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Postgraduate Medicine Sep 2021Levodopa is the most effective symptomatic treatment for Parkinson's disease (PD), but a major treatment challenge is that over time, many patients experience periods of... (Review)
Review
Levodopa is the most effective symptomatic treatment for Parkinson's disease (PD), but a major treatment challenge is that over time, many patients experience periods of return of PD symptoms intermittently through the day, known as OFF periods. OFF periods typically manifest as a return of motor symptoms but can also involve non-motor symptoms and these periods can disrupt good control despite optimization of the oral levodopa regimen. OFF periods emerge in large measure due to a shortening of the duration of clinical benefit from oral levodopa, thought to be related to a progressive loss of dopamine neurons and their ability to store and release levodopa-derived dopamine over many hours. The problem is further compounded by impaired absorption of oral levodopa due to gastroparesis and other factors limiting its uptake in the small intestine, including competition for uptake by meals and their protein content. On-demand therapies are now available for the treatment of OFF episodes in PD and are administered intermittently, on an as-needed basis, on top of the patient's maintenance medication regimen. To be useful, an on-demand medication should take effect more rapidly and reliably than oral levodopa. Options for on-demand therapy for OFF periods have recently increased with the approval of levodopa inhalation powder and sublingual apomorphine as alternatives to the older option of subcutaneous apomorphine injection, each of which avoids the gastrointestinal tract and its potential for absorption delay. On-demand therapy is now available for patients experiencing episodic or intermittent need for rapid and reliable onset of benefit. On-demand therapy may also provide an alternative to more invasive treatment such as infusion of levodopa/carbidopa intestinal gel and for patients whose OFF episodes are not controlled despite deep brain stimulation.
Topics: Antiparkinson Agents; Apomorphine; Carbidopa; Dopamine Agonists; Drug Administration Routes; Drug Combinations; Humans; Levodopa; Parkinson Disease
PubMed: 34082655
DOI: 10.1080/00325481.2021.1936087 -
The Medical Letter on Drugs and... Feb 2020
Topics: Adenosine A2 Receptor Antagonists; Antiparkinson Agents; Carbidopa; Clinical Trials as Topic; Drug Administration Schedule; Humans; Levodopa; Parkinson Disease; Purines
PubMed: 32022788
DOI: No ID Found -
Clinical NeuropharmacologyLevodopa (LD) administered with dopa decarboxylase inhibitor is predominantly metabolized in the periphery by catechol- O -methyltransferase (COMT) to 3- O -methyldopa... (Randomized Controlled Trial)
Randomized Controlled Trial
Opicapone Pharmacokinetics and Effects on Catechol- O -Methyltransferase Activity and Levodopa Pharmacokinetics in Patients With Parkinson Disease Receiving Carbidopa/Levodopa.
OBJECTIVES
Levodopa (LD) administered with dopa decarboxylase inhibitor is predominantly metabolized in the periphery by catechol- O -methyltransferase (COMT) to 3- O -methyldopa (3-OMD). Catechol- O -methyltransferase inhibition can improve treatment outcomes by decreasing variability in circulating LD concentrations. Opicapone is a once-daily COMT inhibitor approved in the US adjunctive to carbidopa (CD)/LD in patients with Parkinson disease experiencing "OFF" episodes. This study aimed to evaluate the pharmacokinetics and pharmacodynamics of once-daily opicapone 50 mg adjunctive to CD/LD in patients with stable Parkinson disease.
METHODS
Once-daily opicapone 50 mg was administered the evenings of days 1 to 14. Participants were randomized to receive CD/LD (25/100 mg) every 3 or 4 hours (Q3H or Q4H). Participants received Q3H or Q4H CD/LD on days 1, 2, and 15 and their usual CD/LD regimen on other days. Serial blood samples were collected to determine plasma opicapone, LD, and 3-OMD concentrations and erythrocyte soluble COMT (S-COMT) activity. The effects of opicapone on S-COMT, LD, and 3-OMD were assessed. Mean (SD) values are presented.
RESULTS
Sixteen participants were enrolled. At steady-state (day 14), opicapone Cmax (peak plasma concentration) and AUC 0-last (area under the curve-time curve) were 459 ± 252 ng/mL and 2022 ± 783 ng/mL·h, respectively. Maximum COMT inhibition was 83.4 ± 4.9% of baseline on day 14. After opicapone administration, LD total AUC, peak concentration, and trough concentration increased; peak-to-trough fluctuation index decreased. Correspondingly, 3-OMD total AUC, peak concentration, and trough concentration decreased.
