Efficacy and safety of morniflumate for the treatment of symptoms associated with soft tissue inflammation.

The effectiveness of nonsteroidal antiinflammatory drugs (NSAIDs) for the management of pain in osteoarthritis and other musculoskeletal diseases is well documented. The role of NSAIDs is less clear in the treatment of conditions involving soft tissue inflammation, including the airways, ear-nose-throat (ENT) system and urogenital tract. These conditions are often treated inappropriately with antibiotics. Morniflumate, the ß-morpholinoethyl ester of niflumic acid, is a member of the fenamate family of NSAIDs indicated for the treatment of inflammatory conditions (with or without pain) affecting airways, the ENT system, urogenital tract and the osteoarticular system. Morniflumate has a 30-year history of clinical use, particularly for the treatment of pain associated with paediatric ENT infection. This article reviews evidence supporting the efficacy and safety of morniflumate. Based on available evidence and the favourable tolerability profile emerging from extensive clinical use, morniflumate appears to be a valid and well-tolerated alternative to other NSAIDs, or to antibiotics, for the treatment of pain and other symptoms of soft tissue inflammation.

Pharmacokinetic and tolerability of i.m. disodium clodronate 200 mg/lidocaine 1%, given twice monthly, in comparison with i.m. disodium clodronate 100 mg/lidocaine 1%, given weekly, in healthy postmenopausal female patients.

BACKGROUND: Clodronate is a bisphosphonate effective in the prevention and treatment of osteoporosis in postmenopausal women. Non-adherence to bisphosphonates, however, is a major issue in clinical practice. Simplifying dose regimens may increase compliance. OBJECTIVES: To assess bioequivalence between an intramuscular (i.m.) clodronate 200 mg/lidocaine 1% twice-a-month formulation and a clodronate 100 mg/lidocaine 1% weekly formulation in 32 postmenopausal women. METHODS: In this double-blind, randomized, two-way crossover study, test and reference formulations were administered in single dose, with a 2-week wash-out between administrations. The primary endpoint was clodronic acid cumulative excretion in the first 24 hours after injection (Xu0-24h). Cumulative excretion in the 72 hours post-dose (Xu0-72h) and maximum excretion rate (Ratemax) were also evaluated. Bioequivalence was assumed if the 90% confidence intervals (CIs) of the geometric means ratios of the dose-normalized parameters were within the 80.00 - 125.00% range. Local tolerability was evaluated. RESULTS: Mean Xu0-24h values were 114.03 ±23.13 mg and 55.22 ±9.73 mg for clodronate 200 mg and 100 mg. The 90% CIs for dose-normalized Xu0-24h, Xu0-72h and Ratemax ere 95 -110%, 94 -107% and 95 - 113%. Local tolerability of both treatments was good. The differences in pain intensity between formulations were not sigificantly different at most assessment times. Headache was the only treatment-related adverse event. CONCLUSIONS: Bioequivalence of the two formulations was confirmed in terms of dose-normalized rate and amount of clodronic acid excretion. This result, together with the favorable tolerability of the novel 200 mg formulation, suggests the possibility of reducing the number of i.m. administrations from once-a-week to twice-a-month.

1-year prospective real life monitoring of asthma control and quality of life in Italy.

