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2.
Ideggyogy Sz ; 75(11-12): 365-368, 2022 Nov 30.
Artigo em Húngaro | MEDLINE | ID: mdl-36541150

RESUMO

In advanced Parkinson's disease, oral medication can often no longer achieve sufficient therapeutic success. As one of the device aided therapies, the intrajejunal levo-dopa administration has been established as valuable treatment option. A modern form of the well-known intestinal levodopa pump offers the opportunity to continue the oral triple combination of levodopa, carbidopa and entacapone that many patients already use. Since February 2021 this modern option is available in Austria and Germany which also contains entacapone, whereby levo-dopa can be saved. In many other countries, including Hungary, approval is expected in the near future. The pump and cartridge are significantly smaller and lighter than in the LCIG pump which should improve the accep-tance of the therapy. The higher acceptance of the smaller pump and the improved user-friendliness has already been reported in an observational study from Sweden. The unwanted effects of entacapone have to be considered.


Assuntos
Carbidopa , Doença de Parkinson , Humanos , Levodopa/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/uso terapêutico , Combinação de Medicamentos , Géis/uso terapêutico , Estudos Observacionais como Assunto
3.
CNS Drugs ; 36(12): 1269-1283, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36414908

RESUMO

INTRODUCTION: Research comparing levodopa/carbidopa intestinal gel (LCIG), deep brain stimulation (DBS), and continuous subcutaneous apomorphine infusion (CSAI) for advanced Parkinson's disease (PD) is lacking. This network meta-analysis (NMA) assessed the comparative effectiveness of LCIG, DBS, CSAI and best medical therapy (BMT) in reducing off-time and improving quality of life (QoL) in patients with advanced PD. METHODS: A systematic literature review was conducted for randomized controlled trials (RCTs), observational and interventional studies from January 2003 to September 2019. Data extracted at baseline and 6 months were off-time, as reported by diary or Unified Parkinson's Disease Rating Scale Part IV item 39, and QoL, as reported by Parkinson's Disease Questionnaire (PDQ-39/PDQ-8). Bayesian NMA was performed to estimate pooled treatment effect sizes and to rank treatments in order of effectiveness. RESULTS: A total of 22 studies fulfilled the inclusion criteria (n = 2063 patients): four RCTs, and 16 single-armed, one 2-armed and one 3-armed prospective studies. Baseline mean age was between 55.5-70.9 years, duration of PD was 9.1-15.3 years, off-time ranged from 5.4 to 8.7 h/day in 9 studies, and PDQ scores ranged from 28.8 to 67.0 in 19 studies. Levodopa/carbidopa intestinal gel and DBS demonstrated significantly greater improvement in off-time and QoL at 6 months compared with CSAI and BMT (p < 0.05). There was no significant difference in the effects of LCIG and DBS, but DBS was ranked first for reduction in off-time, and LCIG was ranked first for improvement in QoL. CONCLUSIONS: This NMA found that LCIG and DBS were associated with superior improvement in off-time and PD-related QoL compared with CSAI and BMT at 6 months after treatment initiation. This comparative effectiveness research may assist providers, patients, and caregivers in the selection of the optimal device-aided therapy.


Assuntos
Carbidopa , Doença de Parkinson , Humanos , Pessoa de Meia-Idade , Idoso , Carbidopa/uso terapêutico , Levodopa/uso terapêutico , Qualidade de Vida , Metanálise em Rede , Doença de Parkinson/tratamento farmacológico , Apomorfina/uso terapêutico
5.
Lancet Neurol ; 21(12): 1099-1109, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36402160