CONCLUSIONS
Adding once-daily opicapone 50 mg to LD resulted in marked and extended COMT inhibition, which increased systemic exposure to LD. These changes translated into higher trough concentrations and decreased peak-to-trough fluctuations for LD.
Topics: Humans; Levodopa; Carbidopa; Parkinson Disease; Antiparkinson Agents; Catechol O-Methyltransferase Inhibitors; Catechol O-Methyltransferase
PubMed: 36688497
DOI: 10.1097/WNF.0000000000000538 -
Journal of Parkinson's Disease 2023Tablet formulations of Parkinson's disease (PD) medications may become ineffective at managing motor fluctuations in advanced PD. The liquid formulation, levodopa... (Review)
Review
BACKGROUND
Tablet formulations of Parkinson's disease (PD) medications may become ineffective at managing motor fluctuations in advanced PD. The liquid formulation, levodopa carbidopa ascorbic acid solution, or LCAS, is an effective and inexpensive treatment for motor fluctuations however it remains underutilized.
OBJECTIVE
We compared the efficacy of LCAS with tablet formulations and Duodopa jejunal infusion through routine inpatient management using hourly functional status measures, the Timed Up and Go Test (TUG). The TUG differentiates between 'off' and 'on' states and quantifies motor fluctuations.
METHODS
Experienced nurses used the TUG times and functional observations recorded hourly throughout the waking day to optimize the LCAS hourly dose and the Duodopa flow rate over several days. When patients were stabilized on each of the interventions, the TUG measures were then recorded to compare the outcomes of the interventions.
RESULTS
Twenty-six participants had TUG times recorded while on one or more of the formulations: 19 had TUG times recorded on tablets, 23 on LCAS and 10 on Duodopa. TUG times on LCAS and Duodopa were significantly faster compared to tablets (p < 0.0001, p = 0.001 respectively). Severity of dyskinesia was not significantly different between formulations (p = 0.35). Daily dose for the three formulations and the hourly doses for LCAS and Duodopa did not differ significantly (p = 0.37, p = 0.19 respectively).
CONCLUSION
This report demonstrated the efficacy of LCAS for improving motor complications and its equivalency with Duodopa jejunal infusion.
Topics: Humans; Carbidopa; Levodopa; Parkinson Disease; Antiparkinson Agents; Postural Balance; Time and Motion Studies; Drug Combinations
PubMed: 37092237
DOI: 10.3233/JPD-225117 -
BJOG : An International Journal of... Sep 2014Pregnant and postpartum women with severe hypertension are at increased risk of stroke and require blood pressure (BP) reduction. Parenteral antihypertensives have been... (Review)
Review
BACKGROUND
Pregnant and postpartum women with severe hypertension are at increased risk of stroke and require blood pressure (BP) reduction. Parenteral antihypertensives have been most commonly studied, but oral agents would be ideal for use in busy and resource-constrained settings.
OBJECTIVES
To review systematically, the effectiveness of oral antihypertensive agents for treatment of severe pregnancy/postpartum hypertension.
SEARCH STRATEGY
A systematic search of MEDLINE, EMBASE and the Cochrane Library was performed.
SELECTION CRITERIA
Randomised controlled trials in pregnancy and postpartum with at least one arm consisting of a single oral antihypertensive agent to treat systolic BP ≥ 160 mmHg and/or diastolic BP ≥ 110 mmHg.
DATA COLLECTION AND ANALYSIS
Cochrane RevMan 5.1 was used to calculate relative risk (RR) and weighted mean difference by random effects.
MAIN RESULTS
We identified 15 randomised controlled trials (915 women) in pregnancy and one postpartum trial. Most trials in pregnancy compared oral/sublingual nifedipine capsules (8-10 mg) with another agent, usually parenteral hydralazine or labetalol. Nifedipine achieved treatment success in most women, similar to hydralazine (84% with nifedipine; relative risk [RR] 1.07, 95% confidence interval [95% CI] 0.98-1.17) or labetalol (100% with nifedipine; RR 1.02, 95% CI 0.95-1.09). Less than 2% of women treated with nifedipine experienced hypotension. There were no differences in adverse maternal or fetal outcomes. Target BP was achieved ~ 50% of the time with oral labetalol (100 mg) or methyldopa (250 mg) (47% labetelol versus 56% methyldopa; RR 0.85 95% CI 0.54-1.33).
CONCLUSIONS
Oral nifedipine, and possibly labetalol and methyldopa, are suitable options for treatment of severe hypertension in pregnancy/postpartum.
