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BACKGROUND: Persistent vasopressor requirements are a common reason for delayed liberation from the intensive care unit (ICU) and adjunct oral agents are sometimes used to hasten time to vasopressor discontinuation. We sought to describe the use of droxidopa for vasopressor weaning in critically ill patients with prolonged hypotension. MATERIALS AND METHODS: This retrospective, single-arm, observational study included adult patients admitted to an ICU at two academic centers between 06/2016-07/2023 who received droxidopa for vasopressor weaning. Patients who received droxidopa prior to admission or for another indication were excluded. The primary outcome was time to vasopressor discontinuation, defined as when vasopressors were stopped and remained off for at least 24 h. Secondary outcomes included rates of tachycardia and hypotension post-initiation, norepinephrine equivalents pre- and post-initiation, concomitant oral agent use, and dosing. A subgroup analysis was conducted in patients receiving droxidopa via feeding tubes. RESULTS: A total of 30 patients met inclusion criteria. Median age was 62 years old, 12 (40%) were female, and 73% were in a cardiac/cardiac surgical ICU. Patients were on vasopressors for a median of 16 days prior to droxidopa initiation. Median (IQR) time to vasopressor discontinuation was 70 h (23-192) and norepinephrine equivalents decreased immediately after initiation (0.08 vs 0.02 mcg/kg/min, p < 0.001). MAP increased after droxidopa initiation (68.8 vs 66.5 mm Hg, p = 0.008) while heart rates were unchanged (86 vs 84 BPM, p = 0.37) after initiation. Patients who weaned from vasopressors within 72 h versus longer than 72 h after droxidopa initiation were more likely to be on lower norepinephrine equivalents prior to initiation (0.05 vs 0.12 mcg/kg/min, p = 0.013). Feeding tube administration did not impact time to vasopressor discontinuation (p = 0.93). CONCLUSIONS: Droxidopa may be considered an adjunct therapy for vasopressor weaning. Effects were similar when analyzing patients receiving droxidopa via feeding tube.

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OBJECTIVE: To evaluate the effects of droxidopa or atomoxetine on intravenous (IV) vasoactive agent discontinuation in cardiothoracic intensive care unit (ICU) patients with hypotension refractory to midodrine. DESIGN: Single-center, retrospective cohort study. SETTING: Tertiary- and quaternary-care university teaching hospital. PARTICIPANTS: Included patients who received at least 4 consecutive doses of droxidopa or atomoxetine and remained on concurrent midodrine. Patients were excluded if they received study medication before admission, had clinical deterioration after study medication initiation requiring additional vasoactives/escalation of IV vasoactive dosage for at least 12 hours, had a diagnosis of hepatorenal syndrome, were prisoners, or were pregnant. INTERVENTIONS: Droxidopa, atomoxetine, or both. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was time to discontinuation of IV vasoactive agents after initiation of study medication, analyzed using a Kaplan-Meier estimate with the Wilcoxon method, censoring death within 24 hours of the last dose of study medication. No adjustment for repetitive analyses was made, as the analysis was hypothesis-generating. Of the 72 charts reviewed, 45 patients met inclusion criteria (18 atomoxetine, 17 droxidopa, and 10 both). There were no differences in median time to discontinuation of IV vasoactive agents (21.9 days v 8.0 days v 13.9 days, respectively; p = 0.259) or ICU or hospital length of stay between groups. A higher percentage of patients who survived to hospital discharge received both study medications or droxidopa alone (90% v 76.5%) than atomoxetine alone (44.4%, p = 0.028). CONCLUSIONS: Droxidopa and atomoxetine are oral vasoactive agents with potential mechanisms to facilitate IV vasopressor weaning for patients in the ICU with hypotension refractory to midodrine, but further prospective research is needed.

