Droxidopa (Northera®) en hipotensión ortostática neurogénica por enfermedad de Parkinson / Droxidopa (Northera®) in orthostatic hypotension neurogenic due to Parkinson's disease

INTRODUCCIÓN: La hipotensión ortostática (HO) es definida como una reducción de la presión arterial sistólica de al menos 20 mmHg o una reducción de la presión arterial diastólica de al menos 10 mmHg, generalmente dentro de los primeros tres minutos después de estar de pie o de inclinar la cabeza hacia arriba sobre una mesa inclinada.1 Muchos trastornos pueden causar HO, siendo los principales mecanismos la disfunción barorrefleja, la depleción grave de volumen y los eventos adversos de los medicamentos. La HO se define como sintomática cuando la persona experimenta mareos, aturdimiento, síncope, dolor muscular en el cuello y los hombros e incluso angina al pararse.2. La OH neurogénica ocurre por disfunción barorrefleja y las neuronas simpáticas posganglionares no liberan noradrenalina de forma adecuada. La presión arterial cae progresivamente después de estar de pie porque la acumulación gravitacional de sangre en las piernas no puede compensarse mediante vasoconstricción simpática. La liberación subnormal de norepinefrina produce vasoconstricción alterada y volumen vascular intratorácico reducido, los cuales contribuyen a la hipotensión ortostática. La disfunción autonómica, incluida la disfunción barorrefleja que causa HO neurogénica, es una característica clínica común de las sinucleinopatías, que se caracterizan patológicamente por inclusiones neuronales citoplasmáticas (cuerpos de Lewy) o gliales que contienen alfasinucleína que se encuentran en el cerebro y los nervios autónomos periféricos de las personas con enfermedad de Parkinson. La prevalencia de HO neurogénica aumenta con la edad y la duración de la enfermedad, estando presente entre el 20 y el 60 % de las personas con esta enfermedad. TECNOLOGÍA: La droxidopa, un análogo de aminoácido sintético que se metaboliza a norepinefrina y puede aumentar la presión arterial al causar vasoconstricción de las arterias y venas periféricas. Se han observado aumentos menores y temporales en los niveles plasmáticos de norepinefrina después de la administración de droxidopa. OBJETIVO: El objetivo del presente informe es evaluar rápidamente los parámetros de eficacia, seguridad, costos y recomendaciones disponibles acerca del empleo del uso de droxidopa (Northera®) en hipotensión ortostática neurogénica por enfermedad de Parkinson. MÉTODOS: Se realizó una búsqueda bibliográfica en las principales bases de datos tales como PUBMED, LILACS, BRISA, COCHRANE, SCIELO, EMBASE, TRIPDATABASE como así también en sociedades científicas, agencias reguladoras, financiadores de salud y agencias de evaluación de tecnologías sanitarias. Se priorizó la inclusión de revisiones sistemáticas, ensayos clínicos controlados aleatorizados, evaluación de tecnología sanitaria y guías de práctica clínica de alta calidad metodológica. EVIDENCIA CLÍNICA: Hauser y cols. publicaron en 2028 un análisis integrado de los estudios disponibles sobre droxidopa frente a placebo para el tratamiento de la HO neurogénica en adultos con enfermedad de Parkinson. 7 El análisis incluyó tres ensayos clínicos de fase III multicéntricos (NOH301, NOH302 y NOH306B) que evaluaron droxidopa en personas con HO neurogénica sintomática por enfermedad de Parkinson y otras causas. 8­10 Estos ensayos inicialmente aleatorizaron un total de 332 personas con enfermedad de Parkinson (droxidopa [n=171] o placebo [n=162]), sin embargo, 25 personas (n=21 para droxidopa y n=5 para placebo) interrumpieron el tratamiento antes de las primeras mediciones de resultados y no se incluyeron en los análisis de eficacia. RECOMENDACIONES: No se hallaron recomendaciones para Argentina o Latinoamérica sobre la tecnología en la indicación evaluada. La Sociedad Internacional de Parkinson y Trastornos del Movimiento en 2019 menciona, entre otros medicamentos, que la droxidopa es posiblemente una opción de tratamiento para la HO neurogénica. 15 Las fundaciones de Parkinson para Estados Unidos y Canadá no la mencionan. El medicamento no ha sido evaluado, y por lo tanto no es cubierto, por la Agencia Canadiense de Medicamentos y Tecnologías en Salud (CADTH, su sigla del inglés Canadian Agency for Drugs and Technologies in Health) y el Plan de Beneficios Farmacéuticos (PBS, su sigla del inglés Pharmaceutical Benefits Scheme) de Australia. CONCLUSIONES: La evidencia que sustenta la aprobación de comercialización por parte de los Estados Unidos de droxidopa (Northera®) en adultos con hipotensión ortostática neurogénica sintomática se basa en tres ensayos clínicos aleatorizados de fase III. Cabe señalar que la agencia estadounidense la ha autorizado en 2014, mientras que la Agencia Europea de Medicamentos aún no lo ha hecho. Estos estudios demostraron que en pocas personas con hipotensión ortostática moderada por enfermedad de Parkinson, la droxidopa frente a placebo podría mejorar al muy corto plazo algunas puntuaciones para la evaluación de los síntomas, y aumentar la presión arterial sistólica y diastólica. Sin embargo, existen dudas si estas mejoras son clínicamente importantes y las personas que recibieron el fármaco presentaron mayores tasas de eventos adversos que llevaron a su discontinuación. No se halló evidencia que evalúe la droxidopa frente a otros tratamientos farmacológicos disponibles para la población objetivo, como tampoco si estos beneficios se mantienen en el tiempo. No se hallaron evaluaciones económicas ni recomendaciones para Argentina y Latinoamérica. Instituciones de referencia relevadas en países de altos ingresos no la mencionan dentro de sus recomendaciones y tampoco dan cobertura. Según los precio de adquisición relevados para Estados Unidos, el costo mensual del tratamiento sería aproximadamente de ARS 655.707 a 3.920.353.