RESUMO

BACKGROUND: Levodopa is the most effective symptomatic therapy for Parkinson's disease, but patients with advanced Parkinson's disease develop motor fluctuations with chronic oral levodopa therapy. Foslevodopa-foscarbidopa is a soluble formulation of levodopa and carbidopa prodrugs that is delivered as a 24-h/day continuous subcutaneous infusion, and we aimed to assess the safety and efficacy of this formulation in patients with advanced Parkinson's disease. METHODS: A 12-week randomised, double-blind, double-dummy, active-controlled study was done at 65 academic and community study centres in the USA and Australia. Patients with levodopa-responsive advanced Parkinson's disease inadequately controlled on current therapy, including at least 2·5 h of average daily off time, were randomly assigned (1:1) to continuous subcutaneous infusion of foslevodopa-foscarbidopa plus oral placebo or to oral immediate-release levodopa-carbidopa plus continuous subcutaneous infusion of placebo solution. Randomisation was stratified by site by means of a permutated-block schedule with a block size of two. The participants, treating investigators, study site personnel, and sponsor were masked to treatment group allocation. The primary and first key secondary endpoint in the hierarchical testing strategy were change from baseline to week 12 in on time without troublesome dyskinesia and off time, respectively; both endpoints were evaluated by an intention-to-treat analysis applying a mixed model for repeated measures analysis. Safety and tolerability were assessed throughout the study. The study is completed and is listed on ClinicalTrials.gov, NCT04380142. FINDINGS: Between Oct 19, 2020, and Sept 29, 2021, of 270 participants screened and 174 enrolled, 141 were randomly assigned and received continuous subcutaneous infusion of foslevodopa-foscarbidopa plus oral placebo capsules (n=74) or oral encapsulated immediate-release levodopa-carbidopa plus continuous subcutaneous infusion of placebo solution (n=67). Compared with levodopa-carbidopa, foslevodopa-foscarbidopa showed a significantly greater increase in on time without troublesome dyskinesia (model-based mean [SE] 2·72 [0·52] vs 0·97 [0·50] h; difference 1·75 h, 95% CI 0·46 to 3·05; p=0·0083) and a significantly greater reduction in off time (-2·75 [0·50] vs -0·96 [0·49] h; difference -1·79 h, -3·03 to -0·54; p=0·0054). Hierarchical testing ended after the first secondary endpoint. Adverse events were reported in 63 (85%) of 74 patients in the foslevodopa-foscarbidopa group versus 42 (63%) of 67 in the levodopa-carbidopa group, and incidences of serious adverse events were similar between the groups (six [8%] of 74 vs four [6%] of 67, respectively). The most frequent adverse events in the foslevodopa-foscarbidopa group were infusion site adverse events (erythema 20 [27%]), pain 19 [26%]), cellulitis (14 [19%]), and oedema (nine [12%]), most of which were non-serious and mild-moderate in severity. The only system organ class that had more than one serious adverse event in the foslevodopa-foscarbidopa group was infections and infestations (catheter site cellulitis [one [1%]] and infusion site cellulitis [one [1%]). Adverse events led to premature discontinuation of study drug in 16 (22%) of 74 participants in the foslevodopa-foscarbidopa group versus one (1%) of 67 participants in the oral levodopa-carbidopa group. INTERPRETATION: Foslevodopa-foscarbidopa improved motor fluctuations, with benefits in both on time without troublesome dyskinesia and off time. Foslevodopa-foscarbidopa has a favourable benefit-risk profile and represents a potential non-surgical alternative for patients with advanced Parkinson's disease. FUNDING: AbbVie.


Assuntos
Discinesias , Doença de Parkinson , Humanos , Carbidopa/efeitos adversos , Levodopa/efeitos adversos , Antiparkinsonianos/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Celulite (Flegmão)/induzido quimicamente , Celulite (Flegmão)/tratamento farmacológico , Agonistas de Dopamina , Discinesias/tratamento farmacológico
6.
Int J Pharm ; 629: 122401, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-36395922

RESUMO

Parkinson's disease is frequently treated with combinations of levodopa/carbidopa and, at the occurrence of motor fluctuations, levodopa/carbidopa/entacapone. For these (and other) medications, using generic versions can reduce costs. To show that generic drugs are equivalent to the originator drug, regulations usually refer to the bioavailability of active ingredients, which is influenced by the selected dosage form and the chosen excipients. However, while registration trials administer drugs under standardized conditions, these conditions often do not reflect the conditions of patients' daily intake. Thus, this study aimed to characterize levodopa combinations from different manufacturers in biorelevant media. Dissolution profiles of bioequivalent levodopa/carbidopa combinations and levodopa/carbidopa/entacapone combinations were tested in different media, such as tap water, gastric fluid without pepsin and whole milk. Results showed distinct discrepancies in the drugs' dissolution profiles between manufactures. Using whole milk as a dissolution medium led to the most differing dissolution profiles. Furthermore, carbidopa was unstable in tap water and milk, and it rapidly degraded. This effect was less pronounced if entacapone was present. In contrast to reports in the literature, stability testing did not show that vitamin C helps to protect against carbidopa degradation. Entacapone hardly dissolved in an acidic environment. This study found that dissolution of bioequivalent levodopa formulations varied with changing media. Further, the stability of carbidopa was found to be critical. As an implication, an acidic environment must be ensured when these drugs are applied, and generic exchange of levodopa combinations should be considered only with great caution.


