Droxidopa in patients with neurogenic orthostatic hypotension associated with Parkinson's disease (NOH306A). Droxidopa for the short-term treatment of symptomatic neurogenic orthostatic hypotension in Parkinson's disease (nOH306B). The treatment of neurogenic orthostatic hypotension with 3,4-DL-threo-dihydroxyphenylserine Efficacy of midodrine vs placebo in neurogenic orthostatic hypotension. A randomized, double-blind multicenter study. Midodrine Study Group. Randomized Withdrawal Study of Patients With Symptomatic Neurogenic Orthostatic Hypotension Responsive to Droxidopa Norepinephrine Precursor Therapy in Neurogenic Orthostatic Hypotension Development of a common outcome data set for fall injury prevention trials: the Prevention of Falls Network Europe consensus. Prevalence of postural hypotension at baseline in the Systolic Hypertension in the Elderly Program (SHEP) cohort. DL‐Threo‐3,4‐dihydroxyphenylserine does not exert a pressor effect in orthostatic hypotension l-threo-dihydroxyphenylserine (l-threo-DOPS; droxidopa) in the management of neurogenic orthostatic hypotension: A multi-national, multi-center, dose-ranging study in multiple system atrophy and pure autonomic failure The Orthostatic Hypotension Questionnaire (OHQ): validation of a novel symptom assessment scale ENDOGENOUS RESTORATION OF NORADRENALINE BY PRECURSOR THERAPY IN DOPAMINE-BETA-HYDROXYLASE DEFICIENCY
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 mm Hg ) in a cohort of elderly persons with isolated systolic hypertension ( ISH ) . DESIGN Baseline cross-sectional analysis of the 4,736 persons r and omized in the Systolic Hypertension in the Elderly Program ( SHEP ) . SETTING A r and omized multi-center double-blind outpatient clinical trial of the impact of treating ISH . PARTICIPANTS Men and women age greater than or equal to 60 years with the systolic blood pressure ( SBP ) greater than or equal to 160 mm Hg and diastolic blood pressure ( DBP ) less than 90 mm Hg . MEASURES Medical histories were obtained using interviewer-administered , st and ardized clinical history forms . At entry into the study ,  seated and st and ing BP was measured by certified BP technicians using a r and om zero sphygmomanometer . Postural hypotension ( PH ) was assessed at 1 and 3 minutes after the participant arose from a seated position . MAIN RESULTS PH was found in 10.4 % of participants at 1 minute and in 12.0 % of participants at 3 minutes . 5.3 % of participants demonstrated PH at both time intervals while 17.3 % demonstrated PH at either or both of the time intervals . Factors significantly ( P less than 0.05 ) associated with the presence of PH were higher mean SBP and a lower mean body mass index . CONCLUSIONS Somewhat different persons were defined as having PH based upon the 1 minute and 3 minute st and ing measures of BP , and prevalence estimates of PH can vary depending on whether one or more intervals of measurement are used . Cross-sectional data analysis indicated that PH , in healthy community-dwelling older persons with ISH , may not be associated with a history of disorders or problems usually thought to be related to PH . However , prospect i ve data are needed to determine the prognostic significance of PH , and whether one or multiple measurements carry more significance DL‐Threo‐3,4‐dihydroxyphenylserine ( DL‐DOPS ) was given to six subjects with severe orthostatic hypotension ( OH ) . On separate days each subject took either 600 or 800 mg DL‐DOPS or placebo . DL‐DOPS  increased norepinephrine ( NE ) excretion 10,000 % and urinary normetanephrine and dihydroxyphenylglycol excretion 400 % . DL‐DOPS , however , led to only slight increases in excretion of the major NE metabolites 3‐methoxy‐4‐hydroxyphenylglycol and vanillylm and elic acid . Only approximately 2.2 % ± 0.5 % ( range 0.65 % to 3.8 % ) of the L‐stereoisomer ( L‐DOPS ) , when given as DL‐DOPS , is converted to NE in vivo over 24 hr . DL‐DOPS did not affect either supine or upright blood pressure in our subjects . Our findings do not support reports that DL‐DOPS may be therapeutically useful in OH This study was design ed to determine the efficacy and tolerability of increasing doses ofl-threo-dihydroxyphenylserine ( l-threo-DOPS ) in treating  symptomatic orthostatic hypotension associated with multiple system atrophy ( MSA ) and pure autonomic failure ( PAF ) . Following a one-week run-in , patients ( 26 MSA ; 6 PAF ) with symptomatic