Monoamine Oxidase Type Research Articles

An explorative study regarding the effect of l-deprenyl on cognitive and functional recovery in patients after stroke

IntroductionSelegiline (l-deprenyl) is a selective monoamine oxidase type B inhibitor that has been shown to have neurotrophic and anti-apoptotic properties and to protect neurons in different experimental models of cerebral ischaemia. The aim of this explorative study was to investigate whether selegiline could enhance cognitive and functional recovery in stroke survivors. MethodsThis was a randomized controlled study in which patients enrolled within two weeks of stroke underwent a clinical and functional evaluation and a neuropsychological assessment. The patients were given selegiline (10mg/day) or matched placebo once a day for six weeks in addition to standard rehabilitation care. ResultsOf 137 stroke survivors, 47 patients met the inclusion criteria and were randomly assigned to the Study Group (n=23) or the Control Group (n=24). The statistical analysis showed a significant improvement in most neuropsychological tests after two and six weeks in the study group; these improvements were not replicated in the control group. The between-group analysis revealed that the domains of attention and executive functions benefited most from the drug treatment. With regard to functional status, comparison of clinical scores at admission and discharge showed a statistically significant enhancement in both groups without statistically significant differences between the groups. ConclusionsThese preliminary results suggest that selegiline administered in the subacute phase can promote cognitive functioning in stroke patients. Further studies will elucidate whether and how this enhancement can impact on functional recovery in the short and in the long term.

Safinamide for symptoms of Parkinson's disease.

Chronic and slow progression of neuronal death in Parkinson's disease is responsible for an altered neurotransmission of various biogenic amines, such as dopamine. Therefore, an individually different pronounced heterogeneity of motor and nonmotor symptoms characterizes each Parkinson's disease patient. Ideal candidates for the balance of these neurotransmitter deficits are compounds like safinamide with broad mechanisms of action such as reversible monoamine oxidase type B inhibition, blockage of voltage-dependent sodium channels, modulation of calcium channels and of glutamate release. Safinamide is administered one time daily with oral doses ranging from 50 to 100 mg. Safinamide was well tolerated and safe, ameliorated motor symptoms when combined with dopamine agonist only or additional levodopa in clinical trials. Safinamide is a novel instrument for the drug therapy of Parkinson's disease with better safety and tolerability particularly concerning diarrhea than inhibitors of catechol-O-methyltransferase, like entacapone, according to an indirect comparison within a meta-analysis with entacapone.

Current treatment and future prospects of dopa-induced dyskinesias.

Levodopa-induced dyskinesias (LID) are one of the main issues in the management of Parkinson's disease (PD); once these dyskinesias are established treatment becomes difficult, so preventive strategies should be first evaluated. Although levodopa (LD) treatment has recently been related as risk factor for LID, the main strategy to delay LID is to start PD treatment with dopamine agonists, adding LD at low doses. After LID onset, approaches include reducing single LD doses, reducing or discontinuing monoamine oxidase type B/catechol O-methyltransferase (MAO-B/COMT) inhibitors and extended-release (ER) LD. Amantadine represents the best antidyskinetic tool, and ER amantadine is the most promising upcoming antidyskinetic drug. New LD formulations such as IPX-066 (able to provide continuous dopaminergic stimulation) also represent promising new approaches. The involvement of a nondopaminergic system in the pathogenesis of LID suggests that the modulation of glutamate, serotonin and adenosine could have potential as new upcoming drug targets, but the role of such drugs will still need to be confirmed in randomized controlled trials.

Characterization of allele-specific expression of the X-linked gene MAO-A in trophectoderm cells of bovine embryos produced by somatic cell nuclear transfer.

Somatic cell nuclear transfer (SCNT) may affect epigenetic mechanisms and alter the expression of genes related to embryo development and X chromosome inactivation (XCI). We characterized allele-specific expression of the X-linked gene monoamine oxidase type A (MAO-A) in the trophectoderm (TF) of embryos produced by SCNT. Total RNA was isolated from individual biopsies (N = 25), and the allele-specific expression assessed by reverse transcription-polymerase chain reaction-restriction fragment length polymorphism. Both paternal and maternal alleles were expressed in the trophectoderm. However, a higher frequency of the mono-allelic expression of a specific allele was observed (N = 17; 68%), with the remaining samples showing the presence of mRNA from both alleles (N = 8; 32%). Considering that MAO-A is subject to XCI in bovine, our results suggest that SCNT may influence XCI because neither an imprinted (mono-allelic expression in all samples) nor a random (presence of mRNA from both alleles in all samples) pattern of XCI was observed in TF. Due to the importance of XCI in mammalian embryo development and its sensitivity to in vitro conditions, X-linked genes subject to XCI are candidates for use in the development of embryo quality molecular markers for assisted reproduction.