Assuntos
Carbidopa , Levodopa , Humanos , Solubilidade , Equivalência Terapêutica , Medicamentos Genéricos
7.
Transl Neurodegener ; 11(1): 43, 2022 10 13.
Artigo em Inglês | MEDLINE | ID: mdl-36229860

RESUMO

Continuous drug delivery (CDD) is used in moderately advanced and late-stage Parkinson's disease (PD) to control motor and non-motor fluctuations ('OFF' periods). Transdermal rotigotine is indicated for early fluctuations, while subcutaneous apomorphine infusion and levodopa-carbidopa intestinal gel are utilised in advanced PD. All three strategies are considered examples of continuous dopaminergic stimulation achieved through CDD. A central premise of the CDD is to achieve stable control of the parkinsonian motor and non-motor states and avoid emergence of 'OFF' periods. However, data suggest that despite their efficacy in reducing the number and duration of 'OFF' periods, these strategies still do not prevent 'OFF' periods in the middle to late stages of PD, thus contradicting the widely held concepts of continuous drug delivery and continuous dopaminergic stimulation. Why these emergent 'OFF' periods still occur is unknown. In this review, we analyse the potential reasons for their persistence. The contribution of drug- and device-related involvement, and the problems related to site-specific drug delivery are analysed. We propose that changes in dopaminergic and non-dopaminergic mechanisms in the basal ganglia might render these persistent 'OFF' periods unresponsive to dopaminergic therapy delivered via CDD.


Assuntos
Carbidopa , Doença de Parkinson , Antiparkinsonianos/uso terapêutico , Apomorfina/uso terapêutico , Carbidopa/uso terapêutico , Dopamina , Humanos , Levodopa , Doença de Parkinson/tratamento farmacológico
8.
Gut Microbes ; 14(1): 2128605, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36217238

RESUMO

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 (Blautia, Clostridium, Enterococcus, Ruminococcus, and Tyzzerella) have the ability to abundantly produce aromatic amines through the action of aromatic amino acid decarboxylase (AADC). In vitro cultivation of human fecal samples revealed that a significant positive correlation between aadc copy number of Ruminococcus gnavus and phenylethylamine (PEA) production. Furthermore, using genetically engineered Enterococcus faecalis-colonized BALB/cCrSlc mouse model, we showed that the gut bacterial aadc 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 En. faecalis.


Assuntos
Carbidopa , Microbioma Gastrointestinal , Animais , Descarboxilases de Aminoácido-L-Aromático/genética , Descarboxilases de Aminoácido-L-Aromático/metabolismo , Benserazida/farmacologia , Humanos , Camundongos , Fenetilaminas , Serotonina/metabolismo
9.
Clin Transl Sci ; 15(11): 2673-2684, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36221799

RESUMO

Myopia is the leading cause of low vision worldwide and can lead to significant pathological complications. Therefore, to improve patient outcomes, the field continues to develop novel interventions for this visual disorder. Accordingly, this first-in-human study reports on the safety profile of a novel dopamine-based ophthalmic treatment for myopia, levodopa/carbidopa eye drops. This phase I, first-in-human, monocenter, placebo-controlled, double-blind, paired-eye, multidose, randomized clinical trial was undertaken in healthy adult males aged 18-30 years (mean age 24.9 ± 2.7) at the University of Canberra Eye Clinic, Australia. Participants were randomly assigned to receive either a low (1.4 levodopa:0.34 carbidopa [µmoles/day], n = 14) or standard dose (2.7 levodopa:0.68 carbidopa [µmoles/day], n = 15) of levodopa/carbidopa eye drops in one eye and placebo in the fellow eye once daily for 4 weeks (28 days). Over this 4-week trial, and after a 4-month follow-up visit, levodopa/carbidopa treatment had no significant effect on ocular tolerability and anterior surface integrity, visual function, ocular health, refraction/ocular biometry, and did not induce any non-ocular adverse events. These results indicate that topical levodopa/carbidopa is safe and tolerable to the eye, paving the way for future studies on the efficacy of this novel ophthalmic formulation in the treatment of human myopia. The findings of this study have implications not only for the treatment of myopia, but in a number of other visual disorders (i.e., amblyopia, diabetic retinopathy, and age-related macular degeneration) in which levodopa has been identified as a potential clinical intervention.


