Fluoksetin ne remeti motornu funkciju kod bolesnika sa Parkinsonovom bolešću - korelacija raspoloženja i motorne funkcije sa koncentracijom fluoksetina/norfluoksetina u plazmi

Background/Aim. Selective serotonin reuptake inhibitors are the most commonly chosen antidepressants in patients with Parkinson's disease (PD). The aim of our study was to assess the influence of fluoxetine (Flu) on motor functions in patients with PD. Methods. In this prospective, controlled, open-label study, 18 patients with PD and mild depression [(10 ≤ Hamilton Rating Scale for Depression (HDRS) ≤ 23)] without dementia [(25 ≤ Mini-Mental State Examination (MMSE)] were treated with Flu. Both single and repeated dose effects of Flu were assessed on days 1-80. Plasma concentrations of Flu and norfluoxetine (NORFlu) were correlated with the results of selected motor function performance scores: The Unified Parkinsons Disease Rating Score (UPDRS), Finger Tapping Test (FTT) and Purdue Pegboard Test (PPT). Severity of PD, depression and dementia were evaluated using standard tests [(Hoehn and Yahr stages (HY), activity of daily living (ADL), UPDRS, HDRS, MMSE)]. Results. Steady-state for Flu/NORFlu was reached after 18 days of treatment. Such a plateau correlated with significant improvements in both scores of depression and Parkinson's disability (HDRS, UPDRS and ADL, respectively). In addition, FTT and PPT scores also increased until day 18, with further slight fluctuations around the plateau. Optimal motor performances correlated with Flu concentrations of approximately 60-110 μg/L. Conclusion. Flu (20 mg/day) significantly reduced depression in PD patients while it did not impair their motor performances. Because substantial placebo effects may arise in studies of PD and depression, large, prospective, randomized, placebo-controlled clinical trials are warranted.Uvod/Cilj. Selektivni inhibitori ponovnog preuzimanja serotonina su antidepresivi koji se najčešće koriste u lečenju obolelih od Parkinsonove bolesti (PB). Cilj ovog istraživanja bio je da se proceni uticaj fluoksetina (Flu) na motorne funkcije bolesnika sa PB. Metode. U ovom prospektivnom, kontrolisanom, otvorenom kliničkom ispitivanju, 18 bolesnika sa PB i blagom depresijom [10 ≤ Hamiltonova skala za depresiju (10 ≤ HDRS) ≤ 23)], bez demencije [(25 ≤ Mini mental test (MMSE)] lečeni su primenom Flu. Procenjivana su dejstva kako pojedinačne, tako i ponovljene doze Flu od prvog do osamdesetog dana. Plazma koncentracije Flu i norfluoksetina (NORFlu) korelisane su sa rezultatima odeđenih testova za motorne funkcije: skala za procenu težine PB (UPDRS), test spretnosti kucanja (FTT) i Purdue pegboard Test PPT). Izraženost PD, depresije i demencije procenjivane su korišćenjem standardnih testova [(test dnevnih aktivnosti (ADL), Hoehn.-Yahr. stadijumi (HJ), HDRS, MMSE)]. Rezultati. Ravnotežno stanje za Flu/NORFlu postignuto je 18. dana lečenja. Takav plato u koncentraciji Flu/NORFlu bio je praćen značajnim poboljšanjem rezultata, kako testova za depresiju, tako i za izraženost PB (HDRS, UPDRS i ADL, sledstveno). Dodatno, rezultati FTT-a i PPT-a bili su u porastu do 18. dana, sa blagim fluktuacijama oko platoa. Optimalna motorna postignuća zabeležena su pri koncentraciji Flu od oko 60-110 μg/L. Zaključak. Flu (20 mg/dan) značajno redukuje depresiju kod bolesnika sa PB i ne remeti motorne funkcije. S obzirom na mogući placebo efekat u istraživanjima sa PB i depresijom, neophodna su obimnija, prospektivna, randomizovana, placebo- kontrolisana klinička ispitivanja

Why is nitric oxide important for our brain?

