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: BACKGROUND Neurogenic orthostatic hypotension ( nOH ) is common in Parkinson 's disease ( PD ) , and represents a failure to generate norepinephrine responses appropriate for postural change . Droxidopa ( L-threo-3,4-dihydroxyphenylserine ) is an oral norepinephrine prodrug . OBJECTIVE Interim analyses of the initial patients enrolled in a multicenter , r and omized , double-blind , placebo-controlled phase 3 trial of droxidopa for nOH in PD ( Clinical Trials.gov Identifier : NCT01176240 ) . METHODS PD patients with documented nOH underwent ≤ 2 weeks of double-blind droxidopa or placebo dosage optimization followed by 8 weeks of maintenance treatment ( 100 - 600 mg t.i.d . ) . The primary efficacy measure was change in Orthostatic Hypotension Question naire ( OHQ ) composite score from baseline to Week 8 . Key secondary variables included dizziness/lightheadedness score ( OHQ item 1 ) and patient-reported falls . RESULTS Among 24 droxidopa and 27 placebo recipients  , mean OHQ composite-score change at Week 8 was -2.2 versus -2.1 ( p = 0.98 ) ; in response to this pre-planned futility analysis , the study was temporarily stopped and all data from these patients were considered exploratory . At Week 1 , mean dizziness/lightheadedness score change  favored droxidopa by 1.5 units ( p = 0.24 ) , with subsequent numerical differences favoring droxidopa throughout the observation period , and at Week 1 , mean st and ing systolic blood-pressure change  favored droxidopa by 12.5 mmHg ( p = 0.04 ) . Compared with placebo , the droxidopa group exhibited an approximately 50 % lower rate of reported falls ( p = 0.16 ) and fall-related injuries ( post-hoc analysis ) . CONCLUSIONS This exploratory analysis of a small data set failed to show benefit of droxidopa , as compared with placebo by the primary endpoint . Nonetheless , there were signals of potential benefit for nOH , including improvement in dizziness/lightheadedness and reduction in falls , meriting evaluation in further trials Neurogenic orthostatic hypotension ( nOH ) results from failure of norepinephrine responses to postural change to maintain st and ing systolic blood pressure ( s-SBP ) . Droxidopa is an oral prodrug of norepinephrine . Study nOH306 enrolled patients with Parkinson 's disease ( PD ) and symptomatic nOH . Subjects underwent up to 2 weeks of double-blind titration of droxidopa or placebo , followed by 8 weeks of double-blind maintenance treatment ( 100 - 600 mg thrice-daily ) . For the initial 51 subjects ( study nOH306A , previously reported ) , the primary efficacy measure , Orthostatic Hypotension Question naire ( OHQ ) composite score , did not demonstrate significant change versus placebo at maintenance week 8 . For the subsequent 171 subjects ( study nOH306B , reported here ) , the primary efficacy measure was change versus placebo on item 1 ( " dizziness , lightheadedness , feeling faint , or feeling like you might black out " ) of the Orthostatic Hypotension Symptom Assessment ( OHSA ) subsection of the OHQ at maintenance week 1 . At week 1 , mean ( st and ard deviation ) improvement on OHSA item 1 was 2.3 ( 2.95 ) for droxidopa versus 1.3 ( 3.16 ) for placebo ( P = 0.018 ) . In addition , mean increase in s-SBP at week 1 was 6.4 ( 18.85 ) for droxidopa versus 0.7 ( 20.18 ) mmHg for placebo ( nominal P value : 0.032 ) . Differences in change in OHSA item 1 scores from baseline to maintenance weeks 2 , 4 , and 8 were not statistically significant . Adverse-event ( AE ) incidence was similar across groups , but 12.4 % of droxidopa and 6.1 % of placebo subjects withdrew because of AEs . The most common AEs on droxidopa ( vs. placebo ) were headache ( 13.5 % vs. 7.3 % ) and dizziness ( 10.1 % vs. 4.9 % ) . Study nOH306B demonstrated subjective ( OHSA item 1 ) and objective ( s-SBP ) evidence of short-term droxidopa efficacy ( vs. placebo ) for symptomatic nOH in PD Objective : To study the therapeutic effect and mechanism of action of 3,4-DL-threo-dihydroxyphenylserine ( DL-DOPS ) in neurogenic orthostatic hypotension . Methods : The blood pressure ( BP ) response to an orthostatic challenge on