Treatment of early Parkinson's disease.

This review summarizes currently available treatment options and treatment strategies, investigational treatments, and the importance of exercise for early Parkinson's disease. The available treatment options for early Parkinson's disease have changed little in the past decade and include carbidopa/levodopa, dopamine agonists, and monoamine oxidase type B (MAO-B) inhibitors. However, we discuss changes in treatment strategies, including dosing and the use of combination therapy used in an attempt to reduce or delay the appearance of motor complications and other adverse events. We will also review several investigational treatments that have shown promise for the treatment of early Parkinson's disease, including a new extended release formulation of carbidopa/levodopa (IPX066), safinamide which inhibits MAO-B, dopamine uptake and glutamate and pardoprunox which is a 5HT-1A agonist and a partial dopamine agonist. Finally, we discuss recent studies focusing on exercise as an important component in the management of early Parkinson's disease. Advances in the management of early Parkinson's disease include evolving treatment strategies, new investigational treatments, and earlier implementation of various forms of exercise.

Association of gene polymorphisms encoding dopaminergic system components and platelet MAO-B activity with alcohol dependence and alcohol dependence-related phenotypes.

The present study aimed to evaluate the association of alcohol dependence and alcohol dependence-related phenotypes with platelet monoamine oxidase type B (MAO-B) activity, Val108/158Met of catechol-o-methyltransferase (COMT), variable number of tandem repeats (VNTR) in the third exon of dopamine receptor D4 (DRD4) gene, VNTR in the 3'-untranslated region of dopamine transporter (DAT) gene, -1021C/T of dopamine beta-hydroxylase (DBH) and MAO-B intron 13 polymorphisms. The study included 1270 Caucasian men and women of Croatian origin: 690 patients with alcohol dependence and 580 healthy controls. Patients with alcohol dependence were subdivided according to the presence or absence of withdrawal symptoms, aggressive behavior, severity of alcohol dependence, delirium tremens, comorbid depression, suicidal behavior, lifetime suicide attempt and early/late onset of alcohol abuse. The results, corrected for multiple testing, revealed increased platelet MAO-B activity in patients with alcohol dependence, subdivided into those with or without alcohol-related liver diseases, compared to control subjects (P<0.001). In addition, we found an increased frequency of the COMT Met/Met genotype among suicidal (P=0.002) and patients who attempted suicide (P<0.001) and an increased frequency of COMT Val/Val genotype in patients with an early onset of alcohol dependence (P=0.004). This study provides data from a sample of ethnically homogeneous unrelated Caucasian subjects for future meta-analyses and suggests that the increased platelet MAO-B activity might be used as independent peripheral indicator of alcohol dependence, while COMT Val108/158Met polymorphism is associated with increased suicidality and early onset of alcohol dependence.

Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson's disease (PD MED): a large, open-label, pragmatic randomised trial