Advances in the Pharmacological and Non-pharmacological Management of Non-motor Symptoms in Parkinson's Disease: An Update Since 2017.

BACKGROUND: Non-motor symptoms (NMS) are an important and ubiquitous determinant of quality of life in Parkinson's disease (PD). However, robust evidence for their treatment is still a major unmet need. OBJECTIVE: This study aimed to provide an updated review on advances in pharmacological, nonpharmacological, and exercise-based interventions for NMS in PD, covering the period since the publication of the MDS Task Force Recommendations. METHODS: We performed a literature search to identify pharmacological, non-pharmacological, and exercise-based interventions for NMS in PD. As there are recent reviews on the subject, we have only included studies from the 1st of January 2017 to the 1st of December 2021 and limited our search to randomised and non-randomised (including open-label) clinical trials. RESULTS: We discuss new strategies to manage NMS based on data that have become available since 2017, for instance, on the treatment of orthostatic hypotension with droxidopa, several dopaminergic treatment options for insomnia, and a range of non-pharmacological and exercise-based interventions for cognitive and neuropsychiatric symptoms, pain, and insomnia and excessive sleepiness. CONCLUSION: Recent evidence suggests that targeted non-pharmacological treatments, as well as some other NMS management options, may have a significant beneficial effect on the quality of life and need to be considered in the pathways of treatment of PD.

Droxidopa in the Management of Hepatorenal Syndrome.