The freely diffusible gaseous compound nitric oxide (NO) has been shown to be an important messenger in many organ systems throughout the body, and particularly in the central nervous system (CNS). The importance of NO as an intermediary in cell communication in the brain is highlighted by the fact that the excitatory amino acid glutamate, the most abundant CNS neurotransmitter, is an initiator of the reaction that forms NO. Because of its numerous physiological and pathophysiological roles, the impact of NO on clinical medicine is developing. NO can act as a “double-edged sword” and it has been demonstrated that clarification of the dual effect of NO might have implications for clinical medicine, and could lead to the emergence of therapeutic opportunities. Accordingly, NO was proclaimed “Mole cule of the Year” in 1992 by the journal Science, while discovery of the pathways and roles of NO was acknowledged with the Nobel Prize in 1998. Additionally, the ubiquity of NO in the CNS implies that drugs designed to modify the biological activity of NO may have distinct effects. Thus, further clinical applications of NO, of its analogs or of newly developed NOS inhibitors are forthcoming. The therapeutic challenge would be to succeed in manipulating the NO pathways selectively

Dopa-responsive dystonia

Backgrround/Aim. Dystonia is considered to be a prolonged involuntary contractions of the muscles leading to twisting, repetitive movements or irregular postures. Etiologically, it could be classified as primary and secondary dystonia. Dopa-responsive dystonia (DRD) belongs to a group of primary dystonia. The aim of this study was to detect the presence of gene GCH-I mutation in our population in patients with dopa-responsive dystonic dyskinesia and to analyze clinical specificity of the affected. Methods. Out of the group of patients with dystonia of different distribution four patients were separated whose clinical picture indicated the diagnosis of DRD. Two patients had a positive family anamnesis while the other two were sporadic. Genetic analysis was performed by the use of a standard protocol, which included PCR amplification and DNK sequencing according to the method of Senger and autoradiografy. Results. In the patients from the family DRD-1 new hetaerazygote point mutation 520G→A in 4-m exson gene GCH-I was revealed. First symptoms of the disease showed in the age of seven by the torsion of the left foot, progressively advanced and got into the evolution of numbness in the legs, aggravated gait, tending to worsen in the evening, and the therapy with levodopa (500 mg) produced a dramatic effect. The second mutation in the female patient from the family DRD-2 was homozygote deletion in1-m intron gene GCH-I (IVS1-85delA). Unwilling torsion of the foot, feeling of weakness in the lower extremities (that caused falling without loss of the consciousness) were clinical demonstrations of the disease. The application of levodopa (300 mg) caused regression of the symptoms of the disease. Hetaerazygote deletion of adenine in the position 209 in the first exon (209del A) was identificated in the patient DRD-3 with negative family anamnesis, in who in the age of ten the torsion of the foot inside occurred for the first time following by trembling of both the left and right legs at rest; after a few years, tremor of hands also appeared, which became worse in stressful situations. The father of the patient was an asymptomatic bearer of mutation. The fourth mutation in gene GCH-I was found in I exon gene GCH- I, 208delA. The disease was started by torsion of the left foot, progressing easily, and worsening in the evenings, but at the age of 30, moving became harder, fatigue and pain in muscles, increased and at the age of 40 the patient recognized the change of speech. The application of levodopa (300 mg/daily) made the patient feel better and walk independently. Conclusion. The study presented four patients with genetic confirmation of the diagnosis of dopa-responsive dystonia. This entity is very significant in differential diagnostics of both early dystonia (< 26 years) and early parkinsonism (< 40 years) since it can be successfully managed by applying relatively low doses of levodopa over a long period of time

Vitamin D Serum Levels and Vitamin D Receptor Genotype in Patients with Parkinson's Disease

Background: Vitamin D is a steroid hormone, known to be involved in the pathogenesis of various neurodegenerative disorders, including Parkinson's disease (PD). We aimed to clarify the relationship between hypovitaminosis D and the predisposition for PD and its clinical presentation. An additional aim was to examine the specific gene polymorphisms associated with vitamin D level. Material and methods: Total level of 25(OH)-vitamin D (25(OH)D) was measured in the serum of parkinsonian patients (n = 113) and controls (n = 82) using a commercial immunoassay. Genetic analyses were performed using Taqman assays on Real Time PCR amplification system. Results: Higher frequency of vitamin D deficiency ( 0.05). Conclusions: Findings of this study confirm the hypothesis of a significant relationship between hypovitaminosis D and PD. We demonstrated higher prevalence of vitamin D deficiency in PD patients, as well as its predictive potential for the onset and progression of PD

