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Drug-induced parkinsonism  

Microsoft Academic Search

Opinion statement  Drug-induced parkinsonism (DIP) is condition that mimics Parkinson’s disease. Characterized mainly by rigidity and bradykinesia,\\u000a it has less prominent tremor and gait instability. DIP is generally caused by lipophilic drugs that “block” dopamine D2 receptors\\u000a in the brain, although presynaptic dopamine depletion, false transmitters, mitochondrial respiratory chain dysfunction, and\\u000a overactivity in the ?-aminobutyric acid (GABA)ergic system or cholinomimetic action

Frandy Susatia; Hubert H. Fernandez



Drug induced parkinsonism: a common cause of parkinsonism in older people  

Microsoft Academic Search

Drug induced parkinsonism is the second most common cause of parkinsonism in older people after idiopathic Parkinson’s disease (PD). Risk factors for developing drug induced parkinsonism include: older age; female gender; dose and duration of treatment; type of agent used; cognitive impairment; acquired immunodeficiency syndrome (AIDS); tardive dyskinesia; and pre-existing extrapyramidal disorder. In most patients parkinsonism is reversible upon stopping

B Thanvi; S Treadwell



Drug-induced parkinsonism: a review of 17 years' experience in a regional pharmacovigilance center in France.  


Besides antipsychotics, several drugs can induce parkinsonism. We review spontaneous notifications of drug-induced or -worsened parkinsonism to a French regional pharmacovigilance center between 1993 and 2009. During these 17 years, 20,855 adverse drug reactions have been reported, including 155 (0.7%) cases of drug-induced or -worsened parkinsonism. Most of the notifications have involved aged patients (48% between 60 and 79 years) and females (60%). "Seriousness" was found in 43.9% of cases. Worsening of parkinsonism occurred in 28 patients suffering from idiopathic Parkinson's disease. Sixty-nine percent of drug-induced or -worsened parkinsonism cases were observed during the first 3 months after introduction of the "suspect" drug (involving mainly central dopaminergic antagonists). A second peak (20%) was found 12 months after drug introduction (mainly caused by calcium channel blockers). The most frequently reported parkinsonian symptom was rigidity (78.7%). The three cardinal symptoms were found in 37.4% of notifications. Evolution was favorable (after partial or complete withdrawal of suspect drug[s]) in 88.7% of cases. Among the 261 suspect drugs, most involved central dopaminergic antagonists (49%), followed by antidepressants (8%), calcium channel blockers (5%), peripheral dopaminergic antagonists (5%), and H1 antihistamines (5%). Cases with lithium, valproic acid, amiodarone, anticholinesterases, or trimetazidine were also found. Three notifications were the result of pharmacokinetic interactions. We found that drug-induced or -worsened parkinsonism is an often "serious," but reversible, adverse drug reaction. It occurred more frequently between 60 and 79 years. Rigidity was the most frequently reported symptom. Approximately 50% of drug-induced or -worsened parkinsonism cases spontaneously reported were related to drugs other than antipsychotics. Drug-induced or -worsened parkinsonism can also be explained by pharmacokinetic drug interactions. PMID:21674626

Bondon-Guitton, Emmanuelle; Perez-Lloret, Santiago; Bagheri, Haleh; Brefel, Christine; Rascol, Olivier; Montastruc, Jean-Louis



Drug-induced impulse control disorders in Parkinson's disease.  


Dopamine replacement treatment with excessive or aberrant dopamine receptor stimulation can cause behavioral disturbances in Parkinson's disease, comprising dopamine dysregulation syndrome, punding, and impulse control disorders. Common impulse control disorders are compulsive buying, pathological gambling, binge eating, hypersexuality, and compulsive reckless driving. PMID:21560063

Reiff, J; Jost, W H



The interhemispheric connections of the striatum: implications for Parkinson's disease and drug-induced dyskinesias  

PubMed Central

Parkinson’s disease (PD) is characterized by loss of nigrostriatal neurons and depletion of dopamine. This pathological feature leads to alterations to basal ganglia circuitry and subsequent motor disability. Pharmacological dopamine replacement therapy with medications such as levodopa ameliorates the symptoms of PD but can lead to motor complications known as drug-induced dyskinesias. We have recently shown that clinically hemiparkinsonian rhesus monkeys do not develop levodopa-induced dyskinesias despite chronic intermittent exposure and significant unilateral loss of nigrostriatal neurons and dopamine. It is currently unclear what mechanisms prevent the onset of dyskinesias in these animals. However, based on our study and results from previous lesioning studies in both the rat and monkey models of PD, we hypothesize that one potential mechanism that may prevent the genesis of dyskinesias in these animals is interhemispheric inhibition. Two potential interhemispheric connections that may modulate dyskinesias are the interhemispheric nigrostriatal and corticostriatal pathways. Few investigators have examined the interhemispheric nigrostriatal and corticostriatal connections and the functional role they may play in drug-induced dyskinesias in PD. Therefore, in the following review, we assess the neuroanatomical, electrophysiological and behavioral properties of these interhemispheric connections. Future studies evaluating these interhemispheric striatal pathways and the pathophysiological changes that occur to these pathways in the dyskinetic state are warranted to further develop treatments that prevent or mitigate drug-induced dyskinesias in PD.

Lieu, Christopher A.; Subramanian, Thyagarajan



Manganese-induced parkinsonism among ephedrone users and drug policy in poland.  


A recent government's prohibition policy in Poland was partially successful with a reduction of the synthetic drugs market and a decrease in drug-related poisoning mortality rates. However, a new threatening trend is observed. There are a growing number of individuals in Poland and other European countries using legal pharmaceuticals containing ephedrine or pseudoephedrine to produce stimulants. This case report describes a history of a male patient with polysubstance dependence who administered self-designed ephedrone derived from Sudafed using potassium permanganate. He revealed significant clinical symptoms of manganese-induced parkinsonism. No effective treatment could be recommended. Awareness of this severe neurological and social consequences should lead to prevention efforts including educational programs and initiatives reducing availability of the legal medications containing ephedrine or pseudoephedrine. More research is needed to enhance our knowledge about manganism and potential treatment regimens. PMID:23609215

Fudalej, Sylwia; Ko?odziejczyk, Iwona; Gajda, Tomasz; Majkowska-Zwoli?ska, Beata; Wojnar, Marcin


Drug treatment of Parkinson's disease.  

