Once-daily Combination Therapy Research Articles

Calcipotriol Used as Monotherapy or Combination Therapy with Betamethasone Dipropionate in the Treatment of Nail Psoriasis

Nail psoriasis is estimated to affect 80–90% of psoriatic patients at some point in their lives (1). Psoriatic patients with more severe nail disease tend to have a worse skin condition, a higher rate of unremitting and progressive arthritis, and more associated anxiety and depression (2, 3). In addition, nail psoriasis may considerably impair manual dexterity and foot biomechanics.However, ma-nagement of nail psoriasis is often overlooked.The most practicable management of nail psoriasis involves the use of topical vitamin D analogues and corticosteroids (1, 4), usually applied twice daily. Alternative treatments, such as topical 5-fluorouracil, tazarotene, and systemic acitretin, cyclosporine, and infliximab, have also been reported with some success (5–9). Compared with calcipotriol monotherapy, com-bination therapy using calcipotriol on weekdays and clobetasol on weekends provided better control of nail psoriasis (10). In plaque psoriasis, Guenther et al. (11) demonstrated that even once-daily combination therapy sufficed. The purpose of the present study was to com-pare the efficacy and safety of once-daily calcipotriol combination therapy with betamethasone dipropionate and twice-daily calcipotriol monotherapy in the treat-ment of nail psoriasis. SUBJECTS AND METHODS

Spotlight on fluticasone furoate/vilanterol trifenatate for the once-daily treatment of asthma: design, development and place in therapy.

The use of inhaled corticosteroids (ICSs) plays a key role in the treatment of asthmatic patients, and international guidelines have designated ICSs as an early maintenance therapy in controlling asthma symptoms. When asthmatic patients remain symptomatic on ICSs, one common option is to add a long-acting beta2 agonist (LABA) to the maintenance treatment. Fixed combination inhalers that contain both an ICS and a LABA have been popular for both chronic obstructive pulmonary disease (COPD) and asthma. Historically, these inhalers have been dosed twice daily. However, currently, there is a once-daily combination therapy with the ICS fluticasone furoate (FF) and the LABA vilanterol trifenatate (VI) with indications for use in both COPD and asthma. This dry powder inhaler (DPI) comes in two doses of FF (100 or 200 μg) both combined with VI (25 μg). This article reviews the clinical trial data for FF, VI and FF/VI combination inhalers and documents the efficacy and safety of once-daily inhaled maintenance therapy by DPI in asthmatic patients.

The Efficacy and Safety of the Novel Long-Acting β2 Agonist Vilanterol in Patients With COPD: A Randomized Placebo-Controlled Trial

Vilanterol (GW642444M) (VI) is a novel, inhaled, long-acting β(2) agonist with inherent 24-h activity under development as a once-daily combination therapy with an inhaled corticosteroid for COPD and asthma. This study assessed the dose response, efficacy, and safety of VI at doses of 3 to 50 μg in patients with moderate to severe COPD. Six hundred two patients (intent-to-treat) were randomized (double-blind) to VI 3, 6.25, 12.5, 25, or 50 μg or placebo once daily for 28 days. The primary end point was change from baseline in trough FEV1 at the end of the 28-day treatment period. Secondary end points included 0- to 24-h weighted mean FEV(1) on days 1 and 28 and time to increases of ≥ 100 mL or ≥ 12% from baseline FEV(1) on day 1. Safety assessments included adverse events, vital signs, ECG assessment, and clinical laboratory tests. VI once daily for 28 days significantly improved trough FEV(1) in a dose-dependent manner vs placebo. Clinically relevant treatment differences of ≥ 130 mL in trough and 0- to 24-h weighted mean FEV(1) were observed with VI 25- and 50-μg doses vs placebo. All doses of VI were associated with a low incidence of treatment-related adverse events/serious adverse events, with no suggestion of effects on BP, pulse rate, QT intervals corrected for heart rate calculated by Fridericia formula, or blood glucose and potassium levels. VI 25 and 50 μg once daily provided both statistically and clinically relevant 24-h improvements in lung function in patients with COPD compared with placebo. All doses of VI had a safety and tolerability profile similar to placebo.

