human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: A multicentre , r and omised , placebo-controlled parallel group study comparing various doses of the combination diltiazem SR ( DTZ SR)/hydrochlorothiazide ( HCTZ ) with the monotherapies was performed to delineate the optimal antihypertensive dosage of the two drug combinations . The study was carried out in 298 patients with mild to moderate essential hypertension ( stable supine diastolic blood pressure , DBP , greater than or equal to 95 and less than or equal to 110 mmHg ) . After a single-blind placebo lead-in period lasting 4 - 6 weeks to establish stable baseline BP , the patients were r and omised to receive either placebo ( n = 75 ) , HCTZ ( n = 76 ) , DTZ SR ( n = 72 ) , or the combination of DTZ SR/HCTZ ( n = 75 ) . There were three 4-week evaluation periods with forced escalation of therapy as follows : HCTZ ( 6.25 , 6.25 , 12.5 mg twice daily ) , DTZ SR ( 60 , 90 , 120 mg twice daily ) , and the combination of DTZ SR/HCTZ ( 60/6.25 , 90/6.25 , 120/12.5 mg twice daily ) . DTZ SR/HCTZ ( 120/12.5 mg ) produced statistically significantly greater reductions in supine DBP compared with each monotherapy and placebo . The lower doses of DTZ SR/HCTZ ( 60/6.25 mg and 90/6.25 mg ) produced statistically significantly greater supine DBP reductions compared with DTZ SR monotherapy and placebo , but not compared with HCTZ monotherapy . A comparison of reduction in supine DBP between evaluation periods demonstrated a dose-response relationship for the combination therapy in reducing BP over the dosage range studied . Adverse clinical and laboratory events were not significantly different between the therapies . ( ABSTRACT TRUNCATED AT 250 WORDS The effect of long-term treatment with indapamide in platelet alpha 2-adrenoceptors has been evaluated in 10 patients with essential hypertension , in a double-blind , cross-over study with placebo . After three months of therapy , indapamide significantly reduced mean blood pressure ( from 137 + /- 12 to 116 + /- 6 mm Hg , p less than 0.001 ) , whereas heart rate did not change ( from 72 + /- 8 to 73 + /- 7 beats/minute ) . At the same time , platelet alpha 2-adrenoceptor number increased ( from 168.2 + /- 48.4 to 256.8 + /- 14.5 fmol/mg protein , p less than 0.02 ) , whereas the dissociation constant did not change ( from 3.79 + /- 2.9 to 4.97 + /- 4.48 ) . The plasma norepinephrine level was significantly reduced after long-term treatment with indapamide ( from 275 + /- 118 to 210 + /- 56 pg/ml , p less than 0.02 ) . These results bring about an inhibition of norepinephrine release from sympathetic nerve endings with a likely secondary increase of the number of platelet alpha 2-adrenoceptors 1 . The anti-hypertensive actions of timolol and hydrochlorothiazide were analysed in a double-blind 2 x 2 factorial trial in twenty patients with essential hypertension . Each patient went through four phases of 8 weeks in r and omized order , receiving timolol alone , hydrochlorothiazide alone , timolol plus hydrochlorothiazide , and placebo . 2 . Supine mean arterial pressure fell from 119 mmHg in the placebo phase , to 110 mmHg during the thiazide phase , 106 mmHg during the timolol phase , and to 101 mmHg during the combined timolol plus hydrochlorothiazide phase . 3 . Factorial analysis revealed that the hypotensive actions of the beta-receptor-blocking drug and the diuretic were additive , without any synergism or antagonism . 4 . Plasma renin activity measured in ng 3 h-1 ml-1 rose from 5 - 02 in the placebo phase to 9 - 54 in the diuretic phase , but fell to 1 - 79 in the beta-receptor blockade . It was unchanged in the combined therapy phase , despite the greater drop in blood pressure . These results suggest that the fall in plasma renin activity during beta-receptor blockade is of little importance in the hypotensive action of beta-receptor-blocking drugs In a double‐blind study , 28 patients having mild to moderate essential hypertension were r and omly assigned to a 6‐week regimen of ticrynafen , hydrochlorothiazide , or placebo .  