Asunto(s)

Droxidopa , Hipotensión , Midodrina , Humanos , Droxidopa/efectos adversos , Midodrina/efectos adversos , Clorhidrato de Atomoxetina/uso terapéutico , Enfermedad Crítica , Estudios Retrospectivos , Hipotensión/diagnóstico , Hipotensión/tratamiento farmacológico , Vasoconstrictores

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Neurogenic orthostatic hypotension (nOH) is a disabling problem of autonomic dysfunction in patients with Parkinson's disease, which is associated with poor quality of life and higher mortality rates. The purpose of this literature review was to explore and compare the efficacy and safety of droxidopa (an existing treatment) and ampreloxetine (a newer medication) in the treatment of nOH. We used a mixed-method literature review that addresses the epidemiology, pathophysiology, and pharmacological and non-pharmacological management of nOH in Parkinson's disease in a general way, with a more exploratory approach to droxidopa- and ampreloxetine-controlled trial studies. We included a total of 10 studies of randomized controlled trials with eight studies focused on droxidopa and two studies focused on ampreloxetine. These two drugs were analyzed and compared based on the collected individual study results. Treatment of nOH in Parkinson's disease patients with droxidopa or ampreloxetine showed clinically meaningful and statistically significant improvements relative to placebo on the components of the OHSA (Orthostatic Hypotension Symptom Assessment) composite score and OHDAS (Orthostatic Hypotension Daily Activity Scale composite scores) composite score. Droxidopa had an improved effect on daily activities, with an associated increase in standing systolic blood pressure (BP), but the long-term efficacy of droxidopa has not been documented. Standing systolic BP was maintained by ampreloxetine and worsened after the withdrawal phase. This highlights the importance of conducting further research which will help us to improve the therapeutic approach for patients with nOH and Parkinson's disease.

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A man hospitalized for cerebral infarction developed drug-induced belly dancer syndrome, which improved after withdrawal of droxidopa and amantadine. Drugs that modulate dopamine neurotransmission have been reported to be associated with this syndrome. When belly dancer syndrome is suspected, clinicians should consider drug-induced abdominal dyskinesia and medication withdrawal.

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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.

Asunto(s)

Droxidopa , Síndrome Hepatorrenal , Midodrina , Humanos , Masculino , Persona de Mediana Edad , Droxidopa/uso terapéutico , Midodrina/uso terapéutico , Síndrome Hepatorrenal/diagnóstico , Síndrome Hepatorrenal/tratamiento farmacológico , Octreótido/uso terapéutico , Norepinefrina

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Mycobacterium tuberculosis (M.tb) remains a formidable global health threat. The increasing drug resistance among M.tb clinical isolates is exacerbating the current tuberculosis (TB) burden. In this study we focused on identifying novel repurposed drugs that could be further investigated as potential anti-TB drugs. We utilized M.tb RNA methyltransferase Rv3366 (spoU) as a potential drug target due to its imperative activity in RNA modification and no structural homology with human proteins. Using computational modeling approaches the structure of Rv3366 was determined followed by high throughput virtual screening of Food and Drug Administration (FDA) approved drugs to screen potential binders of Rv3366. Molecular dynamics (MD) simulations were performed to assess the drug-protein binding interactions, complex stability and rigidity. Through this multi-step structure-based drug repurposing workflow two promising inhibitors of Rv3366 were identified, namely, Levodopa and Droxidopa. This study highlights the significance of targeting M.tb RNA methyltransferases to combat drug-resistant M.tb. and proposes Levodopa and Droxidopa as promising inhibitors of Rv3366 for future pre-clinical investigations.

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The worldwide spread of the coronavirus disease 2019 (COVID-19) pandemic and the significant morbidity and mortality rate associated with it led to the rapid development of several COVID-19 vaccines. While serious side effects related to the vaccines are rare, various adverse events have been reported to occur after COVID-19 messenger RNA (mRNA) vaccination, including myocarditis, Guillain-Barré syndrome, and thrombosis. Postural orthostatic tachycardia syndrome (POTS) is a chronic cardiovascular dysautonomia among young and middle-aged individuals. Although the pathophysiology of POTS is thought to be heterogeneous, vaccine-induced immune-mediated autonomic dysfunction is hypothesized to be one cause of the syndrome. In this report, we present a case of myocarditis and POTS occurring in a 13-year-old male following COVID-19 mRNA vaccination. He presented with persistent severe fatigue and headache. The patient's symptoms improved after intravenous immunoglobulin for myocarditis, non-pharmacologic interventions, and multiple medications for POTS.

