Thirdly, studies comparing the different "add-on" options were identified. The addition of a LABA is more effective than increasing the dose of ICS in improving asthma control. By increasing the dose of ICS, clinical improvement is likely to be of small magnitude. Addition of a LTRA or theophylline to the treatment regimen appears to be equivalent to doubling the dose of ICS. Addition of a LABA seems to be superior to an LTRA in improving lung function. However, addition of LABA and LTRA may be equal with respect to asthma exacerbations. However, more and longer studies are needed to better clarify the role of LTRAs and theophylline as add-on therapies.Many patients with persistent asthma can be controlled with inhaled corticosteroids (ICS). However, a considerable proportion of patients remain symptomatic, despite the use of ICS. We present systematically evidence that supports the different treatment options. A literature search was made of Medline/PubMed to identify randomised and blinded trials. To demonstrate the benefit that can be obtained by increasing the dose of ICS, dose-response studies with at least three different ICS doses were identified. To demonstrate whether more benefit can be obtained by adding long-acting β Daily rescue therapy is usually needed. Typical findings include low values of PEF or FEV1, a marked variation in daily PEF recordings and/or a significant response to bronchodilators. Thus, asthma is not adequately controlled, and the treatment needs to be optimized.Inhaled corticosteroids (ICS) are the mainstay of current asthma management and should be used in all patients with persistent asthma. Many patients with persistent asthma can be controlled with regular ICS. However, a considerable proportion of patients treated with ICS remain symptomatic, despite the use of low to moderate doses , 3. Addition of a leukotriene receptor antagonist  and 4. Addition of theophylline. Currently, the National Heart, Lung and Blood Institute guideline [According to current guidelines the therapeutic options in the treatment of asthma not adequately controlled by low to moderate doses of ICS are as follows: 1. Increase in the dose of the ICS, 2. Addition of long-acting βuideline ,8. Severuideline ,9-16. HoThe paper reviews studies where participants were adults or adolescents (≥12 years) with clinical evidence of asthma not adequately controlled with ICS. The general inclusion criteria in this review were: randomized, blinded and controlled trials with either parallel group or cross-over design published as a full-length paper. Steroid-tapering studies were not included as they are difficult to interpret. Studies published in abstract form only were not included. Similarly, studies lasting less than 4 weeks, containing less than 10 patients per group or studies containing a significant proportion (>10%) of patients using systemic steroids were excluded. Similarly "add-on" studies where a significant proportion (>10%) of patients were not using inhaled steroids were excluded.in vitro results or results from open, non-randomized or uncontrolled trials or meta-analysis of particular relevance to the present topic may be cited.We made a search of Medline from January 1 1966 to October 2001. All searches were limited to studies published in the English language. To identify the latest studies published, another search was made by using the drug names  from Medline on October 2003. The searches were manually (HK) evaluated to identify studies fulfilling the inclusion criteria and full papers were retrieved. In the case of uncertainty based on the abstract full papers were retrieved. All studies fulfilling the inclusion criteria for the ICS dose-response studies or "add-on" studies (see below) were scored for quality using the method described by Jadad et al. . FurtherTo find the dose-response studies with ICS the term "anti-inflammatory agents, steroidal" was combined with the term: "dose-response relationship, drug" (MeSH), which combination produced 249 papers. To demonstrate the dose-response effect of ICS only controlled studies with at least three different ICS doses and a parallel-group design were included. Studies using consecutive doses of steroids were not included because it makes it impossible to differentiate the dose-response relation from the time course relation of efficacy.When the basic search done with the term "anti-inflammatory agents, steroidal" was combined with another made with terms: "salmeterol OR formoterol" it produced 97 papers, when combined with a search made with a term "leukotriene antagonists" (MeSH), it produced 26 papers and when combined with a search with a term "theophylline" (MeSH) it produced 342 papers. Only studies where the addition of LABA, LTRA or theophylline to the treatment with inhaled steroid was compared with the addition of a corresponding placebo to an increased dose  of inhaled steroid were included. In addition, studies comparing the different "add-on" options were identified.Table 1 . In this review, both ways of analysis are accepted as evidence for the presence of dose-response. In the following discussion the important difference between the formal dose-response studies presented in this review and the results reported in some meta-analysis is that the data of the meta-analyses may result from studies assessing one or more doses of ICS and comparing their effects with placebo or baseline. Thus, the data derived from some the published meta-analyses [We identified 14 studies -31 assesle 1 see . The incanalyses ,11,14,321 in the treatment of chronic asthma in 9 (69%) and 5 (31%) studies of the 14 studies included, respectively  out of 12 studies where it was analyzed , night-time symptom score and rescue β2-agonist use  and FVC . Similarly, the difference between the two consecutive doses of ICS was very seldom statistically significant  was evaluated in asthmatic subjects who had deterioration in asthma control after discontinuation of ICS . There w1 and morning PEF and reduction in night-time symptom score compared to baseline. Studies that assessed BDP 1000 v 500 μg/d and BDP 1600 v 400 μg/d demonstrated a significant advantage of the higher dose compared to the lower dose for percentage improvement in airway responsiveness to histamine and FEV1 compared to baseline. No differences between higher and lower daily doses of BDP were apparent for daytime symptoms, withdrawals due to asthma exacerbations or oropharyngeal side effects.A recent meta-analysis  analysed1. In this study, there was no statistically significant difference between the doubling doses of budesonide   results 1, but not in evening PEF, FVC, symptom scores or rescue β2-agonist use. Instead, even the lowest dose of budesonide (200 μg/d) was superior to placebo for all parameters studied. The improvement induced by these low doses is much greater than the difference between the lowest and highest doses of budesonide studied, despite the 8-fold difference in the dose  or the highest dose (1600 μg/d) did not differ from the two medium doses (400–800 μg/d). When evening PEF, FVC, daytime or nighttime asthma symptom scores or the use of rescue medication were analysed, there was no significant differences between any of the studied budesonide doses [In a randomised, double-blind, placebo-controlled study of parallel-group design lasting 12 weeks four different doses of budesonide . Increasing the dose of budesonide  results de doses .1, morning PEF, symptom scores or rescue β2-agonist use were apparent across a dose range of 200–1600 μg/d. However, in moderate to severe asthma there was a significant reduction in the likelihood of trial withdrawal due to asthma exacerbation with budesonide 800 μg/d compared with budesonide 200 μg/d. The reviewers also conclude that budesonide exhibits a significant improvements favouring high dose (1600 μg/d) over low dose (200 μg/d) for improvement in FEV1 in severe asthma [1 but not for evening PEF [The dose-relationship of budesonide in the treatment of chronic asthma is a subject of a recent Cochrane review . In thise asthma . Anotherning PEF .Table 1, see 1, FVC and daytime symptom score . How does this translate into clinical practice? When assessing a response to a bronchodilator or when assessing a response to inhaled or oral steroid an improvement of 10–20% above the previous values is often considered significant. Thus, in the above study, this would mean >36 L/min increase in morning PEF values. Recently, the average minimal patient perceivable improvements have been estimated as 18.8 L/min for PEF and 0.23 L for FEV1 [In a dose-response study  with patfor FEV1 . Based o1, morning PEF, evening PEF, nighttime awakening score and physician-rated efficacy. It is important to appreciate that this was only evident when improvements over placebo were compared for the highest dose of FP (1000 μg/d) and lowest dose of FP (100 μg/d). There were no significant differences when any other doses were compared . Sixty percent  of the effect on FEV1 with FP 1000 μg/d  was achieved with tenth of the dose. No dose-response effect was apparent for change in symptom score or for rescue β2-agonist use [1, daily symptom score, night-time awakenings and daily use of rescue β2-agonist use. No significant advantage was obtained with the use of FP at doses of 400–500 μg/d over 200 μg/d for morning or evening PEF, FEV1, daily symptom score or rescue β2-agonist use. Patients treated with higher dose (800 – 1000 μg/d) of FP achieved significantly greater improvements in morning PEF  and evening PEF  compared to the lower dose (50–100 μg/d). Another recent meta-analysis [1 or β2-agonist use.In a recent meta-analysis  the dosenist use . Anothernist use  found a analysis  includinTable 2a, see Table 2a, see 1 or daytime or total symptom score. In contrast, no significant dose-dependency was found for FVC, nighttime symptom score or rescue β2-agonist use  in the treatment of moderate to severe asthma across the dose-range of 150 to 600 μg/d or 200 to 1600 μg/d for most variables in the two studies included in this review  shows that even the lowest dose significantly differs from placebo, and there appears to be no clear dose-response. However, no formal statistical analysis was reported for the presence of a dose-response and thus this study is not included in Tables 1–2. A recent meta-analysis [1.A placebo-controlled, double-blind parallel-group study assessed the effects of three different doses of TAA  in patients with chronic symptomatic asthma and using ICS . The datanalysis  includin2-agonists, PEF or lung function. However, the steepness of the dose-response curve for different outcomes may vary. For example, an open dose-response evaluation of different sequential doses of budesonide in patients with mild-to-moderate asthma (38) shows that the dose-response curves for FEV1/PEF and FEF25–75 are not identical. Similarly, the dose-response curves of budesonide on adenosine monophosphate (AMP) and methacholine bronchial challenges were significantly different [Taken together these results indicate that the change in the ICS dose from low dose to moderate dose is at the flat part of the ICS dose-response curve for most lung function and symptom parameters studied Figure . Furthere asthma  shows the asthma 8 shows tThe studies discussed above present mean data for groups of patients, but do not address the issue of differences in