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1.
Neuroscience ; 491: 43-64, 2022 05 21.
Article in English | MEDLINE | ID: covidwho-2269494

ABSTRACT

Under normal conditions, dopamine (DA) clearance after release largely depends on uptake by the DA transporter (DAT). DAT expression/activity is reduced in some neuropsychiatric and neurological disorders. Our aim was to characterize the behavioral, neurochemical and electrophysiological effects of eliminating DAT in a novel knockout rat model we generated using CRISPR/Cas9. Consistent with existing DAT-KO models, our DAT-KO rats displayed increased locomotion, paradoxical calming by amphetamine, and reduced kinetics of DA clearance after stimulated release. Reduced DA kinetics were demonstrated using fast-scan cyclic voltammetry in brain slices containing the striatum or substantia nigra pars compacta (SNc) and in the dorsal striatum in vivo. Cocaine enhanced DA release in wild-type (WT) but not DAT-KO rats. Basal extracellular DA concentration measured with fast-scan controlled-adsorption voltammetry was higher in DAT-KO rats both in the striatum and SNc and was enhanced by L-DOPA (particularly after pharmacological block of monoamine oxidase), confirming that DA release after L-DOPA is not due to DAT reversal. The baseline firing frequency of SNc neurons was similar in both genotypes. However, D2 receptor-mediated inhibition of firing (by quinpirole or L-DOPA) was blunted in DAT-KO rats, while GABAB-mediated inhibition was preserved. We have also provided new data for the DAT-KO rat regarding the effects of slowing DA diffusion with dextran and blocking organic cation transporter 3 with corticosterone. Together, our results validate our DAT-KO rat and provide new insights into the mechanisms of chronic dysregulation of the DA system by addressing several unresolved issues in previous studies with other DAT-KO models.


Subject(s)
Dopamine Plasma Membrane Transport Proteins , Dopamine , Amphetamine/pharmacology , Animals , Corpus Striatum/metabolism , Dopamine/pharmacology , Dopamine Plasma Membrane Transport Proteins/metabolism , Levodopa/pharmacology , Rats
2.
Cells ; 12(1)2022 12 20.
Article in English | MEDLINE | ID: covidwho-2243524

ABSTRACT

The SARS-CoV-2 infection was previously associated with the expression of the dopamine biosynthetic enzyme L-Dopa decarboxylase (DDC). Specifically, a negative correlation was detected between DDC mRNA and SARS-CoV-2 RNA levels in in vitro infected epithelial cells and the nasopharyngeal tissue of COVID-19 patients with mild/no symptoms. However, DDC, among other genes related to both DDC expression and SARS-CoV-2-infection (ACE2, dACE2, EPO), was upregulated in these patients, possibly attributed to an orchestrated host antiviral response. Herein, by comparing DDC expression in the nasopharyngeal swab samples of severe/critical to mild COVID-19 cases, we showed a 20 mean-fold reduction, highlighting the importance of the expression of this gene as a potential marker of COVID-19 severity. Moreover, we identified an association of SARS-CoV-2 infection with the expression of key catecholamine biosynthesis/metabolism-related genes, in whole blood samples from hospitalized patients and in cultured cells. Specifically, viral infection downregulated the biosynthetic part of the dopamine pathway (reduction in DDC expression up to 7.5 mean-fold), while enhanced the catabolizing part (increase in monoamine oxidases A and B expression up to 15 and 10 mean-fold, respectively) in vivo, irrespectively of the presence of comorbidities. In accordance, dopamine levels in the sera of severe cases were reduced (up to 3.8 mean-fold). Additionally, a moderate positive correlation between DDC and MAOA mRNA levels (r = 0.527, p < 00001) in the blood was identified upon SARS-CoV-2-infection. These observations were consistent to the gene expression data from SARS-CoV-2-infected Vero E6 and A549 epithelial cells. Furthermore, L-Dopa or dopamine treatment of infected cells attenuated the virus-derived cytopathic effect by 55% and 59%, respectively. The SARS-CoV-2 mediated suppression of dopamine biosynthesis in cell culture was, at least in part, attributed to hypoxia-like conditions triggered by viral infection. These findings suggest that L-Dopa/dopamine intake may have a preventive or therapeutic value for COVID-19 patients.