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The increasing interest in the molecular mechanism of the binding of different agonists and antagonists to ß2-adrenergic receptor (ß2AR) inactive and active states has led us to investigate protein-ligand interactions using molecular docking calculations. To perform this study, the 3.2 Å X-ray crystal structure of the active conformation of human ß2AR in the complex with the endogenous agonist adrenaline has been used as a template for investigating the binding of two exogenous catecholamines to this adrenergic receptor. Here, we show the derivation of L-DOPA and Droxidopa OPLS all atom (AA) force field (FF) parameters via quantum mechanical (QM) calculations, molecular dynamics (MD) simulations in aqueous solutions of the two catecholamines and the molecular docking of both ligands into rigid and flexible ß2AR models. We observe that both ligands share with adrenaline similar experimentally observed binding anchor sites, which are constituted by Asp113/Asn312 and Ser203/Ser204/Ser207 side chains. Moreover, both L-DOPA and Droxidopa molecules exhibit binding affinities comparable to that predicted for adrenaline, which is in good agreement with previous experimental and computational results. L-DOPA and Droxidopa OPLS AA FFs have also been tested by performing MD simulations of these ligands docked into ß2AR proteins embedded in lipid membranes. Both hydrogen bonds and hydrophobic interaction networks observed over the 1 µs MD simulation are comparable with those derived from molecular docking calculations and MD simulations performed with the CHARMM FF.

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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.

Asunto(s)

Droxidopa , Hipotensión Ortostática , Enfermedad de Parkinson , Antiparkinsonianos/uso terapéutico , Droxidopa/uso terapéutico , Humanos , Hipotensión Ortostática/tratamiento farmacológico , Hipotensión Ortostática/etiología , Enfermedad de Parkinson/complicaciones , Enfermedad de Parkinson/tratamiento farmacológico , Reflejo

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INTRODUCTION: Droxidopa is approved to treat neurogenic orthostatic hypotension (nOH) symptoms in patients with autonomic failure based on short-term clinical trial data. Additional data on the long-term efficacy of droxidopa are needed. We have evaluated the 12-week efficacy and tolerability of droxidopa in patients with nOH in an open-label period of an ongoing phase 4 study . METHODS: Patients received 12 weeks of open-label treatment with an individually optimized droxidopa dose (100-600 mg, 3 times daily) as identified during a preceding titration period. Patient-reported outcomes included the Orthostatic Hypotension Symptom Assessment (OHSA), Orthostatic Hypotension Daily Activity Scale (OHDAS), and clinician- and patient-rated Clinical Global Impression-Severity (CGI-S) scales. Supine blood pressure (BP) and adverse events (AEs) were recorded. RESULTS: Data from 114 patients enrolled into the 12-week open-label period were available for analyses. After 12 weeks of droxidopa treatment, patients reported significant (P < 0.0001) improvements from baseline in OHSA and OHDAS composite and individual item scores and on clinician and patient CGI-S scores. Mean ± SD supine systolic and diastolic BP at week 12 increased by 15.5 ± 22.9 and 7.8 ± 11.7 mmHg from baseline, respectively (P < 0.0001 for both). The most frequently reported AEs were falls (17%), headache (13%), and dizziness (9%); one (0.9%) patient reported an AE of supine hypertension. CONCLUSION: During 12 weeks of open-label treatment, droxidopa was associated with significant improvement from baseline in nOH symptoms and activities of daily living. No clinically important changes in supine hypertension or AEs of concern were observed. These results support the efficacy of droxidopa beyond 2 weeks of treatment. TRIAL REGISTRATION: NCT02586623.