Assuntos
Carbidopa , Miopia , Masculino , Adulto , Humanos , Adulto Jovem , Carbidopa/efeitos adversos , Levodopa/efeitos adversos , Soluções Oftálmicas/efeitos adversos , Acuidade Visual , Miopia/induzido quimicamente , Miopia/tratamento farmacológico , Método Duplo-Cego
11.
Biomed Pharmacother ; 155: 113718, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36152409

RESUMO

Parkinson's disease is the second most prevalent neurodegenerative disease after Alzheimer's disease, mostly happened in the elder population and the prevalence gradually increased with age. Parkinson's disease is a movement disorder that severely affects patients' daily life. The mechanism of Parkinson's disease still remains unknown, however, studies already proved that the damage or absence of dopaminergic neurons located in the substantia nigra and the decreased dopamine in the striatum are significantly related to Parkinson's disease. To date, the mainstream treatment of Parkinson's disease has been achieved by alleviating its associated morbid symptoms, such as the use of levodopa, carbidopa, dopamine receptor agonists, monoamine oxidase type B inhibitors, anticholinergic drugs, etc. However, strong side effects, even toxicity, have been reported after using these drugs, with reduced effectiveness over time. Plant compounds have shown good therapeutic effects in neurodegenerative diseases as a less toxic treatment. In this review, we have compiled several natural plant compounds and classified the currently reported compounds for therapeutic use based on their structural parent nuclei and constituent elements. We wish to inspire new ideas for the treatment of Parkinson's disease by summarizing their mechanisms.


Assuntos
Produtos Biológicos , Doenças Neurodegenerativas , Doença de Parkinson , Humanos , Idoso , Doença de Parkinson/tratamento farmacológico , Levodopa , Carbidopa , Dopamina , Agonistas de Dopamina/uso terapêutico , Produtos Biológicos/uso terapêutico , Doenças Neurodegenerativas/tratamento farmacológico , Monoaminoxidase/uso terapêutico , Antagonistas Colinérgicos
12.
Invest New Drugs ; 40(6): 1216-1230, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36070108

RESUMO

Estrogen receptor-α (ERα) promotes breast cancer, and ER-positive cancer accounts for ~ 80% of breast cancers. This subtype responds positively to hormone/endocrine therapies involving either inhibition of estrogen synthesis or blockade of estrogen action. Carbidopa, a drug used to potentiate the therapeutic efficacy of L-DOPA in Parkinson's disease, is an agonist for aryl hydrocarbon receptor (AhR). Pharmacotherapy in Parkinson's disease decreases the risk for cancers, including breast cancer. The effects of carbidopa on ER-positive breast cancer were evaluated in cell culture and in mouse xenografts. The assays included cell proliferation, apoptosis, cell migration/invasion, subcellular localization of AhR, proteasomal degradation, and tumor growth in xenografts. Carbidopa decreased proliferation and migration of ER-positive human breast cancer cells in vitro with no significant effect on ER-negative breast cancer cells. Treatment of ER-positive cells with carbidopa promoted nuclear localization of AhR and expression of AhR target genes; it also decreased cellular levels of ERα via proteasomal degradation in an AhR-dependent manner. In vivo, carbidopa suppressed the growth of ER-positive breast cancer cells in mouse xenografts; this was associated with increased apoptosis and decreased cell proliferation. Carbidopa has therapeutic potential for ER-positive breast cancer either as a single agent or in combination with other standard chemotherapies.


Assuntos
Neoplasias da Mama , Doença de Parkinson , Humanos , Camundongos , Animais , Feminino , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptores de Hidrocarboneto Arílico/agonistas , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Neoplasias da Mama/patologia , Receptores de Estrogênio/metabolismo , Carbidopa/farmacologia , Carbidopa/uso terapêutico , Estrogênios , Linhagem Celular Tumoral
13.
Mov Disord ; 37(11): 2272-2283, 2022 11.
Artigo em Inglês | MEDLINE | ID: mdl-36054562