Topics: Administration, Oral; Antihypertensive Agents; Female; Humans; Hydralazine; Hypertension, Pregnancy-Induced; Labetalol; Methyldopa; Nifedipine; Postpartum Period; Pregnancy; Pregnancy Complications, Cardiovascular; Randomized Controlled Trials as Topic; Treatment Outcome; Vasodilator Agents
PubMed: 24832366
DOI: 10.1111/1471-0528.12737 -
The American Journal of Medicine Jan 2021Age-related macular degeneration (AMD) is a common cause of blindness worldwide. Neovascular AMD (nAMD) is an advanced form of the disease, in which excess vascular...
BACKGROUND
Age-related macular degeneration (AMD) is a common cause of blindness worldwide. Neovascular AMD (nAMD) is an advanced form of the disease, in which excess vascular endothelial growth factor (VEGF) induces growth of new blood vessels that leak fluid, accounting for 90% of vision loss in AMD. Dysfunction of the retinal pigment epithelium likely initiates AMD. Retinal pigment epithelial cells express a G protein-coupled receptor, GPR143, which downregulates VEGF in response to levodopa. Anti-VEGF therapy effectively treats nAMD, suggesting that excessive VEGF activity drives the pathology.
METHODS
In an open-label pilot study, in patients with newly diagnosed nAMD and naïve to anti-VEGF injections (Cohort-1), the effects of carbidopa-levodopa on vision and anatomic outcomes were evaluated for 4 weeks. Then patients were followed 5 months further with ascending levodopa doses. Patients previously treated with anti-VEGF injection therapy (Cohort-2) were also treated with ascending levodopa doses and evaluated for 6 months.
RESULTS
Levodopa was safe, well tolerated, and delayed anti-VEGF injection therapy while improving visual outcomes. In the first month, retinal fluid decreased by 29% (P = .02, n = 12) without anti-VEGF treatment. Through 6 months the decrease in retinal fluid was sustained, with a mean frequency of 0.38 injections/month. At month 6, mean visual acuity improved by 4.7 letters in Cohort-1 (P = .004, n = 15) and by 4.8 letters in Cohort-2 (P = .02, n = 11). Additionally, there was a 52% reduction in the need for anti-VEGF injections in Cohort-2 (P = .002).
CONCLUSIONS
Our findings suggest efficacy and support the pharmacological targeting of GPR143 with levodopa for the treatment of nAMD in future studies.
Topics: Aged; Aged, 80 and over; Carbidopa; Cohort Studies; Dopamine Agents; Drug Combinations; Female; Humans; Levodopa; Macular Degeneration; Male; Middle Aged; Pilot Projects; Treatment Outcome
PubMed: 32628915
DOI: 10.1016/j.amjmed.2020.05.038 -
Movement Disorders : Official Journal... Feb 2024IPX203 is a novel oral extended-release formulation of carbidopa/levodopa (CD/LD) developed to address the short half-life of immediate-release CD/LD. In the phase 3... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
IPX203 is a novel oral extended-release formulation of carbidopa/levodopa (CD/LD) developed to address the short half-life of immediate-release CD/LD. In the phase 3 RISE-PD trial, IPX203 significantly improved "Good On" time in patients with Parkinson's disease compared with immediate-release CD/LD.
OBJECTIVES
To evaluate the safety and efficacy of IPX203 in an open-label extension of the pivotal phase 3 study.
METHODS
This 9-month extension enrolled patients who completed the randomized, double-blind trial. Key efficacy endpoints included Movement Disorder Society-Unified Parkinson's Disease Rating Scale and Patient and Clinical Global Impression scores. Adverse events (AEs) were recorded.
RESULTS
Improvements in efficacy were maintained and dosing frequency and total daily dose remained stable through the trial. A total of 52.7% of patients experienced ≥1 treatment-emergent AE, mostly mild or moderate and occurred within the first 90 days of treatment.
CONCLUSIONS
In this phase 3 open-label extension, IPX203 exhibited a favorable safety and tolerability profile and sustained efficacy of comparable magnitude to the end of the double-blind study. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; Parkinson Disease; Antiparkinson Agents; Levodopa; Carbidopa; Delayed-Action Preparations; Research; Drug Combinations; Double-Blind Method
PubMed: 38111267
DOI: 10.1002/mds.29685 -
Clinical NeuropharmacologyOral levodopa is the most effective treatment for Parkinson disease, but OFF periods emerge over time. Gastrointestinal dysfunction and food effects impact levodopa...
