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Gut Microbes 2022Colonic luminal aromatic amines have been historically considered to be derived from dietary source, especially fermented foods; however, recent studies indicate that...
Colonic luminal aromatic amines have been historically considered to be derived from dietary source, especially fermented foods; however, recent studies indicate that the gut microbiota serves as an alternative source of these amines. Herein, we show that five prominent genera of Firmicutes , and ) have the ability to abundantly produce aromatic amines through the action of aromatic amino acid decarboxylase (AADC). cultivation of human fecal samples revealed that a significant positive correlation between copy number of and phenylethylamine (PEA) production. Furthermore, using genetically engineered -colonized BALB/cCrSlc mouse model, we showed that the gut bacterial stimulates the production of colonic serotonin, which is reportedly involved in osteoporosis and irritable bowel syndrome. Finally, we showed that human AADC inhibitors carbidopa and benserazide inhibit PEA production in .
Topics: Animals; Aromatic-L-Amino-Acid Decarboxylases; Benserazide; Carbidopa; Gastrointestinal Microbiome; Humans; Mice; Phenethylamines; Serotonin
PubMed: 36217238
DOI: 10.1080/19490976.2022.2128605 -
Expert Opinion on Pharmacotherapy 2015The search for consistent, effective treatments in Parkinson's disease (PD) is ongoing. The importance of continuous dopaminergic stimulation (CDS) is understood to... (Review)
Review
INTRODUCTION
The search for consistent, effective treatments in Parkinson's disease (PD) is ongoing. The importance of continuous dopaminergic stimulation (CDS) is understood to underlie best medical therapy for PD by providing closer replication of physiological patterns of dopamine release in healthy brains.
AREAS COVERED
An overview of interventions to improve motor fluctuations in PD is presented. Significant improvements in off-time are achieved by providing continuous therapy using targeted deep brain stimulation (DBS), subcutaneous apomorphine infusion and carbidopa/levodopa enteral suspension (Duopa). Duopa is a newly approved treatment in the US for advanced PD that delivers levodopa pumped to the intestinal tract through a percutaneous gastrostomy with jejunum tube extension (PEG-J tube). Trials with carbidopa/levodopa enteral suspension show improvement in motor fluctuations, reduction in plasma levodopa variation and improvement in overall "on" time compared with oral immediate release formulation of carbidopa/levodopa.
EXPERT OPINION
The degree of improvement in number of off hours per day on carbidopa/levodopa enteral suspension infusion rivals that seen with DBS and apomorphine infusion and makes this new treatment a valuable option in advanced fluctuating PD patients, especially those who are neither candidates for DBS or who do not have access to apomorphine infusion therapy or who have failed either or both therapies.
Topics: Antiparkinson Agents; Carbidopa; Drug Therapy, Combination; Humans; Infusions, Parenteral; Levodopa; Parkinson Disease; Suspensions
PubMed: 26595228
DOI: 10.1517/14656566.2015.1111336 -
Arquivos de Neuro-psiquiatria Dec 2018Optimizing idiopathic Parkinson's disease treatment is a challenging, multifaceted and continuous process with direct impact on patients' quality of life. The basic... (Review)
Review
Optimizing idiopathic Parkinson's disease treatment is a challenging, multifaceted and continuous process with direct impact on patients' quality of life. The basic tenet of this task entails tailored therapy, allowing for optimal motor function with the fewest adverse effects. Apomorphine, a dopamine agonist used as rescue therapy for patients with motor fluctuations, with potential positive effects on nonmotor symptoms, is the only antiparkinsonian agent whose capacity to control motor symptoms is comparable to that of levodopa. Subcutaneous administration, either as an intermittent injection or as continuous infusion, appears to be the most effective and tolerable route. This review summarizes the historical background, structure, mechanism of action, indications, contraindications and side effects, compares apomorphine infusion therapy with other treatments, such as oral therapy, deep brain stimulation and continuous enteral infusion of levodopa/carbidopa gel, and gives practical instructions on how to initiate treatment.
Topics: Antiparkinson Agents; Apomorphine; Carbidopa; Deep Brain Stimulation; Dopamine Agonists; Drug Combinations; Humans; Levodopa; Parkinson Disease
PubMed: 30698208
DOI: 10.1590/0004-282X20180140 -
PloS One 2022To compare maternal and infant outcomes with different antihypertensive medications in pregnancy.
OBJECTIVE
To compare maternal and infant outcomes with different antihypertensive medications in pregnancy.