Whether initial treatment for Parkinson's disease should consist of levodopa, dopamine agonists, or monoamine oxidase type B inhibitors (MAOBI) is uncertain. We aimed to establish which of these three classes of drug, as initial treatment, provides the most effective long-term control of symptoms and best quality of life for people with early Parkinson's disease. In this pragmatic, open-label randomised trial, patients newly diagnosed with Parkinson's disease were randomly assigned (by telephone call to a central office; 1:1:1) between levodopa-sparing therapy (dopamine agonists or MAOBI) and levodopa alone. Patients and investigators were not masked to group assignment. Primary outcomes were the mobility dimension on the 39-item patient-rated Parkinson's disease questionnaire (PDQ-39) quality-of-life scale (range 0-100 with six points defined as the minimally important difference) and cost-effectiveness. Analysis was intention to treat. This trial is registered, number ISRCTN69812316. Between Nov 9, 2000, and Dec 22, 2009, 1620 patients were assigned to study groups (528 to levodopa, 632 to dopamine agonist, 460 to MAOBI). With 3-year median follow-up, PDQ-39 mobility scores averaged 1·8 points (95% CI 0·5-3·0, p=0·005) better in patients randomly assigned to levodopa than those assigned to levodopa-sparing therapy, with no increase or attrition of benefit during 7 years' observation. PDQ-39 mobility scores were 1·4 points (95% CI 0·0-2·9, p=0·05) better in patients allocated MAOBI than in those allocated dopamine agonists. EQ-5D utility scores averaged 0·03 (95% CI 0·01-0·05; p=0·0002) better with levodopa than with levodopa-sparing therapy; rates of dementia (hazard ratio [HR] 0·81, 95% CI 0·61-1·08, p=0·14), admissions to institutions (0·86, 0·63-1·18; p=0·4), and death (0·85, 0·69-1·06, p=0·17) were not significantly different, but the upper CIs precluded any substantial increase with levodopa compared with levodopa-sparing therapy. 179 (28%) of 632 patients allocated dopamine agonists and 104 (23%) of 460 patients allocated MAOBI discontinued allocated treatment because of side-effects compared with 11 (2%) of 528 patients allocated levodopa (p<0·0001). Very small but persistent benefits are shown for patient-rated mobility scores when treatment is initiated with levodopa compared with levodopa-sparing therapy. MAOBI as initial levodopa-sparing therapy was at least as effective as dopamine agonists. UK National Institute for Health Research Health Technology Assessment Programme and UK Department of Health.

Initiating dopaminergic treatment in Parkinson's disease

In The Lancet, Richard Gray and the UK PD MED Collaborative Group1 report the highly anticipated results of a very large, pragmatic trial assessing outcomes during a median follow-up of 3 years and maximum 7 years in patients with early Parkinson's disease. A total of 1620 patients were managed with three different initial treatment regimens: levodopa (528 patients) or two levodopa-sparing approaches, either a dopamine agonist (632 patients) or a monoamine oxidase type B inhibitor (MAOBI; 460 patients).

Pharmacological Treatment of Parkinson Disease

Parkinson disease is the second most common neurodegenerative disease worldwide. Although no available therapies alter the underlying neurodegenerative process, symptomatic therapies can improve patient quality of life. To provide an evidence-based review of the initial pharmacological management of the classic motor symptoms of Parkinson disease; describe management of medication-related motor complications (such as motor fluctuations and dyskinesia), and other medication adverse effects (nausea, psychosis, and impulse control disorders and related behaviors); and discuss the management of selected nonmotor symptoms of Parkinson disease, including rapid eye movement sleep behavior disorder, cognitive impairment, depression, orthostatic hypotension, and sialorrhea. References were identified using searches of PubMed between January 1985 and February 2014 for English-language human studies and the full database of the Cochrane Library. The classification of studies by quality (classes I-IV) was assessed using the levels of evidence guidelines from the American Academy of Neurology and the highest-quality data for each topic. Although levodopa is the most effective medication available for treating the motor symptoms of Parkinson disease, in certain instances (eg, mild symptoms, tremor as the only or most prominent symptom, aged <60 years) other medications (eg, monoamine oxidase type B inhibitors [MAOBIs], amantadine, anticholinergics, β-blockers, or dopamine agonists) may be initiated first to avoid levodopa-related motor complications. Motor fluctuations may be managed by modifying the levodopa dosing regimen or by adding several other medications, such as MAOBIs, catechol-O-methyltransferase inhibitors, or dopamine agonists. Impulse control disorders are typically managed by reducing or withdrawing dopaminergic medication, particularly dopamine agonists. Evidence-based management of some nonmotor symptoms is limited by a paucity of high-quality positive studies. Strong evidence supports using levodopa and dopamine agonists for motor symptoms at all stages of Parkinson disease. Dopamine agonists and drugs that block dopamine metabolism are effective for motor fluctuations and clozapine is effective for hallucinations. Cholinesterase inhibitors may improve symptoms of dementia and antidepressants and pramipexole may improve depression. Evidence supporting other therapies for motor and nonmotor features is less well established.