PurposeHepatorenal syndrome (HRS) is renal dysfunction associated with the hemodynamic consequences of advanced liver disease and cirrhosis. HRS is associated with a high mortality, and there remain high failure rates with first-line therapy aimed at improving perfusion. We report the use of droxidopa, an oral norepinephrine precursor, to aid in the management of HRS-AKI refractory to first-line therapy. Summary: A 51-year-old Caucasian male with alcohol-related cirrhosis presented with 1-week history of pre-syncope and falls. He was found to have acute kidney injury meeting diagnostic criteria of HRS based on absence of identifiable contributing factors. After no response to volume expansion, medical management was initiated with midodrine and octreotide and eventually escalated to norepinephrine intravenous infusion. The patient's renal function and urine output improved initially on norepinephrine, but worsened when attempting to wean to a suitable outpatient regimen, becoming dependent upon norepinephrine. On day 13 of hospitalization, droxidopa was initiated at a dose of 100 mg three times daily and titrated to a dose of 400 mg three times daily. Norepinephrine infusion was weaned and discontinued on day 16 of hospitalization. The patient remained hemodynamically stable and was able to be discharged on droxidopa 400 mg three times daily, midodrine 20 mg three times day, and octreotide 200 mcg three times daily. Conclusion: Droxidopa, an oral norepinephrine precursor, presents a novel adjunctive agent for management of HRS refractory to first-line medical management.

Droxidopa reduces postural sway in Parkinson disease patients with orthostatic hypotension.

We evaluate the effect of droxidopa on gait and balance measures in nine patients with Parkinson's disease and neurogenic orthostatic hypotension. Computerized gait/balance analysis showed a significant effect of droxidopa in reducing postural sway. Future studies may determine if such effect translates into improvement in postural reflexes and falls.

The cause of eyelid ptosis, orthostatic hypotension and exercise intolerance.

To provide more insight in the delay in diagnosis and expectation of treatment adapted for the paediatrician, the data were collected from patients described with dopamine beta-hydroxylase deficiency are evaluated. More insight in clinical features of dopamine beta-hydroxylase deficiency consisting mainly of eyelid ptosis, orthostatic hypotension, hypoglycaemia and exercise intolerance, explains the delay in diagnosis of this congenital disorder, although all symptoms some more concealed are present. An increasing experience by L-DOPS, a resurrection for the patient, allows recommendations for early treatment. An explanation for the delay in diagnosis is provided together with the advice for treatment.

Orthostatic Hypotension: A Practical Approach.

Orthostatic hypotension is defined as a decrease in blood pressure of 20 mm Hg or more systolic or 10 mm Hg or more diastolic within three minutes of standing from the supine position or on assuming a head-up position of at least 60 degrees during tilt table testing. Symptoms are due to inadequate physiologic compensation and organ hypoperfusion and include headache, lightheadedness, shoulder and neck pain (coat hanger syndrome), visual disturbances, dyspnea, and chest pain. Prevalence of orthostatic hypotension in the community setting is 20% in older adults and 5% in middle-aged adults. Risk factors such as diabetes mellitus increase the prevalence of orthostatic hypotension in all age groups. Orthostatic hypotension is associated with a significant increase in cardiovascular risk and falls, and up to a 50% increase in relative risk of all-cause mortality. Diagnosis is confirmed by performing a bedside simplified Schellong test, which consists of blood pressure and heart rate measurements after five minutes in the supine position and three minutes after moving to a standing position. If the patient is unable to stand safely or the clinical suspicion for orthostatic hypotension is high despite normal findings on the bedside test, head-up tilt table testing is recommended. Orthostatic hypotension is classified as neurogenic or nonneurogenic, depending on etiology and heart rate response. Treatment goals for orthostatic hypotension are reducing symptoms and improving quality of life. Initial treatment focuses on the underlying cause and adjusting potentially causative medications. Nonpharmacologic strategies include dietary modifications, compression garments, physical maneuvers, and avoiding environments that exacerbate symptoms. First-line medications include midodrine and droxidopa. Although fludrocortisone improves symptoms, it has concerning long-term effects.

Clinical presentation and long-term follow-up of dopamine beta hydroxylase deficiency.

