (valsartan 80-160 mg) in both obese and non-obese patients. BP control was achieved in 44% of obese and 56% of non-obese patients. Following re-randomization, non-obese patients experienced an increase in BP during placebo treatment, albeit levels remained below baseline, whereas BP reductions were maintained in valsartan recipients (P<.05). The most frequent adverse events during the open-label phase were headache and fever. Valsartan provides similar antihypertensive efficacy in obese and non-obese hypertensive children and adolescents, with good tolerability in both patient populations.

P01-186 Effectiveness of the new extended-release formulation of quetiapine as monotherapy for the treatment of acute bipolar depression (trial D144CC00002)

Objectives:To evaluate the effectiveness of extended-release quetiapine fumarate (quetiapine XR) as once-daily monotherapy for bipolar depression.Method:Patients in this double-blind, placebo-controlled study were acutely depressed adults with bipolar I or II disorder (with or without rapid cycling), and were randomized to 8 weeks of once-daily treatment with quetiapine XR 300 mg (n=133) or placebo (n=137). The primary outcome measure was change from baseline to endpoint (Week 8) in Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Secondary outcome measures included response (MADRS total score reduction ≥50%) and remission (MADRS total score ≤12) rates at endpoint, changes from baseline to endpoint in MADRS item scores, and Clinical Global Impressions-Bipolar (CGI-BP) severity of illness and change. Change from baseline was compared between groups with analysis of covariance using last observation carried forward approach.Results:Quetiapine XR 300 mg/d was significantly more effective than placebo in improving depressive symptoms, from first assessment (Week 1; P&lt; 0.001) to endpoint (P&lt; 0.001). Compared with placebo, quetiapine XR was associated with higher response (P&lt; 0.001) and remission (P&lt; 0.05) rates and greater improvements from baseline to endpoint in MADRS total score (-17.43 vs -11.92; P&lt; 0.001), MADRS item scores for core symptoms of depression, and CGI-BP-related outcomes at Week 8. Most common adverse events with quetiapine XR were dry mouth, somnolence, and sedation.Conclusions:Quetiapine XR (300 mg) once-daily monotherapy was efficacious (from Weeks 1 through 8) compared with placebo and generally well tolerated in bipolar depression.Supported by funding from AstraZeneca Pharmaceuticals LP.

Durable islet effects on insulin secretion and protein kinase A expression following exendin-4 treatment of high-fat diet-fed mice

Glucagon-like peptide 1 (GLP-1) augments glucose-stimulated insulin secretion (GSIS) through cAMP-induced activation of protein kinase A (PKA), and stimulates beta-cell proliferation and reduces beta-cell apoptosis in rodent islets. This study explored islet GSIS, PKA expression, and markers of apoptosis (caspase 3/7 activity) and proliferation (PKBalpha and pancreatic and duodenal homeobox gene 1, Pdx-1) after 2 weeks of treatment with the GLP-1 receptor agonist exendin-4 (2 nmol/kg once daily) in female mice with high-fat diet-induced insulin resistance (HFD; 58% fat by energy). Islets were isolated 20 h after the last exendin-4 injection, when effects of circulating exendin-4 had vanished. The glucose responsiveness in islets from HFD-fed mice at 8.3 mM glucose was reduced compared with islets from control mice fed a normal diet due to increased basal insulin secretion. However, GSIS increased in islets from HFD-fed exendin-4-treated animals (0.124+/-0.012 ng/h per islet in HFD-Ex-4 versus 0.062+/-0.010 in HFD, P=0.006). Furthermore, the insulin response to forskolin was increased (2.7+/-0.3 in HFD-Ex-4 versus 2.0+/-0.2 ng/h per islet in HFD, P=0.011) and PKAcat expression was increased, while PKAreg was reduced in islets from exendin-4-treated mice. In contrast, protein expression of PKBalpha, Pdx-1, and caspase 3/7 activity was not affected by exendin-4 treatment. We conclude that GLP-1 receptor activation in HFD-fed mice has durable effects on GSIS, in association with augmented signaling through the PKA pathway. These effects are seen beyond those induced by circulating exendin-4 already after 2 weeks of once-daily treatment in mice, whereas markers for islet proliferation and apoptosis were unaffected by this treatment.

