Droxidopa 300mg capsules

Orthostatic hypotension (OH), defined as a sustained drop in systolic (≥20 mmHg) or diastolic (≥10 mmHg) blood pressure upon standing, is a debilitating condition prevalent in older adults and individuals with neurodegenerative disorders. It significantly impacts quality of life, leading to dizziness, falls, and syncope, and is associated with increased morbidity and mortality. This systematic review evaluates the efficacy and safety of pharmacological treatments for OH. Following the PRISMA 2020 guidelines, 25 studies, including randomized (RCTs) and non-randomized controlled trials (NRCTs), were analyzed. Study quality was assessed using the Cochrane Risk of Bias 2 (ROB 2) tool, the Joanna Briggs Institute (JBI) Checklist, and the Newcastle-Ottawa Scale (NOS). The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) framework was applied to evaluate the certainty of evidence across key outcomes. Drugs approved by the U.S. Food and Drug Administration (FDA), such as droxidopa and midodrine, consistently improve orthostatic symptoms and are recommended as first-line therapies. Atomoxetine and fludrocortisone showed moderate efficacy, while pyridostigmine in combination therapies provided additional benefits. Octreotide demonstrated potential for refractory OH but lacked robust evidence. Adverse effects, including supine hypertension, dizziness, gastrointestinal disturbances, and fatigue, highlight the need for personalized therapy to balance efficacy and tolerability. While pharmacological treatments show promise, further comparative and long-term studies are necessary to refine therapeutic strategies and improve patient outcomes.

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BackgroundMenkes disease is an X-linked recessive disorder of human copper metabolism. Droxidopa is a synthetic amino acid effective in reversing neurogenic orthostatic hypotension and correcting neurochemical abnormalities in congenital absence of dopamine-beta-hydroxylase (DBH), a copper-dependent enzyme that influences autonomic function. Individuals with disorders associated with variants in the copper transport gene ATP7A may manifest symptoms of dysautonomia, due to deficient DBH activity. We aimed to evaluate the safety and efficacy of droxidopa for dysautonomia in adults with Menkes disease or with occipital horn syndrome (an ATP7A allelic variant).MethodsWe conducted a phase 1/2a, randomised, double-blind, placebo-controlled, crossover trial at one academic medical centre in Columbus, OH, USA. We compared placebo versus droxidopa treatment in adults with Menkes disease or occipital horn syndrome who manifested symptoms of dysautonomia (including orthostatic hypotension). Participants were recruited by invitation, screened, and randomly assigned to receive droxidopa or placebo for 6 weeks (Arm 1). Following a 7-10 day washout period, participants received the opposite treatment for 6 weeks (Arm 2/Crossover treatment). An open-label dose titration was utilised in advance to determine each participant's maximally tolerated dose (100, 200, or 300 mg) of droxidopa. The primary outcome of this trial was safety and tolerability assessed at 6 weeks, as reflected in the type and incidence of adverse events in the droxidopa treatment versus placebo groups. This trial is registered with ClinicalTrials.gov, NCT04977388.FindingsBetween July 12, 2021 and Oct 30, 2023, three male participants were enrolled: two individuals with Menkes disease (19 and 26 years old) and one individual with occipital horn syndrome (age 35). We found significant improvements in norepinephrine levels (P InterpretationIn this early phase trial, droxidopa was well tolerated in adults with Menkes disease and occipital horn syndrome and was associated with correction of orthostatic hypotension. These preliminary findings suggest that droxidopa at doses adjusted for patient tolerance is likely to be efficacious for treatment of dysautonomia in adults with ATP7A-related disorders. Further research is required, including in younger individuals with these conditions.FundingThe Menkes Disease Foundation UK, Associazione Angeli Per La Vita, and the Abigail Wexner Research Institute at Nationwide Children's Hospital.

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