Cardiac safety of rasagiline, a selective monoamine oxidase type B inhibitor for the treatment of Parkinson’s disease: a thorough QT/QTc study

Rasagiline is a selective, irreversible monoamine oxidase type B inhibitor, developed for the treatment of Parkinson's disease. In compliance with current regulatory requirements, rasagiline underwent a thorough QT/QTc (TQT) study to assess its potential to prolong cardiac repolarization. The primary aim of this study was to evaluate the effects of clinical (1 mg/day) and supratherapeutic (2 mg/day and 6 mg/day) multiple oral doses of rasagiline on the baseline- and placebo-adjusted QTc interval (delta delta QTc (ddQTc)). Other electrocardiogram parameters, pharmacokinetic assessments, safety and tolerability as well as vital signs were investigated. This was a five-arm, randomized, double-blind, placebo- and active-controlled, and parallel study in healthy subjects. Moxifloxacin (400 mg) positive control was included to demonstrate assay sensitivity. 247 of 250 randomized subjects completed the study. Time-matched analysis of ddQTc yielded two-sided 90% confidence intervals for all rasagiline doses below the 10 ms regulatory threshold, showing no effect on cardiac repolarization. Concentration-effect analysis demonstrated no relationships between rasagiline (and its metabolite 1-aminoindan), plasma concentrations, and ddQTc. The pharmacokinetic profile of rasagiline was consistent with previous studies. Adverse events were mild to moderate in intensity and were similar across all treatment groups. There were no clinically significant changes in heart rate and systolic blood pressure. This TQT study demonstrated a favorable cardiac safety profile of rasagiline.

The upstream Variable Number Tandem Repeat polymorphism of the monoamine oxidase type A gene influences trigeminal pain‐related evoked responses

Monoamines have an important role in neural plasticity, a key factor in cortical pain processing that promotes changes in neuronal network connectivity. Monoamine oxidase type A (MAOA) is an enzyme that, due to its modulating role in monoaminergic activity, could play a role in cortical pain processing. The X-linked MAOA gene is characterized by an allelic variant of length, the MAOA upstream Variable Number Tandem Repeat (MAOA-uVNTR) region polymorphism. Two allelic variants of this gene are known, the high-activity MAOA (HAM) and low-activity MAOA (LAM). We investigated the role of MAOA-uVNTR in cortical pain processing in a group of healthy individuals measured by the trigeminal electric pain-related evoked potential (tPREP) elicited by repeated painful stimulation. A group of healthy volunteers was genotyped to detect MAOA-uVNTR polymorphism. Electrical tPREPs were recorded by stimulating the right supraorbital nerve with a concentric electrode. The N2 and P2 component amplitude and latency as well as the N2-P2 inter-peak amplitude were measured. The recording was divided into three blocks, each containing 10 consecutive stimuli and the N2-P2 amplitude was compared between blocks. Of the 67 volunteers, 37 were HAM and 30 were LAM. HAM subjects differed from LAM subjects in terms of amplitude of the grand-averaged and first-block N2-P2 responses (HAM>LAM). The N2-P2 amplitude decreased between the first and third block in HAM subjects but not LAM subjects. The MAOA-uVNTR polymorphism seemed to influence the brain response in a repeated tPREP paradigm and suggested a role of the MAOA as a modulator of neural plasticity related to cortical pain processing.

New perspectives in non-oral drug delivery in Parkinson's disease: Highlights of a satellite symposium held at the XX world congress on Parkinson's disease and related disorders, Geneva, Switzerland, 8-11 December 2013