orthostatic hypotension  received increasing doses ofl-threo-DOPS ( 100 , 200 and 300 mg , twice daily ) in an open , dose-ranging study . Incremental dose adjustment ( after weeks two and four of outpatient treatment ) was based on clinical need until blood pressure ( BP ) , and symptoms improved . Final dosage was maintained for six weeks . Withl-threo-DOPS  , systolic BP decrease was reduced during orthostatic challenge ( −22±28 mm Hg reduction from a baseline decrease of 54.3±27.7 mm Hg , p=0.0001 , n=32 ; supine systolic BP at final visit was 118.9±28.2 mm Hg ) . By the end of the study , 25 patients ( 78 % ) improved , and in 14 patients ( 44 % ) orthostatic hypotension was no longer observed . Decreased orthostatic systolic BP decrease occurred in 22 % ( 7/32 ) , 24 % ( 6/25 ) and 61 % ( 11/18 ) of patients treated with 100 , 200 , and 300 mgl-threo-DOPS twice daily , respectively . An improvement occurred in symptoms associated with orthostatic hypotension , such as light-headedness , dizziness ( p=0.0125 ) , and blurred vision (p=0.0290).l-threo-DOPS was well tolerated , with the 2 serious adverse events reported being a possible complication of the disease under study , and with no reports of supine hypertension . I conclusion , l-threo-DOPS ( 100 , 200 , and 300 mg , twice daily ) was well tolerated . The dosage of 300 mg twice dailyl-threo-DOPS seemed to offer the most effective control of symptomatic orthostatic hypotension in MSA and PAF Background There is no widely accepted vali date d scale to assess the comprehensive symptom burden and severity of neurogenic orthostatic hypotension ( NOH ) . The Orthostatic Hypotension Question naire ( OHQ ) was developed , with two components : the six-item symptoms assessment scale and a four-item daily activity scale to assess the burden of symptoms . Validation analyses were then performed on the two scales and a composite score of the OHQ . Methods The validation analyses of the OHQ were performed using data from patients with NOH participating in a phase IV , double blind , r and omized , cross over , placebo-controlled trial of the alpha agonist midodrine .  Convergent validity was assessed by correlating OHQ scores with clinician global impression scores of severity as well as with generic health question naire scores . Test – retest reliability was evaluated using intraclass correlation coefficients at baseline and crossover in a subgroup of patients who reported no change in symptoms across visits on a patient global impression scores of change . Responsiveness was examined by determining whether worsening or improvement in the patients ’ underlying disease status produced an appropriate change in OHQ scores . Results Baseline data were collected in 137 enrolled patients , follow-up data were collected in 104 patients r and omized to treatment arm . Analyses were conducted using all available data . The floor and ceiling effects were minimal . OHQ scores were highly correlated with other patient reported outcome measures , indicating excellent convergent validity . Test – retest reliability was good . OHQ scores could distinguish between patients with severe and patients with less severe symptoms and responded appropriately to midodrine , a pressor agent commonly used to treat NOH . Conclusion These findings provide empirical evidence that the OHQ can accurately evaluate the severity of symptoms and the functional impact of NOH as well as assess the efficacy of treatment DL-dihydroxyphenylserine was given by mouth in a single-blind , placebo-controlled trial to two patients with orthostatic hypotension due to dopamine-beta-hydroxylase deficiency , in the hope of providing noradrenaline by endogenous decarboxylation . Dose-dependent increases in blood pressure were obtained over the range 150 - 600 mg . After 600 mg mean arterial pressure rose 33 and 19 mm Hg and these rises were tightly correlated with an increase in plasma noradrenaline ( r = 0.995 , p less than 0.001 and r = 0.88 , p less than 0.05 ) . Urinary noradrenaline increased from undetectable levels to 338 and 511 micrograms/24 h. St and ing time ( a correlate of functional capacity ) also increased significantly in both patients . No side-effects were noted
OBJECTIVE The systematic review and meta- analysis aims to determine the efficacy and safety of droxidopa in the treatment of orthostatic hypotension , following its recent approvals in the United States .