Dopamine beta hydroxylase (DBH) deficiency is an extremely rare autosomal recessive disorder with severe orthostatic hypotension, that can be treated with L-threo-3,4-dihydroxyphenylserine (L-DOPS). We aimed to summarize clinical, biochemical, and genetic data of all world-wide reported patients with DBH-deficiency, and to present detailed new data on long-term follow-up of a relatively large Dutch cohort. We retrospectively describe 10 patients from a Dutch cohort and 15 additional patients from the literature. We identified 25 patients (15 females) from 20 families. Ten patients were diagnosed in the Netherlands. Duration of follow-up of Dutch patients ranged from 1 to 21 years (median 13 years). All patients had severe orthostatic hypotension. Severely decreased or absent (nor)epinephrine, and increased dopamine plasma concentrations were found in 24/25 patients. Impaired kidney function and anemia were present in all Dutch patients, hypomagnesaemia in 5 out of 10. Clinically, all patients responded very well to L-DOPS, with marked reduction of orthostatic complaints. However, orthostatic hypotension remained present, and kidney function, anemia, and hypomagnesaemia only partially improved. Plasma norepinephrine increased and became detectable, while epinephrine remained undetectable in most patients. We confirm the core clinical characteristics of DBH-deficiency and the pathognomonic profile of catecholamines in body fluids. Impaired renal function, anemia, and hypomagnesaemia can be part of the clinical presentation. The subjective response to L-DOPS treatment is excellent and sustained, although the neurotransmitter profile in plasma does not normalize completely. Furthermore, orthostatic hypotension as well as renal function, anemia, and hypomagnesaemia improve only partially.

Clinical Trials for Neurogenic Orthostatic Hypotension: A Comprehensive Review of Endpoints, Pitfalls, and Challenges.

Neurogenic orthostatic hypotension (nOH) is among the most debilitating nonmotor features of patients with Parkinson's disease (PD) and other synucleinopathies. Patients with PD and nOH generate more hospitalizations, make more emergency room visits, create more telephone calls/mails to doctors, and have earlier mortality than those with PD but without nOH. Overall, the health-related cost in patients with PD and OH is 2.5-fold higher compared with patients with PD without OH. Hence, developing effective therapies for nOH should be a research priority. In the last few decades, improved understanding of the pathophysiology of nOH has led to the identification of therapeutic targets and the development and approval of two drugs, midodrine and droxidopa. More effective and safer therapies, however, are still needed, particularly agents that could selectively increase blood pressure only in the standing position because supine hypertension is the main limitation of available drugs. Here we review the design and conduct of nOH clinical trials in patients with PD and other synucleinopathies, summarize the results of the most recently completed and ongoing trials, and discuss challenges, bottlenecks, and potential remedies.

Neurogenic Orthostatic Hypotension: An Underrecognized Complication of Parkinson Disease.

BACKGROUND: Neurogenic orthostatic hypotension (nOH) is a common source of disability but is an often untreated nonmotor symptom of Parkinson disease. The key manifestations of nOH include lightheadedness, dizziness, weakness, and fatigue when standing and engaging in activities in the upright position and result in falls, impaired activities of living, decreased quality of life, and short-term cognitive impairment. Early diagnosis and treatment of nOH are necessary to mitigate its adverse effects and reduce nOH-related symptom burden. CASE STUDY: The management of nOH is illustrated through a case study. MANAGEMENT CONSIDERATIONS: Alerting providers about the impact and treatment of nOH, accurate measurement of orthostatic blood pressure, and educating patients and caregivers about nonpharmacological treatment options are important strategies to manage nOH. The goal of nOH treatment is to mitigate symptoms and improve the patient's quality of life. CONCLUSIONS: Nurses can play a crucial role in the recognition and management of nOH. Nurses who are educated about nOH are well suited to partner with care providers to treat disabling motor and nonmotor symptoms of Parkinson disease.

Droxidopa as an effective treatment for refractory neurogenic orthostatic hypotension and reflex bradycardia in amyloid light-chain amyloidosis: a case report.