DESIGN
Retrospective cohort study.
SETTING
Kaiser Permanente, a large healthcare system in the United States.
POPULATION
Women aged 15-49 years with a singleton birth from 2005-2014 treated for hypertension.
METHODS
We identified medication exposure from automated pharmacy data based on the earliest dispensing after the first prenatal visit. Using logistic regression, we calculated weighted outcome prevalences, adjusted odds ratios (aORs) and 95% confidence intervals, with inverse probability of treatment weighting to address confounding.
MAIN OUTCOME MEASURES
Small for gestational age, preterm delivery, neonatal and maternal intensive care unit (ICU) admission, preeclampsia, and stillbirth or termination at > 20 weeks.
RESULTS
Among 6346 deliveries, 87% with chronic hypertension, the risk of the infant being small for gestational age (birthweight < 10th percentile) was lower with methyldopa than labetalol (prevalence 13.6% vs. 16.6%; aOR 0.77, 95% CI 0.63 to 0.92). For birthweight < 3rd percentile the aOR was 0.57 (0.39 to 0.80). Compared with labetalol (26.0%), risk of preterm delivery was similar for methyldopa (26.5%; aOR 1.10 [0.95 to 1.27]) and slightly higher for nifedipine (28.5%; aOR 1.25 [1.06 to 1.46]) and other β-blockers (31.2%; aOR 1.58 [1.07 to 2.23]). Neonatal ICU admission was more common with nifedipine than labetalol (25.9% vs. 23.3%, aOR 1.21 [1.02 to 1.43]) but not elevated with methyldopa. Risks of other outcomes did not differ by medication.
CONCLUSIONS
Risk of most outcomes was similar comparing labetalol, methyldopa and nifedipine. Risk of the infant being small for gestational age was substantially lower for methyldopa, suggesting this medication may warrant further consideration.
Topics: Antihypertensive Agents; Birth Weight; Female; Humans; Hypertension, Pregnancy-Induced; Infant; Infant, Newborn; Infant, Newborn, Diseases; Labetalol; Methyldopa; Nifedipine; Pregnancy; Pregnancy Outcome; Premature Birth; Retrospective Studies
PubMed: 35576217
DOI: 10.1371/journal.pone.0268284 -
Expert Review of Neurotherapeutics Jun 2022Levodopa is the most effective medication for the treatment of motor symptoms of Parkinson's disease (PD). Several factors may affect the efficacy and tolerability of... (Review)
Review
INTRODUCTION
Levodopa is the most effective medication for the treatment of motor symptoms of Parkinson's disease (PD). Several factors may affect the efficacy and tolerability of levodopa. These include the timing, dosage and administration of levodopa, concomitant drugs, food, PD-associated non-motor symptoms, and various neurologic and non-neurologic comorbidities. If not appropriately addressed, these issues may limit levodopa efficacy, tolerability, and compliance.
AREAS COVERED
This article reviews the basics of the metabolism of orally administered levodopa, its side effects, and the factors that may affect its tolerability and efficacy. We provide several practical pearls to improve the tolerability and efficacy of levodopa.
EXPERT OPINION
Protein-rich food delays and reduces levodopa absorption. Hence, levodopa should preferably be administered in a relatively empty stomach. Carbidopa dosing is crucial as it not only enhances the entry of levodopa into the central nervous system but also reduces levodopa's peripheral adverse effects. Patients experiencing the early side effects such as nausea/vomiting should be prescribed with anti-nausea medications that do not block dopamine receptors. Non-oral routes of administration can be used to obviate persistent gastrointestinal side effects. Implementation of these and other tips may help improve the tolerability and efficacy of levodopa.
Topics: Antiparkinson Agents; Carbidopa; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Humans; Levodopa; Parkinson Disease
PubMed: 35710101
DOI: 10.1080/14737175.2022.2091436 -
The Cochrane Database of Systematic... Jan 2018Tardive dyskinesia (TD) is a disabling movement disorder associated with the prolonged use of antipsychotic medication. Several strategies have been examined in the... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Tardive dyskinesia (TD) is a disabling movement disorder associated with the prolonged use of antipsychotic medication. Several strategies have been examined in the treatment of TD. Currently, however, there is no clear evidence of the effectiveness of these drugs in TD and they have been associated with many side effects. One particular strategy would be to use pharmaceutical agents which are known to influence the catecholaminergic system at various junctures.