Primary lymphoma of the brain in a young man whose brother died of hemophagocytic lymphohistiocytosis: Case report

Introduction. We represent the unique occurrence of primary central nervous system lymphoma (PCNSL) in a patient whose brother died of genetically confirmed hemophagocytic lymphohistiocytosis (HLH). Case Outline. We report a case of a 25-year-old male patient with primary aggressive diffuse large B-cell lymphoma affecting the brain and PCNSL. Despite one year of medical treatment outcome was lethal. However, our patient had a relatively longer survival compared to median survival time for PCNSL. Additionally, he had two older brothers who died at the age of about 11 years. One died of fulminate malignancy, shortly after pediatric admission, before the diagnosis could be established. The other one died from genetically confirmed (perforin mutation/PRF1) HLH. Our patient was heterozygous carrier of perforin mutation representing the genetic marker for HLH. Our patient’s father was the carrier of the same mutation but had no symptoms of any disease. Conclusion. This case points at the presence of HLH and diffuse large B-cell PCNSL in brothers. Extensive assessment of patients with probable PCNSL and familial HLH is necessary, including genetic analysis for HLH. [Projekat Ministarstva nauke Republike Srbije, br. 175090

Homocysteine serum levels and MTHFR C677T genotype in patients with Parkinson's disease, with and without levodopa therapy

Both methylenetetrahydrofolate (MTHFR) C677T genotype and levodopa treatment may give rise to elevated serum homocysteine levels in parkinsonian patients. We aimed to clarify the interplay of these factors in pathogenesis of Parkinson's disease (PD)-related hyperhomocysteinemia. Total serum levels of homocysteine (tHcy) and MTHFR C677T genotype were investigated in levodopa-treated and -untreated parkinsonian ("de novo") patients, as well as in control healthy subjects matched by age and gender (N=83, 30 and 53, respectively). MTHFR C677T genotypes were equally distributed in PD patients and control subjects, the T allele homozygosity being observed in app. 12-17% cases. tHcy concentrations were significantly higher in both levodopa-treated and -untreated PD patients than in control subjects, and in TT homozygotes than in CT or CC genotype carriers. tHcy levels significantly correlated with the duration of the disease in PD treated patients only, reaching the maximum after 3-6 years. However, there was no correlation between tHcy levels and total daily intake of levodopa in the same group of PD patients. In conclusion, MTHFR C677T genotype is a significant factor for hyperhomocysteinemia. in patients with PD, levodopa-untreated and probably even more in levodopa-treated PD patients

Fluoxetine does not impair motor function in patients with Parkinson's disease: Correlation between mood and motor functions with plasma concentrations of fluoxetine/norfluoxetine

Background/Aim. Selective serotonin reuptake inhibitors are the most commonly chosen antidepressants in patients with Parkinson's disease (PD). The aim of our study was to assess the influence of fluoxetine (Flu) on motor functions in patients with PD. Methods. In this prospective, controlled, open-label study, 18 patients with PD and mild depression [(10 ≤ Hamilton Rating Scale for Depression (HDRS) ≤ 23)] without dementia [(25 ≤ Mini-Mental State Examination (MMSE)] were treated with Flu. Both single and repeated dose effects of Flu were assessed on days 1-80. Plasma concentrations of Flu and norfluoxetine (NORFlu) were correlated with the results of selected motor function performance scores: The Unified Parkinsons Disease Rating Score (UPDRS), Finger Tapping Test (FTT) and Purdue Pegboard Test (PPT). Severity of PD, depression and dementia were evaluated using standard tests [(Hoehn and Yahr stages (HY), activity of daily living (ADL), UPDRS, HDRS, MMSE)]. Results. Steady-state for Flu/NORFlu was reached after 18 days of treatment. Such a plateau correlated with significant improvements in both scores of depression and Parkinson's disability (HDRS, UPDRS and ADL, respectively). In addition, FTT and PPT scores also increased until day 18, with further slight fluctuations around the plateau. Optimal motor performances correlated with Flu concentrations of approximately 60-110 μg/L. Conclusion. Flu (20 mg/day) significantly reduced depression in PD patients while it did not impair their motor performances. Because substantial placebo effects may arise in studies of PD and depression, large, prospective, randomized, placebo-controlled clinical trials are warranted. [Acknowledgment. Projekat Ministarstva nauke Republike Srbije, br. 175090)