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Hypotension secondary to autonomic dysfunction is a common complication of acute spinal cord injury (SCI) that may worsen neurologic outcomes. Midodrine, an enteral α-1 agonist, is often used to facilitate weaning intravenous (IV) vasopressors, but its use can be limited by reflex bradycardia. Alternative enteral agents to facilitate this wean in the acute post-SCI setting have not been described. We aim to describe novel application of droxidopa, an enteral precursor of norepinephrine that is approved to treat neurogenic orthostatic hypotension, in the acute post-SCI setting. Droxidopa may be an alternative enteral therapy for those intolerant of midodrine due to reflex bradycardia. We describe two patients suffering traumatic cervical SCI who were successfully weaned off IV vasopressors with droxidopa after failing with midodrine. The first patient was a 64-year-old male who underwent C3-6 laminectomies and fusion after a ten-foot fall resulting in quadriparesis. Post-operatively, the addition of midodrine in an attempt to wean off IV vasopressors resulted in significant reflexive bradycardia. Treatment with droxidopa facilitated rapidly weaning IV vasopressors and transfer to a lower level of care within 72 hours of treatment initiation. The second patient was a 73-year-old male who underwent C3-5 laminectomies and fusion for a traumatic hyperflexion injury causing paraplegia. The addition of midodrine resulted in severe bradycardia, prompting consideration of pacemaker placement. However, with the addition of droxidopa, this was avoided, and the patient was weaned off IV vasopressors on dual oral therapy with midodrine and droxidopa. Droxidopa may be a viable enteral therapy to treat hypotension in patients after acute SCI who are otherwise not tolerating midodrine in order to wean off IV vasopressors. This strategy may avoid pacemaker placement and facilitate shorter stays in the intensive care unit, particularly for patients who are stable but require continued intensive care unit admission for IV vasopressors, which can be cost ineffective and human resource depleting.

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Treatment of patients with α-synucleinopathies (e.g., Parkinson disease, multiple system atrophy, diffuse Lewy body disease) may require clinicians to manage both neurologic and cardiovascular issues due to autonomic dysfunction. In addition to the underlying neurodegenerative condition, patients often experience blood pressure dysregulation, such as neurogenic orthostatic hypotension (nOH) and/or supine hypertension. This commentary details the collaborative care between a cardiologist and neurologist to effectively manage medically complex patients with nOH by illustrating the case of a 76-year-old man with a history of multiple system atrophy who experienced recurrent syncope when standing or sitting and falls with loss of consciousness. The patient could walk only a few steps before experiencing a substantial drop in systolic blood pressure (100 mmHg). He also had features of profound parkinsonism (e.g., tremor, facial masking) that required treatment with levodopa, but orthostatic symptoms related to the blood pressure drop needed improvement first. The neurologist and cardiologist collaborated to diagnose nOH and initiate droxidopa treatment, which led to resolution of syncope, control of orthostatic symptoms, and improvement of orthostatic blood pressure. Considerations in the collaborative care of patients with nOH are outlined, including screening protocols, treatment goals and options, mitigation of supine hypertension risk (a condition that frequently coexists with nOH), and management of other comorbidities. In conclusion, collaboration between neurologists and cardiologists is an efficient method to improve outcomes for patients with nOH because this care model allows specialist providers to leverage their areas of expertise to manage the wide spectrum of clinical features associated with nOH. Further, communication and cooperation of the patient care team can lead to reduced patient morbidity, optimal relief of nOH symptoms, improvements in activities of daily living and quality of life, and decreased caregiver burden. Management of Neurogenic Orthostatic Hypotension in Neurodegenerative Disorders: A Collaboration Between Cardiology and Neurology (MP4 73511 kb).