OBJECTIVES
1. To determine the effects of any of the following drugs for antipsychotic-induced TD in people with schizophrenia or other chronic mental illnesses.i. Drugs which influence the noradrenergic system.ii. Dopamine receptor agonists.iii. Dopamine receptor antagonists.iv. Dopamine-depletor drugs.v. Drugs that increase the production or release of dopamine.2. To examine whether any improvement occurred with short periods of intervention (less than 6 weeks) and, if this did occur, whether this effect was maintained at longer periods of follow-up.3. To examine if there was a differential effect for the various compounds.4. To examine whether the use of non-antipsychotic catecholaminergic drugs are most effective in those with more recent onset TD (less than five years).
SEARCH METHODS
We retrieved 712 references from searching the Cochrane Schizophrenia Group Trials Register (July 2015 and April 2017). We also inspected references of all identified studies for further trials and contacted authors of trials for additional information.
SELECTION CRITERIA
We selected studies if they were randomised controlled trials focusing on people with schizophrenia or other chronic mental illnesses and antipsychotic-induced tardive dyskinesia. We compared the use of catecholaminergic interventions versus placebo, no intervention, or any other intervention for the treatment of antipsychotic-induced tardive dyskinesia.
DATA COLLECTION AND ANALYSIS
We independently extracted data from these trials and we estimated risk ratios (RRs) with 95% confidence intervals (CIs). We assumed that people who left the studies early had no improvement.
MAIN RESULTS
There are 10 included trials (N = 261) published between 1973 and 2010; eight are new from the 2015 and 2017 update searches. Forty-eight studies are excluded. Participants were mostly chronically mentally ill inpatients in their 50s, and studies were primarily of short (2 to 6 weeks) duration. The overall risk of bias in these studies was unclear, mainly due to poor reporting of allocation concealment and generation of the sequence. Studies were also not clearly blinded and we are unsure if data are incomplete or selectively reported, or if other biases were operating.One small, three-arm trial found that both alpha-methyldopa (N = 20; RR 0.33, 95% CI 0.14 to 0.80; low-quality evidence) and reserpine (N = 20; RR 0.52 95% CI 0.29 to 0.96; low-quality evidence) may lead to a clinically important improvement in tardive dyskinesia symptoms compared with placebo after 2 weeks' treatment, but found no evidence of a difference between alpha-methyldopa and reserpine (N = 20; RR 0.60, 95% CI 0.19 to 1.86; very low quality evidence). Another small trial compared tetrabenazine and haloperidol after 18 weeks' treatment and found no evidence of a difference on clinically important improvement in tardive dyskinesia symptoms (N = 13; RR 0.93, 95% CI 0.45 to 1.95; very low quality evidence). No study reported on adverse events.For remaining outcomes there was no evidence of a difference between any of the interventions: alpha-methyldopa versus placebo for deterioration of tardive dyskinesia symptoms (1 RCT; N = 20; RR 0.33, 95% CI 0.02 to 7.32; very low quality evidence), celiprolol versus placebo for leaving the study early (1 RCT; N = 35; RR 5.28, 95% CI 0.27 to 102.58; very low quality evidence) and quality of life (1 RCT; N = 35; RR 0.87, 95% CI 0.68 to 1.12; very low quality evidence), alpha-methyldopa versus reserpine for deterioration of tardive dyskinesia symptoms (1 RCT; N = 20; not estimable, no reported events; very low quality evidence), reserpine or carbidopa/levodopa versus placebo for deterioration of tardive dyskinesia symptoms (2 RCTs; N = 37; RR 1.18, 95% CI 0.35 to 3.99; very low quality evidence), oxypertine versus placebo for deterioration of mental state (1 RCT; N = 42; RR 2.20, 95% CI 0.22 to 22.45; very low quality evidence), dopaminergic drugs (amantadine, bromocriptine, tiapride, oxypertine, carbidopa/levodopa) versus placebo for leaving the study early (6 RCTs; N = 163; RR 1.29, 95% CI 0.65 to 2.54; very low quality evidence), and tetrabenazine versus haloperidol for deterioration of tardive dyskinesia symptoms (1 RCT; N = 13; RR 1.17, 95% CI 0.09 to 14.92) and leaving the study early (1 RCT; N = 13; RR 0.23, 95% CI 0.01 to 4.00).
AUTHORS' CONCLUSIONS
Although there has been a large amount of research in this area, many studies were excluded due to inherent problems in the nature of their cross-over designs. Usually data are not reported before the cross-over and the nature of TD and its likely response to treatments make it imprudent to use this data. The review provides little usable information for service users or providers and more well-designed and well-reported studies are indicated.