Blood pressure fell after ticrynafen and hydrochlorothiazide .  Serum uric acid fell strikingly with ticrynafen whereas it rose with hydrochlorothiazide .  Serum potassium declined very little with ticrynafen ; much less than with hydrochlorothiazide . Serum creatinine and blood urea nitrogen rose slightly more with ticrynafen than with hydrochlorothiazide . There were no clinical adverse effects to either of the medications . Ticrynafen appears to be an effective antihypertensive with a substantial hypouricemic effect The antihypertensive effects of atenolol and hydrochlorothiazide were compared with placebo in a r and omized , double-blind crossover study , with the blood pressure responses related to sympathetic nervous system activity . Twelve patients with essential hypertension were given atenolol ( 100 mg ) , hydrochlorothiazide ( 50 mg ) , and placebo as single daily doses , each for 6 weeks . Mean supine , st and ing , and post-exercise blood pressures ( mm Hg ) on atenolol ( 155/94 , 152/95 , 177/93 , respectively ) and hydrochlorothiazide ( 154/99 , 150/103 , 172/96 ) were lower ( p less than 0.01 ) than corresponding placebo values ( 172/109 , 166/113 , 204/111 ) at 6 weeks . The role of the sympathetic nervous system in the antihypertensive actions of atenolol and hydrochlorothiazide was examined . The supine plasma norepinephrine on placebo was used as an index of sympathetic activity to categorize each patient 's " adrenergic status . " The six " hyperadrenergic " patients with high resting norepinephrine values ( mean , 302 pg/ml ) exhibited a greater ( p = 0.05 ) decrease in BP ( -30/-20 mm Hg ) on atenolol compared with the BP fall of -9/-11 mm Hg observed in the lower norepinephrine group ( mean , 211 pg/ml ) . Resting plasma norepinephrine values did not predict the BP fall on hydrochlorothiazide . The " adrenergic status " of each patient as measured by the plasma norepinephrine concentration tended to be relatively constant regardless of therapy or the state of activity . In this study , atenolol was an effective antihypertensive agent comparable to hydrochlorothiazide in potency . Adrenergic status tended to predict the BP response to atenolol and was a relatively constant feature of the patients in all treatment phases Two hundred and eleven patients with mild or moderate hypertension , mean age 53.5 + /- 9.5 years ( range 24 - 70 ) were r and omised double-blind to treatment with either captopril 50 mg ( C50 ) , hydrochlorothiazide 25 mg ( HCTZ 25 ) , the fixed combination of captopril 50 mg and hydrochlorothiazide 25 mg ( C50/HCTZ 25 ) or placebo .  Blood pressure , heart rate , body weight and side effects were assessed at the end of the run-in period on placebo and after 4 , 6 , 8 weeks treatment at the same time , 20 - 24 h after the last dosing . Routine biochemical examinations were carried out on all patients after the placebo period as well as after 4 and 8 weeks . Blood pressure significantly decreased in all groups , but the mean percentage change from baseline was highly statistically significant at 8 weeks , for C50 and C50/HCTZ 25 groups . The incidence of clinical side effects was low and not statistically different for the four groups with few specific adverse effects ( one transient alteration of taste in captopril group ) . No patient was withdrawn from the study due to side effects . A better anti-hypertensive efficacy was obtained with the fixed combination captopril 50 mg/hydrochlorothiazide 25 mg once daily compared to placebo or each component alone , and without any difference in side effects BACKGROUND Most patients with hypertension require more than one agent to control blood pressure ( BP ) . The purpose of this study was to assess the efficacy and safety of the angiotensin II receptor blocker olmesartan medoxomil in combination with hydrochlorothiazide ( HCTZ ) . METHODS This was a r and omized , double-blind , factorial design study . After a placebo run-in period , eligible patients ( n = 502 ) with a baseline mean seated diastolic blood pressure ( SeDBP ) of 100 to 115 mm Hg were r and omized to one of 12 groups :  placebo , olmesartan medoxomil monotherapy ( 10 , 20 , or 40 mg/day , HCTZ monotherapy ( 12.5 or 25 mg/day ) , or one of six groups of olmesartan medoxomil/HCTZ combination therapy . The primary endpoint was the change in mean trough SeDBP from baseline at week 8 . Statistical analyses were conducted to determine whether at least one combination produced a larger reduction in SeDBP at week 8 than the individual corresponding component doses , but did not compare BP reductions with different combination doses . RESULTS Olmesartan medoxomil plus HCTZ produced greater reductions in both SeDBP and seated systolic blood pressure ( SeSBP ) at week 8 than did monotherapy with either component . All olmesartan medoxomil/HCTZ combinations significantly reduced SeDBP and SeSBP compared with placebo in a dose-dependent manner . Reductions from baseline in mean trough SeSBP/SeDBP were 3.3/8.2 mm Hg , 20.1/16.4 mm Hg , and 26.8/21.9 mm Hg with placebo , olmesartan medoxomil/HCTZ 20/12.5 mg , and olmesartan medoxomil/HCTZ 40/25 mg , respectively . All treatments were well tolerated . CONCLUSIONS Olmesartan medoxomil/HCTZ combination therapy produced BP reductions of up to 26.8/21.9 mm Hg and was well tolerated This placebo-controlled multifactorial design trial assessed the antihypertensive efficacy of nebivolol , a novel cardioselective beta 1-blocker with vasodilating properties , and hydrochlorothiazide monotherapy and in combination . After a 4-week placebo period , 240 white patients with a mean daytime ambulatory blood pressure of > or = 90 mm Hg were r and omized to receive either placebo , nebivolol ( 1 , 5 , or 10 mg ) , hydrochlorothiazide ( 12.5 or 25 mg ) , or one of the six possible combinations of nebivolol and hydrochlorothiazide for 12 weeks . A dose-related reduction in clinic and ambulatory blood pressure was demonstrated for each drug as monotherapy and for the two drugs in combination . Nebivolol , 5- and 10-mg doses , showed a larger effect than hydrochlorothiazide doses on clinic blood pressure and over the 24-h interval . Moreover , the combination doses had substantial antihypertensive effects that were sustained over the entire 24-h profile with a greater effect observed with the higher dose combinations . The reduction in ambulatory blood pressure was further substantiated by the reduction of blood pressure loads ( % of BP > 140/90 mm Hg awake and > 120/80 mm Hg asleep ) to as low as 11.5 % with 10 mg of nebivolol combined with 25 mg of hydrochlorothiazide . Nebivolol and hydrochlorothiazide were well tolerated . We provided evidence that nebivolol , given as monotherapy or in combination with low dose of hydrochlorothiazide , is effective in reducing clinic and 24-h ambulatory blood pressure in patients with ambulatory hypertension . The results provided further evidence for the use of ambulatory blood pressure monitoring and factorial design s when investigating new antihypertensive agents Objective To establish the optimal dose of the perindopril/indapamide combination ( Per/Ind ) in the treatment of mild or moderate hypertension . Design This was a r and omized , double-blind , placebo-controlled , seven-way parallel-group , dose-ranging study , set in multicenter , outpatient offices/clinics in Europe and Canada . Patients A total of 438 patients aged between 18 and 75 years whose supine diastolic blood pressure was between 95 and 11 
    Output:
    
agent
Direct comparison of doses did not show evidence of dose dependence for blood pressure-lowering for any of the other thiazides for which RCT data were available : bendrofluazide , chlorthalidone , cyclopenthiazide , metolazone or indapamide .
This is based on an informal indirect comparison of results observed in other Cochrane review s on ACE inhibitors , ARBs and renin inhibitors compared with placebo , which used similar inclusion /exclusion criteria to the present review .Thiazides reduced potassium , increased uric acid and increased total cholesterol and triglycerides .