responsiveness to the anti-inflammatory effects of corticosteroids between individual patients. It may be possible that increasing the dose of ICS may be beneficial for some patients.We were not able to identify any studies that would have studied the dose-dependency of the anti-inflammatory effects of ICS in asthma and would have satisfied the inclusion criteria for the present review.20 from 259 to 467 μg and FP from 271 to 645 μg, both showing a dose-dependency. However, no statistical comparison was made between individual doses. The PD20 was increased 1.67-fold and 1.96-fold when the patients were switched from the lowest dose to the highest dose of budesonide and FP, respectively. An apparently dose-dependent decrease in the blood eosinophil count was obtained with budesonide but not with FP treatment [2-agonist were analysed. Allergen PC15 and methacholine PC20 values were determined before and after treatment with budesonide at 200, 400 and 800 μg/d for 7 days in a double-blind, randomized and cross-over study (6 day washout period) in eleven atopic subjects with inhalation allergy [15 and methacholine PC20 were significantly larger for all doses of budesonide as compared with placebo, but there was no significant difference between the 3 doses of budesonide. In an open trial with patients with moderate to severe asthma the effects of progressively increasing doses of budesonide  were studied [20 to inhaled budesonide but a plateau response of exhaled NO was found at a dose of 400 μg/d [1, exhaled nitric oxide (FENO) and methacholine PC20 [1 and methacholine PC20 from baseline or placebo treatment, but with no significant separation of active BDP doses. All doses of BDP resulted in a significant change in FENO from placebo treatment, but with significant separation of only the 100 μg and 800 μg doses by FENO. Another study assessed the dose-response relationship of the anti-inflammatory effects of BDP  in the treatment of mild to moderate asthma for 8 weeks in a randomised, placebo-controlled, double-blind trial of parallel-group design [15 to saline were followed. There was a significant linear relationship between BDP dose and exhaled NO concentration, FEV1 and changes in sputum eosinophils at the end of treatment. In contrast no relationship was found between BDP dose and PD15 to saline. However, the results of this study may be confounded because the patients were treated with oral prednisolone for two days in the beginning of the study.In a study  with patreatment . In cont studied . Budeson400 μg/d . In a st400 μg/d . Compareine PC20 . All dos1 after placebo treatment was 24% and was significantly reduced in a dose-dependent manner to 12%, 11% and 6% for the 100, 200 and 800 μg daily treatments. The allergen-induced sputum eosinophilia (×104 cells/ml) 24 h after challenge during placebo treatment was 60.2 and was significantly reduced to 24.0, 15.3 and 6.2 for the 100, 200 and 800 μg daily treatments, respectively. Although a statistically significant dose-response relationship was present, the difference between the lowest and highest dose (8-fold difference) for late maximal fall in FEV1 or allergen-induced sputum eosinophilia was less than the difference between placebo and the lowest dose of MF.In a recent randomized and double-blinded study, 12 atopic mild stable asthmatic subjects were treated with placebo or mometasone furoate  for six days  in a croTaken together, the results suggest that there is tendency towards slightly higher anti-inflammatory efficacy with higher doses of ICS. At the moment there are only a few studies that assess the dose-dependency of the anti-inflammatory effects of ICS. Most of these studies included only small numbers of patients. However, despite the 4–8–16-fold differences in the doses of ICS studied, it has not been easy to demonstrate the dose-dependency of the anti-inflammatory effects of inhaled glucocorticoids. Thus, based on the scarce published evidence we would predict that doubling of the commonly used low to moderate doses of ICS is likely to produce only a small increase in the anti-inflammatory effect, suggesting that inflammation may be suppressed in most patients by relatively low doses of ICS.Glucocorticoids suppress corticotrophin levels, which may eventually lead to atrophy of the adrenal cortex and diminished levels of endogenous cortisol. The diminished levels of endogenous cortisol or reduced cortisol excretion have been used as markers of systemic activity of ICS. These systemic effects may include osteoporosis, behavioural effects, growth suppression, posterior subcapsular cataracts, risk for ocular hypertension and glaucoma as well as skin thinning and bruising . In the Table 2b, see Table 2b, see Of the 14 studies included in this review, in 8 the effects on HPA-axis suppression were analysed. No data on the effects of BDP, budesonide or TAA on HPA-axis were reported. Six of the 7 randomised, double-blind dose-response studies with FP also analysed its effect on HPA axis, measuring either basal morning cortisol levels, post-cosyntropin stimulation test levels or urinary excretion of cortisol metabolites (The dose-related effects of HFA-BDP (200–800 μg/d) were studied in 43 steroid-naïve asthmatic patients in a randomized double-blind fashion for 14 days . When thA randomized double-blind study with consecutive dose design  comparinFP has also been shown to suppress 8 am serum cortisol and urinary cortisol/creatinine ratio in a dose-dependent manner in a single-blind placebo-controlled cross-over study for 9 days in patients (n = 12) with mild to moderate asthma . SimilarA Cochrane review  collecteBased on the recent Cochrane review and meta-analysis  it seemsIn two randomized studies, TAA in the dose range of 400–1600 μg/d ,51 did nTaken together, the data on the systemic adverse effects of ICS is conflicting and seems also to reflect the study design. Several studies have measured only the basal morning cortisol levels or levels after stimulation with high cosyntrophin doses. However, these may be insensitive markers for HPA-axis suppression . Differe2-agonists may have several other actions that may contribute to their efficacy in relieving asthma symptoms. β2-Agonists inhibit plasma exudation in the airways by acting on β2-receptors on postcapillary venule cells. They inhibit the secretion of bronchoconstrictor mediators from airway mast cells and may inhibit release of mediators from eosinophils, macrophages, T-lymphocytes and neutrophils. In addition, β2-agonists may have an inhibitory effect on the release of neuropeptides from sensory nerves [2-receptors in inflammatory cells to overcome the desensitisation in response to chronic β2-agonist exposure [LABA provide long-lasting relaxation of airway smooth muscle, while the ICS provide potent topical anti-inflammatory action. In addition to these complementary actions, βy nerves . Corticoexposure . In addiexposure ,66.1 reversibility of at least 10–15% was required –50% of predicted and a clearly positive symptom score was required in most studies  varied between 61 and 87% in different studies, being 61–70% in 4 studies, 70–80% in 3 studies, 81–87% in two studies and was not reported in three studies. The mean absolute PEF values varied from 299 to 404 L/min and FEV1 from 2.12 to 2.54 L  with an increase in FEV1 ≥15% after inhalation of terbutaline. Addition of formoterol was superior to the increase in steroid dose in increasing FEV1 and morning PEF  in the dose of inhaled budesonide (from 200 μg/d to 800 μg/d) in patients with moderate to severe symptomatic chronic asthma . The pat®) with an increased dose of budesonide (400 μg/d) in adults with mild to moderate asthma (mean FEV1 81–82%) not fully controlled on low doses of ICS alone. The increase in mean morning and evening PEF was significantly higher for budesonide/formoterol compared with budesonide alone. In addition, the percentage of symptom-free days and asthma control days were significantly improved in the budesonide/formoterol group. Budesonide and formoterol decreased the relative risk of an asthma exacerbation by 26% as compared with higher dose budesonide alone.Another study  compared1 86–87% of predicted and using approximately 1 rescue inhalation per day) [1 and morning PEF in the patients already treated with a low dose of ICS, but not in steroid-naïve patients (Table 5), or in reducing the percentage of days with symptoms, number of rescue inhalations or nights with awakenings in the patients with mild persistent asthma already treated with low doses of ICS  . In thisA subgroup of the patients participating in the formoterol study  was analAs compared with the abovementioned three studies, similar superiority of addition of formoterol on morning PEF, rescue medication use and asthma symptoms were reported in an open randomised parallel-group study comparing the addition of formoterol to the low-dose BDP with 2-fold higher dose of BDP in patients suffering from symptomatic asthma, despite the use of inhaled BDP .Tables 3 and 4, see 1 better than increasing the dose of ICS 2–4-fold in 5 studies  and mean morning PEF in 7 studies , respectively , have r2-agonists may mask an increase in the underlying airway inflammation in asthma. Also, some proinflammatory effects have been described for β2-agonists such as delay of constitutive eosinophil apoptosis [The results of the above mentioned studies favour the addition of a LABA instead of increasing the dose of ICS in patients not adequately controlled with low to moderate doses of ICS. However, there have been concerns that regular use of inhaled βpoptosis  or reverpoptosis . Furtherpoptosis -86 do nopoptosis .In a randomised, double-blind and parallel-group study (n = 61) with similar inclusion and exclusion criteria than in the formoterol add-on study , the eff+ and CD8+ lymphocytes and lymphocyte activation as assessed as proportions of lymphocytes expressing HLA-DR were measured in BAL samples before and after treatment. There were no significant changes after salmeterol treatment. In another double-blind, parallel-group, placebo-controlled study [1 and PEF. In the week before clinical exacerbation, sputum eosinophil counts were higher in the salmeterol-treatment arm as compared with placebo, whereas there were no differences in PC20 or serum ECP. Five subjects showed >10% sputum eosinophilia before exacerbation during salmeterol treatment, compared to two receiving placebo. This suggests that the use of salmeterol allowed subjects to tolerate a greater degree of inflammation without increased symptoms or reduced lung function. Thus, during progressive reduction of ICS the bronchodilator and symptom-relieving effects of salmeterol may mask increasing inflammation and delay awareness of worsening asthma. These findings strengthen guideline recommendations that LABA should not be described as sole anti-asthma medication and that they should be used as "add-on" therapy rather than for steroid tapering purposes.In a small study (n = 9) with asthma patients using regular inhaled glucocorticoids and inhaled salbutamol for symptom relief, the addition of salmeterol for 8 weeks was studied in a double-blind crossover placebo-controlled protocol . Bronchoed study  the effeed study . SubjectThe effect of addition of salmeterol (50 μg bd), FP (200 μg/d) or placebo for 3 months on airway wall vascular remodelling has been studied in 45 