Topics: Adrenergic Uptake Inhibitors; Anti-Dyskinesia Agents; Antipsychotic Agents; Celiprolol; Disease Progression; Dopamine Antagonists; Dyskinesia, Drug-Induced; Haloperidol; Humans; Methyldopa; Randomized Controlled Trials as Topic; Reserpine; Tetrabenazine; Tiapamil Hydrochloride
PubMed: 29342497
DOI: 10.1002/14651858.CD000458.pub3 -
Expert Opinion on Drug Metabolism &... May 2020: Parkinson's disease is a chronic, neurodegenerative disease entity with heterogeneous features and course. Levodopa is the most efficacious dopamine substituting drug.... (Review)
Review
: Parkinson's disease is a chronic, neurodegenerative disease entity with heterogeneous features and course. Levodopa is the most efficacious dopamine substituting drug. Particularly, long-term application of oral levodopa/decarboxylase inhibitor formulations sooner or later supports onset of fluctuations of movement. It also shifts levodopa turnover to O-methylation, which impairs human methylation capacity and increases oxidative stress.: This narrative review summarizes pharmacokinetic and pharmacodynamic features of available levodopa cotherapies on the basis of a literature search with the terms L-dopa, inhibitors of catechol-O-methyltransferase and monoamine oxidase-B.: Long-term levodopa/dopa decarboxylase inhibitor application with concomitant inhibition of both, catechol-O-methyltransferase and monoamine oxidase-B supports a more continuous dopamine substitution, which ameliorates fluctuations of motor behavior. This triple combination also enhances both, antioxidative defense and methylation capacity. Inhibition of monoamine oxidase-B reduces generation of oxidative stress in the brain. Constraint of catechol-O-methyltransferase reduces homocysteine synthesis due to diminished consumption of methyl groups for levodopa turnover at least in the periphery. An additional nutritional supplementation with methyl group donating and free radical scavenging vitamins is recommendable, when future drugs are developed for long-term levodopa/dopa decarboxylase treated patients. Personalized medicine treatment concepts shall also consider nutritional aspects of Parkinson's disease.
Topics: Animals; Antiparkinson Agents; Carbidopa; Catechol O-Methyltransferase Inhibitors; Drug Combinations; Humans; Levodopa; Monoamine Oxidase Inhibitors; Oxidative Stress; Parkinson Disease
PubMed: 32238065
DOI: 10.1080/17425255.2020.1750596 -
The New England Journal of Medicine Jan 2019Levodopa is the main treatment for symptoms of Parkinson's disease. Determining whether levodopa also has a disease-modifying effect could provide guidance as to when in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Levodopa is the main treatment for symptoms of Parkinson's disease. Determining whether levodopa also has a disease-modifying effect could provide guidance as to when in the course of the disease the treatment with this drug should be initiated.
METHODS
In a multicenter, double-blind, placebo-controlled, delayed-start trial, we randomly assigned patients with early Parkinson's disease to receive levodopa (100 mg three times per day) in combination with carbidopa (25 mg three times per day) for 80 weeks (early-start group) or placebo for 40 weeks followed by levodopa in combination with carbidopa for 40 weeks (delayed-start group). The primary outcome was the between-group difference in the mean change from baseline to week 80 in the total score on the Unified Parkinson's Disease Rating Scale (UPDRS; scores range from 0 to 176, with higher scores signifying more severe disease). Secondary analyses included the progression of symptoms, as measured by the UPDRS score, between weeks 4 and 40 and the noninferiority of early initiation of treatment to delayed initiation between weeks 44 and 80, with a noninferiority margin of 0.055 points per week.
RESULTS
A total of 445 patients were randomly assigned: 222 to the early-start group and 223 to the delayed-start group. The mean (±SD) UPDRS score at baseline was 28.1±11.4 points in the early-start group and 29.3±12.1 points in the delayed-start group. The change in UPDRS score from baseline to week 80 was -1.0±13.1 points and -2.0±13.0 points, respectively (difference, 1.0 point; 95% confidence interval [CI], -1.5 to 3.5; P=0.44); this finding of no significant between-group difference at week 80 implies that levodopa had no disease-modifying effect. Between weeks 4 and 40, the rate of progression of symptoms, as measured in UPDRS points per week, was 0.04±0.23 in the early-start group and 0.06±0.34 in the delayed-start group (difference, -0.02; 95% CI, -0.07 to 0.03). The corresponding rates between weeks 44 and 80 were 0.10±0.25 and 0.03±0.28 (difference, 0.07; two-sided 90% CI, 0.03 to 0.10); the difference in the rate of progression between weeks 44 and 80 did not meet the criterion for noninferiority of early receipt of levodopa to delayed receipt. The rates of dyskinesia and levodopa-related fluctuations in motor response did not differ significantly between the two groups.