OBJECTIVES: The study aimed at prospectively evaluating the evolution of asthma control in Italy, to evaluate the reasons for lack of asthma control, perceived quality of life (QoL) and association with level of asthma control, the impact of pharmacological treatment, the number of exacerbations and the healthcare resource consumption. METHODS: PRISMA (PRospectIve Study on asthMA control) was an observational study performed in asthmatic patients including a cross-sectional phase and a 12-month prospective phase. Asthma control was assessed with the Asthma Control Test™ (ACT) and QoL was evaluated with EuroQoL-5D questionnaire filled in and collected during 5 clinic visits together with all the other data. RESULTS: The prospective phase included 1017 patients with uncontrolled (55.7%) or partly controlled asthma (44.3%). Out of the 739 patients evaluable after 12 months, 22.2% achieved full asthma control (ACT score = 25) and 58.7% reached a good control (ACT score: 20-24). The improvement in asthma control was associated with improved QoL and reduced hospital visits. The main reasons for lack of asthma control were comorbidities, continued exposure to irritants/triggers and poor adherence to therapy. The frequency of exacerbations was lower in patients with controlled asthma.A fixed combination therapy with an inhaled corticosteroid and a long-acting ß2 agonist was reported by 77.0% of patients. A better asthma control and improved QoL were achieved with extrafine beclomethasone/formoterol compared to either budesonide/formoterol or fluticasone/salmeterol. CONCLUSIONS: An improvement in asthma control and QoL can be achieved during a 1-year monitoring in a real life setting. Extrafine beclomethasone/formoterol was associated with significant benefit in terms of asthma control and QoL compared to large-particles combinations.ClinicalTrials.gov number NCT01110460.

Efficacy and safety of delapril/indapamide compared to different ACE-inhibitor/hydrochlorothiazide combinations: a meta-analysis.

The main objective of this meta-analysis was to compare the efficacy of the combination of delapril and indapamide (D+I) to different angiotensin-converting enzyme inhibitor (ACEi) plus hydrochlorothiazide (HCTZ) combinations for the treatment of mild-to-moderate hypertension. A secondary objective was to examine the safety of these two combinations. Studies comparing the efficacy of D+I to ACEi+HCTZ combinations in hypertensive patients and published on computerized databases (1974-2010) were considered. Endpoints included percentage of normalized patients, of responders, change in diastolic and systolic blood pressure (DBP/SBP) at different time-points, percentage of adverse events (AEs), and percentage of withdrawal. Four head-to-head randomized controlled trials (D+I-treated, n = 643; ACEi+HCTZ-treated, n = 629) were included. Meta-analysis indicated that D+I-treated patients had a higher proportion with normalized blood pressure (P = 0.024) or responders (P = 0.002) compared to ACEi+HCTZ-treated patients. No difference was observed between treatments on absolute values of DBP and SBP at different time-points. Although the rate of patients reporting at least one AE was similar in both groups (10.4% versus 9.9%), events leading to study withdrawal were lower in the D+I group versus the ACEi+HCTZ group (2.3% versus 4.8%, respectively; P = 0.018). This meta-analysis suggests that treatment with D+I could provide a higher proportion of normalized or responder patients with good tolerability compared to ACEi+HCTZ combinations.

Cost-effectiveness and cost-utility of beclomethasone/formoterol versus fluticasone propionate/salmeterol in patients with moderate to severe asthma.

BACKGROUND: Asthma is a chronic disease characterized by acute symptomatic episodes with variable severity and duration. Pharmacological asthma management aims to achieve and maintain control without side effects, thus improving quality of life and reducing the economic impact. Recently, a clinical trial showed the non-inferiority of beclomethasone/formoterol (BDP/F) versus fluticasone propionate/salmeterol (FP/S) in adults with moderate to severe persistent asthma. However, this study did not provide evidence on costs and did not quantify quality-of-life parameters. OBJECTIVE: The objective of the present study was to assess the cost effectiveness and cost utility of BDP/F versus FP/S in patients with moderate to severe asthma from the perspective of the Italian National Health Service (NHS). METHODS: A Markov model (MM) was used, with five health states for the different levels of asthma control: successful control, sub-optimal control, outpatient-managed exacerbation, inpatient-managed exacerbation, and death. Model data were derived from the ICAT SE study and from expert panels. Three outcomes were considered: time spent in successful control state, costs and quality-adjusted life-years (QALYs). RESULTS: The model shows that BDP/F treatment led to a slight increase of weeks in successful control compared with FP/S, with a lower cost. The probabilistic sensitivity analysis highlights that in 64% and 68% of the Monte Carlo simulations, BDP/F outperformed FP/S in terms of weeks in successful control and QALYs. Considering the expected cost of the two strategies, in 90% of simulations BDP/F was the least expensive choice. In particular, BDP/F was cost saving as compared with FP/S in about 63% and 59% of simulations as shown by the cost-utility and cost-effectiveness analysis, respectively. CONCLUSION: Overall, from the Italian NHS perspective, BDP/F treatment is associated with a reduction in cost and offers a slight increase of effectiveness in terms of weeks spent in successful control and QALYs.