symptomatic patients with asthma who were receiving treatment with ICS (range 400–1000 μg/d) . BronchiIf there were a marked masking of pulmonary inflammation by LABA, one would expect to see an increase in the number and severity of asthma exacerbations during their long-term use. There is some difficulty in comparing the different studies done with formoterol and salmeterol as the definition of exacerbation varies. In formoterol studies ,68 a sevTable 7, see In the formoterol study  the mainTable 7, see In contrast to that described in moderate to severe asthma, in the other formoterol study  addition®) with an increased dose of budesonide (400 μg/d) in adults with mild to moderate asthma (mean FEV1 81–82%) not fully controlled on low doses of ICS alone. Budesonide/formoterol combination significantly decreased the relative risk of an asthma exacerbation by 26% as compared with higher dose budesonide alone. In contrast, the estimated risk of having a severe exacerbation was 6% lower in patients treated with budesonide/formoterol compared with those receiving budesonide alone, but this was not statistically significant.Another study  comparedOnly two studies ,78 of thTable 7, see In the salmeterol studies lasting 3–6 months the numbers of patients with exacerbations were analysed. The meta-analysis  revealedRecently, the exacerbation rates and clinical measures of asthma worsening were assessed in an analysis combining results from two double-blind studies (n = 925) comparing addition of salmeterol to low-dose-FP with increasing the dose of FP 2.5-fold . The addThe addition of LABA to the treatment regimen usually results in a slight increase in those pharmacologically predictable adverse events such as tremor and tachycardia. However, generally these do not lead to the discontinuation of the treatment. In the formoterol studies -69, no sCysteinyl leukotriene receptor-antagonists (LTRA), such as montelukast, pranlukast and zafirlukast, are a new class of asthma medication, whose role in the stepwise management of asthma has not yet been fully established. Leukotriene antagonists blunt the obstructive response and have weak anti-inflammatory activity. In some studies corticosteroids are not very effective inhibitors of cysteinyl leukotriene pathways, at least when assessed by their inability to reduce cysteinyl leukotriene concentrations ,92 and t1 ≥50% predicted at visits 1 and 3, with a ≥12% bronchodilator response and symptoms requiring β-agonist treatment of at least 1 puff/day during the last 2 weeks of the run in period . Both groups showed progressive improvement in several measures of asthma control compared with baseline. Mean morning PEF improved similarly in the last 10 weeks of treatment compared with baseline in both the montelukast + budesonide group and in the double dose budesonide group (33.5 vs 30.1 L/min). The improvement in montelukast + budesonide group was faster as the mean morning PEF was significantly higher during days 1–3 after start of treatment in this group as compared with the double dose budesonide group (20.1 vs 9.6 L/min) .We identified one randomised, double-blind, parallel-group 16 week study (Jadad score 3) comparing the addition of montelukast (10 mg/d) to budesonide (800 μg/d) with doubling the dose of budesonide (1600 μg/d) in patients inadequately controlled on inhaled budesonide  . The inc1 ≥55%, a bronchodilator response greater than 12%, symptoms and rescue β2 agonist use of at least 1 puff/day. The mean FEV1 at baseline was 81% predicted. The patients were randomised to obtain either montelukast (10 mg/d) or placebo in a double-blind manner. The ICS dose remained constant throughout the study. The primary efficacy end point was the percentage of asthma exacerbation days. The major advantage of this study is that this study adopted several different definitions for asthma exacerbation days from previously published other studies, making comparison to other studies more easy. The median percentage of asthma exacerbation days was 35% lower  and the median percentage of asthma free days was 56% higher  in the montelukast group than in the placebo group. Thus, the NNT with montelukast to avoid one exacerbation day was 13, and the NNT to avoid one day not free of asthma – that is, to gain an asthma free day – was 10. Patients receiving concomitant treatment with montelukast had significantly less  nocturnal awakenings, and significantly greater reductions in β2-agonist use , and morning PEF . No significant difference was found in asthma specific quality of life or in morning FEV1. The results of this study suggest that although the effect of montelukast on endpoints such as morning PEF, FEV1 and rescue β2-agonist use are only small or modest, addition of montelukast may produce a significant improvement of asthma control by reducing the number of asthma exacerbation days.A large (n = 639) study  recruite1 and PEF, asthma symptom score and the percentage of asthma exacerbation free days better than placebo during 16 week treatment period [1 was approximately 140 mL and in morning PEF 10 L/min. There was a tendency towards reduced rescue medication use with the combination therapy, but the reduction was only 0.2 puffs/day. Addition of montelukast to ICS seemed to prevent the increase in the number of peripheral blood eosinophils seen in other treatment groups.In another study with patients (n = 642) with symptomatic persistent asthma despite the treatment with BDP (400 μg/d), addition of montelukast (10 mg/d), improved morning FEVt period . The inc2-agonist use, or morning or evening PEF. When treatment response was defined as a 15% or greater increase in mean PEF recordings, there were four responders to montelukast and seven responders to placebo. Although several points in this study may be criticised , the results suggest that the effects of montelukast are not as evident in unselected population than in the more clearly defined patients included in other trials [In an atypical "add-on" study , addition of montelukast (10 mg/d) was compared with placebo in patients with asthma (n = 72) and symptoms despite treatment with ICS and additional therapy . Most ofr trials -95.1 or histamine PC20 between the two treatment regimens. There was no difference in the efficacy of either treatment in decreasing T cell, CD45RO+, mast cell or activated eosinophil numbers in bronchial biopsies. In a third study [The additional anti-inflammatory activity obtained by adding montelukast to the treatment regimen has been assessed in three randomised, double-blind, cross-over studies lasting 10 days–8 weeks. In one study , additiord study , the addAddition of high-dose zafirlukast (80 mg b.i.d.: 4-fold greater than the approved dose) improved asthma control better than placebo in patients (n = 368) on high-dose ICS (1000 – 4000 μg/d) ,102, in According to recent meta-analyses (12 adult studies and 1 in children) ,102, leuAlthough theophylline has traditionally been classified as a bronchodilator, its ability to control chronic asthma is greater than can be explained by its relatively small degree of bronchodilator activity. In fact, theophylline has immunomodulatory, anti-inflammatory and bronchoprotective effects that may contribute to its efficacy as an anti-asthma drug . There iThe addition of theophylline has been compared with doubling the dose of ICS  in two separate studies with 195 patients with symptomatic asthma for 6 to 12 weeks ,107. The1 predicted normal ≥50%, bronchodilator response of at least 15% and to have symptoms despite the use of ICS . The overall treatment effect of addition of theophylline was superior to double-dose budesonide in improving FVC and FEV1  or non-inferiority between the treatments.In the study (Jadad score 4) of Evans and coworkers  addition1 Figure , althoug1 50–85% predicted normal and a documented reversibility of at least 15% of FEV1 over baseline and to be not controlled by BDP (400 μg/d) or equivalent. The sample size of this study was powered to detect equivalence. No significant differences were found between the high-dose BDP and low-dose BDP plus theophylline groups in outcomes such as morning or evening PEF, PEF variability, FEV1, daytime or nighttime symptom scores or rescue medication use. Both treatments were well tolerated.A randomised, double-blind parallel-group study (Jadad score 3) by Ukena and coworkers  comparedet al. [2-agonist use, symptom scores or in the number of exacerbations. Of note is that there were no difference between the low dose BDP alone and high dose BDP groups in any of the parameters. This study was powered to detect superiority of theophylline plus BDP as compared with high-dose BDP. There were no significant differences between the treatment groups for any of the commonly reported adverse effects. The results of this study suggest that when the benefit of an "add-on" therapy is evaluated as compared with double-dose inhaled steroid, additional group using low-dose steroid alone should be included to see whether even the doubling of the dose of steroid produces any benefit to the patient.Lim et al.  recruiteTaken together, the results from two relatively small studies suggest that addition of low-dose theophylline may be equal to doubling the dose of ICS in the treatment of asthma not adequately controlled by low dose of ICS. However, one needs to remember that the effect of doubling the dose of ICS on asthma control is generally small or negligible (see above). Furthermore, a placebo group should be included in these studies to see whether an improvement in asthma control is obtained by doubling the dose of ICS. Thus, more data is needed to confirm the present results. Use of theophylline at concentrations at the lower limit or slightly below the recommended therapeutic range may help to limit the adverse effects.1 between 50% and 80% predicted normal, and at least 1 additional sign of inadequate asthma control during the 7 preceding days. Salmeterol/FP combination was superior to montelukast/FP in improving morning PEF (24.9 vs 13.0 L/min), evening PEF (18.9 vs 9.6 L/min), FEV1 (0.34 vs 0.20 L) and shortness of breath symptom score (-0.56 vs -0.40) as well as increasing the percentage of days without rescue medication (26.3 vs 19.1%). In contrast, there was no significant difference in outcomes such as chest tightness, wheeze and overall symptom scores. Asthma exacerbation rates were significantly (P = 0.031) lower in the FP + salmeterol group (2%) than in the FP+ montelukast group (6%). Adverse event profiles were reported to be similar.Combination of fluticasone (100 μg bid) and salmeterol (50 μg bid) in a single inhaler has recently been shown to provide more effective asthma control than montelukast (10 mg daily) combined with FP (100 μg bid) in a 12 weeks study  in patients (n = 447) whose symptoms were suboptimally controlled by ICS only . The inc1 above 50% and at least 15% bronchodilator response, and asthma symptoms at least at 4/7 days during run-in. Salmeterol/FP combination was superior to montelukast/FP in improving morning PEF (36 vs 19 L/min), evening PEF (29 vs 14 L/min), FEV1 (0.26 vs 0.17 L), percentage of symptom-free days (42.9 vs 31.5%), percentage of symptom-free nights (46.5 vs 41.1%) as well as increasing the percentage of days without rescue medication (47.9 vs 46%). In contrast, there was no significant difference in percentage of rescue free nights. The