CONCLUSIONS
Among patients with early Parkinson's disease who were evaluated over the course of 80 weeks, treatment with levodopa in combination with carbidopa had no disease-modifying effect. (Funded by the Netherlands Organization for Health Research and Development and others; LEAP Current Controlled Trials number, ISRCTN30518857 .).
Topics: Aged; Antiparkinson Agents; Carbidopa; Disease Progression; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Levodopa; Male; Middle Aged; Parkinson Disease; Time-to-Treatment
PubMed: 30673543
DOI: 10.1056/NEJMoa1809983 -
Movement Disorders : Official Journal... Jan 2015Ever since its early clinical use in the 1960s, levodopa has remained the gold standard of symptomatic efficacy in the drug treatment of Parkinson's disease (PD). Motor... (Review)
Review
Ever since its early clinical use in the 1960s, levodopa has remained the gold standard of symptomatic efficacy in the drug treatment of Parkinson's disease (PD). Motor response fluctuations and drug-induced dyskinesias seriously compromise the unparalleled symptomatic efficacy of l-dopa during long-term treatment. Discontinuous drug delivery resulting from the short half-life of l-dopa and erratic gastrointestinal absorption plays a major role in the pathophysiology of these motor complications. Several approaches to improve the pharmacokinetics and ways of administration of l-dopa are in different stages of clinical development and include novel formulations as well as nonoral routes of drug delivery. IPX066 is a novel extended-release l-dopa capsule that has successfully completed phase III clinical trials while the l-dopa prodrug XP21279 and a gastric retention formulation ("accordion pill") are in earlier phases of clinical development. Novel enzyme inhibitors enhancing l-dopa efficacy and half-life are also still being developed, including a novel catechol-O-methyltransferase inhibitor with once-daily pharmacokinetics, and there are studies testing the effects of increasing the dose of amino acid decarboxylase inhibitors given concomitantly with l-dopa. Intrajejunal infusion of a gel formulation of l-dopa/carbidopa is in clinical use in Europe, and its efficacy to smooth out motor fluctuations has recently been shown in a randomized, controlled trial. Subcutaneous and intrapulmonal delivery routes of l-dopa have reached phase III of clinical development. After more than 50 years of clinical use, l-dopa not only remains the gold standard of symptomatic efficacy, but it also remains a drug in active clinical development.
Topics: Animals; Antiparkinson Agents; Carbidopa; Drug Combinations; Drug Delivery Systems; Humans; Levodopa; Parkinson Disease
PubMed: 25476691
DOI: 10.1002/mds.26078 -
British Journal of Nursing (Mark Allen... Mar 2018The inability to achieve adequate nutrition and weight loss are serious problems for patients with advanced Parkinson's disease (PD). To ensure the optimal intake of... (Review)
Review
The inability to achieve adequate nutrition and weight loss are serious problems for patients with advanced Parkinson's disease (PD). To ensure the optimal intake of nutrition and fluids and to administer levodopa-carbidopa intestinal gel (LCIG) (which patients need to increase or maintain their mobility as long as possible), different artificial feeding tubes can be used. Although percutaneous endoscopic gastrostomy (PEG) tubes are frequently used in medical practice, there is little research that addresses key questions, including if and when to administer artificial fluids, nutrition and/or LCIG via tubes. Weight gain through tube feeding is only possible for some patients; nurses should keep in mind that tube insertion and feeding may lead to frequent adverse events. Administering LCIG via tubes is usually advisable as it seems to enhance patients' mobility and therefore has positive outcomes in terms of the quality of life of patients and their families ( Lim et al, 2015 ). The authors aimed to examine the use and consequences of providing nutrition and LCIG via gastrostomy tubes in PD patients with advanced disease.
Topics: Antiparkinson Agents; Carbidopa; Drug Combinations; Enteral Nutrition; Female; Gels; Humans; Intestines; Levodopa; Male; Parkinson Disease; Quality of Life
PubMed: 29517331
DOI: 10.12968/bjon.2018.27.5.259