RESUMO

BACKGROUND: Inhibiting catechol-O-methyltransferase extends the plasma half-life of levodopa, potentially allowing physicians to optimize the levodopa regimen in patients with Parkinson's disease (PD) experiencing motor fluctuations. OBJECTIVES: To evaluate the effects of once-daily opicapone on levodopa plasma pharmacokinetics and motor response when added to two different levodopa dosing regimens. METHODS: A total of 24 patients with PD and motor fluctuations were enrolled in an exploratory, open-label, modified cross-over trial. Participants first received levodopa/carbidopa 500/125 mg (five intakes) for 2 weeks and were then randomly assigned (1:1) to levodopa/carbidopa 400/100 mg given over either four or five daily intakes plus opicapone 50 mg for an additional 2 weeks. Levodopa 12-hour pharmacokinetics was the primary outcome (ie, excluding the effect of last/evening levodopa/carbidopa intake), with motor complications evaluated as secondary outcomes. RESULTS: Over 12-hour pharmacokinetics and compared with five-intake levodopa/carbidopa 500/125 mg without opicapone, maximal levodopa concentrations were similar or nonsignificantly higher on both levodopa/carbidopa 400/100 mg regimens plus opicapone. Despite a 100 mg lower total levodopa/carbidopa daily dose, adding opicapone 50 mg at least doubled the levodopa plasma half-life and minimal concentrations, with a significant ≈30% increase in total exposure. The levodopa fluctuation index was only significantly lower for the five intakes plus opicapone regimen (difference of -71.8%; P < 0.0001). Modifications to levodopa pharmacokinetics were associated with decreased off time and increased on time. CONCLUSIONS: Combining opicapone 50 mg with a 100 mg lower daily dose of levodopa provides higher levodopa bioavailability with avoidance of trough levels. Despite the lower levodopa dose, modifying the levodopa pharmacokinetic profile with opicapone was associated with decreased off time and increased on time. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.


Assuntos
Levodopa , Doença de Parkinson , Humanos , Antiparkinsonianos/efeitos adversos , Carbidopa/uso terapêutico , Catecol O-Metiltransferase , Inibidores de Catecol O-Metiltransferase/uso terapêutico , Levodopa/efeitos adversos , Doença de Parkinson/tratamento farmacológico , Estudos Cross-Over
14.
Parkinsonism Relat Disord ; 103: 85-91, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36087571

RESUMO

INTRODUCTION: Advanced Parkinson's disease is characterized by motor and non-motor fluctuations to oral dopamine replacement therapy. The BALANCE study evaluated the clinical practice in Germany and Switzerland, when patients eligible for levodopa/carbidopa intestinal gel (LCIG) therapy decided to either switch to LCIG or to stay on optimized standard of care (SoC) oral therapy as a non-randomized regular clinical decision. METHODS: In this non-interventional, multicenter, prospective observational study, patients were recruited between 2015 and 2020. We obtained comprehensive baseline characteristics in both groups. As primary endpoint, we evaluated whether LCIG led to higher quality-of-life (QoL) improvement than SoC after 12 months. As secondary endpoints, we studied several motor and non-motor outcomes. RESULTS: About half of the 137 patients decided for LCIG treatment (n = 73, 53.5%). Those were aged >70 years more often, had more advanced disease stage, higher burden of motor and neuropsychiatric symptoms, and cognitive impairment including dementia compared to SoC. QoL change after 12 months did not differ between groups (P = 0.286). The LCIG group improved in secondary outcomes, including the UPDRS III in ON, UPDRS IV, Unified Dyskinesia Rating Scale, and Non-Motor Symptoms Scale. Clinical Global Impression-Improvement scale improved in 78.0% and 19.5% of patients receiving LCIG and SoC, respectively. Caregiver burden remained stable in LCIG but worsened with SoC. CONCLUSION: In current practice, patients and physicians delayed LCIG treatment and started substantially beyond the established indication criteria. This practice bears the risk to produce inferior results compared to the results from existing high-level evidence.


Assuntos
Carbidopa , Doença de Parkinson , Humanos , Carbidopa/uso terapêutico , Levodopa/farmacologia , Levodopa/uso terapêutico , Antiparkinsonianos/uso terapêutico , Doença de Parkinson/tratamento farmacológico , Qualidade de Vida , Suíça , Dopamina , Géis/uso terapêutico , Combinação de Medicamentos , Alemanha
16.
Spectrochim Acta A Mol Biomol Spectrosc ; 283: 121741, 2022 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-35994995