PubMed Central

A wide variety of drugs is available for treating Parkinson's disease, including anticholinergics, amantadine levodopa, dopamine agonists, and selegiline. In younger patients (less than 50) levodopa is usually delayed provided that adequate relief of symptoms can be achieved with other drugs. In older patients (greater than 70) levodopa should be started as soon as symptom relief is required. Between these ages there is no consensus, but at present most such patients should probably be given controlled release levodopa before a dopamine agonist is added. Fluctuations can often be alleviated by giving controlled release preparations of levodopa, by giving small doses at frequent intervals, by adding selegiline or a long acting oral agonist, or by subcutaneous apomorphine. Dyskinesia can be peak dose, diphasic, or "off period." The diphasic form is hardest to alleviate. Psychiatric side effects should initially be managed by changing the antiparkinsonian treatment before resorting to antipsychotic drugs.

Quinn, N.



Drug therapy in patients with Parkinson's disease  

PubMed Central

Parkinson`s disease (PD) is a progressive, disabling neurodegenerative disorder with onset of motor and non-motor features. Both reduce quality of life of PD patients and cause caregiver burden. This review aims to provide a survey of possible therapeutic options for treatment of motor and non motor symptoms of PD and to discuss their relation to each other. MAO-B-Inhibitors, NMDA antagonists, dopamine agonists and levodopa with its various application modes mainly improve the dopamine associated motor symptoms in PD. This armentarium of PD drugs only partially influences the onset and occurrence of non motor symptoms. These PD features predominantly result from non dopaminergic neurodegeneration. Autonomic features, such as seborrhea, hyperhidrosis, orthostatic syndrome, salivation, bladder dysfunction, gastrointestinal disturbances, and neuropsychiatric symptoms, such as depression, sleep disorders, psychosis, cognitive dysfunction with impaired execution and impulse control may appear. Drug therapy of these non motor symptoms complicates long-term PD drug therapy due to possible occurrence of drug interactions, - side effects, and altered pharmacokinetic behaviour of applied compounds. Dopamine substituting compounds themselves may contribute to onset of these non motor symptoms. This complicates the differentiation from the disease process itself and influences therapeutic options, which are often limited because of additional morbidity with necessary concomitant drug therapy.



Drug-induced parkinsonism in relation to choline-containing compounds measured by 1H-MR spectroscopy in putamen of chronically medicated patients with schizophrenia.  


Extrapyramidal side-effects (EPS), the most frequent and severe side-effects of antipsychotics, sometimes become irreversible and cause severe psychosocial disturbance in patients with schizophrenia. However, the neurobiological basis of EPS has not yet been elucidated. In this study, neurochemical correlates of EPS were examined by 1H-MR spectroscopy (1H-MRS). Sixteen medicated patients with schizophrenia and 15 age-, gender- and parental-socioeconomic-status-matched normal controls were examined using single-voxel 1H-MRS. Absolute concentrations of N-acetyl aspartate (NAA), choline-containing compounds (Cho), creatine/phosphocreatine, myo-inositol, and Glx (glutamate and glutamine) in the left putamen were evaluated. The patient group showed mild EPS and no significant metabolic abnormalities in this region. The more severe drug-induced parkinsonism assessed by the Simpson-Angus Scale, however, significantly correlated with the higher Cho concentration and tended to be correlated with the higher NAA concentration in the patient group. These results suggest a potential of 1H-MRS as a non-invasive monitoring method of neurobiological correlates of EPS associated with neuroleptic treatments in patients with schizophrenia. PMID:14604450

Yamasue, Hidenori; Fukui, Tsunehiro; Fukuda, Rin; Kasai, Kiyoto; Iwanami, Akira; Kato, Nobumasa; Kato, Tadafumi



[Guidelines of drug therapies for Parkinson's disease].  


Treatment of Parkinson's disease has progressed steadily for the last decades after introduction of levodopa. For recovery of striatal dysfunction caused by loss of projecting nigral cells, supplementation of neurotransmitter dopamine (DA), facilitation of neural transmission by DA agonists and amantadine, suppression of acetyl-choline neurons, having antagonistic action to DA cells, are all effective especially at the early to middle stages of illness. As prevention of neuronal cell death in parkinsonian brain has not yet been succeeded, difficulties in treatment with symptom fluctuation and CNS side effects such as dyskinesia or psychic symptoms develop inevitably in the long course of evodopa treatment. Proper choice of drugs for parkinsonian core and accompanying symptoms and selection of methods of medication for maintenance of natural daily life activities are necessary for attainment of good QOL for whole time course of the disease. PMID:9014423

Yanagisawa, N



Has drug therapy changed the natural history of Parkinson’s disease?  