DL-DOPS was compared with that of placebo in a r and omized , double-blind , placebo-controlled , crossover trial in 10 patients . The mechanism of action of DOPS was studied by measuring forearm vascular resistance and changes in supine and upright plasma DL-DOPS and norepinephrine levels . The effect of DL-DOPS on the quality of life was determined by question naire . Results : DL-DOPS increased the supine ( p < 0.001 ) and upright ( p < 0.05 ) systolic blood pressure ( SBP ) and diastolic blood pressure ( DBP ) ( both p < 0.01 ) . The peak SBP on DL-DOPS in the supine position occurred 300 minutes after ingestion of the medication . The increase in BP was accompanied by an increase in plasma levels of norepinephrine and DL-DOPS  in both the supine and upright positions after DL-DOPS ingestion ( p < 0.0001 ) . There was a trend toward improvement in symptoms of orthostatic intolerance . Conclusion : DL-DOPS improved features of neurogenic orthostatic hypotension in patients with central and peripheral autonomic nervous system disease . There was an increase in plasma norepinephrine . No major side effects occurred OBJECTIVE To evaluate the efficacy of a 10-mg dose of midodrine 3 times per day in improving blood pressure ( BP ) and ameliorating symptoms of orthostatic hypotension in patients with neurogenic orthostatic hypotension .  Midodrine hydrochloride , an alpha-agonist , could improve orthostatic BP by increasing vasomotor and venomotor tone . DESIGN / METHODS A total of 171 patients with orthostatic hypotension participated in a multicenter , r and omized , placebo-controlled study . They were r and omized to a 10-mg dose of midodrine or placebo 3 times per day in a 6-week study , comprising single-blind run-in ( at week 1 ) and washout at weeks 5 and 6 , with an intervening double-blind period ( weeks 2 to 4 ) . SETTING Twenty-five centers , with most patients evaluated in referral centers . MAIN OUTCOME MEASURES The primary end points were improvement in st and ing systolic BP , symptoms of lightheadedness , and a global symptom relief score ( by the investigator and patient separately ) . RESULTS Nine patients were not evaluable because of noncompliance or taking concomitant vasoactive medications ( 3 in the midodrine group , 6 in the placebo group ) . In the evaluable patients , midodrine result ed in improvements in st and ing systolic BP at all time points ( P<.001 at visits 2 , 3 , 4 , and 5 ) , in reported symptoms by the end of the second week of treatment ( P=.001 ) , and in the global symptom relief score rated by both the patient ( P=.03 ) and the investigator ( P<.001 ) . There was no effect by center , severity of orthostatic hypotension , use of fludrocortisone or compression garments , or diagnosis . The main adverse effects were those of pilomotor reactions , urinary retention , and supine hypertension . CONCLUSIONS Midodrine is efficacious and safe in the treatment of neurogenic orthostatic hypotension Abstract —We evaluated whether droxidopa , a prodrug converted to norepinephrine , is beneficial in the treatment of symptomatic neurogenic orthostatic hypotension , which results from failure to generate an appropriate norepinephrine response to postural challenge . Patients with symptomatic neurogenic orthostatic hypotension and Parkinson disease , multiple system atrophy , pure autonomic failure , or nondiabetic autonomic neuropathy underwent open-label droxidopa titration ( 100–600 mg , 3 × daily ) . Responders then received an additional 7-day open-label treatment at their individualized dose . Patients were subsequently r and omized to continue with droxidopa or withdraw to placebo for 14 days . We then assessed patient-reported scores on the Orthostatic Hypotension Question naire and blood pressure measurements . Mean worsening of Orthostatic Hypotension Question naire dizziness/lightheadedness score from r and omization to end of study ( the primary outcome ; N=101 ) was 1.9±3.2 with placebo and 1.3±2.8 units with droxidopa ( P=0.509 ) . Four of the other 5 Orthostatic Hypotension Question naire symptom scores and all 4 symptom-impact scores  favored droxidopa , with statistical significance