Real-life prospective study on asthma control in Italy: cross-sectional phase results.

OBJECTIVES: To estimate the prevalence of partly controlled and uncontrolled asthmatic patients, to evaluate quality of life and healthcare resource consumption. METHODS: Cross-sectional phase followed by a 12-month prospective phase. Asthma Control Test and the EQ-5D were used. RESULTS: 2853 adult patients recruited in 56 Hospital Respiratory Units in Italy were evaluated: 64.4% had controlled asthma, 15.8% partly controlled asthma and 19.8% were uncontrolled. The mean (SD) EQ-5D score was 0.86 (0.17) in controlled, 0.75 (0.20) in partly controlled and 0.69 (0.23) in uncontrolled patients (p<0.001 between groups). The number of patients requiring hospitalization or emergency room visits was lower in controlled (1.8% and 1.6%, respectively) than in partly controlled (5.1% and 11.5%) and uncontrolled (6.4% and 18.6%). A combination of an inhaled corticosteroid and a long-acting beta-2 agonist was the reported therapy by 56.0% of patients, with the rate of controlled asthma and improved quality of life being higher in patients on extrafine beclomethasone/formoterol compared to budesonide/formoterol (p<0.05) and fluticasone/salmeterol (p<0.05 for quality of life). CONCLUSIONS: Asthma control is achieved in a good proportion of Italian patients. Differences may be detected in a real-life setting in favor of extrafine beclomethasone/formoterol combination.

Combination delapril/manidipine as antihypertensive therapy in high-risk patients.

The majority of patients with hypertension, and in particular high-risk patients or those with diabetes mellitus or renal dysfunction, are likely to require combination therapy with at least two antihypertensive agents (from different classes) to achieve their blood pressure (BP) target. The delapril/manidipine fixed-dose combination consists of two antihypertensive agents with different, yet complementary, mechanisms of action. Delapril/manidipine has demonstrated short- and long-term antihypertensive efficacy in a number of clinical studies in patients with hypertension with an inadequate response to monotherapy. Comparative studies have demonstrated that delapril/manidipine is as effective as enalapril/hydrochlorothiazide (HCTZ) in patients with hypertension with an inadequate response to monotherapy, and as effective as irbesartan/HCTZ, losartan/HCTZ, olmesartan medoxomil/HCTZ, ramipril/HCTZ and valsartan/HCTZ in reducing BP in patients with hypertension and diabetes, or in obese patients with hypertension. Therapy with delapril/manidipine also appears to exert beneficial effects that extend beyond a reduction in BP, including nephroprotective activity and an improvement in fibrinolytic balance, supporting its value as a treatment option in these patient populations at high or very high cardiovascular risk because of the presence of organ damage, diabetes or renal disease.

Manidipine reduces pro-inflammatory cytokines secretion in human endothelial cells and macrophages.