Subject(s)
COVID-19 , Humans , SARS-CoV-2/metabolism , Catecholamines , Dopamine , Levodopa/metabolism , RNA, Viral/metabolism , Biosynthetic Pathways , RNA, Messenger/metabolism
3.
J Neurol ; 269(10): 5606-5614, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-2041278

ABSTRACT

INTRODUCTION: Levodopa/carbidopa intestinal gel (LCIG) is an effective treatment in patients with advanced Parkinson's disease (PD) with consolidated evidence of clinical efficacy. However, only few studies have assessed long-term safety, causes of discontinuation, mortality, and relative predictors. METHODS: We conducted a retrospective analysis of 79 PD patients treated with LCIG between 2005 and 2020 in two Italian Neurological Centers, recording all adverse events (AEs), including weight loss (WL). Kaplan-Meier curve was used to estimate the time to discontinuation and survival. Cox proportional hazard model was employed to identify predictors of discontinuation and mortality, while Pearson's correlation was used to analyze predictors of WL. RESULTS: The average follow-up was 47.7 ± 40.5 months and the median survival from disease onset was 25 years. There were three cases of polyradiculoneuropathy Guillain-Barre syndrome-like, all occurred in the early years of LCIG treatment. Twenty-five patients died (32%), 18 on LCIG (including one suicide) and seven after discontinuation. The mean WL was 3.62 ± 7.5 kg, which correlated with levodopa dose at baseline (p = 0.002), levodopa equivalent daily dose (LEDD) baseline (p = 0.017) and off-duration (p = 0.0014), but not dyskinesia. Peristomal complications emerged as a negative predictor of discontinuation (p = 0.008). CONCLUSIONS: LCIG has a relatively satisfactory long-term safety profile and efficacy and a relatively low rate of discontinuation. Peristomal complications may represent a predictor of longer duration of therapy. According to the mortality analysis, LCIG patients show a long lifespan. Delaying the initiation of LCIG does not affect the sustainability of LCIG therapy.


Subject(s)
Carbidopa , Parkinson Disease , Antiparkinson Agents/adverse effects , Drug Combinations , Gels/therapeutic use , Humans , Levodopa/therapeutic use , Parkinson Disease/drug therapy , Retrospective Studies , Weight Loss
4.
Drug Res (Stuttg) ; 72(8): 466-472, 2022 Oct.
Article in English | MEDLINE | ID: covidwho-1991713

ABSTRACT

BACKGROUND: Coronaviruses are emerging threats for human health, as demonstrated by the ongoing coronavirus disease 2019 (COVID-19) pandemic that is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 is closely related to SARS-CoV-1, which was the cause of the 2002-2004 SARS outbreak, but SARS-CoV-1 has been the subject of a relatively limited number of studies. Understanding the potential pathways and molecular targets of SARS-CoV-1 will contribute to current drug repurposing strategies by helping to predict potential drug-disease associations. METHODS: A microarray dataset, GSE1739, of 10 SARS patients and 4 healthy controls was downloaded from NCBI's GEO repository, and differential expression was identified using NCBI's GEO2R software. Pathway and enrichment analysis of the differentially expressed genes was carried out using Ingenuity Pathway Analysis and Gene Set Enrichment Analysis, respectively. RESULTS: Our findings show that the drugs dexamethasone, filgrastim, interferon alfacon-1, and levodopa were among the most significant upstream regulators of differential gene expression in SARS patients, while neutrophil degranulation was the most significantly enriched pathway. CONCLUSION: An enhanced understanding of the pathways and molecular targets of SARS-CoV-1 in humans will contribute to current and future drug repurposing strategies, which are an essential tool to combat rapidly emerging health threats.


Subject(s)
COVID-19 Drug Treatment , SARS-CoV-2 , Dexamethasone , Filgrastim , Humans , Levodopa
5.
Cardiol J ; 29(5): 739-750, 2022.
Article in English | MEDLINE | ID: covidwho-1975249

ABSTRACT

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.


Subject(s)
Amiodarone , COVID-19 , Amiodarone/therapeutic use , C-Reactive Protein , Carbidopa , Drug Combinations , Humans , Ion Channels , Levodopa/analogs & derivatives , SARS-CoV-2 , Verapamil/therapeutic use
6.
Neurol Sci ; 43(9): 5165-5168, 2022 Sep.
Article in English | MEDLINE | ID: covidwho-1877850

ABSTRACT

BACKGROUND: Several neurological complications have been reported following SARS-Cov-2 vaccination, without a clear causal relationship ever being verified, including some cases of worsening of Parkinson's disease (PD) symptoms and new onset of movement disorders in non-parkinsonian patients. METHODS: We describe two new cases of PD patients treated with device-aided therapy who developed worsening of parkinsonian symptoms after receiving the third vaccine dose (booster). We also conducted a short review of the cases reported in literature of PD symptoms worsening and new onset of movement disorders in non-parkinsonian patients after SARS-Cov-2 vaccination. RESULTS: The first patient, a 46-year-old man implanted with bilateral Subthalamic Deep Brain Stimulation, experienced temporary motor and non-motor symptoms worsening after mRNA-1273 booster, improved after stimulation settings modification. The second patient, a 55-year-old man implanted with percutaneous endoscopic transgastric jejunostomy (PEG-J) for levodopa-carbidopa intestinal gel (LCIG) infusion experienced severe temporary worsening of dyskinesia and managed through temporary LCIG dose reduction. Other seven cases of vaccine-related movement disorder are currently reported in literature, four describing PD symptoms worsening and three the onset of new movement disorders in otherwise healthy people. CONCLUSION: Both our patients and the cases described so far completely recovered after few days with parkinsonian therapy modification, symptomatic treatment, or even spontaneously, underlining the transient and benign nature of side effects from vaccine. Patients should be reassured about these complications, manageable through a prompt evaluation by the reference neurologist.