for the patient ’s self-reported ability to perform activities requiring st and ing a short time ( P=0.033 ) and st and ing a long time ( P=0.028 ) . Furthermore , a post hoc analysis of a predefined composite score of all symptoms ( Orthostatic Hypotension Question naire composite ) demonstrated a significant benefit for droxidopa ( P=0.013 ) . There was no significant difference between groups for st and ing systolic blood pressure ( P=0.680 ) . Droxidopa was well tolerated . In summary , this r and omized withdrawal droxidopa study failed to meet its primary efficacy end point . Additional clinical trials are needed to confirm that droxidopa is beneficial in symptomatic neurogenic orthostatic hypotension , as suggested by the positive secondary outcomes of this trial . Clinical Trial Registration —URL : http://www . clinical trials.gov . Unique identifier : NCT00633880 Background —In patients with neurogenic orthostatic hypotension ( NOH ) , the availability of the sympathetic neurotransmitter norepinephrine ( NE ) in the synaptic cleft is insufficient to maintain blood pressure while in the st and ing posture . Methods and Results —We determined the effect of oral administration of the synthetic amino acid L-threo-3,4-dihydroxyphenylserine ( L-DOPS ) , which is decarboxylated to NE by the enzyme L – aromatic amino acid decarboxylase ( L-AADC ) in neural and nonneural tissue , on blood pressure and orthostatic tolerance in 19 patients with severe NOH ( 8 with pure autonomic failure and 11 with multiple-system atrophy ) . A single-blind dose-titration study determined the most appropriate dose for each patient . Patients were then enrolled in a double-blind , placebo-controlled , crossover trial . L-DOPS significantly raised mean blood pressure both supine ( from 101±4 to 141±5 mm Hg ) and st and ing ( from 60±4 to 100±6 mm Hg ) for several hours and improved orthostatic tolerance in all patients . After L-DOPS , blood pressure increases were closely associated with increases in plasma NE levels . Oral administration of carbidopa , which inhibits L-AADC outside the blood-brain barrier , blunted both the increase in plasma NE and the pressor response to L-DOPS in all patients Conclusions —Acute administration of L-DOPS increases blood pressure and improves orthostatic tolerance in patients with NOH . The pressor effect results from conversion of L-DOPS to NE outside the central nervous system The prevention of injury associated with falls in older people  is a public health target in many countries around the world . Although there is good evidence that interventions such as multifactorial fall prevention and individually prescribed exercise are effective in reducing falls , the effect on serious injury rates is unclear . Historically , trials have not been adequately powered to detect injury endpoints , and variations in case definition across trials have hindered meta- analysis . It is possible that fall-prevention strategies have limited effect on falls that result in injuries or are ineffective in population s who are at a higher risk of injury . Further research is required to determine whether fall-prevention interventions can reduce serious injuries . Prevention of Falls Network Europe ( ProFaNE ) is a collaborative project to reduce the burden of fall injury in older people through excellence in research and promotion of best practice ( www.profane.eu.org ) . The European Commission funds the network , which links clinicians , members of the public , and research ers worldwide . The aims are to identify major gaps in knowledge in fall injury prevention and to facilitate the collaboration necessary for large-scale clinical research activity , including clinical trials , comparative research , and prospect i ve meta- analysis . Work is being undertaken in a 4-year program . As a first step , the development of a common set of outcome definitions and measures for future trials or meta- analysis was considered OBJECTIVE The objective of this study was to examine the prevalence and correlates of postural hypotension ( defined as a drop in systolic blood pressure of greater than or equal to 20 
    Output:
    
agent