Oral levodopa is the most effective treatment for Parkinson disease, but OFF periods emerge over time. Gastrointestinal dysfunction and food effects impact levodopa absorption, contributing to unpredictable control of OFF periods. Inhaled levodopa powder (Inbrija) is approved for on-demand treatment of OFF periods in patients receiving oral levodopa-dopa decarboxylase inhibitors. The 84-mg dose is administered via a breath-actuated inhaler. It provides pulmonary delivery of levodopa to the systemic circulation and is taken when a patient has an OFF period in between doses of regular oral levodopa medication. The pivotal SPAN-PD trial in patients experiencing OFF periods on oral dopaminergic therapy showed that levodopa inhalation powder 84 mg produced significant improvement in Unified Parkinson Disease Rating Scale Part III score, as measured 30 minutes postdose at week 12, and improvement was seen as early as 10 minutes. More patients in the levodopa inhalation powder group turned ON within 60 minutes of treatment and remained ON at 60 minutes than in the placebo group. Levodopa inhalation powder can also be used to treat early-morning OFF periods and, when used for up to 12 months, produced no clinically significant differences in pulmonary function compared with an untreated cohort. Levodopa inhalation powder 84 mg increased plasma levodopa concentration rapidly and with less variability than oral levodopa/carbidopa (25/100 mg). Most common adverse event associated with levodopa inhalation powder is cough, found in ~15% of patients in the SPAN-PD trial; otherwise, reported adverse events were consistent with those known to be associated with oral levodopa.
Topics: Humans; Levodopa; Parkinson Disease; Antiparkinson Agents; Powders; Administration, Inhalation; Carbidopa
PubMed: 36715241
DOI: 10.1097/WNF.0000000000000540 -
The Cochrane Database of Systematic... Aug 2017Hypertension is an important risk factor for adverse cardiovascular events including stroke, myocardial infarction, heart failure and renal failure. The main goal of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Hypertension is an important risk factor for adverse cardiovascular events including stroke, myocardial infarction, heart failure and renal failure. The main goal of treatment is to reduce these events. Systematic reviews have shown proven benefit of antihypertensive drug therapy in reducing cardiovascular morbidity and mortality but most of the evidence is in people 60 years of age and older. We wanted to know what the effects of therapy are in people 18 to 59 years of age.
OBJECTIVES
To quantify antihypertensive drug effects on all-cause mortality in adults aged 18 to 59 years with mild to moderate primary hypertension. To quantify effects on cardiovascular mortality plus morbidity (including cerebrovascular and coronary heart disease mortality plus morbidity), withdrawal due adverse events and estimate magnitude of systolic blood pressure (SBP) and diastolic blood pressure (DBP) lowering at one year.
SEARCH METHODS
The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to January 2017: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. We contacted authors of relevant papers regarding further published and unpublished work.
SELECTION CRITERIA
Randomized trials of at least one year' duration comparing antihypertensive pharmacotherapy with a placebo or no treatment in adults aged 18 to 59 years with mild to moderate primary hypertension defined as SBP 140 mmHg or greater or DBP 90 mmHg or greater at baseline, or both.
DATA COLLECTION AND ANALYSIS
The outcomes assessed were all-cause mortality, total cardiovascular (CVS) mortality plus morbidity, withdrawals due to adverse events, and decrease in SBP and DBP. For dichotomous outcomes, we used risk ratio (RR) with 95% confidence interval (CI) and a fixed-effect model to combine outcomes across trials. For continuous outcomes, we used mean difference (MD) with 95% CI and a random-effects model as there was significant heterogeneity.
MAIN RESULTS
The population in the seven included studies (17,327 participants) were predominantly healthy adults with mild to moderate primary hypertension. The Medical Research Council Trial of Mild Hypertension contributed 14,541 (84%) of total randomized participants, with mean age of 50 years and mean baseline blood pressure of 160/98 mmHg and a mean duration of follow-up of five years. Treatments used in this study were bendrofluazide 10 mg daily or propranolol 80 mg to 240 mg daily with addition of methyldopa if required. The risk of bias in the studies was high or unclear for a number of domains and led us to downgrade the quality of evidence for all outcomes.Based on five studies, antihypertensive drug therapy as compared to placebo or untreated control may have little or no effect on all-cause mortality (2.4% with control vs 2.3% with treatment; low quality evidence; RR 0.94, 95% CI 0.77 to 1.13). Based on 4 studies, the effects on coronary heart disease were uncertain due to low quality evidence (RR 0.99, 95% CI 0.82 to 1.19). Low quality evidence from six studies showed that drug therapy may reduce total cardiovascular mortality and morbidity from 4.1% to 3.2% over five years (RR 0.78, 95% CI 0.67 to 0.91) due to reduction in cerebrovascular mortality and morbidity (1.3% with control vs 0.6% with treatment; RR 0.46, 95% CI 0.34 to 0.64). Very low quality evidence from three studies showed that withdrawals due to adverse events were higher with drug therapy from 0.7% to 3.0% (RR 4.82, 95% CI 1.67 to 13.92). The effects on blood pressure varied between the studies and we are uncertain as to how much of a difference treatment makes on average.