24-Hour ambulatory blood pressure control with triple-therapy amlodipine, valsartan and hydrochlorothiazide in patients with moderate to severe hypertension

To determine the effectiveness and safety of once-daily combination therapy with amlodipine, valsartan and hydrochlorothiazide for reducing ambulatory blood pressure (ABP) in patients with moderate to severe hypertension, a multicenter, double-blind study was performed (N=2271) that included ABP monitoring in a 283-patient subset. After a single-blind, placebo run-in period, patients were randomized to receive amlodipine/valsartan/hydrochlorothiazide (10/320/25 mg), valsartan/hydrochlorothiazide (320/25 mg), amlodipine/valsartan (10/320 mg) or amlodipine/hydrochlorothiazide (10/25 mg) each morning for 8 weeks. Efficacy assessments included change from baseline in 24-h, daytime and night time mean ambulatory systolic BP (SBP) and diastolic BP (DBP). Statistically significant and clinically relevant reductions from baseline in all these parameters occurred in all treatment groups (P<0.0001, all comparisons versus baseline). At week 8, least squares mean reductions from baseline in 24-h, daytime and night time mean ambulatory SBP/DBP were 30.3/19.7, 31.2/20.5 and 28.0/17.8 mm Hg, respectively, with amlodipine/valsartan/hydrochlorothiazide; corresponding reductions with dual therapies ranged from 18.8–24.1/11.7–15.5, 19.0–25.1/12.0–16.0 and 18.3–22.6/11.1–14.3 mm Hg (P⩽0.01, all comparisons of triple versus dual therapy). Treatment with amlodipine/valsartan/hydrochlorothiazide maintained full 24-h effectiveness, including during the morning hours; all hourly mean ambulatory SBP and mean ambulatory DBP measurements were ⩽130/85 mm Hg at end point. Amlodipine/valsartan/hydrochlorothiazide combination therapy was well tolerated. Once-daily treatment with amlodipine/valsartan/hydrochlorothiazide (10/320/25 mg) reduces ABP to a significantly greater extent than component-based dual therapy and maintains its effectiveness over the entire 24-h dosing period.

Efficacy of Fixed-Dose Combination Therapy in the Treatment of Patients with Hypertension

Early initiation of rational and effective combination therapy consisting of antihypertensive drugs with two different and complementary mechanisms of actions is increasingly becoming accepted in clinical practice and by guidelines as a first-line approach to control blood pressure (BP) and prevent cardiovascular outcomes in patients with hypertension. Once-daily combination therapy provides more rapid control of BP, which is important for preventing cardiovascular events, with similar or improved tolerability compared with the component monotherapies, and improved adherence because of regimen simplification. Combination therapy with a calcium channel antagonist (calcium channel blocker [CCB]) and an inhibitor of the renin-angiotensin-aldosterone system (RAAS) is a rational approach to achieve BP goals and provide protection against renal and cardiovascular morbidity and mortality. A number of CCB/RAAS inhibitor combinations, including CCB/angiotensin-converting enzyme (ACE) inhibitor and CCB/ angiotensin II type 1 receptor antagonist (angiotensin receptor blocker [ARB]) combinations are available as fixed-dose formulations. There is substantial evidence for the BP-lowering efficacy of CCB/RAAS inhibitor combinations in diverse patient populations, and their use in combination is associated with favourable tolerability and fewer adverse metabolic effects than some other combination therapies. Recent evidence from large outcome trials supports the use of CCB/RAAS inhibitor combinations for reducing the risk of cardiovascular and renal events, particularly in high-risk patients, together with evidence that the benefits of CCB/RAAS inhibitor combinations may extend beyond their efficacy in lowering BP in terms of protecting against fatal and nonfatal stroke, myocardial infarction and cardiovascular-related deaths. The efficacy of the CCB amlodipine and the ARB valsartan in lowering BP and protecting against cardiovascular events and stroke across a range of hypertensive patient populations has been established over many years. Fixed-dose amlodipine/valsartan combinations are available in many countries and have shown greater BP reductions and better BP control than the respective monotherapies in diverse patient populations, together with a favourable tolerability profile. Once-daily amlodipine/valsartan is a rational and convenient treatment option for the effective management of patients with hypertension, improving adherence to antihypertensive medication and protecting against cardiovascular and renal morbidity and mortality.

