ABSTRACT
Afferent lesions of the arterial baroreflex occur in familial dysautonomia. This leads to excessive blood pressure variability with falls and frequent surges that damage the organs. These hypertensive surges are the result of excess peripheral catecholamine release and have no adequate treatment. Carbidopa is a selective DOPA-decarboxylase inhibitor that suppresses catecholamines production outside the brain. To learn whether carbidopa can inhibit catecholamine-induced hypertensive surges in patients with severe afferent baroreflex failure, we conducted a double-blind randomized crossover trial in which patients with familial dysautonomia received high dose carbidopa (600 mg/day), low-dose carbidopa (300 mg/day), or matching placebo in 3 4-week treatment periods. Among the 22 patients enrolled (13 females/8 males), the median age was 26 (range, 12-59 years). At enrollment, patients had hypertensive peaks to 164/116 (range, 144/92 to 213/150 mm Hg). Twenty-four hour urinary norepinephrine excretion, a marker of peripheral catecholamine release, was significantly suppressed on both high dose and low dose carbidopa, compared with placebo (P=0.0075). The 2 co-primary end points of the trial were met. The SD of systolic BP variability was reduced at both carbidopa doses (low dose: 17±4; high dose: 18±5 mm Hg) compared with placebo (23±7 mm Hg; P=0.0013), and there was a significant reduction in the systolic BP peaks on active treatment (P=0.0015). High- and low-dose carbidopa were similarly effective and well tolerated. This study provides class Ib evidence that carbidopa can reduce blood pressure variability in patients with congenital afferent baroreflex failure. Similar beneficial effects are observed in patients with acquired baroreflex lesions.
Subject(s)
Baroreflex , Blood Pressure , Carbidopa , Dysautonomia, Familial , Hypertension , Adult , Afferent Pathways/drug effects , Afferent Pathways/metabolism , Afferent Pathways/physiopathology , Aromatic Amino Acid Decarboxylase Inhibitors/administration & dosage , Aromatic Amino Acid Decarboxylase Inhibitors/pharmacokinetics , Baroreflex/drug effects , Baroreflex/physiology , Blood Pressure/drug effects , Blood Pressure/physiology , Carbidopa/administration & dosage , Carbidopa/pharmacokinetics , Catecholamines/metabolism , Cross-Over Studies , Dose-Response Relationship, Drug , Double-Blind Method , Drug Monitoring/methods , Dysautonomia, Familial/diagnosis , Dysautonomia, Familial/drug therapy , Dysautonomia, Familial/metabolism , Dysautonomia, Familial/physiopathology , Female , Humans , Hypertension/drug therapy , Hypertension/etiology , Hypertension/physiopathology , Male , Treatment OutcomeABSTRACT
INTRODUCTION: Parkinson's disease is a chronic, neurodegenerative disease. Its symptoms and course are heterogeneous. After several years of investigative drug studies, levodopa remains the most efficacious drug despite its long-term limitations. Consequently, research into new drug delivery modes is ongoing. AREAS COVERED: This review summarizes past and current advances of levodopa therapy with a focus on long-term patient management. Current research aims to increase drug bioavailability and to deliver it to the brain continuously. Reduced fluctuations improve drug efficacy and levodopa-associated motor complications. Less considered metabolic long-term consequences of levodopa are impaired methylation capacity and antioxidant defense. Both may contribute to disease progression and weaken physiological available human neuronal repair mechanisms. EXPERT OPINION: New developed formulations will improve pharmacokinetic and pharmacodynamic behavior. The authors suggest the regular supplementation with methyl group-donating and free radical scavenging substrates to weaken the metabolic consequences of chronic and high levodopa dosing. Many patients perform this nutrient supplementation in their diet already.
Subject(s)
Antiparkinson Agents/therapeutic use , Levodopa/therapeutic use , Parkinson Disease/drug therapy , Antioxidants/metabolism , Antiparkinson Agents/adverse effects , Antiparkinson Agents/pharmacokinetics , Aromatic Amino Acid Decarboxylase Inhibitors/pharmacokinetics , Aromatic Amino Acid Decarboxylase Inhibitors/therapeutic use , Brain/metabolism , Catechol O-Methyltransferase Inhibitors/pharmacokinetics , Catechol O-Methyltransferase Inhibitors/therapeutic use , Drug Therapy, Combination , Humans , Levodopa/adverse effects , Levodopa/pharmacokinetics , Oxidative Stress , Parkinson Disease/pathologyABSTRACT
Oral opicapone (Ongentys(®)), a potent, third-generation, long-acting, peripheral catechol-O-methyltransferase (COMT) inhibitor, is approved as adjunctive treatment to levodopa (L-Dopa)/dopa-decarboxylase inhibitor (DDCI) therapy in adults with Parkinson's disease (PD) and end-of-dose motor fluctuations who cannot be stabilized on those combinations. In 14- to 15-week, double-blind, multinational trials and in 1-year, open-label extension studies in this patient population, opicapone was an effective and generally well tolerated adjunctive therapy to L-Dopa plus a DDCI and other PD therapy. During the double-blind phase, adjunctive opicapone 50 mg once daily provided significantly greater improvements in motor fluctuations than placebo, with these improvements noninferior to those with entacapone. These beneficial improvements in motor fluctuations with opicapone were maintained in patients who continued adjunctive opicapone during the extension studies, with patients who switched from placebo or entacapone to opicapone experiencing significant improvements in motor fluctuations during this year. No new unexpected safety concerns were identified after ≈1.4 years' treatment with opicapone, with no serious cases of hepatotoxicity reported in clinical trials. With its convenient once-daily regimen, oral opicapone is an emerging COMT inhibitor option for use as adjunctive therapy to L-Dopa/DDCI therapy in adults with PD and end-of dose motor fluctuations who cannot be stabilized on those combinations.