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People with nervous system disorders such as Parkinson disease, multiple system atrophy, or diffuse Lewy body dementia often experience neurogenic orthostatic hypotension (nOH). nOH occurs when blood pressure becomes too low when a person stands up after lying down or sitting, which can cause weakness, loss of consciousness, and falls. Other common symptoms of nOH include lightheadedness, fainting/feeling faint, trouble thinking clearly, pain in the neck and shoulders ("coat hanger" pain), and feeling tired. People with nOH are at risk of incurring injuries from a fall. A neurologist or cardiologist can identify if a person has nOH by asking about symptoms and measuring the person's blood pressure when lying down and after standing. They may also ask the patient to keep a diary of blood pressure measurements taken at home. When a patient's neurologist and cardiologist work together as a team, they can ensure that nOH is treated safely and effectively, and patients may find their nOH symptoms are better managed. nOH can be treated with lifestyle changes such as drinking more water, eating more salty food, or gentle exercises. If needed, healthcare providers can prescribe medications to treat nOH.

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BACKGROUND: Patients with chronic heart failure (CHF) are often treated using many diuretics for symptom relief; however, diuretic use may have to continue despite hypotension development in these patients. Here, we present a case of heart failure with preserved ejection fraction (HFpEF), which is defined as ejection fraction ≥50% in CHF, and refractory hypotension, which was treated with midodrine and droxidopa to normalize blood pressure. CASE PRESENTATION: The patient was a 62-year-old man with a history of HFpEF due to mitral regurgitation and complaints of dyspnea on exertion. He had been prescribed multiple medications at an outpatient clinic for CHF management, including azosemide 60 mg/day, bisoprolol 2.5 mg/day, enalapril 2.5 mg/day, spironolactone 50 mg/day, and tolvaptan 15 mg/day. The systolic blood pressure (SBP) of the patient remained at 70-80 mmHg because the use of the diuretic could not be reduced or discontinued owing to edema and weight gain. He was hospitalized for the exacerbation of CHF. Although midodrine 8 mg/day was administered to improve hypotension, the SBP of the patient increased only up to 90 mmHg. On the 35th day after hospitalization, the urine volume decreased significantly (< 100 mL/day) due to hypotension. When droxidopa 200 mg/day replaced intravenous noradrenaline on the 47th day, the SBP remained at 100-120 mmHg and the urine volume increased. CONCLUSIONS: Oral combination treatment with midodrine and droxidopa might contribute to the maintenance of blood pressure and diuretic activity in HFpEF patients with refractory hypotension. However, further long-term studies evaluating the safety and efficacy of this combination therapy for patients with HFpEF are needed.

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PURPOSE OF REVIEW: In autonomic failure, neurogenic orthostatic hypotension (nOH) and neurogenic supine hypertension (nSH) are interrelated conditions characterized by postural blood pressure (BP) dysregulation. nOH results in a sustained BP drop upon standing, which can lead to symptoms that include lightheadedness, orthostatic dizziness, presyncope, and syncope. nSH is characterized by elevated BP when supine and, although often asymptomatic, may increase long-term cardiovascular and cerebrovascular risk. This article reviews the pathophysiology and clinical characteristics of nOH and nSH, and describes the management of patients with both nOH and nSH. RECENT FINDINGS: Pressor medications required to treat the symptoms of nOH also increase the risk of nSH. Because nOH and nSH are hemodynamically opposed, therapies to treat one condition may exacerbate the other. The management of patients with nOH who also have nSH can be challenging and requires an individualized approach to balance the short- and long-term risks associated with these conditions. Approaches to manage neurogenic BP dysregulation include nonpharmacologic approaches and pharmacologic treatments. A stepwise treatment approach is presented to help guide neurologists in managing patients with both nOH and nSH.

Asunto(s)

Enfermedades del Sistema Nervioso Autónomo , Droxidopa , Hipertensión , Hipotensión Ortostática , Presión Sanguínea , Humanos , Hipertensión/complicaciones , Hipertensión/tratamiento farmacológico , Hipertensión/epidemiología , Hipotensión Ortostática/complicaciones , Hipotensión Ortostática/epidemiología , Hipotensión Ortostática/terapia