Oral therapies, including levodopa, dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors, form the mainstay of medical treatment for Parkinson's disease (PD). However, over time, chronic treatment with multiple daily doses of oral agents is often associated with the development of motor fluctuations and dyskinesias. Alternative methods of dopaminergic drug delivery, particularly if they bypass the gastrointestinal system, may be of value for PD patients who have developed motor complications despite optimised oral therapy, in particular those with gastrointestinal absorption issues, including gastroparesis. This satellite symposium, held at the XX World Congress on Parkinson's Disease and Related Disorders, Geneva, Switzerland, from 8-11 December 2013, was chaired by Professor Werner Poewe (Austria) and Professor Andrew Lees (UK) and discussed recent evidence regarding the benefits of using non-oral drug-delivery strategies with therapies such as subcutaneous apomorphine. Beginning with the history of apomorphine and its well-established use in PD both as an intermittent injection and a continuous infusion, the presenters set out the evidence for its efficacy in managing both motor and non-motor symptoms in PD. The significance of gastrointestinal involvement in PD and how this may influence responses to oral medications was also reviewed. Interim results from the ongoing Apokyn for Motor IMProvement of Morning AKinesia Trial (AM IMPAKT) study of the use of subcutaneous apomorphine in PD patients with morning akinesia were also presented and the continuing main role of apomorphine in the treatment of PD was discussed, including the selection of the most appropriate patients for this effective yet underused therapy.

New Perspectives in Non-oral Drug Delivery in Parkinson’s Disease

Oral therapies, including levodopa, dopamine agonists and monoamine oxidase type B (MAO-B) inhibitors, form the mainstay of medical treatment for Parkinson’s disease (PD). However, over time, chronic treatment with multiple daily doses of oral agents is often associated with the development of motor fluctuations and dyskinesias. Alternative methods of dopaminergic drug delivery, particularly if they bypass the gastrointestinal system, may be of value for PD patients who have developed motor complications despite optimised oral therapy, in particular those with gastrointestinal absorption issues, including gastroparesis. This satellite symposium, held at the XX World Congress on Parkinson’s Disease and Related Disorders, Geneva, Switzerland, from 8–11 December 2013, was chaired by Professor Werner Poewe (Austria) and Professor Andrew Lees (UK) and discussed recent evidence regarding the benefits of using non-oral drug-delivery strategies with therapies such as subcutaneous apomorphine. Beginning with the history of apomorphine and its well-established use in PD both as an intermittent injection and a continuous infusion, the presenters set out the evidence for its efficacy in managing both motor and non-motor symptoms in PD. The significance of gastrointestinal involvement in PD and how this may influence responses to oral medications was also reviewed. Interim results from the ongoing Apokyn for Motor IMProvement of Morning AKinesia Trial (AM IMPAKT) study of the use of subcutaneous apomorphine in PD patients with morning akinesia were also presented and the continuing main role of apomorphine in the treatment of PD was discussed, including the selection of the most appropriate patients for this effective yet underused therapy.

Effect of Therapeutic Interventions on Health-related Quality of Life in Parkinson’s Disease

Health-related quality of life (HRQoL) used to be considered a secondary parameter in clinical trials of Parkinson’s disease (PD) and in routine clinical practice, but is now increasingly recognised as an important measure of patient status. A number of studies have shown that the severity of PD is strongly associated with poor HRQoL scores and that measuring HRQoL domains provides a valuable assessment of overall patient status. Current guidelines from the Movement Disorder Society Task Force and the European Parkinson’s Disease Association recommend the use of HRQoL measures in the diagnosis and monitoring of patients. The European Medicines Agency PD Guidelines, however, do not yet recommend the use of such indirect endpoints in clinical trials. A series of phase III and post-marketing studies evaluating the selective monoamine oxidase type B inhibitor, rasagiline in PD, including between 404 and 1,176 patients, showed that treatment with rasagiline leads to significant improvements in HRQoL parameters such as the Parkinson’s Disease Quality of Life questionnaire (PDQUALIF), the 39-Item Parkinson’s Disease Questionnaire (PDQ-39), the PDQ-8 and other HRQoL-related parameters. Other clinical trials have shown significant improvements in parameters including: Short-Form-36, EuroQuol 5D, PDQUALIF, PDQ-39 and HRQoL-related parameters in PD patients treated with dopamine agonists, selegiline, tocopherol or levodopa/carbidopa/entacapone or levodopa/carbidopa combinations. Experience gained with these instruments is likely to increase the attention paid to HRQoL in PD assessment and could improve diagnosis and monitoring of PD and may ultimately improve patient outcomes.