Microsoft Academic Search

This narrative review examines the effects of drug therapy on the natural history of Parkinson’s disease. In terms of modifying\\u000a the underlying disease process, it is possible that immediate therapy, rather than deferred treatment, can have a positive\\u000a effect on the underlying disease process. However, it is unlikely that drug therapy has changed mortality from the condition\\u000a and there is

C. E. Clarke



Drug-related problems in Parkinson’s disease: the role of community pharmacists in primary care  

Microsoft Academic Search

Objective Although Parkinson’s disease is a common disorder in the elderly, there have been very few studies of the role of the pharmaceutical\\u000a care services in detecting and reducing problems associated with drug treatment in community settings. The aim of this study\\u000a was therefore to investigate the type and frequency of drug-related problems identified in patients with Parkinson’s disease\\u000a by

Sabrina Schröder; Peter Martus; Per Odin; Marion Schaefer



Analysis of the Metabolism of Haloperidol and Its Neurotoxic Pyridinium Metabolite in Patients with Drug-Induced Parkinsonism  

Microsoft Academic Search

The blood levels of the neurotrophic drug haloperidol (HP) and its pyridinium metabolite, HPP+, have been analyzed by liquid chromatography\\/electrospray ionization-mass spectrometry in 10 schizophrenic patients treated with HP, without carbamazepine (HP, oral daily dose of 0.3–0.5 mg\\/kg body weight for more than 1 year, females, aged 41 ± 8.5 years). There was a significant difference (t-test, d.f. = 8,

K. Iwahashi; K. Anemo; K. Nakamura; I. Fukunishi; K. Igarashi



Non-Steroidal Anti-Inflammatory Drug Use and the Risk of Parkinson’s Disease  

Microsoft Academic Search

Background: Experimental evidence supports a preventative role for non-steroidal anti-inflammatory drugs (NSAIDs) in Parkinson’s disease (PD). Methods: We investigated associations between use of aspirin, nonaspirin NSAIDs, and acetaminophen and PD in a large population-based case-control study using Danish health and pharmacy registries. We identified 1,931 PD cases reported in hospital or outpatient clinic records who had received a primary diagnosis

Angelika D. Manthripragada; Eva S. Schernhammer; Jiaheng Qiu; Soren Friis; Lene Wermuth; Jorgen H. Olsen; Beate Ritz



Pet Evaluation of Drugs in Alzheimer's and Parkinson's Diseases  

Microsoft Academic Search

In addition to the study of the distribution and kinetics of labeled drugs, positron emission tomography (PET) can improve the accuracy of diagnosis of Alzheimer's and Parkinson's diseases by imaging major metabolic changes (glucose metabolism, dopamine synthesis) that are typical for these diseases. It may thus reduce the variance of results and improve the statistical power of clinical trials. Subgroups

Karl Herholz



New drugs in the future treatment of Parkinson's disease  

Microsoft Academic Search

During the last few decades, there has been a remarkable progress in our understanding of the biology of Parkinson's disease (PD), which has been translated into the development of numerous antiparkinsonian drugs. There are different therapeutic strategies for patients in an early stage versus patients in a late stage of the disease. The current therapeutic arsenal includes levodopa preparations, MAO-B

Ruth Djaldetti; Eldad Melamed



Piracetam and vinpocetine ameliorate rotenone-induced Parkinsonism in rats  

PubMed Central

Objective: To evaluate the neuroprotective effect of the nootropic drugs, piracetam (PIR) and vinpocetine (VIN), in rotenone-induced Parkinsonism in rats. Materials and Methods: Sixty male rats were divided into 6 groups of 10 rats each. The groups were administered vehicle, control (rotenone, 1.5 mg/kg/48 h/6 doses, s.c.), PIR (100 and 200 mg/kg/day, p.o.) and VIN (3 and 6 mg/kg/day, p.o.). The motor performance of the rats was evaluated by the open field and pole test. Striatal dopamine level, malondialdehyde (MDA), reduced glutathione (GSH) and tumor necrosis factor-? (TNF-?) were assayed. Histopathological study of the substantia nigra was also done. Results: Results showed that rotenone-treated rats exhibited bradykinesia and motor impairment in the open-field test. In addition, GSH level was decreased whereas MDA and TNF-? increased in striata of rotenone-treated rats as compared to vehicle-treated rats. Marked degeneration of the substantia nigra pars compacta (SNpc) neurons and depletion of striatal dopamine was also observed in the rotenone-treated rats. Treatment with PIR or VIN significantly reversed the locomotor deficits and increased striatal dopamine level. Treatment with VIN significantly (P < 0.05) reduced the striatal level of MDA and GSH in comparison to rotenone group whereas TNF-? production was found to be significantly decreased in PIR group (P < 0.05). Conclusion: VIN and PIR exhibit neuroprotective activity in rotenone-induced Parkinsonism. Hence, these nootropic agents may be considered as possible candidates in the treatment of Parkinson's disease.

Zaitone, Sawsan A.; Abo-Elmatty, Dina M.; Elshazly, Shimaa M.



[Drug treatment of dementia with Lewy bodies and Parkinson's disease dementia--common features and differences].  


Dementia with Lewy-bodies (DLB) and Parkinson's disease dementia (PDD) are no rare causes of dementia. Both have neuropathologically, clinically, and neurochemically much in common. In the course of both conditions frequently psychotic symptoms occur, often induced by antiparkinsonian medication. Treatment of psychotic features with conventional antipsychotics is not tolerated in many cases. Therefore low-dose clozapine treatment is acknowledged usual practise for psychosis in Parkinson's disease and a case report indicates efficacy for psychosis in DLB, too. All other atypical antipsychotics except risperidone are not licensed for dementia in Germany, but risperidone is contraindicated in DLB due to manufacturer's notice and usually not well tolerated in DLB and Parkinson's disease. Open trials indicate safety for treatment of psychosis in DLB and PDD with quetiapine. Randomized controlled trials indicate, that quetiapine is less effective than clozapine against psychotic symptoms in both conditions, although comparatively safe. Cholinesterase inhibitors, especially rivastigmine, are a therapeutic alternative for treating both psychotic and cognitive symptoms in both conditions. Parkinsonism in DLB-patients responds worse to levodopa compared to patient with Parkinson's disease. Anticholinergic drugs often induce delirium in demented patients and therefore should be avoided. The same problem is associated with dopamine agonists in PDD and DLB. Amantadine, a NMDA-receptor antagonist like memantine, potentially bears the same risk of worsening psychotic symptoms. The following preliminary recommendation for drug treatment of PDD and DLB can be given: Stop all anticholinergic medication and reduce levodopa and other antiparkinsonian medication to the tolerated minimum. Levodopa alone is preferred. Treat with cholinesterase inhibitors to the maximum tolerated dose. If there is no adequate response regarding psychotic symptoms, add quetiapine. If this approach fails, replace quetiapine by low-dose clozapine. If behavioural disturbances are due to depression, anxiety, or irritability, treatment with an antidepressant, preferably citalopram, is an option. PMID:21428015