The dihydropyridine calcium antagonists (DHP-CA), commonly used for the treatment of hypertension, may exert antiatherosclerotic activity independent of the blood-pressure lowering properties. The aim of this study was to evaluate the effect in cell culture of the third generation DHP-CA Manidipine on the release of interleukin-6 (IL-6) and interleukin-8 (IL-8) from human endothelial cells and human macrophages, in response to different pro-inflammatory signals. In endothelial cells, incubation with acetylated LDL (acLDL), oxidized LDL (oxLDL) or tumor necrosis factor-alpha (TNF-alpha), increased the release of IL-6 from 50% to 100%. Manidipine 1-5 microM was able to completely inhibit IL-6 production induced by either of these factors. In these cells TNF-alpha increased by about 4 times the secretion of IL-8 and Manidipine 5 microM reduced the amount of IL-8 in the culture media by about 40%. In human macrophages THP-1, treatment with different cytokines was able to stimulate by about 3-folds the release of IL-6 and Manidipine 1 microM showed a 25% inhibition on TNF-alpha-induced IL-6 secretion. In these cells, a combined treatment with multiple cytokines, induced IL-6 production of about 6-folds and Manidipine was able to reduce such inflammatory response by 30%. Our experiments highlighted the anti-inflammatory properties of Manidipine in either human endothelial cells or macrophages. The mechanism by which Manidipine exert this effect is not related to its blocking activity on calcium channels and it involves an inhibition of NF-kappaB activation, that, in analogy with what is observed for other DHP-CA, may be related to the high lipophilicity and the antioxidant activity of this compound.

Inhaled corticosteroid therapy with nebulized beclometasone dipropionate.

Inhaled corticosteroids (ICS) are the most effective anti-inflammatory agents for the management of chronic persistent asthma and are therefore recommended as first-line antiasthmatic therapy in children and adults. In various settings, the administration of ICS via nebulizer rather than hand-held inhaler (HHI) may have certain advantages, as many patients with HHI fail to use these devices properly or efficiently. In particular, young children, the elderly, the acutely ill, and those with restricted dexterity may be unable to coordinate inhalation with actuation of the device or to generate sufficient inspiratory flow to operate breath-actuated devices effectively. Compliance with nebulized therapy may also be better than that with a pressurized metered-dose inhaler (pMDI) plus spacer. Systematic reviews conclude that there is no significant difference in clinical effects between nebulizers and HHI. Performance and clinical effect of nebulization are influenced by several technical aspects such as the nebulizer-drug combination, nebulizer type, output and lung deposition. Among the currently available ICS, nebulized beclometasone dipropionate (BDP) has been in clinical use for more than 35 years, and has demonstrated marked clinical efficacy and a favorable tolerability profile in children and adults with chronic persistent asthma. The clinical efficacy of nebulized beclometasone is discussed in the present review using data from 13 published studies, which included a total of 1250 patients. Three multicenter, randomized, double-blind studies showed that nebulized BDP is as effective as BDP via pMDI plus spacer in a 2:1 dose ratio. Controlled trials involving 497 adults and children demonstrated similar clinical efficacy between nebulized BDP and either nebulized fluticasone propionate or nebulized budesonide. In all these trials, treatment-related adverse effects were generally uncommon, most were mild-to-moderate in severity, and most were associated with the respiratory system. Meta-analyses show that BDP, like other inhaled corticosteroids, has no major influence on patient height, urinary cortisol concentration, or bone metabolism, thus suggesting the absence of growth retardation or any marked effect on adrenal function or the hypothalamic-pituitary-adrenal axis when used in the approved dose range. Overall, nebulized BDP appears to have a particularly important place in asthma therapy: as a general alternative to HHIs (e.g. in patients with poor HHI compliance); when patients such as children or the elderly are unable to operate HHIs because of poor hand-lung coordination, lack of cooperation, or low inspiratory flow rate; and when high dosages of ICS are required, such as in adults with severe, corticosteroid-dependent asthma.

Clodronic acid formulations available in Europe and their use in osteoporosis: a review.