Inhibition of monoamine oxidase by selected phenylalkylcaffeine analogues

Caffeine represents a useful scaffold for the design of monoamine oxidase (MAO) type B inhibitors. Specifically, substitution on the C8 position yields structures which are high-potency MAO-B inhibitors. To explore the structure-activity relationships of MAO-B inhibition by caffeine-derived compounds, this study examines the MAO inhibitory properties of a series of phenylalkylcaffeine analogues. Employing the recombinant human enzymes, the potencies (IC50 values) by which the caffeine analogues inhibit MAO-A and MAO-B were measured. The reversibility of inhibition of a selected inhibitor was determined by measuring the recovery of enzyme activity after dilution and dialysis of enzyme-inhibitor mixtures. The results document that the phenylalkylcaffeine analogues are reversible and selective MAO-B inhibitors with a competitive mode of inhibition. The most potent analogue, 8-(7-phenylheptyl)caffeine, exhibits IC50 values for the inhibition of MAO-A and MAO-B of 3.01 μm and 0.086 μm, respectively. Increasing the length of the alkyl side chain leads to enhanced MAO-A and MAO-B inhibitory potency while introduction of a carbonyl group reduces MAO-B inhibitory potency. Phenylalkylcaffeines represent a new class of high-potency MAO-B inhibitors with the longer alkyl side chains yielding enhanced inhibitory activity. Such compounds may represent useful leads for the development of anti-parkinsonian therapies.

Exposure of cardiomyocytes to angiotensin II induces over-activation of monoamine oxidase type A: Implications in heart failure

Several evidences indicate that increased cardiac mitochondrial monoamine oxidase type A (MAO-A) activity associates with a failing phenotype. Till now, the mechanism underlying such relation is largely unknown. We explored the hypothesis that exposure of cardiomyocytes to AT-II caused activation of MAO-A and also of catalase and aldehyde dehydrogenase activities, enzymes involved in degrading MAO's end products.Left ventricular cardiomyocytes were isolated from normoglycemic (N) and streptozotocin-injected (50mg/kg) rats (D) treated or not treated with losartan (20mg/kg/day in drinking water; DLos and NLos, respectively), a type 1 receptor (AT1) antagonist, for 3 weeks. In each group of cells, MAO, catalase and aldehyde dehydrogenase activities were measured radiochemically and spectrophotometrically. The same enzymes were also measured in HL-1 immortalized cardiomyocytes not exposed and exposed to AT-II (100nM for 18h) in the absence and in the presence of irbesartan (1μM), an AT1 antagonist. MAO-A catalase and aldehyde dehydrogenase activities were found significantly higher in D, than in N cells. MAO-A positively correlated with catalase activity in D cells. MAO-A and aldehyde dehydrogenase but not catalase over-activation, were prevented in DLos cells. Similarly, MAO-A activity, but not catalase and aldehyde dehydrogenase increased significantly in HL-1 cells acutely exposed to AT-II and this increase was prevented when irbesartan, an AT1 antagonist was present. Over-activation of cardiomyocyte MAO-A activity is among acute (18h) and short-term (2-weeks of diabetes) cardiac effects of AT-II and a novel target of AT1 antagonists, first line treatments of diabetic cardiomyopathy.

Efficacy and safety of rasagiline as an adjunct to levodopa treatment in Chinese patients with Parkinson's disease: a randomized, double-blind, parallel-controlled, multi-centre trial

Rasagiline mesylate is a highly potent, selective and irreversible monoamine oxidase type B (MAOB) inhibitor and is effective as monotherapy or adjunct to levodopa for patients with Parkinson's disease (PD). However, few studies have evaluated the efficacy and safety of rasagiline in the Chinese population. This study was designed to investigate the safety and efficacy of rasagiline as adjunctive therapy to levodopa treatment in Chinese PD patients. This was a randomized, double-blind, placebo-controlled, parallel-group, multi-centre trial conducted over a 12-wk period that enrolled 244 PD patients with motor fluctuations. Participants were randomly assigned to oral rasagiline mesylate (1 mg) or placebo, once daily. Altogether, 219 patients completed the trial. Rasagiline showed significantly greater efficacy compared with placebo. During the treatment period, the primary efficacy variable--mean adjusted total daily off time--decreased from baseline by 1.7 h in patients treated with 1.0 mg/d rasagiline compared to placebo (p < 0.05). Scores using the Unified Parkinson's Disease Rating Scale also improved during rasagiline treatment. Rasagiline was well tolerated. This study demonstrated that rasagiline mesylate is effective and well tolerated as an adjunct to levodopa treatment in Chinese PD patients with fluctuations.