Drach, Lutz M



Levodopa-induced Dyskinesia in Parkinson’s disease: Epidemiology, etiology, and treatment  

Microsoft Academic Search

Although levodopa is the gold standard for treating motor symptoms of Parkinson’s disease (PD), long-term therapy leads to\\u000a levodopa-induced dyskinesia (LID). Dyskinesia refers to involuntary movements other than tremor and most commonly consists\\u000a of chorea that occurs when levodopa-derived dopamine is peaking in the brain (“peak-dose dyskinesia”). However, dyskinesia\\u000a can also consist of dystonia or myoclonus and occur during other

Theresa A. Zesiewicz; Kelly L. Sullivan; Robert A. Hauser



Drug-induced hepatitis  


Toxic hepatitis ... to get liver damage. Some drugs can cause hepatitis with small doses, even if the liver breakdown ... liver. Many different drugs can cause drug-induced hepatitis. Painkillers and fever reducers that contain acetaminophen are ...


Drug-induced cholestasis.  


Drug-induced cholestasis manifests as an acute self-limiting injury or as a chronic perpetuating injury, resulting in duct loss and cirrhosis. The number of drugs implicated in drug-induced cholestasis grows every year as new drugs are developed and approved. Other agents such as herbals, nutritional supplements, and complementary and alternative medicines are also reported to cause cholestatic liver injury. Recent literature on molecular transporters involved in bile transport has improved our understanding of patterns of drug-induced liver injury and the mechanisms of cholestasis. This article summarizes the probable offending drugs, and the diagnosis and management of drug-induced cholestasis. PMID:24099015

Bhamidimarri, Kalyan Ram; Schiff, Eugene



Apathy in drug-naďve patients with incident Parkinson’s disease: the Norwegian ParkWest study  

Microsoft Academic Search

Apathy is a common behavioural problem in Parkinson’s disease (PD), with important clinical consequences for patients and\\u000a their families. However, little is known about apathy in early PD. We examined the frequency and clinical characteristics\\u000a of apathy in 175 nondemented, drug-naďve patients with newly diagnosed PD and 165 control subjects matched for age, sex and\\u000a education level in Western and

Kenn Freddy Pedersen; Guido Alves; Kolbjřrn Brřnnick; Dag Aarsland; Ole-Bjřrn Tysnes; Jan Petter Larsen



Drug discovery in Parkinson's disease--Update and developments in the use of cellular models  

PubMed Central

Parkinson’s disease (PD) is the second most common neurodegenerative disorder and is characterized by the degeneration of dopaminergic (DA) neurons within the substantia nigra. Dopamine replacement drugs remain the most effective PD treatment but only provide temporary symptomatic relief. New therapies are urgently needed, but the search for a disease-modifying treatment and a definitive understanding of the underlying mechanisms of PD has been limited by the lack of physiologically relevant models that recapitulate the disease phenotype. The use of immortalized cell lines as in vitro model systems for drug discovery has met with limited success, since efficacy and safety too often fail to translate successfully in human clinical trials. Drug discoverers are shifting their focus to more physiologically relevant cellular models, including primary neurons and stem cells. The recent discovery of induced pluripotent stem (iPS) cell technology presents an exciting opportunity to derive human DA neurons from patients with sporadic and familial forms of PD. We anticipate that these human DA models will recapitulate key features of the PD phenotype. In parallel, high-content screening platforms, which extract information on multiple cellular features within individual neurons, provide a network-based approach that can resolve temporal and spatial relationships underlying mechanisms of neurodegeneration and drug perturbations. These emerging technologies have the potential to establish highly predictive cellular models that could bring about a desperately needed revolution in PD drug discovery.

Skibinski, Gaia; Finkbeiner, Steven



Use of non-steroidal anti-inflammatory drugs and risk of Parkinson’s disease: nested case-control study  

Microsoft Academic Search

Objective To evaluate the relation between Parkinson’s disease and prior use of non-steroidal anti-inflammatory drugs (NSAIDs) in a large cohort of men.Design Case-control analysis nested in the Physicians’ Health Study. Participants 22 007 male physicians aged 40–84 years without indications for or contraindications to regular NSAID use and free of Parkinson’s disease at baseline. Cases and controls were matched by

Jane A Driver; Giancarlo Logroscino; Linda Lu; J Michael Gaziano; Tobias Kurth



[Disinhibitory abnormal behavior induced by treatment of Parkinson disease].  


The treatment of Parkinson disease has considerably progressed in the last 20 years. However, such treatments results in the adverse event of disinhibitory abnormal behavior, which includes impulse control disorders, punding, and dopamine dysregulation syndrome. Pathological gambling is the most extensively studied among such abnormal behaviors. It has been associated with the use of dopamine agonists and its prevalence increases according to the does of the drugs. The maximum dose of the ergot dopamine agonist pergolide is 1.25 mg/day in Japan, which is a quarter of that used in Western countries. The maximum dose of the non-ergot dopamine agonist, pramipexole is 4.5 mg/day in Japan, which is the same as in Western countries. Pramipexole was launched in 2004 in Japan, and since then cases of pathological gambling associated with dopamine agonists used has been increasing. Because of the excellent health-care system in Japan, patients can easily acquire expensive dopamine agonists. Although the prevalence of these abnormal behaviors has not been studied in Japan, it could be highly proportionate to the amount of dopamine agonists. Disinhibitory abnormal behavior is also induced by deep brain stimulation of the subthalamic nucleus. This technology was approved in 2000 in Japan. The mechanisms by which these behaviors are induced are different between dopamine replacement therapy and deep brain stimulation. Parkinson disease patients and their caregivers occasionally believe the disinhibitory abnormal behavior as arising from the original personality of the patient rather than as an adverse event of treatment. Neurologists should be aware of the occurrence of disinhibitory abnormal behavior in the clinical practice. PMID:22481510

Fujimoto, Ken-Ichi



Thrombocytopenia - drug induced  


... the blood that help the blood clot. A low platelet count makes bleeding more likely. When drugs or medications are the causes of a low platelet count, it is called drug-induced thrombocytopenia. See also: ...