***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: BACKGROUND Neurogenic orthostatic hypotension ( nOH ) is common in Parkinson 's disease ( PD ) , and represents a failure to generate norepinephrine responses appropriate for postural change . Droxidopa ( L-threo-3,4-dihydroxyphenylserine ) is an oral norepinephrine prodrug . OBJECTIVE Interim analyses of the initial patients enrolled in a multicenter , r and omized , double-blind , placebo-controlled phase 3 trial of droxidopa for nOH in PD ( Clinical Trials.gov Identifier : NCT01176240 ) . METHODS PD patients with documented nOH underwent ≤ 2 weeks of double-blind droxidopa or placebo dosage optimization followed by 8 weeks of maintenance treatment ( 100 - 600 mg t.i.d . ) . The primary efficacy measure was change in Orthostatic Hypotension Question naire ( OHQ ) composite score from baseline to Week 8 . Key secondary variables included dizziness/lightheadedness score ( OHQ item 1 ) and patient-reported falls . RESULTS Among 24 droxidopa and 27 placebo recipients  , mean OHQ composite-score change at Week 8 was -2.2 versus -2.1 ( p = 0.98 ) ; in response to this pre-planned futility analysis , the study was temporarily stopped and all data from these patients were considered exploratory . At Week 1 , mean dizziness/lightheadedness score change  favored droxidopa by 1.5 units ( p = 0.24 ) , with subsequent numerical differences favoring droxidopa throughout the observation period , and at Week 1 , mean st and ing systolic blood-pressure change  favored droxidopa by 12.5 mmHg ( p = 0.04 ) . Compared with placebo , the droxidopa group exhibited an approximately 50 % lower rate of reported falls ( p = 0.16 ) and fall-related injuries ( post-hoc analysis ) . CONCLUSIONS This exploratory analysis of a small data set failed to show benefit of droxidopa , as compared with placebo by the primary endpoint . Nonetheless , there were signals of potential benefit for nOH , including improvement in dizziness/lightheadedness and reduction in falls , meriting evaluation in further trials Neurogenic orthostatic hypotension ( nOH ) results from failure of norepinephrine responses to postural change to maintain st and ing systolic blood pressure ( s-SBP ) . Droxidopa is an oral prodrug of norepinephrine . Study nOH306 enrolled patients with Parkinson 's disease ( PD ) and symptomatic nOH . Subjects underwent up to 2 weeks of double-blind titration of droxidopa or placebo , followed by 8 weeks of double-blind maintenance treatment ( 100 - 600 mg thrice-daily ) . For the initial 51 subjects ( study nOH306A , previously reported ) , the primary efficacy measure , Orthostatic Hypotension Question naire ( OHQ ) composite score , did not demonstrate significant change versus placebo at maintenance week 8 . For the subsequent 171 subjects ( study nOH306B , reported here ) , the primary efficacy measure was change versus placebo on item 1 ( " dizziness , lightheadedness , feeling faint , or feeling like you might black out " ) of the Orthostatic Hypotension Symptom Assessment ( OHSA ) subsection of the OHQ at maintenance week 1 . At week 1 , mean ( st and ard deviation ) improvement on OHSA item 1 was 2.3 ( 2.95 ) for droxidopa versus 1.3 ( 3.16 ) for placebo ( P = 0.018 ) . In addition , mean increase in s-SBP at week 1 was 6.4 ( 18.85 ) for droxidopa versus 0.7 ( 20.18 ) mmHg for placebo ( nominal P value : 0.032 ) . Differences in change in OHSA item 1 scores from baseline to maintenance weeks 2 , 4 , and 8 were not statistically significant . Adverse-event ( AE ) incidence was similar across groups , but 12.4 % of droxidopa and 6.1 % of placebo subjects withdrew because of AEs . The most common AEs on droxidopa ( vs. placebo ) were headache ( 13.5 % vs. 7.3 % ) and dizziness ( 10.1 % vs. 4.9 % ) . Study nOH306B demonstrated subjective ( OHSA item 1 ) and objective ( s-SBP ) evidence of short-term droxidopa efficacy ( vs. placebo ) for symptomatic nOH in PD Objective : To study the therapeutic effect and mechanism of action of 3,4-DL-threo-dihydroxyphenylserine ( DL-DOPS ) in neurogenic orthostatic hypotension . Methods : The blood pressure ( BP ) response to an orthostatic challenge