RESUMO

In this study, a UV-vis spectrophotometric method coupled with net analyte signal (NAS) and principal component regression (PCR) as multivariate calibration methods were used for the simultaneous determination of levodopa (LEV) and carbidopa (CBD) in prepared mixtures, pharmaceutical formulation, and breast milk sample. The mean recovery of the NAS model was 98.10% and 99.60% for LEV and CBD, respectively. Also, the relative standard deviation (RSD%) values were found to be lower than 5.5% and 4% for LEV and CBD, respectively. On the other hand, the mean recovery of LEV and CBD related to the PCR method was obtained at 96.86% and 92.43%, respectively. K-Fold cross-validation was used to estimate the number of components, which was 7 and 3 with a mean square error prediction (MSEP) of 1.50 and 7.14 for LEV and CBD, respectively. The results revealed that the NAS model was better than the PCR model. Additionally, the proposed NAS-based calibration method was successfully developed for the simultaneous analyses of LEV and CBD in a commercial tablet and breast milk.


Assuntos
Carbidopa , Levodopa , Animais , Calibragem , Carbidopa/análise , Composição de Medicamentos , Feminino , Humanos , Análise dos Mínimos Quadrados , Levodopa/análise , Leite/química , Espectrofotometria/métodos
17.
Cardiol J ; 29(5): 739-750, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35912711

RESUMO

BACKGROUND: Ion channel inhibition may offer protection against coronavirus disease 2019 (COVID-19). Inflammation and reduced platelet count occur during COVID-19 but precise quantification of risk thresholds is unclear. The Recov ery-SIRIO study aimed to assess clinical effects of amiodarone and verapamil and to relate patient phenotypes to outcomes. METHODS: RECOVERY-SIRIO is a multicenter open-label 1:1:1 investigator-initiated randomized trial with blinded event adjudication. A sample of 804 symptomatic hospitalized nonintensive-care COVID-19 patients, follow-up for 28 days was initially planned. RESULTS: The trial was stopped when a total of 215 patients had been randomized to amiodarone (n = 71), verapamil (n = 72) or standard care alone (n = 72). At 15 days, the hazard ratio (hazard ratio [HR], 95% confidence interval [CI]) for clinical improvement was 0.77 (0.52-1.14) with amiodarone and 0.97 (0.81-1.17) with verapamil as compared to usual care. Clinically relevant associations were found between mortality or lack of clinical improvement and higher peak C-reactive protein (CRP) levels or nadir platelet count at 7, 10 and 15 days. Mortality rate increased by 73% every 5 mg/dL increment in peak CRP (HR 1.73, 95% CI 1.27-2.37) and was two-fold higher for every decrement of 100 units in nadir platelet count (HR 2.19, 95% CI 1.37-3.51). By cluster analysis, thresholds of 5 mg/dL for peak CRP and 187 × 103/mcL for nadir platelet count identified the phenogroup at greatest risk of dying. CONCLUSIONS: In this randomized trial, neither amiodarone nor verapamil were found to significantly accelerate short-term clinical improvement. Peak CRP and nadir platelet counts were associated with increased mortality both in isolation and by cluster analysis.


Assuntos
Amiodarona , COVID-19 , Amiodarona/uso terapêutico , Proteína C-Reativa , Carbidopa , Combinação de Medicamentos , Humanos , Canais Iônicos , Levodopa/análogos & derivados , SARS-CoV-2 , Verapamil/uso terapêutico
18.
J Parkinsons Dis ; 12(7): 2171-2178, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35938258

RESUMO

BACKGROUND: In the Levodopa in EArly Parkinson's disease (LEAP) study, 445 patients were randomized to levodopa/carbidopa 100/25 mg three times per day for 80 weeks (early-start) or placebo for 40 weeks followed by levodopa/carbidopa 100/25 mg three times per day for 40 weeks (delayed-start). OBJECTIVE: This paper reports the results of the economic evaluation performed alongside the LEAP-study. METHODS: Early-start treatment was evaluated versus delayed-start treatment, in which the cost-effectiveness analysis (CEA) and the cost-utility analysis (CUA) were performed from the societal perspective, including health care costs among providers, non-reimbursable out-of-pocket expenses of patients, employer costs of sick leave, and lowered productivity while at work. The outcome measure for the CEA was the extra cost per unit decrease on the Unified Parkinson's Disease Rating Scale 80 weeks after baseline. The outcome measure for the CUA was the extra costs per additional quality adjusted life year (QALY) during follow-up. RESULTS: 212 patients in the early-start and 219 patients in the delayed-start group reported use of health care resources. With savings of € 59 per patient (BCa 95% CI: -829, 788) in the early-start compared to the delayed-start group, societal costs were balanced. The early-start group showed a mean of 1.30 QALYs (BCa 95% CI: 1.26, 1.33) versus 1.30 QALYs (BCa 95% CI: 1.27, 1.33) for the delayed-start group. Because of this negligible difference, incremental cost-effectiveness and cost-utility ratios were not calculated. CONCLUSION: From an economic point of view, this study suggests that early treatment with levodopa is not more expensive than delayed treatment with levodopa.