[Drug-induced edema].  


It is well known that there are many drugs which induce edema. Drug-induced edema can be divided into three types by the mechanism as follows, 1) sodium overload, 2) renal dysfunction and 3) hyperpermeability of blood vessel. In the category of sodium overload, edema is induced by much fluid replacement and antibiotics which contain large amount of sodium and sodium bicarbonate. As the category of renal dysfunction, NSAIDs, antihypertensive drugs, anticancer drugs and so on induce edema in patients with renal dysfunction. In the category of hyperpermeability of blood vessel, edema is induced by calcium antagonist, insuline and so on. In order to diagnose drug-induced edema early, it is important that we interrupt or reduce the quantity of suspicious drug. PMID:15675326

Kaizu, Kazo; Abe, Masanori



Drug-induced phospholipidosis.  


Drug-induced phospholipidosis is characterized by intracellular accumulation of phospholipids with lamellar bodies, most likely from an impaired phospholipid metabolism of the lysosome. Organs affected by phospholipidosis exhibit inflammatory reactions and histopathological changes. Despite significant advances in the understanding of drug-altered lipid metabolism, the relationship between impaired phospholipid metabolism and drug-induced toxicity remains enigmatic. Here we review molecular features of inheritable lysosomal storage disorders as a molecular mimicry of drug-induced phospholipidosis for an improved understanding of adverse drug reaction. PMID:16979167

Anderson, Nora; Borlak, Jürgen



Drug-induced dyskinesia in Parkinson's disease. Should success in clinical management be a function of improvement of motor repertoire rather than amplitude of dyskinesia?  

PubMed Central

Background Dyskinesia, a major complication in the treatment of Parkinson's disease (PD), can require prolonged monitoring and complex medical management. Discussion The current paper proposes a new way to view the management of dyskinesia in an integrated fashion. We suggest that dyskinesia be considered as a factor in a signal-to-noise ratio (SNR) equation where the signal is the voluntary movement and the noise is PD symptomatology, including dyskinesia. The goal of clinicians should be to ensure a high SNR in order to maintain or enhance the motor repertoire of patients. To understand why such an approach would be beneficial, we first review mechanisms of dyskinesia, as well as their impact on the quality of life of patients and on the health-care system. Theoretical and practical bases for the SNR approach are then discussed. Summary Clinicians should not only consider the level of motor symptomatology when assessing the efficacy of their treatment strategy, but also breadth of the motor repertoire available to patients.



Assessment of drugs in schizophrenia. Asessment of drug-induced extrapyramidal reactions and of drugs given for their control.  

PubMed Central

I have tried to bring out some of the important methodological problems found in examining the effectiveness of drugs used in the control of druginduced parkinsonism by referring mainly to studies in which I have taken part. I hope I have shown that the whole topic is far less well understood than is often assumed. The main points may be summarized as follows: there is doubt as to whether many of the drugs used in controlling drug-induced parkinsonism are really effective; the results of many studies are conflicting; many studies contain serious flaws in design; methods for assessing extrapyramidal signs are not well developed; we are ignorant of the way in which drug-induced extrapyramidal signs change spontaneously. There is a clear need for further research in this area to improve techniques of assessment, to provide basic information on drug-induced syndromes, and to rigorously examine the efficacy of the drugs used in controlling them.

Mindham, R H



Theta burst stimulation over the primary motor cortex does not induce cortical plasticity in Parkinson’s disease  

Microsoft Academic Search

The purpose of this study was to investigate whether a period of continuous theta burst stimulation (cTBS) induces cortical\\u000a plasticity and thus improves bradykinesia of the upper limb in Parkinson’s disease. In eight patients with Parkinson’s disease\\u000a (two females; mean age: 68.5 ± 5 years; disease duration: 4 ± 3 years) electrophysiological (motor evoked potentials, contralateral\\u000a and ipsilateral silent period) and behavioural (Purdue pegboard test, UPDRS

Carsten Eggers; Gereon R. Fink; Dennis A. Nowak



Movement parameters that distinguish between voluntary movements and levodopa-induced dyskinesia in Parkinson’s disease  

Microsoft Academic Search

It is well known that long-term use of levodopa by patients with Parkinson’s disease causes dyskinesia. Several methods have been proposed for the automatic, unsupervised detection and classification of levodopa induced dyskinesia. Recently, we have demonstrated that neural networks are highly successful to detect dyskinesia and to distinguish dyskinesia from voluntary movements. The aim of this study was to use

Noël L. W Keijsers; Martin W. I. M. Horstink; Stan C. A. M. Gielen



Vitiligo, drug induced (image)  


... this person's face have resulted from drug-induced vitiligo. Loss of melanin, the primary skin pigment, occasionally ... is the case with this individual. The typical vitiligo lesion is flat (macular) and depigmented, but maintains ...



PubMed Central

Recent progress in understanding the molecular mechanisms of bile formation and cholestasis have led to new insights into the pathogenesis of drug induced cholestasis. This review summarizes their variable clinical presentations, examines the, role of transport proteins in hepatic drug clearance and toxicity and addresses the increasing importance of genetic determinants, as well as practical aspects of diagnosis and management.

Padda, Manmeet S.; Sanchez, Mayra; Akhtar, Abbasi J.; Boyer, James L.