These effects were dose-related and were least for hydrochlorothiazide .
Chlorthalidone increased serum glucose but the evidence was unclear for other thiazides .
This systematic review shows that hydrochlorothiazide has a dose-related blood pressure-lowering effect .
Thiazides reduced potassium , increased uric acid and increased total cholesterol and triglycerides
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: A multicentre , r and omised , placebo-controlled parallel group study comparing various doses of the combination diltiazem SR ( DTZ SR)/hydrochlorothiazide ( HCTZ ) with the monotherapies was performed to delineate the optimal antihypertensive dosage of the two drug combinations . The study was carried out in 298 patients with mild to moderate essential hypertension ( stable supine diastolic blood pressure , DBP , greater than or equal to 95 and less than or equal to 110 mmHg ) . After a single-blind placebo lead-in period lasting 4 - 6 weeks to establish stable baseline BP , the patients were r and omised to receive either placebo ( n = 75 ) , HCTZ ( n = 76 ) , DTZ SR ( n = 72 ) , or the combination of DTZ SR/HCTZ ( n = 75 ) . There were three 4-week evaluation periods with forced escalation of therapy as follows : HCTZ ( 6.25 , 6.25 , 12.5 mg twice daily ) , DTZ SR ( 60 , 90 , 120 mg twice daily ) , and the combination of DTZ SR/HCTZ ( 60/6.25 , 90/6.25 , 120/12.5 mg twice daily ) . DTZ SR/HCTZ ( 120/12.5 mg ) produced statistically significantly greater reductions in supine DBP compared with each monotherapy and placebo . The lower doses of DTZ SR/HCTZ ( 60/6.25 mg and 90/6.25 mg ) produced statistically significantly greater supine DBP reductions compared with DTZ SR monotherapy and placebo , but not compared with HCTZ monotherapy . A comparison of reduction in supine DBP between evaluation periods demonstrated a dose-response relationship for the combination therapy in reducing BP over the dosage range studied . Adverse clinical and laboratory events were not significantly different between the therapies . ( ABSTRACT TRUNCATED AT 250 WORDS The effect of long-term treatment with indapamide in platelet alpha 2-adrenoceptors has been evaluated in 10 patients with essential hypertension , in a double-blind , cross-over study with placebo . After three months of therapy , indapamide significantly reduced mean blood pressure ( from 137 + /- 12 to 116 + /- 6 mm Hg , p less than 0.001 ) , whereas heart rate did not change ( from 72 + /- 8 to 73 + /- 7 beats/minute ) . At the same time , platelet alpha 2-adrenoceptor number increased ( from 168.2 + /- 48.4 to 256.8 + /- 14.5 fmol/mg protein , p less than 0.02 ) , whereas the dissociation constant did not change ( from 3.79 + /- 2.9 to 4.97 + /- 4.48 ) . The plasma norepinephrine level was significantly reduced after long-term treatment with indapamide ( from 275 + /- 118 to 210 + /- 56 pg/ml , p less than 0.02 ) . These results bring about an inhibition of norepinephrine release from sympathetic nerve endings with a likely secondary increase of the number of platelet alpha 2-adrenoceptors 1 . The anti-hypertensive actions of timolol and hydrochlorothiazide were analysed in a double-blind 2 x 2 factorial trial in twenty patients with essential hypertension . Each patient went through four phases of 8 weeks in r and omized order , receiving timolol alone , hydrochlorothiazide alone , timolol plus hydrochlorothiazide , and placebo . 2 . Supine mean arterial pressure fell from 119 mmHg in the placebo phase , to 110 mmHg during the thiazide phase , 106 mmHg during the timolol phase , and to 101 mmHg during the combined timolol plus hydrochlorothiazide phase . 3 . Factorial analysis revealed that the hypotensive actions of the beta-receptor-blocking drug and the diuretic were additive , without any synergism or antagonism . 