BACKGROUND: Droxidopa is an oral treatment for the stepwise treatment of neurogenic orthostatic hypotension from autonomic dysfunction. It has been shown to be useful predominantly with neurogenic orthostatic hypotension secondary to Parkinson's disease, but only a few cases have documented its usefulness in patients with neurogenic orthostatic hypotension due to amyloidosis, which is often severe and refractory. In addition, only one source in the literature reports the concomitant use of midodrine and droxidopa for such patients. Finally, we argue that droxidopa seems to have a protective effect against episodes of reflex bradycardia, which is not previously reported. CASE PRESENTATION: A 64-year-old white man was admitted for 1 year of worsening syncopal episodes, diarrhea, failure to thrive, heart failure, and neuropathy. Medical emergencies were called five times on the overhead hospital intercom over a 4-day period in the beginning of his admission due to severe hypotension and bradycardia. He was eventually diagnosed as having amyloid light-chain amyloidosis and myeloma. After starting droxidopa, both his systolic blood pressure and reflex bradycardia improved, and no more medical emergency events were called during the remaining 30 days of admission. He felt much better subjectively and was able to sit upright and engage in physical therapy. CONCLUSIONS: We show that droxidopa is effective when used with midodrine to treat refractory neurogenic orthostatic hypotension in patients with amyloidosis. There are very few cases reporting the use of droxidopa in amyloidosis, with only one study that uses droxidopa and midodrine concomitantly. In addition, our patient's reflex bradycardia improved drastically after starting droxidopa, which we believe is mediated by increased systemic norepinephrine. There were no side effects to droxidopa, and the benefits lasted well beyond the reported duration of 1-2 weeks that was noted to be a limitation in some studies.

Cardiovascular Safety Considerations in the Treatment of Neurogenic Orthostatic Hypotension.

Neurogenic orthostatic hypotension (nOH), a drop in blood pressure upon standing resulting from autonomic malfunction, may cause debilitating symptoms that can affect independence in daily activities and quality-of-life. nOH may also be associated with cardiovascular comorbidities (e.g., supine hypertension, heart failure, diabetes, and arrhythmias), making treatment decisions complicated and requiring management that should be based on a patient's cardiovascular profile. Additionally, drugs used to treat the cardiovascular disorders (e.g., vasodilators, ß-blockers) can exacerbate nOH and concomitant symptoms. When orthostatic symptoms are severe and not effectively managed with nonpharmacologic strategies (e.g., water ingestion, abdominal compression), droxidopa or midodrine may be effective. Droxidopa may be less likely than midodrine to exacerbate supine hypertension, based on conclusions of a limited meta-analysis. In conclusion, treating nOH in patients with cardiovascular conditions requires a balance between symptom relief and minimizing adverse outcomes.

Persistent unexplained chest pain and dyspnea in a patient with coronary artery disease: a case report.

BACKGROUND: Neurogenic orthostatic hypotension, a sustained decrease in blood pressure upon standing, is caused by autonomic nervous system failure and characterized by an insufficient increase in heart rate needed to maintain blood pressure upon standing. In this case, neurogenic orthostatic hypotension symptoms preceded a diagnosis of Parkinson disease. A diagnosis of underlying neurogenic orthostatic hypotension significantly changed the course of treatment for this patient. CASE PRESENTATION: An 84-year-old woman was referred to a cardiologist by her primary care practitioner for evaluation of exertional dyspnea and chest pain upon walking a few feet. Her medical history included hypertension, hypothyroidism, and osteoarthritis. Based on her continued symptoms, the patient underwent 2 cardiac catheterizations for coronary artery stenosis. After the catheterizations, exertional dyspnea and chest pain continued, and subsequently, dysphagia to solid foods and episodic dizziness developed. Orthostatic evaluation showed a supine blood pressure of 150/80 mmHg with a heart rate of 70 beats per min. Upon standing for 3 min, the patient's blood pressure decreased to 110/74 mmHg with a heart rate of 76 beats per min. The diagnostic criteria for orthostatic hypotension were met, and the lack of an adequate compensatory heart rate increase upon standing was consistent with a neurogenic cause (ie, neurogenic orthostatic hypotension), which was supported by tilt-table testing results. Although nonpharmacologic treatments were initially successful, episodes of lightheadedness, chest pain, and dyspnea upon standing became more frequent, and the patient was prescribed droxidopa (200 mg; 3 times daily). Droxidopa significantly improved her symptoms, with the patient reporting resolution of her chest pain and significant improvement of dyspnea and dizziness. She was diagnosed with Parkinson disease approximately 6 months later. CONCLUSIONS: This case highlights the importance of evaluating and identifying potential causes of symptoms of cardiovascular disease when persistent symptoms do not improve after cardiac interventions. This case complements findings demonstrating that signs of autonomic failure, such as neurogenic orthostatic hypotension, may precede the motor symptoms of Parkinson disease. Importantly, this case provides real-world evidence for the efficacy of droxidopa to treat the symptoms of neurogenic orthostatic hypotension, after an appropriate diagnosis.