number of patients experiencing at least one asthma exacerbation (any severity) was significantly (P < 0.05) lower in the FP + salmeterol group (9.6%) than in the FP+ montelukast group (14.6%). The percentage of patients who had at least one asthma exacerbation of either moderate or severe intensity was 4.8% in the salmeterol + FP group and 8.4% in the montelukast + FP group, but this difference did not reach statistical significance. The time to the first exacerbation was significantly (P < 0.05) longer in the salmeterol + FP group than in the montelukast + FP group. Adverse event profiles were reported to be similar.A similar study  comparin1 50–90% predicted and at least 12% bronchodilator response, short-acting β2-agonist use of one puff/day or more and asthma symptoms. Salmeterol/FP combination was superior to montelukast/FP in improving morning PEF (34.6 vs 17.7 L/min), FEV1 (0.19 vs 0.11 L). In contrast, there was no significant difference in nocturnal awakenings and asthma specific quality of life score. The percentage of patients experiencing at least one asthma exacerbation (any severity) was shown to be similar in the FP + salmeterol group (19.1%) than in the FP+ montelukast group (20.1%). Also there was no difference in the time to the first exacerbation between the salmeterol + FP and the montelukast + FP groups. Peripheral blood eosinophils were reported to be reduced significantly more in the montelukast + FP group (-0.04 × 103/μl) than in the salmeterol + FP group (-0.01 × 103/μl). Interestingly more serious adverse events were reported in the salmeterol + FP group.Another very similar study  was desi1 between 50% and 80% predicted and at least 12% bronchodilator response. Treatment with salmeterol resulted in significantly greater improvements from baseline compared with montelukast for most efficacy measurements, including morning PEF (35.0 vs 21.7 L/min), percentage of symptom-free days (24 v 16%) and percentage of rescue-free days (27 vs 20%). Also total supplemental salbutamol use (-1.90 vs -1.66 puffs per day) and nighttime awakenings per week (-1.42 vs -1.32) decreased significantly more with salmeterol than with montelukast. Six percent of patients in the salmeterol group experienced a total of 27 asthma exacerbations compared with 5% of patients in the montelukast group who experienced 24 asthma exacerbations during the 12 weeks treatment period. However, the patients experiencing an asthma exacerbation were withdrawn from the study. Thus, annualised incidences of exacerbations cannot be compared [In another randomised, double-blind, double-dummy, parallel-group study (Jadad score 3) in patients (n = 948) with symptomatic asthma despite treatment with ICS, addition of montelukast (10 mg daily) was compared with addition of salmeterol (50 μg bid) for 12 weeks . Patientcompared . The saf1 in response to β2-agonist were 23–24% [2-agonist. However, one needs to remember that many of those studies done with leukotriene receptor antagonist to prove their efficacy in the treatment of asthma have been performed with patients displaying a significant response to β2-agonist. Another factor that might be considered to produce bias is that all the above three studies that report salmeterol to be better have been sponsored by the producer of salmeterol and that study reporting the non-inferiority of montelukast as compared with salmeterol has been sponsored by producer of montelukast.Taken together, addition of salmeterol seems to produce better improvement of asthma control when lung function is assessed than addition of montelukast in patients with asthma suboptimally controlled by small to moderate doses of ICS. However, in one long-term study  additione 23–24% , 27.0–27e 23–24%  and 18.4e 23–24%  in the s1, compared to placebo, there were significant differences with the first and last doses of montelukast as well as the first but not the last dose of salmeterol, thus indicating the development of some tolerance with salmeterol. Only montelukast produced a significant, albeit trivial, suppression of blood eosinophil count. There were significant improvements with the first doses of salmeterol for all parameters of lung function. After 2 weeks of treatment, there were significant improvements with both drugs on rescue bronchodilator requirement and morning PEF. There were no significant differences between drugs for any endpoints except blood eosinophils. Thus, the results suggest some anti-inflammatory activity for montelukast when used as an "add-on" therapy.In addition to the normal clinical endpoints, the effects of addition of salmeterol (50 μg bid) or montelukast (10 mg/d) to the treatment regimen were analysed on AMP bronchial challenge, blood eosinophil counts and exhaled NO in a placebo-controlled, double-dummy, crossover study in patients (n = 20) with persistent asthma not controlled with ICS . For the1 percentage predicted normal between 50 and 70% with or without asthma symptoms, or FEV1 of 70.1% to 80% of predicted normal values and symptoms or requirement for rescue β2-agonist use ≥4 puffs/day or diurnal PEF-variation of more than 20% at two days during 6 days run-in. Both inhaled salmeterol and oral zafirlukast resulted in within-group improvements from baseline in measures of pulmonary function (morning and evening PEF and FEV1), asthma symptoms, and supplemental salbutamol use. Salmeterol treatment resulted in significantly greater improvements from baseline compared with zafirlukast for most efficacy measurements, including morning PEF (28.8 vs 13.0 L/min), evening PEF (21.8 vs 11.2 L/min), combined patient-rated symptom scores for all symptoms (-35 vs 21%), daytime albuterol use (41 vs 25%) and night-time salbutamol use (42% vs 16%). Also, statistically significant differences favouring the addition of salmeterol were noted on patient-rated symptom scores for shortness of breath and chest tightness, percentage of symptom-free days, sleep symptoms, nighttime awakenings and percentage of days and nights with no albuterol use. There was no difference between the groups in symptom score for wheezing. Interestingly, the difference between salmeterol and zafirlukast was clear at week 1, but not at 4 weeks when the effect on FEV1 was analysed. One factor that may affect the results of this study is that there may be a randomisation bias as the proportions of patients using FP or TAA were not similar in the salmeterol and zafirlukast groups. This study was funded by the producer of salmeterol.In a randomised, double-blind, double-dummy parallel-group trial (Jadad score 3) addition of zafirlukast (20 mg bid) was compared with the addition of salmeterol (50 μg bid via MDI) for 4 weeks in adult and adolescent patients (n = 429) with persistent asthma . Patient1), asthma symptoms, and supplemental salbutamol use. Salmeterol treatment resulted in significantly greater improvements from baseline compared with zafirlukast for most efficacy measurements, including morning PEF (29.6 vs 13.0 L/min), percentage of symptom-free days (22.2% vs 8.8%) and percentage of days and nights with no supplemental albuterol use (30.5% vs. 11.3%).As a part of the above study , a rando1 reversibility of at least 15%. Patients (n = 64) were randomised to three different treatments budesonide (800 μg/d) plus formoterol (9 μg bid), budesonide (800 μg/d) plus zafirlukast (20 mg bid) or budesonide (800 μg/d) plus sustained-release theophylline (400 mg/d) for three months. After three months there were no between group differences in endpoints such as morning and evening PEF, PEF variability, FEV1, daytime or nighttime symptom scores and rescue terbutaline use. However, the addition of formoterol produced earlier improvements compared with the two other groups in criteria such as PEF variability, day- and night-time asthma symptom scores and supplemental terbutaline use. Patients in budesonide plus zafirlukast group experienced most adverse effects, but no statistical analysis was presented. The authors conclude that in patients who still have symptoms despite the treatment with ICS, the addition of any of these medications to the treatment is a logical approach and may be chosen.An open, randomised Turkish study  recruiteLABA  seem to have superior efficacy as add-on therapy in persistent asthma not controlled by low to moderate doses of ICS as compared with LTRA . More studies comparing the different add-on options are needed as well as studies with longer duration as the current evidence is mostly limited to follow-up period of 3 months.When assessing a patient with persistent asthma who is not adequately controlled by low to moderate doses of ICS:• It is important to find out whether the patient is using the prescribed medication correctly. Poor compliance in asthma patients treated with ICS is a very common reason for treatment failure. Compliance with ICS is often less than 50% ,118. Ora• Secondly, it is important to check whether the inhalation technique is adequate. Problems with the inhalation techniques are very common, especially among children and the elderly . Good pa• Thirdly, it is important to search for possible environmental factors, such as changes in home and working environment, hobbies and pets.If asthma exacerbations are the dominant problem, guided self-management of asthma has been proven to be an efficient treatment strategy. In a Cochrane review  self-manAddition of formoterol or salmeterol seems to be superior as compared with the increase in the dose of the ICS in improving lung function, controlling asthma symptoms and reducing the use of rescue bronchodilator treatment. By increasing (doubling) the dose of the ICS the clinical improvement is likely to be of small magnitude. However, if frequent exacerbations are the major problem, increasing the dose of ICS may significantly help to reduce the number of exacerbations. By avoiding doses above 1000 – 1500 μg/d (budesonide and BDP) or 500 – 750 μg/d (FP) the risk of systemic adverse effects remains low. However, it should be noted that the evidence on the superiority of LABA is limited to symptomatic patients with mild to severe persistent asthma currently treated with low to moderate doses of ICS and presenting with a significant bronchodilator response. Also, addition of the LTRA montelukast or zafirlukast may improve asthma control in patients remaining symptomatic with ICS and addition of montelukast may be equal to double-dose ICS. Addition of LABA  seems to produce better asthma control as compared with a LTRA (montelukast or zafirlukast) whereas the long-term efficacy of LTRA (montelukast) on asthma exacerbations may be equal to LABA . There is evidence that addition of low-dose theophylline to the treatment regimen may be equal to doubling of the dose of ICS. However, more studies are needed to better clarify the role of leukotriene antagonists and theophylline as "add on"-therapies. For patients with inappropriate inhalation technique the value of LTRA or theophylline are especially worth considering. More studies are now needed to compare between different add-on therapies and to explore the effect of more than one add-on therapy in patients with more severe asthma as well as in those having symptoms but not significant bronchodilator response.Another issue not addressed by these studies of large patient groups are the different responses of patients to the different add-on therapies. This needs to be studied by comparing add-on treatments in the same patients, but these studies are difficult and prolonged. In the future it may be possible to predict factors that predict the value of a particular add-on therapy in a particular patient, but the currently published studies unfortunately provide no guidance.50: forced expiratory flow when 50% of vital capacity has been exhaled, FENO: exhaled nitric oxide, FEV1: forced expiratory volume in one second, FP: fluticasone propionate, FVC: forced vital capacity, HFA: hydrofluoroalkane-134a formulation, HPA: hypothalamic-pituitary-adrenal, ICS: inhaled corticosteroid, LABA: long-acting β2-agonist, LTRA: leukotriene receptor antagonist, MDI: metered dose inhaler, NNH: number needed to harm, NNT: number needed to treat, PC20: provocative concentration causing a 20% fall in FEV1, PD20: provocative dose causing a 20% fall in FEV1, PEF: peak expiratory flow, TAA: triamcinolone acetonideACTH: corticotrophin, AMP: adenosine monophosphate, AQLQ: asthma quality of life questionnaire, BAL: bronchoalveolar lavage, BDP: beclomethasone dipropionate, ECP: eosinophil cationic protein, FEFHK carried out the literature searches, evaluated the studies, conceived the review and drafted the manuscript. AL, EM and PJB participated in the design and writing of the review. All authors read and approved the final manuscript.Tables 1–7-Kankaanranta.doc contains tables 1–7 of this review.Click here for file