on DL-DOPS was compared with that of placebo in a r and omized , double-blind , placebo-controlled , crossover trial in 10 patients . The mechanism of action of DOPS was studied by measuring forearm vascular resistance and changes in supine and upright plasma DL-DOPS and norepinephrine levels . The effect of DL-DOPS on the quality of life was determined by question naire . Results : DL-DOPS increased the supine ( p < 0.001 ) and upright ( p < 0.05 ) systolic blood pressure ( SBP ) and diastolic blood pressure ( DBP ) ( both p < 0.01 ) . The peak SBP on DL-DOPS in the supine position occurred 300 minutes after ingestion of the medication . The increase in BP was accompanied by an increase in plasma levels of norepinephrine and DL-DOPS  in both the supine and upright positions after DL-DOPS ingestion ( p < 0.0001 ) . There was a trend toward improvement in symptoms of orthostatic intolerance . Conclusion : DL-DOPS improved features of neurogenic orthostatic hypotension in patients with central and peripheral autonomic nervous system disease . There was an increase in plasma norepinephrine . No major side effects occurred OBJECTIVE To evaluate the efficacy of a 10-mg dose of midodrine 3 times per day in improving blood pressure ( BP ) and ameliorating symptoms of orthostatic hypotension in patients with neurogenic orthostatic hypotension .  Midodrine hydrochloride , an alpha-agonist , could improve orthostatic BP by increasing vasomotor and venomotor tone . DESIGN / METHODS A total of 171 patients with orthostatic hypotension participated in a multicenter , r and omized , placebo-controlled study . They were r and omized to a 10-mg dose of midodrine or placebo 3 times per day in a 6-week study , comprising single-blind run-in ( at week 1 ) and washout at weeks 5 and 6 , with an intervening double-blind period ( weeks 2 to 4 ) . SETTING Twenty-five centers , with most patients evaluated in referral centers . MAIN OUTCOME MEASURES The primary end points were improvement in st and ing systolic BP , symptoms of lightheadedness , and a global symptom relief score ( by the investigator and patient separately ) . RESULTS Nine patients were not evaluable because of noncompliance or taking concomitant vasoactive medications ( 3 in the midodrine group , 6 in the placebo group ) . In the evaluable patients , midodrine result ed in improvements in st and ing systolic BP at all time points ( P<.001 at visits 2 , 3 , 4 , and 5 ) , in reported symptoms by the end of the second week of treatment ( P=.001 ) , and in the global symptom relief score rated by both the patient ( P=.03 ) and the investigator ( P<.001 ) . There was no effect by center , severity of orthostatic hypotension , use of fludrocortisone or compression garments , or diagnosis . The main adverse effects were those of pilomotor reactions , urinary retention , and supine hypertension . CONCLUSIONS Midodrine is efficacious and safe in the treatment of neurogenic orthostatic hypotension Abstract —We evaluated whether droxidopa , a prodrug converted to norepinephrine , is beneficial in the treatment of symptomatic neurogenic orthostatic hypotension , which results from failure to generate an appropriate norepinephrine response to postural challenge . Patients with symptomatic neurogenic orthostatic hypotension and Parkinson disease , multiple system atrophy , pure autonomic failure , or nondiabetic autonomic neuropathy underwent open-label droxidopa titration ( 100–600 mg , 3 × daily ) . Responders then received an additional 7-day open-label treatment at their individualized dose . Patients were subsequently r and omized to continue with droxidopa or withdraw to placebo for 14 days . We then assessed patient-reported scores on the Orthostatic Hypotension Question naire and blood pressure measurements . Mean worsening of Orthostatic Hypotension Question naire dizziness/lightheadedness score from r and omization to end of study ( the primary outcome ; N=101 ) was 1.9±3.2 with placebo and 1.3±2.8 units with droxidopa ( P=0.509 ) . Four of the other 5 Orthostatic Hypotension Question naire symptom scores and all 4 symptom-impact scores  favored droxidopa , with statistical