Five-Year Follow up of Once-Daily Therapy with Emtricitabine, Didanosine and Efavirenz (Montana ANRS 091 Trial)

Once-daily combination therapy with emtricitabine, didanosine and efavirenz has been highly effective in clinical trials but its long-term efficacy and safety has not been previously reported. This multicentre, single-arm, open-label trial enrolled 40 antiretroviral-naive HIV-1-infected patients who received a once-daily regimen of emtricitabine, didanosine and efavirenz. The objective was to assess the long-term effects of this combination on plasma HIV RNA levels, CD4+ T-cell counts, safety and tolerability. After 5 years, 73% and 68% of patients had plasma HIV RNA levels < 400 and < 50 copies/ml, respectively, in an intent-to-treat, missing-equals-failure analysis. Genotypic resistance on treatment emerged in six patients. There was a significant increase in CD4+ T-cell count of 294 x 10(6) cells/l. Only six patients discontinued study treatment, because of non-severe adverse events. Lipodystrophy was infrequent, and lipid and glucose profiles were favourable with a significant increase in high-density lipoprotein cholesterol. A convenient once-daily regimen of emtricitabine, didanosine and efavirenz provided durable antiretroviral response and was well tolerated through 5 years of therapy.

Once-Daily Combination Therapy for Uncomplicated Malaria: Is This the Way Forward?

There are several problems associated with treatment of malaria especially in sub-Saharan Africa: effectiveness access (financial and physical) safety and tolerability and adherence. Even in an ideal situation in which the first 3 factors are not a problem adherence would still be problematic especially when dealing with rural populations in developing countries where relief of symptoms of malaria is often interpreted as “cure” and where there is therefore great reluctance to continue taking the rest of the medication as prescribed. Adherence has been defined as “the extent to which a patient fulfills the intention of the prescriber in taking medication.” Several drug-associated factors may affect adherence including appropriateness of the prescription side effects dose regimen drug presentation and formulation number of drugs prescribed concurrently and duration of treatment. (excerpt)

Efficacy and Safety of Once-Daily Combination Therapy with Didanosine, Lamivudine and Nevirapine in Antiretroviral-Naive HIV-Infected Patients

Simplified antiretroviral regimens are needed to improve patient adherence and quality of life. The purpose of this study was to evaluate the efficacy and safety of a once-daily regimen consisting of didanosine (ddI), lamivudine (3TC) and nevirapine (NVP) for adult antiretroviral-naive patients with HIV-1 infection. This was a prospective, one-arm, multicentre pilot study. Daily drug dosage was 250 or 400 mg didanosine, 300mg lamivudine and 400 mg nevirapine. The primary outcome measure was the percentage of patients with a plasma HIV-RNA level <50 copies/ml at 12 months on an intention-to-treat (ITT) basis. Seventy patients were enrolled in the study. At baseline, mean plasma HIV-1 RNA was 5.10log10 copies/ml, and mean CD4 cell count was 262 cells/microl. At month 12, 67% (95% CI: 56-78) of patients maintained a viral load of <50 copies/ml in the ITT analysis and CD4 counts increased a median of 201 cells/microl. The treatment was more effective in patients with baseline CD4 counts >100 cells/microl than in those with a poorer immunological status at baseline, although the number of patients with CD4 counts <100 was low. Four patients died during the study period. Therapy was discontinued in 18 patients due to virological failure in 11, adverse events in seven, loss to follow-up or withdrawal of consent in four and death in one. Eight out of nine patients with available genotype after virological failure showed resistance mutations to NVP (Y181C and others) and 3TC (M184V/I), and four of them also had ddI resistance (L74V). The lipid profile was favourable, with a decrease in the ratio of total-to-high density lipoprotein cholesterol. A once-daily combination of ddI, 3TC and NVP seems to be an effective, safe and easy-to-take regimen in antiretroviral-naive patients, at least in those who do not have severe immunodepression at baseline.