Subject(s)
COVID-19 Vaccines , COVID-19 , Movement Disorders , Parkinson Disease , Vaccination , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Carbidopa/therapeutic use , Deep Brain Stimulation , Drug Combinations , Humans , Immunization, Secondary/adverse effects , Levodopa/therapeutic use , Male , Middle Aged , Movement Disorders/etiology , Movement Disorders/therapy , Parkinson Disease/etiology , Parkinson Disease/therapy , Treatment Outcome , Vaccination/adverse effects
7.
Int Rev Neurobiol ; 165: 229-249, 2022.
Article in English | MEDLINE | ID: covidwho-1803313

ABSTRACT

Under the traditional models of care for People with Parkinson's Disease (PD, PwP), many of their needs remain unmet and a substantial burden of motor and non-motor symptoms they experience may not be tackled sufficiently. An introduction of palliative care (PC) interventions early in the course of PD offers profound benefits: it may improve quality of life of patients, their families and caregivers through the prevention and relief of medical symptoms, while, at the same time, emphasizing their emotional needs and spiritual wellbeing, establishing goals of care, and engaging in the advance care planning (ACP). The ongoing Coronavirus Disease 2019 (Covid-19) pandemic poses an unprecedented set of challenges for PwP and has in many ways (both directly and indirectly) magnified their suffering, thus rapidly raising the demand for PC interventions. Covid-19, as well as the repercussions of prolonged mobility restrictions and limited health-care access might exacerbate the severity of PD motor symptoms and interact negatively with a range of non-motor symptoms, with a detrimental effect on quality of life. Greater motor disability, higher amount of levodopa-induced motor fluctuations with an increased daily off-time, fatigue, anxiety, depression, sleep disturbances, pain and worsening of cognitive complaints might dominate the clinical presentation in PwP during the Covid-19 pandemic, alongside raising psychological and spiritual concerns and anticipatory grief. Here, we aim to provide a foundation for pragmatic and clinically orientated PC approach to improve quality of life and relieve suffering of PwP in the context of the current, ongoing Covid-19 pandemic.


Subject(s)
COVID-19 , Disabled Persons , Motor Disorders , Parkinson Disease , Ethnicity , Humans , Levodopa , Palliative Care , Pandemics , Parkinson Disease/diagnosis , Parkinson Disease/epidemiology , Parkinson Disease/therapy , Quality of Life/psychology
10.
ESC Heart Fail ; 9(1): 721-728, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1520187

ABSTRACT

AIMS: The coronavirus disease-2019 (COVID-19) pandemic has changed the landscape of medical care delivery worldwide. We aimed to assess the influence of COVID-19 pandemic on hospital admissions and in-hospital mortality rate in patients with acute heart failure (AHF) in a retrospective, multicentre study. METHODS AND RESULTS: From 1 January 2019 to 31 December 2020, a total of 101 433 patients were hospitalized in 24 Cardiology Departments in Poland. The number of patients admitted due to AHF decreased by 23.4% from 9853 in 2019 to 7546 in 2020 (P < 0.001). We noted a significant reduction of self-referrals in the times of COVID-19 pandemic accounting 27.8% (P < 0.001), with increased number of AHF patients brought by an ambulance by 15.9% (P < 0.001). The length of hospital stay was overall similar (7.7 ± 2.8 vs. 8.2 ± 3.7 days; P = not significant). The in-hospital all-cause mortality in AHF patients was 444 (5.2%) in 2019 vs. 406 (6.5%) in 2020 (P < 0.001). A total number of AHF patients with concomitant COVID-19 was 239 (3.2% of AHF patients hospitalized in 2020). The rate of in-hospital deaths in AHF patients with COVID-19 was extremely high accounting 31.4%, reaching up to 44.1% in the peak of the pandemic in November 2020. CONCLUSIONS: Our study indicates that the COVID-19 pandemic led to (i) reduced hospital admissions for AHF; (ii) decreased number of self-referred AHF patients and increased number of AHF patients brought by an ambulance; and (iii) increased in-hospital mortality for AHF with very high mortality rate for concomitant AHF and COVID-19.