Clodronic acid (Cl(2)-MBP [dichloromethylene bisphosphonic acid], clodronate) is a halogenated non-nitrogen-containing bisphosphonate with antiresorptive efficacy in a variety of diseases associated with excessive bone resorption. The drug is believed to inhibit bone resorption through induction of osteoclast apoptosis, but appears also to possess anti-inflammatory and analgesic properties that contrast with the acute-phase and inflammatory effects seen with nitrogen-containing bisphosphonates. Clodronic acid has been shown to be effective in the maintenance or improvement of bone mineral density when given orally, intramuscularly or intravenously in patients with osteoporosis. Use of the drug is also associated with reductions in fracture risk. The intramuscular formulation, which is given at a dose of 100 mg weekly or biweekly, is at least as effective as daily oral therapy and appears more effective than intermittent intravenous treatment. Intramuscular clodronic acid in particular has also been associated with improvements in back pain. The drug is well tolerated, with no deleterious effects on bone mineralization, and use of parenteral therapy eliminates the risk of gastrointestinal adverse effects that may be seen in patients receiving bisphosphonate therapy.

Metabolic effects of manidipine.

The calcium channel antagonists (CCAs) were originally introduced as vasodilators for the treatment of coronary heart disease, but are now also noted for their clinical efficacy in the management of hypertension. Data from large clinical studies have shown that CCAs are not associated with the undesirable metabolic effects (e.g. worsening of dyslipidemia and reduction of insulin sensitivity) seen with older agents such as thiazide diuretics and beta-adrenoceptor antagonists (beta-blockers) that are used to treat hypertension. Indeed, reductions in cardiovascular risk and rates of onset of new cases of diabetes mellitus have been reported in trials in patients with hypertension treated with CCAs. These beneficial effects extend beyond those expected to accompany reductions in BP. Until recently, the biochemical effects underlying these metabolic changes were only poorly understood, but pharmacologic studies have now started to shed more light on these issues. Of particular interest are studies with manidipine, some of which suggest that this agent may be associated with greater improvements in insulin sensitivity and may have better renal protective properties than other CCAs. Confirmation of potential differences among CCAs in terms of the relative magnitude of any beneficial metabolic effects requires further study. Ongoing research is expected to clarify further the action of these agents at the cellular level and to assist with the optimization of antihypertensive therapy, particularly in patients with elevated cardiovascular risk profiles.

Delapril plus indapamide: a review of the combination in the treatment of hypertension.

Although many data indicate that the management of hypertension has improved over the last two decades, there is still a large proportion of hypertensive individuals who do not receive adequate management of their blood pressure (BP). Combination therapy with two or more antihypertensive agents from different drug classes is increasingly being recognised as the most effective means of achieving target BP values by pharmacological means, particularly in the large number of patients in whom monotherapy proves to be ineffective. Use of an angiotensin-converting enzyme (ACE) inhibitor combined with a diuretic is a well established antihypertensive combination that is very effective because of the different, yet synergistic, mechanisms of actions of agents from these two drug classes. Delapril is a potent antihypertensive ACE inhibitor, and indapamide is a thiazide-like diuretic with additional antihypertensive properties. The combination of delapril and indapamide provides renoprotective effects, and indapamide is also cardioprotective. Use of these two drugs together is therefore a rational selection for combination therapy, and one that has consistently demonstrated lowering of BP to target values with a level of efficacy that is at least as good as other combinations of ACE inhibitors and diuretics. This combination has also been found to provide favourable effects on haemodynamic parameters, including left ventricular mass index and ejection fraction. Furthermore, combining an ACE inhibitor and a thiazide-type diuretic has been associated with a decreased risk of stroke and is recommended for patients with cerebrovascular disease, a setting in which the combination of delapril and indapamide has therapeutic potential. Because of the additive mechanisms of delapril and indapamide, the dose required for an effective antihypertensive effect is relatively low, and the combination is well tolerated at such doses. In particular, metabolic effects normally associated with diuretics are rare at the therapeutic dose of indapamide used in combination with delapril, making the combination suitable for patients with metabolic disorders in whom diuretic therapy would otherwise not be recommended. Delapril 30 mg and indapamide 2.5mg have been combined in a fixed combination, offering the convenience of a one-tablet-per-day antihypertensive drug regimen for most patients, which, along with good tolerability, helps to address the issue of noncompliance.