Hypertension and diabetes mellitus are closely interrelated and coexist in as many as two-thirds of patients with type 2 diabetes. The consequent risk of such an association is an accelerated development of atherosclerotic cardiovascular disease and nephropathy complications.In choosing an antihypertensive agent, effectiveness needs to be accompanied by favourable metabolic, cardioprotective, and nephroprotective properties. Given the multifactorial nature of hypertension, the approach that has gained widespread agreement is treatment with more than one agent. Agents with different mechanisms of action increase antihypertensive efficacy because of synergistic impacts on the cardiovascular system. Combination therapy allows the use of lower doses of each antihypertensive agent which accounts for the excellent tolerability of combination products.The aim of the present study is to quantify the efficacy of combination therapy of Eprosartan 600 mg respectively Ramipril 5 mg with low-dose Hydrochlorothiazide and Moxonidine on blood pressure levels in patients with essential hypertension and associated diabetes mellitus type 2.The use of monotherapy (Eprosartan or Ramipril) followed by addition of low-dose Hydrochlorothiazide as second agent and of Moxonidine as a third agent will be individualized to the severity of hypertension in the particular patient and to his/her degree of response to current treatment. Cliniortality . Thus, mre < 130/0 mm Hg iThe challenge clinicians are facing is to tighten blood pressure control to less than 130/80 mmHg and to adjust initiation of therapy to the severity of hypertension in the individual patient.This multicenter study will evaluate the efficacy and tolerability of monotherapy, double- and triple- antihypertensive combination therapies in a large spectrum of hypertension & diabetes patient population, as summarised in Table response to that therapy.Table 2 see  specifieThe primary objectives of hypertension management in patients with diabetes are to reduce blood pressure levels to currently recommended target level and thus to reduce the risk of cardiovascular and renal complications without adversely impacting glycemic and lipid control.Previous debate regarding the level of blood pressure reduction that optimizes cardiovascular risk reduction is currently settled. BP goal of < 130/85 mmHg promoted by the JNC-VI guidelines issued 1997  were repA widespread agreement, supported by the above mentioned organizations/societies is in place, regarding the principles governing the use of appropriate antihypertensive drug combinations to maximize hypotensive efficacy while minimizing side effects. Polypharmacy is common place and, with at least one third of patients requiring two or more agents simultaneously, a paradigm shift in the approach of initiating therapy is done by advocating use of two agents in subjects with more severe hypertension . Low-dose thiazide diuretic is favored as one of the two starting agents.In general, monotherapy is likely to be successful in mild hypertensive patients (grade 1 hypertension) without associated major risk factors for CHD. In contrast, patients with type 2 diabetes need more rigorous control of BP in an easier, simpler fashion, given the remarkable complexity of the multiple drug regimens needed to control their comorbid medical problems .A large body of evidence derived from a multitude of international trials have demonstrated both the benefit of low-level, goal blood pressure, in terms of prevention of long-term complications and, the need for multiple drug combinations in order to achieve that goal ,18-20. FIn the HOT study , which rGiven the very poor BP control rate, i.e., 11% in patients with hypertension & diabetes, the use of combination therapy is an important therapeutic consideration, as it facilitates quicker and easier attainment of goal BP and should lead to a greater proportion of people with diabetes who achieve BP goal. Initiation of treatment by combination therapy was effectively tested in the VA study at the beginning of the antihypertensive treatment trial era ,26 and rSubjects will be recruited in outpatient clinics/offices of general practitioners and internal medicine/cardiology specialists from the entire spectrum of patients having coexistent hypertension and diabetes mellitus type 2. The upper limit of blood pressure values targeted (≤ 179/109 mmHg) correspond grade 2 hypertension (according to current ESC/ISH and WHO guidelines).Subjects to be recruited are supposed to have both entities  diagnosed since previously, undergoing current antihypertensive treatment and, to be eligible for the study according to the specific inclusion/exclusion criteria described below.The study consists of five distinct phases: Screening (S) (up to seven days), Placebo Run-in phase (two weeks), monotherapy , double-combination treatment , triple-combination treatment (Eprosartan/HCTZ/Moxonidine versus Ramipril/HCTZ/Moxonidine with HCTZ and Moxonidine open labelled) and Follow-up (two to seven days). Patients allocated to monotherapy will participate in the study for a four weeks period while those starting with double combination therapy will receive medication for a maximum of 12 weeks.The flowchart below captures the main events during the study conduct Fig. .Randomization will be concealed.A stratified randomization will be employed based on the following rules:1. Subjects with blood pressure in range: BP ≥ 130/80 – ≤ 150/90 mm Hg will be randomly allocated to one of the monotherapy arms (Eprosartan or Ramipril). 30 subjects will be recruited for each arm.2. Subjects with blood pressure in the range: BP > 150/90 – ≤ 179/109 mm Hg will be randomly allocated to double-combination therapy (Eprosartan/HCTZ or Ramipril/HCTZ); 190 subjects will be recruited for each arm.The randomization lists will be provided by the Department of Clinical Supplies at Solvay Pharmaceuticals BV with the program ADLS. Patients will be allocated in equal numbers to each sequence. A fixed block size of patients will be used, and only complete blocks of study medication will be provided to the centers.Within each center, randomization numbers will be used in ascending order and patients will be allocated to randomization code numbers in chronological order. The study will be unblinded when all CRFs are in house and the data on the database have been declared clean.The following drugs are to be used in the study:Eprosartan 600 mg, once daily• Ramipril 5 mg, once daily• Hydrochlorothiazide 12.5 mg, once daily• Moxonidine 0.4 mg, once daily• Placebo tablets matching Eprosartan 600 mg and Ramipril 5 mg will be used in the monotherapy, in the double- and in the triple-combination therapy phases. Hydrochlorothiazide tablets will be open labelled in the double- and triple-combination therapy phases. Moxonidine tablets will open-labelled in the triple-combination therapy phase.• Eprosartan and Ramipril and the corresponding placebos will be packaged according to the double-dummy technique. Fig. Patients eligible for participation in the study by the assessment at V2 will be randomized on the basis of the severity of their hypertension and allocated to either monotherapy or to double-combination therapy (described below).Patients with initial blood pressure values in the range ≥ 130/80 – ≤ 150/90 mmHg, will be randomly allocated to one of the monotherapy groups.By the end of the first four-week phase an assessment will be made as to whether patients have reached or not the "goal" hypertension (< 130/80 mmHg).Patients on monotherapy deemed to be responders at the end of four weeks treatment  will terminate their participation in the study and be followed up during the ensuing two to seven days after stopped monotherapy (procedure similar with Follow-up at end of study (V6).Non-responders , will receive double-combination therapy (Eprosartan/HCTZ respectively Ramipril/HCTZ) and will be followed-up for eight weeks (red-dotted line in the flowchart).Patients with initial blood pressure values in the range > 150/90 – ≤ 179/109 mmHg, will be randomly allocated to double-combination therapy. By the end of this first four-week phase an assessment will be made as to whether patients have reached or not the "goal" hypertension (< 130/80 mmHg).Responders will maintain double-combination therapy and will be followed-up for an eight week period  and retain therapy unchanged.Non-responders will receive triple-combination, as described below.Non-responder patients after four weeks of double-combination therapy will receive triple-combination (Eprosartan/HCTZ/Moxonidine vs. Ramipril/HCTZ/Moxonidine) and will be followed-up for an eight weeks period (V3 to V5).After the first four weeks of monotherapy respectively double-combination therapy (V3), patients will be reassessed for compliance, adverse events and supplied with medication for the next eight weeks .During the eight weeks triple-combination therapy all patients will be reassessed for compliance and adverse events . A 12-lead ECG will be performed by S, V3 and V5 while safety laboratory parameters will be performed by S, V2 and finally by visit V5.A Follow-up Visit will be performed on all patients with full physical examination, BP and pulse rate check within the ensuing two to seven days after study end (V6). Further follow-up and optimal treatment will be decided on a case-by-case basis by the physician in charge. Table 3 see  displays1. Males and females aged 40 to 80 years of age. Women of childbearing age will be subject to pregnancy testing and will agree to maintain adequate hormonal contraception.2. Eligible patients should have diagnosed essential hypertension  and diagnosed associated diabetes mellitus type 2, willing to accept withdrawal of any antihypertensive medication by the time of the Screening visit.A multitude of exclusion criteria, carefully listed in the study protocol, can be summarised in three different groups:1. Ineligibility