AUTHORS' CONCLUSIONS
Antihypertensive drugs used to treat predominantly healthy adults aged 18 to 59 years with mild to moderate primary hypertension have a small absolute effect to reduce cardiovascular mortality and morbidity primarily due to reduction in cerebrovascular mortality and morbidity. All-cause mortality and coronary heart disease were not reduced. There is lack of good evidence on withdrawal due to adverse events. Future trials in this age group should be at least 10 years in duration and should compare different first-line drug classes and strategies.
Topics: Adult; Antihypertensive Agents; Bendroflumethiazide; Blood Pressure; Cause of Death; Coronary Disease; Humans; Hypertension; Methyldopa; Middle Aged; Myocardial Infarction; Patient Dropouts; Propranolol; Randomized Controlled Trials as Topic; Stroke; Young Adult
PubMed: 28813123
DOI: 10.1002/14651858.CD008276.pub2 -
MSystems Feb 2022Parkinson's disease (PD) is known to be associated with altered gastrointestinal function and microbiota composition. To date, the effect of PD medication on the...
Parkinson's disease (PD) is known to be associated with altered gastrointestinal function and microbiota composition. To date, the effect of PD medication on the gastrointestinal function and microbiota, at the site of drug absorption, the small intestine, has not been studied, although it may represent an important confounder in reported microbiota alterations observed in PD patients. To this end, healthy (non-PD) wild-type Groningen rats were employed and treated with dopamine, pramipexole (in combination with levodopa-carbidopa), or ropinirole (in combination with levodopa-carbidopa) for 14 sequential days. Rats treated with dopamine agonists showed a significant reduction in small intestinal motility and an increase in bacterial overgrowth in the distal small intestine. Notably, significant alterations in microbial taxa were observed between the treated and vehicle groups; analogous to the changes previously reported in human PD versus healthy control microbiota studies. These microbial changes included an increase in and and a decrease in and . Markedly, certain species correlated negatively with levodopa levels in the systemic circulation, potentially affecting the bioavailability of levodopa. Overall, the study highlights a significant effect of PD medication intrinsically on disease-associated comorbidities, including gastrointestinal dysfunction and small intestinal bacterial overgrowth, as well as the gut microbiota composition. The results urge future studies to take into account the influence of PD medication when seeking to identify microbiota-related biomarkers for PD. Parkinson's disease (PD) is the second most common neurodegenerative disorder and is known to be associated with altered gastrointestinal function and microbiota composition. We previously showed that the gut bacteria harboring tyrosine decarboxylase enzymes interfere with levodopa, the main treatment for PD (S. P. van Kessel, A. K. Frye, A. O. El-Gendy, M. Castejon, A. Keshavarzian, G. van Dijk, and S. El Aidy, Nat Commun 10:310, 2019). Although PD medication could be an important confounder in the reported alterations, its effect, apart from the disease itself, on the microbiota composition or the gastrointestinal function at the site of drug absorption, the small intestine, has not been studied. The findings presented here show a significant impact of commonly prescribed PD medication on the small intestinal motility, small intestinal bacterial overgrowth, and microbiota composition, irrespective of the PD. Remarkably, we observed negative associations between bacterial species harboring tyrosine decarboxylase activity and levodopa levels in the systemic circulation, potentially affecting the bioavailability of levodopa. Overall, this study shows that PD medication is an important factor in determining gastrointestinal motility and, in turn, microbiota composition and may, partly, explain the differential abundant taxa previously reported in the cross-sectional PD microbiota human studies. The results urge future studies to take into account the influence of PD medication on gut motility and microbiota composition when seeking to identify microbiota-related biomarkers for PD.
Topics: Humans; Rats; Animals; Parkinson Disease; Levodopa; Carbidopa; Tyrosine Decarboxylase; Cross-Sectional Studies; Bacteria; Gastrointestinal Microbiome; Gastrointestinal Motility
PubMed: 35076270
DOI: 10.1128/msystems.01191-21