4 . Plasma renin activity measured in ng 3 h-1 ml-1 rose from 5 - 02 in the placebo phase to 9 - 54 in the diuretic phase , but fell to 1 - 79 in the beta-receptor blockade . It was unchanged in the combined therapy phase , despite the greater drop in blood pressure . These results suggest that the fall in plasma renin activity during beta-receptor blockade is of little importance in the hypotensive action of beta-receptor-blocking drugs In a double‐blind study , 28 patients having mild to moderate essential hypertension were r and omly assigned to a 6‐week regimen of ticrynafen , hydrochlorothiazide , or placebo .  Blood pressure fell after ticrynafen and hydrochlorothiazide .  Serum uric acid fell strikingly with ticrynafen whereas it rose with hydrochlorothiazide .  Serum potassium declined very little with ticrynafen ; much less than with hydrochlorothiazide . Serum creatinine and blood urea nitrogen rose slightly more with ticrynafen than with hydrochlorothiazide . There were no clinical adverse effects to either of the medications . Ticrynafen appears to be an effective antihypertensive with a substantial hypouricemic effect The antihypertensive effects of atenolol and hydrochlorothiazide were compared with placebo in a r and omized , double-blind crossover study , with the blood pressure responses related to sympathetic nervous system activity . Twelve patients with essential hypertension were given atenolol ( 100 mg ) , hydrochlorothiazide ( 50 mg ) , and placebo as single daily doses , each for 6 weeks . Mean supine , st and ing , and post-exercise blood pressures ( mm Hg ) on atenolol ( 155/94 , 152/95 , 177/93 , respectively ) and hydrochlorothiazide ( 154/99 , 150/103 , 172/96 ) were lower ( p less than 0.01 ) than corresponding placebo values ( 172/109 , 166/113 , 204/111 ) at 6 weeks . The role of the sympathetic nervous system in the antihypertensive actions of atenolol and hydrochlorothiazide was examined . The supine plasma norepinephrine on placebo was used as an index of sympathetic activity to categorize each patient 's " adrenergic status . " The six " hyperadrenergic " patients with high resting norepinephrine values ( mean , 302 pg/ml ) exhibited a greater ( p = 0.05 ) decrease in BP ( -30/-20 mm Hg ) on atenolol compared with the BP fall of -9/-11 mm Hg observed in the lower norepinephrine group ( mean , 211 pg/ml ) . Resting plasma norepinephrine values did not predict the BP fall on hydrochlorothiazide . The " adrenergic status " of each patient as measured by the plasma norepinephrine concentration tended to be relatively constant regardless of therapy or the state of activity . In this study , atenolol was an effective antihypertensive agent comparable to hydrochlorothiazide in potency . Adrenergic status tended to predict the BP response to atenolol and was a relatively constant feature of the patients in all treatment phases Two hundred and eleven patients with mild or moderate hypertension , mean age 53.5 + /- 9.5 years ( range 24 - 70 ) were r and omised double-blind to treatment with either captopril 50 mg ( C50 ) , hydrochlorothiazide 25 mg ( HCTZ 25 ) , the fixed combination of captopril 50 mg and hydrochlorothiazide 25 mg ( C50/HCTZ 25 ) or placebo .  Blood pressure , heart rate , body weight and side effects were assessed at the end of the run-in period on placebo and after 4 , 6 , 8 weeks treatment at the same time , 20 - 24 h after the last dosing . Routine biochemical examinations were carried out on all patients after the placebo period as well as after 4 and 8 weeks . Blood pressure significantly decreased in all groups , but the mean percentage change from baseline was highly statistically significant at 8 weeks , for C50 and C50/HCTZ 25 groups . The incidence of clinical side effects was low and not statistically different for the four groups with few specific adverse effects ( one transient alteration of taste in captopril group ) . No patient was withdrawn from the study due to side effects . A better anti-hypertensive efficacy was obtained with the fixed combination captopril 50 mg/hydrochlorothiazide 25 mg once daily compared to placebo or each component alone , and without any difference in side effects BACKGROUND Most patients with hypertension require more than one agent to control blood pressure ( BP ) . The purpose of this study was to assess the efficacy and safety of the angiotensin II receptor blocker olmesartan medoxomil in combination with hydrochlorothiazide ( HCTZ ) . METHODS This was a r and omized , double-blind , factorial design study . After a placebo run-in period , eligible patients ( n = 502 ) with a baseline mean seated diastolic blood pressure ( SeDBP ) of 100 to 115 mm Hg were r and omized to one of 12 groups :  placebo , olmesartan medoxomil monotherapy ( 10 , 20 , or 40 mg/day , HCTZ monotherapy ( 12.5 or 25 mg/day ) , or one of six groups of olmesartan medoxomil/HCTZ combination therapy . The primary endpoint was the change in mean trough SeDBP from baseline at week 8 . Statistical analyses were conducted to determine whether at least one combination produced a larger reduction in SeDBP at week 8 than the individual corresponding component doses , but did not compare BP reductions with different combination doses . RESULTS Olmesartan medoxomil plus HCTZ produced greater reductions in both SeDBP and seated systolic blood pressure ( SeSBP ) at week 8 than did monotherapy with either component . All olmesartan medoxomil/HCTZ combinations significantly reduced SeDBP and SeSBP compared with placebo in a dose-dependent manner . Reductions from baseline in mean trough SeSBP/SeDBP were 3.3/8.2 mm Hg , 20.1/16.4 mm Hg , and 26.8/21.9 mm Hg with placebo , olmesartan medoxomil/HCTZ 20/12.5 mg , and olmesartan medoxomil/HCTZ 40/25 mg , respectively . All treatments were well tolerated . CONCLUSIONS Olmesartan medoxomil/HCTZ combination therapy produced BP reductions of up to 26.8/21.9 mm Hg and was well tolerated This placebo-controlled multifactorial design trial assessed the antihypertensive efficacy of nebivolol , a novel cardioselective beta 1-blocker with vasodilating properties , and hydrochlorothiazide monotherapy and in combination . After a 4-week placebo period , 240 white patients with a mean daytime ambulatory blood pressure of > or = 90 mm Hg were r and omized to receive either placebo , nebivolol ( 1 , 5 , or 10 mg ) , hydrochlorothiazide ( 12.5 or 25 mg ) , or one of the six possible combinations of nebivolol and hydrochlorothiazide for 12 weeks . A dose-related reduction in clinic and ambulatory blood pressure was demonstrated for each drug as monotherapy and for the two drugs in combination . Nebivolol , 5- and 10-mg doses , showed a larger effect than hydrochlorothiazide doses on clinic blood pressure and over the 24-h interval . Moreover , the combination doses had substantial antihypertensive effects that were sustained over the entire 24-h profile with a greater effect observed with the higher dose combinations . The reduction in ambulatory blood pressure was further substantiated by the reduction of blood pressure loads ( % of BP > 140/90 mm Hg awake and > 120/80 mm Hg asleep ) to as low as 11.5 % with 10 mg of nebivolol combined with 25 mg of hydrochlorothiazide . Nebivolol and hydrochlorothiazide were well tolerated . We provided evidence that nebivolol , given as monotherapy or in combination with low dose of hydrochlorothiazide , is effective in reducing clinic and 24-h ambulatory blood pressure in patients with ambulatory hypertension . The results provided further evidence for the use of ambulatory blood pressure monitoring and factorial design s when investigating new antihypertensive agents Objective To establish the optimal dose of the perindopril/indapamide combination ( Per/Ind ) in the treatment of mild or moderate hypertension . Design This was a r and omized , double-blind , placebo-controlled , seven-way parallel-group , dose-ranging study , set in multicenter , outpatient offices/clinics in Europe and Canada . Patients A total of 438 patients aged between 18 and 75 years whose supine diastolic blood pressure was between 95 and 11 
    Output:
    