significance for the patient ’s self-reported ability to perform activities requiring st and ing a short time ( P=0.033 ) and st and ing a long time ( P=0.028 ) . Furthermore , a post hoc analysis of a predefined composite score of all symptoms ( Orthostatic Hypotension Question naire composite ) demonstrated a significant benefit for droxidopa ( P=0.013 ) . There was no significant difference between groups for st and ing systolic blood pressure ( P=0.680 ) . Droxidopa was well tolerated . In summary , this r and omized withdrawal droxidopa study failed to meet its primary efficacy end point . Additional clinical trials are needed to confirm that droxidopa is beneficial in symptomatic neurogenic orthostatic hypotension , as suggested by the positive secondary outcomes of this trial . Clinical Trial Registration —URL : http://www . clinical trials.gov . Unique identifier : NCT00633880 Background —In patients with neurogenic orthostatic hypotension ( NOH ) , the availability of the sympathetic neurotransmitter norepinephrine ( NE ) in the synaptic cleft is insufficient to maintain blood pressure while in the st and ing posture . Methods and Results —We determined the effect of oral administration of the synthetic amino acid L-threo-3,4-dihydroxyphenylserine ( L-DOPS ) , which is decarboxylated to NE by the enzyme L – aromatic amino acid decarboxylase ( L-AADC ) in neural and nonneural tissue , on blood pressure and orthostatic tolerance in 19 patients with severe NOH ( 8 with pure autonomic failure and 11 with multiple-system atrophy ) . A single-blind dose-titration study determined the most appropriate dose for each patient . Patients were then enrolled in a double-blind , placebo-controlled , crossover trial . L-DOPS significantly raised mean blood pressure both supine ( from 101±4 to 141±5 mm Hg ) and st and ing ( from 60±4 to 100±6 mm Hg ) for several hours and improved orthostatic tolerance in all patients . After L-DOPS , blood pressure increases were closely associated with increases in plasma NE levels . Oral administration of carbidopa , which inhibits L-AADC outside the blood-brain barrier , blunted both the increase in plasma NE and the pressor response to L-DOPS in all patients Conclusions —Acute administration of L-DOPS increases blood pressure and improves orthostatic tolerance in patients with NOH . The pressor effect results from conversion of L-DOPS to NE outside the central nervous system The prevention of injury associated with falls in older people  is a public health target in many countries around the world . Although there is good evidence that interventions such as multifactorial fall prevention and individually prescribed exercise are effective in reducing falls , the effect on serious injury rates is unclear . Historically , trials have not been adequately powered to detect injury endpoints , and variations in case definition across trials have hindered meta- analysis . It is possible that fall-prevention strategies have limited effect on falls that result in injuries or are ineffective in population s who are at a higher risk of injury . Further research is required to determine whether fall-prevention interventions can reduce serious injuries . Prevention of Falls Network Europe ( ProFaNE ) is a collaborative project to reduce the burden of fall injury in older people through excellence in research and promotion of best practice ( www.profane.eu.org ) . The European Commission funds the network , which links clinicians , members of the public , and research ers worldwide . The aims are to identify major gaps in knowledge in fall injury prevention and to facilitate the collaboration necessary for large-scale clinical research activity , including clinical trials , comparative research , and prospect i ve meta- analysis . Work is being undertaken in a 4-year program . As a first step , the development of a common set of outcome definitions and measures for future trials or meta- analysis was considered OBJECTIVE The objective of this study was to examine the prevalence and correlates of postural hypotension ( defined as a drop in systolic blood pressure of greater than or equal to 20 
    Output:
    