Antiviral Effect of Oral Administration of Tenofovir Disoproxil Fumarate in Woodchucks with Chronic Woodchuck Hepatitis Virus Infection

Tenofovir disoproxil fumarate (TDF) is a nucleotide analogue approved for treatment of human immunodeficiency virus (HIV) infection. TDF also has been shown in vitro to inhibit replication of wild-type hepatitis B virus (HBV) and lamivudine-resistant HBV mutants and to inhibit lamivudine-resistant HBV in patients and HBV in patients coinfected with the HIV. Data on the in vivo efficacy of TDF against wild-type virus in non-HIV-coinfected or lamivudine-naïve chronic HBV-infected patients are lacking in the published literature. The antiviral effect of oral administration of TDF against chronic woodchuck hepatitis virus (WHV) infection, an established and predictive animal model for antiviral therapy, was evaluated in a placebo-controlled, dose-ranging study (doses, 0.5 to 15.0 mg/kg of body weight/day). Four weeks of once-daily treatment with TDF doses of 0.5, 1.5, or 5.0 mg/kg/day reduced serum WHV viremia significantly (0.2 to 1.5 log reduction from pretreatment level). No effects on the levels of anti-WHV core and anti-WHV surface antibodies in serum or on the concentrations of WHV RNA or WHV antigens in the liver of treated woodchucks were observed. Individual TDF-treated woodchucks demonstrated transient declines in WHV surface antigen serum antigenemia and, characteristically, these woodchucks also had transient declines in serum WHV viremia, intrahepatic WHV replication, and hepatic expression of WHV antigens. No evidence of toxicity was observed in any of the TDF-treated woodchucks. Following drug withdrawal there was prompt recrudescence of WHV viremia to pretreatment levels. It was concluded that oral administration of TDF for 4 weeks was safe and effective in the woodchuck model of chronic HBV infection.

Comparative efficacy and tolerability of two long-acting calcium antagonists, mibefradil and amlodipine, in essential hypertension

In a previous forced-titration trial, mibefradil 100 mg QD was as effective as amlodipine 10 mg QD in reducing sitting diastolic blood pressure (SDBP), and it produced significantly less leg edema than did amlodipine 10 mg QD. The present multicenter, double-masked, randomized, parallel-design trial was performed to assess the reproducibility of these results using a flexible-titration design. Following a 4-week, single-masked, placebo run-in period, 296 patients with a trough SDBP of between 95 and 114 mm Hg (21 to 27 hours postdose) were randomized to receive once-daily treatment with mibefradil 50 mg (n = 146) or amlodipine 5 mg (n = 150). In patients whose trough SDBP was greater than 90 mm Hg after 4 or 8 weeks of double-masked therapy, the dosage was titrated upward to mibefradil 100 mg or amlodipine 10 mg for the remainder of the 12-week active treatment period. A greater proportion of amlodipine-treated patients (65%) than of mibefradil-treated patients (54%) required titration to the higher dose. Despite this difference, statistically equivalent reductions in trough SDBP were observed after 12 weeks of treatment with 50 to 100 mg of mibefradil QD (−11.7 ± 6.4 mm Hg) and 5 to 10 mg of amlodipine QD (−11.9 ± 6.9 mm Hg). SDBP was normalized to ≤90 mm Hg at week 12 in 66% of patients treated with mibefradil and 65% of those receiving amlodipine. The tolerability profile of mibefradil was superior to that of amlodipine, with significantly fewer patients ( P = 0.009) reporting leg edema after mibefradil treatment (7%) than after amlodipine treatment (17%). The results of this study confirm those of the previous trial. Once-daily treatment with mibefradil 50 to 100 mg for 12 weeks was as effective as 12 weeks of once-daily treatment with amlodipine 5 to 10 mg in reducing SDBP and was associated with a significantly lower incidence of leg edema.