Molecular Chaperones as Rational Drug Targets for Parkinson's Disease Therapeutics  

PubMed Central

Parkinson’s disease is a neurodegenerative movement disorder that is caused, in part, by the loss of dopaminergic neurons within the substantia nigra pars compacta of the basal ganglia. The presence of intracellular protein aggregates, known as Lewy bodies and Lewy neurites, within the surviving nigral neurons is the defining neuropathological feature of the disease. Accordingly, the identification of specific genes mutated in families with Parkinson’s disease and of genetic susceptibility variants for idiopathic Parkinson’s disease has implicated abnormalities in proteostasis, or the handling and elimination of misfolded proteins, in the pathogenesis of this neurodegenerative disorder. Protein folding and the refolding of misfolded proteins are regulated by a network of interactive molecules, known as the chaperone system, which is composed of molecular chaperones and co-chaperones. The chaperone system is intimately associated with the ubiquitin-proteasome system and the autophagy-lysosomal pathway which are responsible for elimination of misfolded proteins and protein quality control. In addition to their role in proteostasis, some chaperone molecules are involved in the regulation of cell death pathways. Here we review the role of the molecular chaperones Hsp70 and Hsp90, and the co-chaperones Hsp40, BAG family members such as BAG5, CHIP and Hip in modulating neuronal death with a focus on dopaminergic neurodegeneration in Parkinson’s disease. We also review current progress in preclinical studies aimed at targetting the chaperone system to prevent neurodegeneration. Finally, we discuss potential future chaperone-based therapeutics for the symptomatic treatment and possible disease modification of Parkinson’s disease.

Kalia, S.K.; Kalia, L.V.; McLean, P.J.



Parkinson's disease induced pluripotent stem cells with triplication of the alpha-synuclein locus  

Microsoft Academic Search

A major barrier to research on Parkinson's disease is inaccessibility of diseased tissue for study. One solution is to derive induced pluripotent stem cells from patients and differentiate them into neurons affected by disease. Triplication of SNCA, encoding alpha-synuclein, causes a fully penetrant, aggressive form of Parkinson's disease with dementia. alpha-Synuclein dysfunction is the critical pathogenic event in Parkinson's disease,

Michael J. Devine; Mina Ryten; Petr Vodicka; Alison J. Thomson; Tom Burdon; Henry Houlden; Fatima Cavaleri; Masumi Nagano; Nicola J. Drummond; Jan-Willem Taanman; Anthony H. Schapira; Katrina Gwinn; John Hardy; Patrick A. Lewis; Tilo Kunath



Drug-induced tremor  


... cause. Other causes of tremors may include: Alcohol withdrawal Cigarette smoking Hyperthyroidism Parkinson's disease Pheochromocytoma Too much caffeine Wilson's disease Blood tests and imaging studies (such ...


Levodopa-induced dyskinesias in Parkinson's disease: emerging treatments  

PubMed Central

Parkinson’s disease therapy is still focused on the use of L-3,4-dihydroxyphenylalanine (levodopa or L-dopa) for the symptomatic treatment of the main clinical features of the disease, despite intensive pharmacological research in the last few decades. However, regardless of its effectiveness, the long-term use of levodopa causes, in combination with disease progression, the development of motor complications termed levodopa-induced dyskinesias (LIDs). LIDs are the result of profound modifications in the functional organization of the basal ganglia circuitry, possibly related to the chronic and pulsatile stimulation of striatal dopaminergic receptors by levodopa. Hence, for decades the key feature of a potentially effective agent against LIDs has been its ability to ensure more continuous dopaminergic stimulation in the brain. The growing knowledge regarding the pathophysiology of LIDs and the increasing evidence on involvement of nondopaminergic systems raises the possibility of more promising therapeutic approaches in the future. In the current review, we focus on novel therapies for LIDs in Parkinson’s disease, based mainly on agents that interfere with glutamatergic, serotonergic, adenosine, adrenergic, and cholinergic neurotransmission that are currently in testing or clinical development.

Bargiotas, Panagiotis; Konitsiotis, Spyridon



Investigational Drug May Reduce "Off" Time in Parkinson's  


... reduce "off" time in people with Parkinson's disease (PD) who are taking levodopa therapy. The results appear ... messenger, in the brain. But for many people, PD symptoms return in between doses, when levodopa's effects ...


[Designer drug induced psychosis].  


3,4-methylene-dioxy-pyrovalerone (MDPV) is a popular designer drug in Hungary, known as MP4. We present a case of a 34-year-old man, whose first psychotic episode was observed in the presence of MP4 use. The paranoid ideas of reference and the dereistic thinking could be the consequence of drug-induced psychosis. Within 24 hours after the intoxication was over delirium set in. The patient's history included only the use of MP4, use of other kinds of drugs was negated. The drug tests were negative, amphetamine derivates were not detectable in the urine sample. It is most likely that the MP4 pill contained an amount of MDPV less than detectable. In conclusion we suggest that the clinical picture could be the consequence of regular MDPV use. PMID:22710853

Fullajtar, Mate; Ferencz, Csaba



Classic toxin-induced animal models of Parkinson’s disease: 6-OHDA and MPTP  

Microsoft Academic Search

Neurological disorders in humans can be modeled in animals using standardized procedures that recreate specific pathogenic events and their behavioral outcomes. The development of animal models of Parkinson’s disease (PD) is important to test new neuroprotective agents and strategies. Such animal models of PD have to mimic, at least partially, a Parkinson-like pathology and should reproduce specific features of the

Andreas Schober



The prevalence of Parkinson's disease in British Columbia, Canada, estimated by using drug tracer methodology  

Microsoft Academic Search

Objective: To estimate the prevalence of Parkinson's disease (PD) in British Columbia utilizing the prescription database of the College of Pharmacists.Methods: Patients receiving anti-parkinsonian drug (anti-PD) prescriptions between 1996 and 1998 were stratified by year, age, gender, drug use category, and geographic location. The numbers of patients on levodopa alone, or levodopa and\\/or other anti-PD drugs were adjusted using published

B. C. L. Lai; M. Schulzer; S. Marion; K. Teschke; J. K. C. Tsui



Psychogenic parkinsonism.  