based on hypertension grade 3 (BP ≥ 180/110 mmHg), any form of secondary hypertension or hypotension (SBP ≤ 90 mmHg).2. Any form of organic heart disease requiring medical treatment that might have hypotensive effect, imply need for invasive investigation or surgery.3. The patient is suffering from a severe concomitant illness related to any body organ or system, likely to affect outcome assessment. Likewise, ineligibility is declared for patient anticipated to have compliance problems, participants in another trial during the past 30 days, pregnancy and lactations and known hypersensitivity to ingredients of any of the employed agents . In addition, diabetes mellitus type 1 is exclusion criteria.lifestyle change advice regarding relevant diet and physical activity. Visits are to be scheduled in the context of the study . Any antihypertensive medication should be withdrawn latest by Screening visit and will be prohibited during the whole period of ongoing study.The study protocol calls for every patient to be treated optimally by the physician in charge and to receive comprehensive, individualized The study will be conducted in accordance with ICH GCP and the European Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001  and on the basis of ethical principles laid down in the current revision of the Declaration of Helsinki (Edinburgh 2000). In addition, Solvay Pharmaceuticals GmbH policies and procedures should also be followed.Written consent, involving provision of detailed information regarding the study objectives, design, scope of the intervention, risks and benefits, will be obtained for all patients before initiating any study procedures. Likewise, study documentation is to be subject to the scrutiny of local ethical committees in the two countries participating in the study.goal blood pressure (<130/80 mmHg) at visit V3.The primary objective is to demonstrate the superiority of combination therapy of Eprosartan/HCTZ (600/12.5 mg) versus Ramipril/HCTZ (5/12.5 mg) with the primary parameter of attention being the percentage of patients brought to 0: PE+HCTZ = PR+HCTZNull hypothesis: H1: PE+HCTZ ≠ PR+HCTZ,Alternative hypothesis: HE+HCTZ is the percentage of patients brought to goal blood pressure at visit 3 with Eprosartan/HCTZ and PR+HCTZ is the percentage of patients brought to goal blood pressure at visit V3 with Ramipril/HCTZ.Where PThe primary parameter will be analyzed using the Cochran-Mantel-Haenszel test, controlling for center effects. Statistical significance will be assessed with a two-sided test at 0.05 α level. The confirmative analysis of the primary parameter will be performed on the intent-to-treat patient sample.Secondary efficacy objectives:• To compare the mean change in sitting systolic blood pressure (sitSBP) and sitting diastolic blood pressure (sitDBP) between Eprosartan/HCTZ and Ramipril/HCTZ (V3 vs. V2).• To compare the percentage of patients brought to goal blood pressure by the triple-combination Eprosartan/HCTZ/Moxonidine vs. Ramipril/HCTZ/Moxonidine (V5 vs. V3).• To compare the mean change in sitSBP and sitDBP between triple-combination with Eprosartan/HCTZ/Moxonidine vs. Ramipril/HCTZ/Moxonidine (V5 vs. V3).• To compare the mean change in sitSBP and sitDBP between monotherapy with Eprosartan vs. Ramipril (V3 vs. V2)• To compare the percentage of patients brought to goal blood pressure at visit V5 between Eprosartan/HCTZ and Ramipril/HCTZ in patients not at goal blood pressure after four weeks of monotherapy.at goal) after four weeks of monotherapy (switched to double combination therapy) (V5 vs.V3); and to compare the mean change in sitSBP and sitDBP as well as the responder rate maintenance in patients who reached goal blood pressure value at the end of first four weeks of double-combination therapy and successively entered an eight weeks follow-up period (V5 vs.V3).• To compare the mean change in sitSBP and sitDBP as well as the responder rate in patients non-responders . The model will include the intercept, treatment and center as fixed effects and the baseline value as covariate. For response rates, the treatment groups will be compared using the Cochran-Mantel-Haenszel test, controlling for center effects. Comparisons of the medication regimens will be reported along with 95% confidence intervals of the relative risk ratios. These analyses will be considered as exploratory.All patients who receive at least one dose of double-blind medication will be assessed for clinical safety and tolerability. Evaluation of safety data will be based on comparisons of patient experience by treatment group. Clinical interpretation of safety will be based on reviews of standard displays of adverse events incidence, pulse rate data, and laboratory test values. Summary statistics of laboratory test values and incidence of adverse events according to treatment and time of onset will be presented.A formal sample size estimation has been done for patients with blood pressure in the range: > 150/90 mmHg and ≤ 179/109 mmHg.goal blood pressure as compared with only 40% in the Ramipril/HCTZ group, a 0.05% two-sided significance level with 80% power to detect the targeted 15% difference will imply the need for 346 patients supposed to complete the four-weeks double-combination therapy phase. Further 35 patients  will be recruited to account for drop-outs.Assuming that 55% of the patients in the Eprosartan/HCTZ group would reach In addition, 60 subjects with BP ≥ 130/80 and ≤ 150/90 mmHg will be randomly allocated to either Eprosartan or Ramipril monotherapy group at visit V2. Inclusion of monotherapy phase with a relatively low number of patients (30 subjects per arm) is justified by the intention to therapeutically target the whole spectrum of patient population having coexistent diabetes mellitus type 2 and mild to moderate hypertension, in whom the agents tested are likely to be effective.Office blood pressure will be determined by Riva-Rocci method with a mercury or a mercury calibrated sphygmomanometer throughout the study. All measurements will be made on the same arm supported at heart level, using the same cuff size and the same equipment. If the patient's arm circumference is > 32 cm, a large blood pressure cuff should be used. Diastolic blood pressure will be measured at the disappearance of Korotkoff sounds phaseV. Measurements should be taken by the same staff member at the particular visits.For an individual patient blood pressure measurements should be performed at 24 hours after the last oral dose, at the same time (± 2 hour) in the morning, between 8 and 10 am. Blood pressure will be measured in the following sequence: after the patient sits quietly for at least 5 minutes, blood pressure will be measured twice at approximately 2-minutes interval. The average of these measurements will be recorded. If the difference between measurements is in excess of 5 mmHg a third reading will be performed and the average value recorded as mean sitting systolic and diastolic blood pressure.Measurements should be performed by the same study assistant using the same device, in each of the centres involved in the study.goal blood pressure to be achieved in these patients. Further, common sense in clinical practice dictates that combination therapies should be tailored to severity of hypertension in the individual patient and that, eventual associated risk factors/comorbidities should be accounted for in the process of treatment decision making.The current evidence base is strongly in favour of combining drugs in order to achieve blood pressure goals, in particular in patients with coexistent hypertension & diabetes. Likewise, there is a widespread agreement in the scientific community as to the Patients with high blood pressure and associated impaired glucose tolerance or overt diabetes mellitus type 2, as a group, are insulin resistant,  glucose For every 5 to 10 mmHg decrease in systolic blood pressure achieved with diuretics, ARBs, ACE inhibitors, beta-blockers or calcium channel blockers in patients with diabetes, there is a 20% to 30% relative risk reduction in cardiovascular events -53.Agents belonging to the nine, most well-known different antihypertensive drug classes produce a similar reduction in systolic and diastolic blood pressure (10–15 and 5–10 mm Hg respectively). Differences in terms of magnitude of blood pressure lowering, as indicated by results from comparative efficacy studies, are usually small . HoweverComparisons between different agents in patients with hypertension & diabetes mellitus type 2, convincingly point to ACE inhibitors and ARBs as being the two classes of antihypertensive drugs that reduce the activity of the renin-angiotensin II system, and should be among the preferred first-step drugs for the treatment of these conditions . AngioteClinical trials carried out world-wide have shown that ACE inhibitors have renoprotective effects ,58 and cIn contrast, in placebo-controlled trials, the ARBs have demonstrated almost no side effects . Both ACUse of low-dose thiazide diuretic (< 25 mg) as a second agent in treatment of patients with hypertension & diabetes is well-documented and widely recommended ,70-73. ISince drug combinations may be required for many years in the age-groups in which type 2 diabetes is most prevalent, there have been calls for the use of agents devoid of adverse effects on carbohydrate and lipid metabolism. It has been suggested that such effects may account for the shortfall in reduction of coronary heart disease observed in clinical trials of diuretics and β-blockers ,81.1 receptors in the medulla, thereby reducing central sympathetic drive and attenuating peripheral vascular resistance. In addition, reduced sympathetic drive results in lower plasma concentrations of catecholamines and renin. Randomised comparative studies show that the efficacy of moxonidine as monotherapy is similar to that of other antihypertensive agents [1 receptor greatly reduces the adverse affects attributable to costimulation of medullary α2-adrenoceptors [Moxonidine stimulates imidazoline-Ie agents . Moreoveoceptors  observedIn clinical studies, moxonidine has been shown to have neutral or beneficial effects on lipid and carbohydrate metabolism ,83. A reOn the available evidence, moxonidine seems to be a logical choice as component of combination treatment of patients with hypertension and associated diabetes mellitus type 2 or impaired glucose tolerance.The poor blood pressure control in patients with hypertension & diabetes in everyday life lies, at least in part, in the emphasis in the evidence-based guidelines of the recent past towards advice on initial, single treatments as well as in their lack of clarity and transparency in recommending pre-specified blood pressure targets ,84-86.goal blood pressure and thereby to minimize long term risk of hypertension/diabetes-related complications [Previous consensual advice that combination treatments expose patients to the increased risk of adverse events has been replaced by good evidence to the contrary: use of several agents combined or of fixed-dose combinations treatments have the potential to bring patients to ications -27,87.blood pressure goal and individualized therapy on the basis of hypertension severity (and addition of a third agent in case of uncontrolled BP with two agents), comparative data to guide clinical practice is still lacking and this applies also to the comparison of ARBs versus ACE inhibitors. The present study attempts to explore this area.Despite the apparent simplicity of the paradigm shift towards clear Pater C, Berrou JP, Luszick J and Beckman K are employees of Solvay Pharmaceuticals.Study concept and design: Pater, Berrou, LuszickDrafting of manuscript: Pater, BhatnagarStatistical expertise: BeckmanTable 2 – Blood pressure-adjusted treatment stratificationClick here for fileTable 3 – Investigations ScheduleClick here for file