Sustained improvement in photodamaged skin with reduced tretinoin emollient cream treatment regimen: Effect of once-weekly and three-times-weekly applications

Background: Previous studies have documented reversal of long-term photodamage with once-daily applications of topical tretinoin. Objective: Our purpose was to assess the effectiveness of tretinoin emollient cream in maintaining improvement in photodamage with a reduced frequency of applications. Methods: A total of 126 subjects who completed 48 weeks of once-daily treatment with tretinoin emollient cream 0.05% were enrolled for an additional 24 weeks of tretinoin once weekly, three times weekly, or no therapy. Results: The clinical improvement observed during 48 weeks of once-daily treatment was sustained with three-times weekly applications and to a lesser extent with once-weekly dosing, whereas effects tended to regress in subjects off therapy. The overall incidence of adverse events in the skin and subcutaneous tissues appeared to vary with dose frequency. Conclusion: After 48 weeks of once-daily treatment, the continued use of tretinoin emollient cream 0.05% at a dose of three times per week maintains and, in some cases, may further enhance improvement in photodamage. Discontinuation of therapy results in some reversal of beneficial effects. (J Am Acad Dermatol 1997;37:227-30.)

Double-Blind Comparison of the Efficacy and Tolerability of Simvastatin and Fluvastatin in Patients with Primary Hypercholesterolaemia.

The clinical efficacy and tolerability of simvastatin and fluvastatin were compared in 432 patients with primary hypercholesterolaemia in a multinational, randomised, double-blind trial. Following at least 10 weeks on a lipid-lowering diet, patients continuing to have a total cholesterol level ≥ 6.5 mmol/L and elevated low density lipoprotein (LDL) cholesterol levels received 6 weeks of once-daily treatment with either simvastatin 5mg (n = 109), simvastatin 10mg (n =110), fluvastatin 20mg (n = 105), or fluvastatin 40mg (n = 108). The relative potency rates of simvastatin to fluvastatin in reducing LDL and total cholesterol levels were estimated to be 7.60 and 7.65, respectively. Significantly greater mean reductions in LDL cholesterol levels were found at week 6 with simvastatin 10mg (30%) compared with either fluvastatin 20mg (22%; p < 0.001) or fluvastatin 40mg (26%; p = 0.03). Similarly, LDL cholesterol was lowered more in the simvastatin 5mg group (26%) than in the fluvastatin 20mg group (22%; p = 0.03). No significant difference was seen between simvastatin 5mg and fluvastatin 40mg. Plasma total cholesterol levels were also significantly lower with simvastatin 10mg compared with fluvastatin 20mg (23 vs 16%; p < 0.001) and fluvastatin 40mg (23 vs 19%; p = 0.02), and with simvastatin 5mg compared with fluvastatin 20mg (19 vs 16%; p = 0.01). Simvastatin 5mg and fluvastatin 40mg both lowered total cholesterol levels by 19%. The percentage of patients reaching National Cholesterol Education Program Adult Treatment Panel II (NCEP ATP II) target LDL cholesterol levels after 6 weeks' treatment with simvastatin 5 or 10 mg/day or fluvastatin 20 or 40 mg/day was 24, 25, 12 and 21%, respectively. Tolerability profiles were generally similar, although significantly more gastrointestinal adverse events occurred in the fluvastatin-treated patients (23 vs 11%). In conclusion, simvastatin 10 mg/day is more effective in lowering total and LDL cholesterol levels than the maximum recommended dose of fluvastatin (40 mg/day), whereas simvastatin 5 mg/day and fluvastatin 40 mg/day showed similar efficacy.