Efficacy and safety of delapril plus manidipine compared with enalapril plus hydrochlorothiazide in mild to moderate essential hypertension: results of a randomized trial.

BACKGROUND: The use of combination therapy is required to achieve blood pressure targets in 40% to 75% of patients with hypertension. There have been few studies comparing the efficacy and tolerability of the new fixed combination of the angiotensin-converting enzyme (ACE) inhibitor delapril 30 mg and the calcium channel antagonist manidipine 10 mg with those of a standard combination of another ACE inhibitor and a diuretic. OBJECTIVE: The aim of this study was to compare the antihypertensive efficacy and tolerability of delapril 30 mg given alone or with manidipine 10 mg with those of enalapril 20 mg given alone or with hydrochlorothiazide (HCTZ) 12.5 mg in patients with mild to moderate essential hypertension. METHODS: This was a multicenter, active-controlled, parallel-group trial. After an initial 2-week placebo run-in period, patients aged 18 to 75 years with diastolic blood pressure (DBP) > or =90 and < or =109 mm Hg were randomized in a 2:1 ratio to receive delapril or enalapril for 8 weeks. After the initial 8 weeks, nonresponders (DBP > or =85 mm Hg) received an additional 8 weeks of treatment with a fixed combination of delapril + manidipine or enalapril + HCTZ; patients whose DBP was normalized continued their initial monotherapy through the end of the study. The primary efficacy variable was the change in sitting DBP at the end of treatment. Secondary efficacy variables were the percentage of patients whose DBP was normalized (DBP Z:85 mm Hg) and the percentage of responders (> or =10-mm Hg reduction in DBP or DBP <85 mm Hg). RESULTS: One hundred sixty patients (84 men, 76 women) were randomized to receive delapril (n = 106) or enalapril (n = 54). After 16 weeks of treatment, the mean (SD) reduction in DBP was similar with the 2 treatments (delapril, -14 [8] mm Hg; enalapril, -15 [8] mm Hg). In the delapril and enalapril groups, DBP was normalized in a respective 55 (51.9%) and 29 (53.7%) patients, and 77 (72.6%) and 38 (70.4%) were responders; there was no significant difference between groups. Tolerability was also similar in both groups--10 (9.4%) patients in the delapril group and 5 (9.3%) in the enalapril group experienced adverse events that were judged related to treatment. CONCLUSIONS: The results of this study suggest that delapril alone or combined with manidipine is well tolerated and as effective as enalapril alone or combined with HCTZ in lowering blood pressure in patients with mild to moderate essential hypertension.

Beneficial effects of angiotensin-converting enzyme inhibitor and nitrate association on left ventricular remodeling in patients with large acute myocardial infarction: the Delapril Remodeling after Acute Myocardial Infarction (DRAMI) trial.