Rare mutations of the epithelial sodium channel (ENaC) result in the monogenic hypertension form of Liddle's syndrome. We decided to screen for common variants in the ENaC βand γ subunits in patients with essential hypertension and to relate their occurrence to the activity of circulating renin-angiotensin-aldosterone system.Initially, DNA samples from 27 patients with low renin/low aldosterone hypertension were examined. The DNA variants were subsequently screened for in 347 patients with treatment-resistant hypertension, 175 male subjects with documented long-lasting normotension and 301 healthy  Plasma renin and aldosterone levels were measured under baseline conditions and during postural and captopril challenge tests.Xenopus oocytes, neither of the two ENaC amino acid-changing variants showed a significant difference in activity compared with ENaC wild-type. No direct evidence for a mRNA splicing defect could be obtained for the βENaC intronic variant. The ratio of daily urinary potassium excretion to upright and mean  plasma renin activity was higher in variant allele carriers than in non-carriers (p = 0.034 and p = 0.048).Two commonly occurring βENaC variants (G589S and a novel intronic i12-17CT substitution) and one novel γENaC variant (V546I) were detected. One of these variants occurred in a heterozygous form in 32 patients, a prevalence (9.2%) significantly higher than that in normotensive males  and blood donors . βENaC i12-17CT was significantly more prevalent in the hypertension group than in the two control groups combined . When expressed in At least 9% of Finnish patients with hypertension admitted to a specialized center carry genetic variants of β and γENaC, a three times higher prevalence than in the normotensive individuals or in random healthy controls. Patients with the variant alleles showed an increased urinary potassium excretion rate in relation to their renin levels. Epidemiological studies have shown a significant correlation of blood pressure levels in close relatives and higher concordance values for occurrence of hypertension in monozygotic vs. dizygotic twins, and thus support the idea that genetic factors influence susceptibility to essential hypertension . While rDisappointments in the previous strategies justify alternative approaches in which a better phenotyping of the study individuals is connected to their targeted molecular genetic characterization. There are several features that collectively make the genes encoding the beta (βENaC) and gamma (γENaC) subunits of the kidney tubular epithelial sodium channel as serious candidates for susceptibility genes of low-renin human essential hypertension. First, gain of function mutations in β and γ ENaC subunits cause Liddle's syndrome, a well-known monogenic form of human hypertension associated with low renin activity and low plasma aldosterone level -15. SecoThe clinical records of all consecutive patients with hypertension n = 615) referred to the Hypertension Outpatient Ward, Helsinki University Central Hospital, between 1992–96 were reviewed. Moderate-to-severe hypertension, suspicion of secondary forms of hypertension, or hypertension resistant to drug treatment were causes to the admittance. A letter with request to donate a blood sample for genetic studies on hypertension was sent to those 598 individuals whose address became available in 1998. A total of 399 individuals (67%) of these responded and were subsequently examined at the Hypertension Outpatient Ward in 1998 to 1999. Clinical and family histories were recorded, and venous blood samples taken for DNA analysis. Based on the previous documents and current examinations, altogether 52 individuals were excluded from the present study: clinical records were missing or insufficient in four cases, 22 subjects were considered as normotensive, while 26 were judged to have a secondary form of hypertension. The latter group consisted of the following cases: renal artery stenosis (n = 12), adrenal cortical adenoma (n = 3), hydronephrosis (n = 2), pheochromocytoma (n = 1), IgA glomerulonephritis (n = 1), non-specific chronic glomerulonephritis (n = 1), LED nephritis (n = 1), diabetic nephropathia (n = 1), chronic pyelonephritis (n = 1), hypernephroma (n = 1), fibromuscular dysplasia (n = 1), unspecified renal failure (n = 1). The remaining 347 patients  comprised our final cohort of patients with moderate-to-severe essential hypertension. Antihypertensive drug treatment was in use in 283 (82%) of the patients . At least two concomitant drugs were used by 24% of the patients. A flow-chart of the study design is illustrated in Fig. 5 referreDNA was extracted from 301 randomly selected healthy blood donors aged 40–50 years  visiting the Finnish Red Cross Blood Transfusion Service. Their residences represent the same capital area from which the hypertensive patients originated.These individuals were selected from the participants in the Alpha-Tocopherol, Beta Carotene (ATBC) study  using thThe Ethics Review Committee of the Helsinki University Central Hospital approved this study, and all patients and controls gave their informed consent.The patients were advised to stop using estrogens and spironolactone at least 4 weeks before the tests, diuretics and prostaglandin inhibitors at least two weeks before the tests, and β-adrenergic antagonists and ACE inhibitors at least one week before the test. The only antihypertensive agents permitted at the time of the test were calcium channel blockers. Some of the patients were on oral potassium supplementation because of hypokalemia. The mean baseline blood pressure level at the time of captopril test was 139 ± 16/94 ± 10 mmHg in those without any drugs (n = 79), and 142 ± 16/95 ± 11 mmHg in those with calcium channel blockers (n = 234).Fasting blood samples were taken for determination of serum creatinine, uric acid, cholesterol, potassium, sodium and blood glucose concentrations. Urine samples for determination of the daily (24 h) excretion of potassium and sodium were collected. Most hypertensive patients (n = 298) underwent a test for the responsiveness of serum aldosterone level and plasma renin activity to postural change. To this end, the first blood sample was taken after at least 60 minutes of rest in supine position. After 2 hours of standing and moderate walking, a second blood sample was taken. This test was carried out at the inpatient ward in 220 cases and at the outpatient ward in 78 cases. Urinary electrolyte excretion rates were analyzed in 262 patients (26 ENaC variant carriers and 236 non-carriers) who did not use potassium supplementation.One to three days later, a captopril challenge test (CCT) was carried out as described earlier . This teGenomic DNA was extracted from peripheral venous blood using standard techniques. For targeted search for ENaC variants postulated to be associated with increased channel activity, we chose to sequence the exons 13 coding for the carboxyterminal domains of βENaC (amino acids 515–640) and γENaC (amino acids 524–649), as well as the 5'-flanking intronic regions, using oligonucleotide primers, PCR (polymerase chain reaction) conditions and sequencing instruments described previously by us . DNA samAluI , followed by analysis of the cleavage products on a 12% polyacrylamide gel. The wild-type (wt) allele results in longest fragments of 266 and 137 bp, while the variant allele produces fragments of 266 and 147 bp for βENaC -i12 -17CT, and 240 and 137 bp for βENaC G589S. For the γENaC V546I variant, 2.0 U of SfaNI (New England Biolabs) was used and the cleavage products were analyzed on a 2% agarose gel. The resulting fragment sizes were 357 and 77 bp for the wild-type allele and 279, 78 and 77 bp for the variant allele.Specific PCR-based methods were set up for assaying the three ENaC variants detected during the present study. After PCR of the βENaC fragment, the βENaC -i12 -17CT and βENaC G589S variants could be assayed simultaneously. An aliquot (8 μl) of the PCR product was digested with 3.0 U of in silico using GrailEXP v3.3  exon prediction program 27]), butrtension ,28. The rtension .Xenopus oocytes, these investigators were able to show a borderline 1.3 to 1.5-fold increase in activity for the G589S variant compared with the wild-type subunit. A similar trend was noticed in our experiments  and 175 normotensive males (p = 0.043). Patients with this variant allele displayed the lowest plasma renin levels and responses of all the subgroups examined .The authors declare that they have no competing interests.TH-H collected the clinical material, and participated in the DNA analyses and drafting of the manuscript. KK and TPH designed the study and drafted the manuscript. IT, TT, FF, KH designed the clinical chemical and hormonal assays, and participated in collection of the patient material. HF, HEM and KP participated in DNA analyses and bioinformatics. JV and TK collected the control populations and designed their studies. SS consulted in the statistical analyses and assisted in data handling. IG and LS carried out the electrophysiological studies and participated in drafting of the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:


Lack of antihypertensive use among hypertensive individuals is a major public health problem. It remains unclear as to how much of this lack of treatment is because of failure to diagnose hypertension or failure to initiate drug treatment for those with a diagnosis of hypertension. The primary aim of this study was to determine the proportion of those untreated individuals who would be recommended to start drug therapy for control of blood pressure among those aware or unaware of their diagnosis of hypertension.The Canadian Heart Health Surveys (1986 – 1992), a national, cross-sectional descriptive survey (n = 23 129), was used to determine the proportion of individuals who were untreated, yet satisfied the 2004 Canadian hypertension guidelines for initiating drug therapy. Patients were divided into subgroups of those aware and unaware of having a diagnosis of hypertension according to self reported awareness from the survey.Of those with untreated hypertension (= 140/90 mmHg), only 37% were aware of their diagnosis. 