Subject(s)
COVID-19 , Heart Failure , Acute Disease , Carbidopa , Drug Combinations , Heart Failure/epidemiology , Humans , Levodopa/analogs & derivatives , Pandemics , Retrospective Studies , SARS-CoV-2
13.
Zh Nevrol Psikhiatr Im S S Korsakova ; 121(4): 101-106, 2021.
Article in Russian | MEDLINE | ID: covidwho-1244383

ABSTRACT

The article presents data from recent studies on the mechanisms of action and clinical efficacy of amantadines, and also describes a possible protective effect against COVID-19.


Subject(s)
COVID-19 , Parkinson Disease , Amantadine/therapeutic use , Antiparkinson Agents/therapeutic use , Humans , Levodopa , Parkinson Disease/drug therapy , SARS-CoV-2
14.
J Parkinsons Dis ; 11(2): 445-454, 2021.
Article in English | MEDLINE | ID: covidwho-1159008

ABSTRACT

BACKGROUND: Many studies on Parkinson's disease (PD) patients affected by Coronavirus-disease-2019 (COVID-19) were recently published. However, the small sample size of infected patients enrolled in most studies did not allow to draw robust conclusions on the COVID-19 impact in PD. OBJECTIVE: We aimed to assess whether the prevalence and outcome of COVID-19 in PD patients are different from those observed in the general population. METHODS: We conducted a systematic review of studies reporting data on PD patients with a diagnosis of COVID-19 (PD-COVID+). We extracted prevalence, clinical-demographic data, outcome, and mortality. We also analyzed risk or protective factors based on comparisons between PD-COVID+ and control populations with PD without COVID-19 or without PD with COVID-19. RESULTS: We included 16 studies reporting on a total of 11,325 PD patients, 1,061 with a confirmed diagnosis of COVID-19. The median infection prevalence ranged from 0.6% to 8.5%. PD-COVID+ patients had a median age of 74 and a disease duration of 9.4 years. Pooling all PD-COVID+ patients from included studies, 28.6% required hospitalization, 37.1% required levodopa dose increasing, and 18.9% died. The case fatality was higher in PD-COVID+ patients than the general population, with longer PD duration as a possible risk factor for worse outcome. Amantadine and vitamin D were proposed as potential protective factors. CONCLUSION: Available studies indicate a higher case fatality in PD patients affected by COVID-19 than the general population. Conversely, current literature does not definitively clarify whether PD patients are more susceptible to get infected. The potential protective role of vitamin D and amantadine is intriguing but deserves further investigation.


Subject(s)
Antiparkinson Agents/therapeutic use , COVID-19/epidemiology , Parkinson Disease/epidemiology , COVID-19/blood , Case-Control Studies , Humans , Levodopa/therapeutic use , Parkinson Disease/blood , Parkinson Disease/drug therapy , Vitamin D/therapeutic use , COVID-19 Drug Treatment
15.
BMJ Case Rep ; 14(3)2021 Mar 02.
Article in English | MEDLINE | ID: covidwho-1115107

ABSTRACT

The COVID-19 pandemic has dealt a devastating blow to healthcare systems globally. Approximately 3.2% of patients infected with COVID-19 require invasive ventilation during the course of the illness. Within this population, 25% of patients are affected with neurological manifestations. Among those who are affected by severe neurological manifestations, some may have acute cerebrovascular complications (5%), impaired consciousness (15%) or exhibit skeletal muscle hypokinesis (20%). The cause of the severe cognitive impairment and hypokinesis is unknown at this time. Potential causes include COVID-19 viral encephalopathy, toxic metabolic encephalopathy, post-intensive care unit syndrome and cerebrovascular pathology. We present a case of a 60 year old patient who sustained a prolonged hospitalization with COVID-19, had a cerebrovascular event and developed a persistent unexplained encephalopathy along with a hypokinetic state. He was treated successfully with modafinil and carbidopa/levodopa showing clinical improvement within 3-7 days and ultimately was able to successfully discharge home.


Subject(s)
Brain Diseases , COVID-19 , Carbidopa/administration & dosage , Hypokinesia , Ischemic Stroke , Levodopa/administration & dosage , Modafinil/administration & dosage , Rehabilitation/methods , SARS-CoV-2/isolation & purification , Blood Coagulation , Brain Diseases/physiopathology , Brain Diseases/virology , COVID-19/blood , COVID-19/complications , COVID-19/physiopathology , COVID-19/therapy , Central Nervous System Stimulants/administration & dosage , Cognitive Dysfunction/diagnosis , Cognitive Dysfunction/etiology , Critical Care/methods , Drug Combinations , Humans , Hypokinesia/diagnosis , Hypokinesia/etiology , Hypokinesia/therapy , Ischemic Stroke/diagnostic imaging , Ischemic Stroke/etiology , Ischemic Stroke/physiopathology , Ischemic Stroke/therapy , Magnetic Resonance Imaging/methods , Male , Middle Aged , Respiration, Artificial/methods , Severity of Illness Index , Treatment Outcome , Ventilator Weaning/methods
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