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BACKGROUND AND AIMS: Patients with neurogenic orthostatic hypotension (nOH) due to autonomic dysfunction may also experience supine hypertension (defined as supine systolic blood pressure [SBP] ≥140 mmHg). Because pressor agents used to improve nOH symptoms by increasing standing blood pressure (BP) may exacerbate or cause supine hypertension, changes in supine BP with nOH treatments are of interest. METHODS: This post hoc study examined changes in SBP in patients receiving droxidopa (100-600 mg, three times daily) during a 12-month long-term extension study based on whether patients had supine hypertension (ie, supine SBP ≥140 mmHg) at baseline. Shifts from baseline in supine hypertension categorization and mean supine and standing SBP after 6 and 12 months of treatment with droxidopa were determined. RESULTS: At baseline, 64 patients did not have supine hypertension (mean supine SBP, 120 mmHg) and 38 patients had supine hypertension (mean supine SBP, 157 mmHg). A similar percentage of patients shifted from their respective baseline supine hypertension categorization (ie, with or without supine hypertension) to the other category after receiving droxidopa for 6 or 12 months. After 12 months of droxidopa treatment, patients with supine hypertension at baseline had a mean supine SBP decrease of 3 mmHg and a mean standing SBP increase of 9 mmHg. Patients without supine hypertension at baseline had mean supine and standing SBP increases of 12 and 15 mmHg, respectively. CONCLUSIONS: There was no consistent or progressive elevation in supine SBP over time during the 12-month treatment with droxidopa in patients either with or without supine hypertension at baseline. These data suggest that long-term droxidopa treatment for nOH does not adversely affect supine BP.

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Finding alternative treatments for attention-deficit/hyperactivity disorder (ADHD) is crucial given the safety and efficacy problems of current ADHD medications. Droxidopa, also known as L-threo-dihydroxyphenylserine (L-DOPS), is a norepinephrine prodrug that enhances brain norepinephrine and dopamine levels. In this study, we used electrophysiological tests to examine effects of L-DOPS on the prefrontal cortex (PFC) and dopamine neurons in the ventral tegmental area. We also conducted behavioral tests to assess L-DOPS' effects on ADHD-like behaviors in rats. In chloral hydrate-anesthetized rats, PFC local field potentials oscillated between the active, depolarized UP state and the hyperpolarized DOWN state. Mimicking the effect of d-amphetamine, L-DOPS, given after the peripheral amino acid decarboxylase inhibitor, benserazide (BZ), increased the amount of time the PFC spent in the UP state, indicating an excitatory effect of L-DOPS on PFC neurons. Like d-amphetamine, L-DOPS also inhibited dopamine neurons, an effect significantly reversed by the D2-like receptor antagonist raclopride. In the behavioral tests, BZ + L-DOPS improved hyperactivity, inattention and impulsive action of the adolescent spontaneously hypertensive rat (SHR/NCrl), well-validated animal model of the combined type of ADHD. BZ + L-DOPS also reduced impulsive choice and impulsive action of Wistar rats, but did not ameliorate the inattentiveness of Wistar Kyoto rats (WKY/NCrl), proposed model of the ADHD-predominantly inattentive type. In conclusion, L-DOPS produced effects on the PFC and dopamine neurons characteristic of drugs used to treat ADHD. BZ + L-DOPS ameliorated ADHD-like behaviors in rats suggesting its potential as an alternative ADHD treatment.

Asunto(s)

Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Conducta Animal/efectos de los fármacos , Dopaminérgicos/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Droxidopa/farmacología , Corteza Prefrontal/efectos de los fármacos , Área Tegmental Ventral/efectos de los fármacos , Animales , Atención/efectos de los fármacos , Trastorno por Déficit de Atención con Hiperactividad/metabolismo , Trastorno por Déficit de Atención con Hiperactividad/fisiopatología , Trastorno por Déficit de Atención con Hiperactividad/psicología , Benserazida/farmacología , Descuento por Demora/efectos de los fármacos , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/metabolismo , Quimioterapia Combinada , Locomoción/efectos de los fármacos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Corteza Prefrontal/metabolismo , Corteza Prefrontal/fisiopatología , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Ratas Sprague-Dawley , Especificidad de la Especie , Área Tegmental Ventral/metabolismo , Área Tegmental Ventral/fisiopatología

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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.