Utility of autonomic testing for the efficient diagnosis and effective pharmacological management of neurogenic orthostatic hypotension.

A 62-year-old man presented with a 2-year history of syncope, collapse and fluctuating blood pressure (BP). His medications included midodrine (10 mg, three times per day) and fludrocortisone (0.1 mg, two times per day), but neither treatment afforded symptomatic relief. Autonomic testing was performed. Head-up tilt table testing revealed a supine BP of 112/68 mm Hg (heart rate, 74 beats per minute (bpm)) after 6 min, which dropped to 76/60 mm Hg (83 bpm) within 2 min of 80° head-up tilt. Findings from a heart rate with deep breathing test and a Valsalva test were consistent with autonomic dysfunction. The patient was diagnosed with neurogenic orthostatic hypotension and treated with droxidopa (100 mg, two times per day; titrated to 100 mg, one time per day). After initiating treatment with droxidopa, the patient no longer reported losing consciousness on standing and experienced improvement in activities of daily living. These improvements were maintained through 1 year of follow-up.

Initiation of droxidopa during hospital admission for management of refractory neurogenic orthostatic hypotension in severely ill patients.

Orthostatic hypotension (OH) is a common cause of hospitalization, particularly in the elderly. Hospitalized patients with OH are often severely ill, with complex medical comorbidities and high rates of disability. Droxidopa is a norepinephrine precursor approved for the treatment of neurogenic OH (nOH) associated with autonomic failure that is commonly used in the outpatient setting, but there are currently no data regarding the safety and efficacy of droxidopa initiation in medically complex patients. We performed a retrospective review of patients started on droxidopa for refractory nOH while hospitalized at Vanderbilt University Medical Center between October 2014 and May 2017. Primary outcome measures were safety, change in physician global impression of illness severity from admission to discharge, and persistence on medication after 180-day follow-up. A total of 20 patients were identified through chart review. Patients were medically complex with high rates of cardiovascular comorbidities and a diverse array of underlying autonomic diagnoses. Rapid titration of droxidopa was safe and well tolerated in this cohort, with no cardiovascular events or new onset arrhythmias. Supine hypertension requiring treatment occurred in four patients. One death occurred during hospital admission due to organ failure associated with end-stage amyloidosis. Treating physicians noted improvements in presyncopal symptoms in 80% of patients. After 6 months, 13 patients (65%) continued on droxidopa therapy. In a retrospective cohort of hospitalized, severely ill patients with refractory nOH, supervised rapid titration of droxidopa was safe and effective. Treatment persistence was high, suggesting that symptomatic benefit extended beyond acute intervention.

Droxidopa for the treatment of neurogenic orthostatic hypotension in neurodegenerative diseases.