74% of untreated individuals aware of their diagnosis of hypertension would require drug therapy, compared to 57% of those who were unaware. Of those >65 years of age, 52% of aware individuals needed drug therapy whereas only 34% of unaware elderly would need drug treatment.In both unaware and aware subgroups, the majority of patients with untreated hypertension would benefit from antihypertensive drug therapy according to the 2004 Canadian Hypertension recommendations. The proportion of untreated patients that still need drug therapy was higher among those who were aware compared to those who were unaware. This finding suggests that the major gap in hypertension control may be in initiating drug therapy rather than in diagnosing hypertension. Further studies are needed to confirm these results to ultimately help strategize public health efforts in controlling hypertension. Antihypertensive drug therapy can reduce cardiovascular morbidity and mortality by 25–30% -3 in thoFrom the 2004 Canadian Hypertension Guidelines, pharmacotherapy is recommended if the diastolic blood pressure is > 100 mmHg; the systolic pressure is > 160 mmHg; or the diastolic blood pressure is >90 mmHg in the presence of cardiovascular heart disease or risk factors. To determine the proportions of individuals who satisfied the guidelines for initiation of drug treatment for hypertension, we used the Canadian Heart Health Surveys (1986 – 1992). This national, cross-sectional descriptive survey (n = 23 129) contains data on individual blood pressure measurements using standardized technique as well as information on cardiovascular risk profile, antihypertensive medication use and self reported awareness of hypertension. Further details of this survey have been published elsewhere [Of those with untreated hypertension (= 140/90 mmHg), only 37% (n = 897 786) were aware of their diagnosis. Among those aware and unaware of their diagnosis of hypertension, 35% vs. 36% were female; 14% vs. 12% had any cardiovascular disease and 31% vs. 75% were under the age of 65 years respectively. The proportions of those who would be recommended drug therapy among those who are aware and unaware are presented in Table In both unaware and aware subgroups, the majority of patients with untreated hypertension would benefit from antihypertensive drug therapy according to the 2004 Canadian Hypertension recommendations. This analysis extends the findings from other studies ,7,8 by dThere are several limitations with this study. First, the Canadian Heart Health Survey data are 12 years old and there is some evidence to suggest that prescription rates of antihypertensive drugs have improved since then . HoweverThis study found a considerable number of both unaware and aware patients with untreated hypertension require drug therapy. However, the majority of those who needed drug therapy were actually aware that they had a diagnosis of hypertension compared to those who were not aware. This finding suggests that the major gap in hypertension control may be in initiating drug therapy rather than in diagnosing hypertension. Further studies are needed to confirm these results to ultimately help strategize public health efforts in controlling hypertension.The author(s) declare that they have no competing interests.NK, DW and NC contributed to the design of the project. NK contributed to data analysis. NK, DW and NC contributed to writing the manuscript and for substantive, intellectual editing contributions.The pre-publication history for this paper can be accessed here:


Blood samples weredrawn before induction and 24 hours after surgery. Perioperativelevels of IL-6, TNF-α, CRP, cortisol, and leptin werecomparable among the groups. Twenty four hours after surgery,TNF-α and cortisol did not change; IL-6 and CRP increasedsignificantly in all patients. Significant increase in leptinlevels was found in patients undergoing spinal anaesthesia. Exceptfor the increase in leptin levels, there was no significantdifference related to the effects of general and spinalanaesthesia.Surgery induces release of neuroendocrine hormones (cortisol),cytokines , acute phase proteins . We studied the effects of general and spinal anaesthesiaon stress response to haemorrhoidectomy. Patients were assigned togeneral and spinal anaesthesia groups ( Cytokines are a heterogeneous group ofproteins and mediators of the immune-inflammatory responseto injury and infection. Interleukin-6 (IL-6) and tumour necrosisfactor-α (TNF-α) are proinflammatory components. IL-6 isSurgical stress induces neuroendocrines hormones (cortisol) andcytokines . IL-6 plays a major role ininitiating the acute phase protein (APP) reaction. C-reactiveprotein (CRP) is the main APP which increases during inflammatorystimulus, infection, or physical trauma , 4.Leptin (OB protein), is the adipocyte-derived product ofantiobesity gene and its circulating concentrations indirectlyreflect body fat stores. Serum cytokines may upregulate leptinlevels , 5, 6. LCytokines are elevated during perioperative period. SurgeryThe addition of the spinal block has an advantage over the use ofgeneral anaesthesia alone; reducing the neuroendocrine responsesurgery . The effn = 7) orspinal anaesthesia (n = 7) according to medical considerations andtheir desire, if clinically possible.Fourteen patients undergoing elective haemorrhoidectomy wereenrolled in the study. Local Hospital Ethics Committee approvaland informed consent were obtained from each patient. Exclusioncriteria were congestive heart failure, diabetes mellitus, thyroidpituitary, adrenal, kidney, or liver disease, glucocorticoidmedication, hypertension, hormone replacement therapy, malignancy,signs of acute infection or inflammation, pregnancy, obesity,malnutrition, and some conditions related to contraindication forspinal anaesthesia. Patients were assigned to general (Body mass index (BMI) values of the patients enrolled in the studywere 26 [19–28], 24 [19–27] (median [range]) in general andspinal anaesthesia groups, respectively, since leptin has goodpositive correlation with body fat mass and BMI.In order to avoid the confounding effect of diurnal variation,haemorrhoidectomies performed during morning sessions wereincluded in the study. All patients had Grade III and IVhaemorrhoidal disease. None of the patients had thrombosedhaemorrhoids. All operations were performed by the same surgeonswith standard surgical technique, namely Milligan-Morganhaemorrhoidectomy.For premedication, diazepam 10 mg and atropine 0.5 mgintramuscularly were used in all patients, 1 hour perioperatively.Patients were monitored using Datex monitor  which includedelectrocardiogram, noninvasive arterial blood pressure, and pulseoximetry, during the surgery.In general anaesthesia group , anaesthesia wasinduced with intravenous (iv) thiopental 5–7 mg/kg andfentanyl 0.5 μg/kg. Patients received iv vecuroniumbromide 0.1 mg/kg to facilitate endotracheal intubation. Afterintubation, 50% nitrous oxide in oxygen with 2% sevofluranewas used for maintenance.In spinal anaesthesia group , patients were placedin lateral decubitus position and a 25-gauge spinal needle wasinserted through the L3-4 intervertebral space. Hyperbaricbupivacaine 0.5% 2.5 mL (according to patient's height andweight) was injected into subarachnoid space.2 < 90%) wererecorded perioperatively.Adverse effects such as nausea, vomiting, hypotension , bradycardia (heart rate< 60 beats/min with hypotension), hypertension , tachycardia (heart rate> 100 /min), and low saturation levels (SpOVenous blood samples were drawn just before induction(perioperative) and 24 hours after the operation (postoperative).Blood samples were collected in apirogen tubes with ethylendiaminetetra-acetic acid. After being centrifuged, plasma was stored at−20°C until assayed.The CRP level was measured by immunoturbidimetric method withRoche kits, using modular analytics P module (Roche). The cortisollevels were determined by electrochemiluminescence immunoassaymethod with Roche kits, using E-170 (Roche). IL-6, TNF-α,and leptin were measured by micro ELISA (enzyme-linkedimmunosorbent assay) method with Biosource kits, using μ quantmicroplate reader (Biotek). The sensitivity, dynamic range, andaccuracy of these tests were as follows: < 8 1–1750, and< 2.8% for cortisol; 0.425, 1–280, and < 4.61% for CRP; < 2,7.8–500, and < 9.3% for IL-6; < 1.7, 15.6–1000, and < 8.5for TNF-α; < 0.36, 1.56–100, and < 4.6% for leptin,respectively.P < .05. The results were given as median [range].Statistical analysis was performed with the SPSS for Windows 11.5statistical programme. All parameters of two groups were comparedwith Mann-Whitney U. The changes within the groups were analysedusing Wilcoxon Signed Ranks Test. Statistical significance wasconsidered at The demographic data showed no significant differences between thegroups .Perioperative IL-6, TNF-α, CRP, cortisol, and leptin levelswere comparable among the groups .P = .043 and P = .018 in group-general, and P = .018 and P = .018 in group-spinal, resp). Leptin levels increased in two groups, but the significant increase was found in patientsundergoing spinal anaesthesia (P = .018)  .When comparing the results within the groups, IL-6 levels showedslight increase and TNF-α levels showed slight decrease in group-spinal,postoperatively. These differences were not statisticallysignificant. All other parameters remained similar ranges in twogroups .In group-spinal, hypotension developed in one patient just beforethe operation and iv ephedrine 5 mg was givenand the problem was resolved. In group-general, hypertension andtachycardia were observed in two patients during the operation.These symptoms were corrected with hyperventilation thusincreasing depth of anaesthesia.Neuroendocrine system is activated during and after surgery.Surgical stress-induced release of neuroendocrine hormones  and cytokines  provoke APP  synthesis and leptin has been shown itself to be anacute phase reactant .Opioids, etomidate, and benzodiazepins have inhibitory effects on the release of cortisol in patients undergoing surgery, 16. In In our study no significant changes in TNF-α levels aftersurgery were observed in either group and there were nosignificant differences between the groups. This observationrelated to TNF-α, is in accordance with a previous studyby Høgevold et al  in whichTotal intravenous anaesthesia (TIVA) with propofol and alfentanilare known to suppress IL-6 production in abdominal hysterectomy. Helmy eCho et al  found thA study in patients undergoing cardiac surgery showed thatperioperative haemodilution influenced cytokine measurementssignificantly .Haemorrhoidectomy operations are not accompanied by large fluidshifts and the haemodilution related to fluid therapy in spinalanaesthesia, disappears 24 hours after surgery .A previous study related to the effects of epidural anaesthesia onthe neuroendocrine response indicated that perioperative epiduralblockade of afferent neural impulses did not attenuate thebiochemical mediators of the stress response and has no benefit onclinical outcome . Spinal We could not find any effects of anaesthesia on CRP response tosurgery, as mentioned before in our studies investigating theeffects of anaesthetic techniques on CRP and albumin, duringdelivery  and circThe anaesthetic agents used in spinal anaesthesia, have minimaleffects on operation field due to lower concentration in systemiccirculation than the anaesthetic agents used in generalanaesthesia. Tissue injury of operation field leads to release ofmediators which induce cytokine response. This cytokine productionis correlated with tissue injury, but there may be a change insuppression of leukocyte functions. General anaesthetic agentshave some effects on cytokine response promoting proinflammatoryimmune response or suppressing of leukocyte functions, 22. We In conclusion, we could not find any significant differencerelated to the effects of anaesthetic techniques onproinflammatory and acute phase protein response tohaemorrhoidectomy. Although there was more increase in leptinlevels in spinal anaesthesia group, this difference was notclinically relevant.