Parkinsonism can be psychogenic, and psychogenic parkinsonism is about 10% of psychogenic movement disorder patients. Patients can present with any feature or combination of features of organic Parkinson's disease. There are clinical clues that can lead to the correct diagnosis, and laboratory testing with clinical neurophysiology or DAT (dopamine transporter) scanning can be helpful as well. Patients may have both organic Parkinson's disease and psychogenic parkinsonism, and this might be considered a psychologically induced aggravation of the organic disorder. PMID:21458829

Hallett, Mark



Drug-Induced Hematologic Syndromes  

PubMed Central

Objective. Drugs can induce almost the entire spectrum of hematologic disorders, affecting white cells, red cells, platelets, and the coagulation system. This paper aims to emphasize the broad range of drug-induced hematological syndromes and to highlight some of the newer drugs and syndromes. Methods. Medline literature on drug-induced hematologic syndromes was reviewed. Most reports and reviews focus on individual drugs or cytopenias. Results. Drug-induced syndromes include hemolytic anemias, methemoglobinemia, red cell aplasia, sideroblastic anemia, megaloblastic anemia, polycythemia, aplastic anemia, leukocytosis, neutropenia, eosinophilia, immune thrombocytopenia, microangiopathic syndromes, hypercoagulability, hypoprothrombinemia, circulating anticoagulants, myelodysplasia, and acute leukemia. Some of the classic drugs known to cause hematologic abnormalities have been replaced by newer drugs, including biologics, accompanied by their own syndromes and unintended side effects. Conclusions. Drugs can induce toxicities spanning many hematologic syndromes, mediated by a variety of mechanisms. Physicians need to be alert to the potential for iatrogenic drug-induced hematologic complications.

Mintzer, David M.; Billet, Shira N.; Chmielewski, Lauren



Castration induces Parkinson disease pathologies in young male mice via inducible nitric-oxide synthase.  


Although Parkinson disease (PD) is a progressive neurodegenerative disorder, available animal models do not exhibit irreversible neurodegeneration, and this is a major obstacle in finding out an effective drug against this disease. Here we delineate a new irreversible model to study PD pathogenesis. The model is based on simple castration of young male mice. Levels of inducible nitric-oxide synthase (iNOS), glial markers (glial fibrillary acidic protein and CD11b), and ?-synuclein were higher in nigra of castrated male mice than normal male mice. On the other hand, after castration, the level of glial-derived neurotrophic factor (GDNF) markedly decreased in the nigra of male mice. Accordingly, castration also induced the loss of tyrosine hydroxylase-positive neurons in the nigra and decrease in tyrosine hydroxylase-positive fibers and neurotransmitters in the striatum. Reversal of nigrostriatal pathologies in castrated male mice by subcutaneous implantation of 5?-dihydrotestosterone pellets validates an important role of male sex hormone in castration-induced nigrostriatal pathology. Interestingly, castration was unable to cause glial activation, decrease nigral GDNF, augment the death of nigral dopaminergic neurons, induce the loss of striatal fibers, and impair neurotransmitters in iNOS(-/-) male mice. Furthermore, we demonstrate that iNOS-derived NO is responsible for decreased expression of GDNF in activated astrocytes. Together, our results suggest that castration induces nigrostriatal pathologies via iNOS-mediated decrease in GDNF. These results are important because castrated young male mice may be used as a simple, toxin-free, and nontransgenic animal model to study PD-related nigrostriatal pathologies, paving the way for easy drug screening against PD. PMID:23744073

Khasnavis, Saurabh; Ghosh, Anamitra; Roy, Avik; Pahan, Kalipada



Chronic Dopamimetic Drug Addiction and Pathologic Gambling in Patients with Parkinson's Disease - Presentation of Four Cases  

Microsoft Academic Search

Parkinson's disease (PD) is characterized by motor and neuropsychiatric features. Within the latter, conditions such as psychosis, obsessive compulsive disorder (OCD), levodopa addiction and pathologic gambling are con- sidered as secondary to the use of dopamimetic drugs. We present four patients with PD who developed clini- cal criteria for levodopa and pathologic gambling addiction, generalized anxiety disorder and OCD. They

Marcos Serrano-Dueńas


Dual-target-directed drugs that block monoamine oxidase B and adenosine A 2A receptors for Parkinson’s disease  

Microsoft Academic Search

Summary  Inadequacies of the current pharmacotherapies to treat Parkinson’s disease (PD) have prompted efforts to identify novel drug\\u000a targets. The adenosine A2A receptor is one such target. Antagonists of this receptor (A2A antagonists) are considered promising agents for the symptomatic treatment of PD. Evidence suggests that A2A antagonists may also have neuroprotective properties that may prevent the development of the dyskinesia

Jacobus P. Petzer; Neal Castagnoli; Michael A. Schwarzschild; Jiang-Fan Chen; Cornelis J. Van der Schyf



What is the best treatment for fluctuating Parkinson’s disease: continuous drug delivery or deep brain stimulation of the subthalamic nucleus?  

Microsoft Academic Search

Motor complications impair quality of life and cause severe disability in patients with advanced Parkinson’s disease (PD).\\u000a Since they are often refractory to medical therapy, interventional therapies have been developed, which can provide a considerable\\u000a reduction of daily off-time and dopaminergic dyskinesias. Continuous dopaminergic drug delivery (CDD) is based on the steady\\u000a stimulation of striatal dopamine receptors by subcutaneous apomorphine

Rüdiger Hilker; Angelo Antonini; Per Odin



Evidence of oligodendrogliosis in MPTP-induced Parkinsonism.  