Effects of Once-Daily Formoterol and Budesonide Given Alone or in Combination on Surrogate Inflammatory Markers in Asthmatic Adults

We wished to evaluate the effects of once-daily combination therapy on surrogate inflammatory markers. Fifteen patients with atopic persistent asthma were evaluated (mean age, 32.4 years; FEV(1), 75.2% predicted) in a randomized, double-blind, double-dummy, placebo-controlled crossover study with a 1-week placebo washout period, comparing the following once-daily nighttime treatments: (1) formoterol (FM), 12 microg, for 2 weeks and FM, 24 microg, for 2 weeks; or (2) budesonide (BUD), 400 microg, for 2 weeks and BUD, 800 microg, for 2 weeks; or (3) FM, 12 microg, plus BUD, 400 microg, for 2 weeks and FM, 24 microg, plus BUD, 800 microg, for 2 weeks. Adenosine monophosphate (AMP) bronchial challenge, exhaled nitric oxide (NO), and serum eosinophilic cationic protein (ECP) were evaluated at 12 h postdosing after administration of each placebo and after 2 and 4 weeks of each treatment. The results of AMP challenge (provocative concentration causing a 20% fall in FEV(1)) at 4 weeks showed significant (p<0.05) improvements after patients had received all active treatments compared to placebo (20 mg/mL), with FM plus BUD, 261 mg/mL, being superior (p<0.05) to FM alone, 82 mg/mL, but not to BUD, 201 mg/mL. NO and ECP showed significant (p<0.05) reductions compared to placebo with FM plus BUD or BUD alone but not with FM alone. Combination therapy was associated with optimal patient preference (rank order, FM plus BUD > FM > BUD; p<0.0005), highest domiciliary peak expiratory flow, and lowest rescue inhaler usage. All three treatments produced equivalent improvements in spirometry. Patients preferred once-daily combination therapy, but this had no greater effect on inflammatory markers than therapy with BUD alone. FM alone had no anti-inflammatory activity but exhibited bronchoprotection. This emphasizes the importance of first optimizing anti-inflammatory control with inhaled corticosteroids before considering adding a regular long-acting beta(2)-agonist.

Once‐Daily Combination Therapy with Emtricitabine, Didanosine, and Efavirenz in Human Immunodeficiency Virus–Infected Patients

The safety and efficacy of a once-daily regimen that combines emtricitabine, didanosine, and efavirenz was studied among 40 previously untreated human immunodeficiency virus (HIV)-infected patients. The median plasma HIV RNA level was 4.77 log(10) copies/mL at baseline and decreased by a median of 3.5 log(10) copies/mL at 24 weeks, with 98% and 93% of patients achieving plasma HIV RNA levels <400 and <50 copies/mL, respectively. The median CD4 cell count was 373 cells/microL at baseline and increased by a median of 159 cells/microL at week 24. The most common treatment-related adverse events were mild to moderate central nervous system symptoms (73% of patients), diarrhea (33%), rashes (10%), and biochemical abnormalities. Adverse reactions led to permanent drug discontinuation in only 1 patient. The once-daily combination therapy of emtricitabine, didanosine, and efavirenz was safe and demonstrated strong antiviral and immunologic effects that lasted for the 24-week period of the study.