Asunto(s)

Antiparkinsonianos/uso terapéutico , Bradicardia/tratamiento farmacológico , Droxidopa/uso terapéutico , Hipotensión Ortostática/tratamiento farmacológico , Amiloidosis de Cadenas Ligeras de las Inmunoglobulinas/complicaciones , Humanos , Masculino , Persona de Mediana Edad

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BACKGROUND: Neurogenic orthostatic hypotension (nOH) is a subtype of orthostatic hypotension (OH) observed in the presence of neuropathy and is associated with increased risk of falling, impaired function, and poor quality of life. Droxidopa and midodrine are approved in the United States to treat symptomatic nOH and OH in adults, respectively. In this study, we compared the treatment persistence of droxidopa and midodrine. METHODS: A retrospective analysis of patients prescribed either droxidopa or midodrine was conducted using the Symphony Health Solutions database (Symphony Health Solutions, Phoenix, AZ, USA). Inclusion criteria were (1) a pharmacy insurance claim in at least 16 consecutive quarters from mid-2014 to 2018 and (2) an active prescription for droxidopa or midodrine of ≥30 days' duration during that period. Treatment persistence was defined as the time to the first break in drug coverage of ≥45 days and was capped at 365 days. RESULTS: Data from 2305 patients who received droxidopa and 117,243 patients who received midodrine were included in this analysis. Median (95% CI) treatment persistence was significantly longer in the droxidopa cohort versus the midodrine cohort (303 [274-325] vs 172 [169-176] days; P < 0.001). After adjustment for confounding factors, patients using droxidopa monotherapy (i.e., without any concomitant midodrine and/or fludrocortisone use) were 16% more likely to be persistent at any time point than patients using midodrine (P < 0.001). CONCLUSIONS: In this real-world data analysis, patients using droxidopa without concomitant medications for OH were more likely to remain on treatment than patients on midodrine.

RESUMEN

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.

Asunto(s)

Presión Sanguínea , Dolor en el Pecho/etiología , Enfermedad de la Arteria Coronaria/complicaciones , Estenosis Coronaria/complicaciones , Disnea/etiología , Hipotensión Ortostática/etiología , Enfermedad de Parkinson/complicaciones , Anciano de 80 o más Años , Antiparkinsonianos/uso terapéutico , Dolor en el Pecho/diagnóstico , Dolor en el Pecho/fisiopatología , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/fisiopatología , Enfermedad de la Arteria Coronaria/terapia , Estenosis Coronaria/diagnóstico por imagen , Estenosis Coronaria/fisiopatología , Estenosis Coronaria/terapia , Droxidopa/uso terapéutico , Disnea/diagnóstico , Disnea/fisiopatología , Femenino , Humanos , Hipotensión Ortostática/diagnóstico , Hipotensión Ortostática/fisiopatología , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/tratamiento farmacológico , Enfermedad de Parkinson/fisiopatología , Intervención Coronaria Percutánea , Postura , Resultado del Tratamiento

RESUMEN

Orthostatic hypotension (OH) is a sustained fall in blood pressure on standing that can cause symptoms of organ hypoperfusion. OH is associated with increased morbidity and mortality and leads to a significant number of hospital admissions. OH can be caused by volume depletion, blood loss, cardiac pump failure, large varicose veins, medications, or defective activation of sympathetic nerves and reduced norepinephrine release upon standing. Neurogenic OH is a frequent and disabling problem in patients with synucleinopathies such as Parkinson disease, multiple system atrophy, and pure autonomic failure, and it is commonly associated with supine hypertension. Several therapeutic options are available.

Asunto(s)

Hipotensión Ortostática , Enfermedad de Parkinson , Manejo de Atención al Paciente/métodos , Anciano , Humanos , Hipotensión Ortostática/etiología , Hipotensión Ortostática/terapia , Enfermedad de Parkinson/fisiopatología , Enfermedad de Parkinson/terapia