BACKGROUND: In the large-scale trial, Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico-3 (GISSI-3), patients receiving the combination of lisinopril and glyceryl trinitrate benefited most from experimental therapy. Therefore, a multicenter, randomized, double-blind study, Delapril Remodeling After Acute Myocardial Infarction (DRAMI), was designed to assess (1) the possible additive beneficial effect on left ventricular remodeling of nitrates when combined with an angiotensin-converting enzyme inhibitor (ACEI), and (2) the tolerability of a new ACEI, delapril, in respect to lisinopril in patients with large myocardial infarction (MI). METHODS: A total of 177 patients were randomized to receive delapril plus isosorbide-5-mononitrate (IS5MN) placebo, delapril plus IS5MN, lisinopril plus IS5MN placebo, or lisinopril plus IS5MN starting within the first 36 hours after the onset of symptoms and continuing for 3 months. RESULTS: More than 80% of the patients showed extensive ST-segment changes and 36.7% had signs or symptoms of heart failure during the first 36 hours. Over 3 months, IS5MN reduced, by 76%, the increase in LVEDV (17.4 +/- 5.0 mL placebo vs 4.2 +/- 4.4 mL IS5MN, P =.0439), reversed the increase in LVESV (7.5 +/- 3.9 mL placebo vs -5.5 +/- 2.9 mL IS5MN, P =.0052), and increased the recovery of LVEF (1.9% +/- 1.3% placebo vs 6.7% +/- 1.2% IS5MN, P =.0119). Overall, 3-month mortality was 10.2%; the most frequent clinical events were new episodes of severe heart failure (18.1%), persistent hypotension (10.7%), and post-MI angina (18.1%), with no differences between treatment groups. CONCLUSIONS: Administration for 3 months of IS5MN combined with an ACEI, both started within 36 hours from the onset of symptoms, was safe and effective in reducing LV dilation and dysfunction after MI. The 2 ACEIs, delapril and lisinopril, appeared to be equally well tolerated.

Efficacy and tolerability of delapril plus indapamide versus lisinopril plus hydrochlorothiazide combination treatments in mild to moderate hypertension: a multicenter, randomized clinical study.

BACKGROUND: Several studies have shown that antihypertensive monotherapy is commonly insufficient to control blood pressure (BP) in hypertensive patients and that concomitant use of ≥2 drugs is necessary in ∼50% of these patients. The combination of an angiotensin-converting enzyme (ACE) inhibitor and a diuretic, delapril plus indapamide (D + I), has been shown to be effective and tolerable, with no interaction between the 2 components. Another widely used combination of ACE inhibitor and diuretic is lisinopril plus hydrochlorothiazide (L + H). OBJECTIVES: The aims of this study were to confirm the antihypertensive efficacy and tolerability of the fixed combination of D + I in mild to moderate hypertension, and to compare its therapeutic efficacy and tolerability with that of L + H. METHODS: The antihypertensive efficacy and tolerability of a fixed combination of D + I (30-mg + 2.5-mg tablets once daily) or L + H (20-mg + 12.5-mg tablets once daily) in patients with mild to moderate hypertension were compared in a multinational, multicenter, randomized, 2-armed, parallel-group study. Eligible patients were aged 18 to 75 years and had a diastolic blood pressure (DBP) 95 to 115 mm Hg and a systolic blood pressure (SBP) ≤180 mm Hg, both measured in the sitting position. After a single-blind, placebo run-in period of 2 weeks, patients were randomized to receive 1 of the 2 treatments for a 12-week period. The primary efficacy end point was the BP normalization rate (ie, the percentage of patients with a sitting DBP ≤90 mm Hg) after 12 weeks of treatment. Secondary end points were as follows: (1) the responder rate (ie, the percentage of patients whose sitting DBP was reduced by ≥10 mm Hg from baseline or had a DBP ≤90 mm Hg after 12 weeks of treatment), (2) the percentage of patients with a DBP ≤85 mm Hg, and (3) changes in sitting SBP and DBP after 4, 8, and 12 weeks of treatment. RESULTS: A total of 159 hypertensive patients (88 women, 71 men) were randomized to receive D + I (44 women, 36 men; mean [SD] age, 53 [(11)] years) or L + H (44 women, 35 men; mean [SD] age, 55 [(10)] years). No significant between-group differences were found in any of the primary or secondary end points of the study. Both combinations induced a significant reduction in sitting DBP and SBP from baseline (P<0.001 for both groups at week 12), without significant differences between the groups. Five mild to moderate adverse drug reactions (ADRs) occurred in each treatment group. No patient dropped out of the study because of an ADR. CONCLUSION: This study showed no difference between D + I and L + H interms of antihypertensive efficacy or tolerability in patients with mild to moderate hypertension.