INTRODUCTION: L-threo-3,4-dihydroxyphenylserine (droxidopa), a pro-drug metabolized to norepinephrine in nerve endings and other tissues, has been commercially available in Japan since 1989 for treating orthostatic hypotension symptoms in Parkinson's disease (PD) patients with a Hoehn & Yahr stage III rating, as well as patients with Multiple System Atrophy (MSA), familial amyloid polyneuropathy, and hemodialysis. Recently, the FDA has approved its use in symptomatic neurogenic orthostatic hypotension (NOH). Areas covered: The authors review the effects of droxidopa in NOH with a focus on the neurodegenerative diseases PD, MSA, and pure autonomic failure (PAF). Expert opinion: A few small and short placebo-controlled clinical trials in NOH showed significant reductions in the manometric drop in blood pressure (BP) after posture changes or meals. Larger Phase III studies showed conflicting results, with two out of four trials meeting their primary outcome and thus suggesting a positive yet short-lasting effect of the drug on OH Questionnaire composite score, light-headedness/dizziness score, and standing BP during the first two treatment-weeks. Results appear essentially similar in PD, MSA, and PAF. The FDA granted droxidopa approval in the frame of an 'accelerated approval program' provided further studies are conducted to assess its long-term effects on OH symptoms.

Chemical pharmacotherapy for the treatment of orthostatic hypotension.

INTRODUCTION: Orthostatic hypotension (OH) is a common yet often overlooked condition. Particularly debilitating is neurogenic orthostatic hypotension (nOH) caused by deficient neurotransmission of norepinephrine, which is the primary neurotransmitter released at sympathetic peripheral vascular nerve terminals in response to orthostatic stress. AREAS COVERED: In this review, the author summarizes and critiques established and emerging pharmacologic approaches for the management of nOH. Two drugs are currently approved. Midodrine, an α1-adrenoreceptor agonist, acts on capacitance vessels to increase peripheral vascular tone, thus increases arterial pressure. Droxidopa, an orally administered prodrug of norepinephrine, increases circulating norepinephrine levels, causes peripheral vasoconstriction, and increases standing blood pressure. Preliminary studies support the selective use of several off-label drugs in difficult cases. All of these drugs can potentially unmask or exacerbate neurogenic supine hypertension (nSH), which occurs in about half of patients with nOH. EXPERT OPINION: Chemical pharmacotherapy of nOH is best individualized to the needs and condition of each patient and guided by the underlying pathophysiology, severity of orthostatic incapacity, and minimization of comorbidities such as nSH. The goal of therapy is to maintain cerebral perfusion and increase the patient's ability to engage in upright daily activities. Advances in pharmacogenetics and ambulatory devices hold promise.

Substantial renal conversion of L-threo-3,4-dihydroxyphenylserine (droxidopa) to norepinephrine in patients with neurogenic orthostatic hypotension.

BACKGROUND: The pressor effect of L-threo-3,4-dihydroxyphenylserine (L-DOPS, droxidopa, Northera™) results from conversion of L-DOPS to norepinephrine (NE) in cells expressing L-aromatic-amino-acid decarboxylase (LAAAD). After L-DOPS administration the increase in systemic plasma NE is too small to explain the increase in blood pressure. Renal proximal tubular cells abundantly express LAAAD. Since NE generated locally in the kidneys could contribute to the pressor effect of L-DOPS, in this study we assessed renal conversion of L-DOPS to NE. METHODS: Ten patients who were taking L-DOPS for symptomatic orthostatic hypotension had blood and urine sampled about 2 h after the last L-DOPS dose. L-DOPS and NE were assayed by alumina extraction followed by liquid chromatography with electrochemical detection. Data were compared in patients off vs. on levodopa/carbidopa. RESULTS: In patients off levodopa/carbidopa the ratio of NE/L-DOPS in urine averaged 63 times that in plasma (p = 0.0009 by t test applied to log-transformed data). In marked contrast, in the three patients on levodopa/carbidopa the ratio of NE/L-DOPS in urine did not differ from that in plasma. CONCLUSION: There is extensive renal production of NE from L-DOPS. Carbidopa seems to attenuate the conversion of L-DOPS to NE in the kidneys. Further research is needed to assess whether the proposed paracrine effect of L-DOPS in the kidneys contributes to the systemic pressor response.