Assuntos
Levodopa , Doença de Parkinson , Antiparkinsonianos , Carbidopa , Análise Custo-Benefício , Humanos , Doença de Parkinson/tratamento farmacológico
19.
Parkinsonism Relat Disord ; 105: 139-144, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36008198

RESUMO

INTRODUCTION: Patients with advanced Parkinson's disease (APD) commonly experience motor and nonmotor symptoms (NMS) associated with functional limitations and decreased quality of life. We compared motor and nonmotor outcomes in patients with APD receiving 24- versus 16-h levodopa-carbidopa intestinal gel (LCIG). METHODS: Data from COSMOS, a large, real-world, retrospective and cross-sectional, observational study on LCIG and comedication in APD were obtained from medical records and a single patient visit for patients receiving 24- and 16-h LCIG infusion. Changes from baseline were evaluated for motor symptoms, NMS, and clinical characteristics. Safety was also assessed. RESULTS: Data for 401 patients were included in this subanalysis. At the patient visit there were 35 patients on 24-h LCIG and 366 on 16-h LCIG. "Off" time and dyskinesia (duration and severity) were reduced in both groups. In both LCIG treatment groups, prevalence of most symptoms was reduced. There were significant differences in the change from baseline in severity and frequency of freezing of gait with 24-h LCIG versus 16-h LCIG (p = 0.011 and p = 0.038), severity of urinary symptoms (p = 0.006), and frequency of cognitive impairment (p = 0.014) with 24-h LCIG versus 16-h LCIG. Adverse events were similar for both treatment groups and considered tolerable. CONCLUSIONS: LCIG 24-h infusion may be a useful treatment option, when clinically justified, for select patients with APD. CLINICAL TRIAL NUMBER: NCT03362879.


Assuntos
Transtornos Neurológicos da Marcha , Doença de Parkinson , Humanos , Carbidopa , Levodopa , Antiparkinsonianos/uso terapêutico , Estudos Retrospectivos , Qualidade de Vida , Estudos Transversais , Transtornos Neurológicos da Marcha/tratamento farmacológico , Doença de Parkinson/tratamento farmacológico , Géis/uso terapêutico , Combinação de Medicamentos
20.
Biochem J ; 479(17): 1807-1824, 2022 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-35997090

RESUMO

IDO1 is an immunomodulatory enzyme responsible for tryptophan catabolism. Its expression in immune cells, especially the DCs, has attracted attention because it leads to tryptophan depletion at the immunological synapse, thereby causing T-cell anergy and immune evasion by the tumor cells. Cancer cells also overexpress IDO1. Immunotherapy targeting IDO1 has been one of the focus areas in cancer biology, but lately studies have identified non-immune related functions of IDO1 leading to a paradigm shift with regard to IDO1 function in the context of tumor cells. In this study, we show that PDAC tissues and PDAC cells overexpress IDO1. The expression level is reciprocally related to overall patient survival. We further show that carbidopa, an FDA-approved drug for Parkinson's disease as well as an AhR agonist, inhibits IDO1 expression in PDAC cells. Using athymic nude mice, we demonstrate that carbidopa-mediated suppression of IDO1 expression attenuates tumor growth. Mechanistically, we show that AhR is responsible for carbidopa-mediated suppression of IDO1, directly as a transcription factor and indirectly by interfering with the JAK/STAT pathway. Overall, targeting IDO1 not only in immune cells but also in cancer cells could be a beneficial therapeutic strategy for PDAC and potentially for other cancers as well and that carbidopa could be repurposed to treat cancers that overexpress IDO1.


Assuntos
Neoplasias Pancreáticas , Receptores de Hidrocarboneto Arílico , Animais , Carbidopa/farmacologia , Indolamina-Pirrol 2,3,-Dioxigenase , Janus Quinases/metabolismo , Cinurenina/metabolismo , Camundongos , Camundongos Nus , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Triptofano/metabolismo
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