Preclinical characterization of RO4602522, a novel, selective and orally active monoamine oxidase type B inhibitor for the treatment of Alzheimer's disease

Preclinical characterization of RO4602522, a novel, selective and orally active monoamine oxidase type B inhibitor for the treatment of Alzheimer's disease

La enfermedad de Parkinson: neurología para psiquiatras

La enfermedad de Parkinson es una enfermedad degenerativa y progresiva debida a la pérdida de las neuronas dopaminérgicas de la sustancia nigra del mesencéfalo. Sus manifestaciones son: temblor en reposo, rigidez y enlentecimiento de los movimientos, alteraciones en la postura y en la marcha. La aparición temprana de problemas en la memoria o alucinaciones, no debidas al tratamiento, indica la presencia de demencia con cuerpos de Lewy. Las escalas utilizadas para evaluar el estadio y la gravedad de la enfermedad de Parkinson son: la Escala de los Estadios de Hoehn y Yahr y la Escala Unificada de Calificación de la Enfermedad de Parkinson (UPDRS). Aunque todavía no existe un medicamento que detenga la evolución de la enfermedad de Parkinson, el tratamiento actual consiste en mejorar los síntomas mediante: a) la reposición de la dopamina por medio del uso de su precursor (levodopa, L-Dopa), b) la administración de sustancias que aumentan la actividad dopaminérgica al estimular a sus receptores (ropinirol, pramipexol, bromocriptina) y c) la inhibición de las enzimas que destruyen la dopamina como la catecol- O- metiltransferasa (COMT) con la entacapona, y a la monoamino oxidasa tipo B (MAOB) con la selegilina y la rasagilina. Existe además el tratamiento quirúrgico de la enfermedad de Parkinson que consiste en procedimientos ablativos y la estimulación cerebral profunda. En esta revisión se describen los elementos básicos de la enfermedad, su cuadro clínico y sus complicaciones. En una segunda parte se aborda el tratamiento médico con sus indicaciones, administración y efectos secundarios, y para terminar se describirá el tratamiento quirúrgico.

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Case Reports: We describe the use of transdermal dopaminergic patch, rotigotine, in the ICU management of Parkinson’s disease (PD) patients with strict NPO status who are unable to receive any enteral Parkinson’s medications. We hypothesize that rotigotine would provide adequate PD control in ICU patients with NPO status. We present a case series of two ICU patients with PD who could not receive enteral medication. Case 1: A 71 year-old male with mild PD who took sinemet (levodopa/carbidopa) 25/100 underwent esophagectomy for high-grade Barrett’s esophagus with adenocarcinoma. He was extubated but remained strict NPO and unable to receive sinemet. Examination revealed moderate cogwheel rigidity and bradykinesia. Because of his PD symptoms and the risk of neuromalignant syndrome (NMS) from dopaminergic withdrawal, we initiated a 2 mg/24hr rotigotine patch on postoperative day 1. He had a slight improvement in his bradykinesia. On POP day 2, rotigotine was increased to 4 mg/24hr. Once resumed PO he was gradually backed to sinemet and the rotigotine patch discontinued. Case 2: A 78 year old male with mild PD treated with rasagiline, monoamine oxidase (MAO) type B inhibitor, developed acute herpes encephalitis and aspiration pneumonia, and was intubated for two weeks. The family opted against tracheostomy. The extubation was difficult due to extra-pulmonary chest wall rigidity and drowsiness. NG tube administration of rasagiline was ineffective as well as sinemet possibly due to ileus, and/or underlying autonomic dysfunction from PD. Eventually, he was switched to 2 mg/24hr rotigotine patch, which was increased to 4 mg/24hr. On Day 19 he was extubated successfully. Once he was able to take PO and ambulate, sinemet was restarted, and rotigotine discontinued. No dyskinesias, nausea or other side effects occurred during rotigotine therapy. We conclude that rotigotine transdermal dopaminergic patch may be a ‘bridge’ ICU therapy in strict NPO PD patients or with gastrointestinal problems. It is essential to continue the PD medication as this can lead to worsened dysphagia, extrapulmonary chest wall rigidity, reduced limb movement, and others complications such as DVT or possible NMS.