Aims:? Mice and non-human primates administered with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) represent elective experimental models of Parkinsonism, in which degeneration of the nigro-striatal dopaminergic pathway is associated with prominent neuroinflammation, characterized by activated microglia and astrocytes in both substantia nigra (SN) and striatum. To date, it is unknown whether oligodendrocytes play a role in these events. Methods:? We performed a detailed qualitative and quantitative analysis of oligodendrocyte-associated changes induced by acute and chronic MPTP treatment, in the SN and striatum of mice and macaques, respectively. Oligodendrocytes were immunolabeled by cell-specific markers and analyzed by confocal microscopy. Results:? In both experimental models, MPTP treatment induces an increase in oligodendrocyte cell number and average size, as well as in the total area occupied by this cell type per tissue section, accompanied by evident morphological changes. This multifaceted array of changes, herein referred to as oligodendrogliosis, significantly correlate with the reduction in the level of dopaminergic innervation to the striatum. Conclusions:? This event, associated with early damage of the dopaminergic neuron axons and of the complex striatal circuits of which they are part, may result in an important, although neglected, aspect in the onset and progression of Parkinsonism. © 2012 The Authors. Neuropathology and Applied Neurobiology © 2012 British Neuropathological Society. PMID:22443457

Annese, V; Barcia, C; Ros-Bernal, F; Gómez, A; Ros, C M; De Pablos, V; Fernández-Villalba, E; De Stefano, M E; Herrero, M T



Nicotinic Receptor Agonists Reduce L-DOPA-Induced Dyskinesias in a Monkey Model of Parkinson's Disease.  


Abnormal involuntary movements or dyskinesias are a serious complication of long-term l-DOPA treatment of Parkinson's disease, for which there are few treatment options. Accumulating preclinical data show that nicotine decreases l-DOPA-induced dyskinesias (LIDs), suggesting that it may be a useful antidyskinetic therapy for Parkinson's disease. Here, we investigated whether nicotinic acetylcholine receptor (nAChR) agonists reduced LIDs in nonhuman primates. We first tested the nonselective nAChR agonist 1, 6,7,8,9-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine (varenicline), which offers the advantage that it is approved by the U.S. Food and Drug Administration for use in humans. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys (n = 23) were first administered l-DOPA/carbidopa (10/2.5 mg/kg) twice daily 5 days/week until stably dyskinetic. Oral varenicline (0.03-0.10 mg/kg) decreased LIDs ?50% compared with vehicle-treated monkeys, whereas nicotine treatment (300 µg/ml in drinking water) reduced LIDs by 70% in a parallel group of animals. We next tested the selective ?4?2*/?6?2* nAChR agonist TC-8831 [3-cyclopropylcarbonyl-3,6-diazabicyclo[3.1.1]heptane] on LIDs in the same set of monkeys after a 10-week washout. We also tested TC-8831 in another set of MPTP-lesioned monkeys (n = 16) that were nAChR drug-naďve. Oral TC-8831 (0.03-0.3 mg/kg) reduced LIDs in both sets by 30-50%. After a washout period, repeat TC-8831 dosing led to a greater decline in LIDs (60%) in both sets of monkeys that was similar to the effect of nicotine. Tolerance to any nAChR drug did not develop over the course of the study (3-4 months). NAChR drug treatment did not worsen parkinsonism or cognitive ability. These data suggest that nAChR agonists may be useful for the management of dyskinesias in l-DOPA-treated Parkinson's disease patients. PMID:23902940

Zhang, Danhui; Mallela, Archana; Sohn, David; Carroll, F Ivy; Bencherif, Merouane; Letchworth, Sharon; Quik, Maryka



Drug-induced liver disease.  


Although the year 2001 did not see any prescription drugs withdrawn because of drug-induced liver disease, the US Food and Drug Administration requested that dietary supplements containing comfrey be taken off the market because of the danger of hepatic injury. The Food and Drug Administration remains very involved in the process by which drug-induced liver disease can be detected early in drug development and in the determination of how best to prevent hepatotoxicity after drug approval. A workshop on drug-induced liver disease cosponsored by the Food and Drug Administration, the Pharmaceutical Research and Manufacturers Association, and the American Association for the Study of Liver Diseases was held in Washington, DC, in February 2001, and the resulting white paper outlined several areas for research. A number of agents were newly described as causing various forms of liver injury, and several others had drug-induced liver disease confirmed by additional reports. Several investigators dealt with the difficulties inherent in establishing causality of drug-induced liver disease and the potential negative consequences of wrongly attributing hepatotoxicity to a particular agent. In one recent series, more than half the instances of alleged drug-induced liver disease were found to have other causes, often leading to a delay in the actual diagnosis and appropriate management. Case reports in particular were often misleading. Although several drug assessment scales have been developed, none appears to be foolproof. PMID:17033301

Lewis, James H



Modulation of connexin 43 in rotenone-induced model of Parkinson's disease  

Microsoft Academic Search

Gap junctional communication plays an important role in various models of brain pathology, but the changes of gap junctions in Parkinsonism are still not understood. In this study, we show that a major gap junctional protein, connexin43 (Cx43), in astrocytes is enhanced both in a rat Parkinson's disease (PD) model induced with rotenone, a widely used pesticide that inhibits mitochondrial

A. Kawasaki; T. Hayashi; K. Nakachi; J. E. Trosko; K. Sugihara; Y. Kotake; S. Ohta



Drug-Induced Liver Toxicity  

Center for Drug Evaluation (CDER)

... In the United States, drug-induced liver injury (DILI) is now the leading cause of acute liver failure (ALF), exceeding all other causes combined [see ... More results from


Muscarinic Acetylcholine Receptor Subtypes as Potential Drug Targets for the Treatment of Schizophrenia, Drug Abuse, and Parkinson's Disease  

PubMed Central

The neurotransmitter dopamine plays important roles in modulating cognitive, affective, and motor functions. Dysregulation of dopaminergic neurotransmission is thought to be involved in the pathophysiology of several psychiatric and neurological disorders, including schizophrenia, Parkinson’s disease and drug abuse. Dopaminergic systems are regulated by cholinergic, especially muscarinic, input. Not surprisingly, increasing evidence implicates muscarinic acetylcholine receptor-mediated pathways as potential targets for the treatment of these disorders classically viewed as “dopamine based”. There are five known muscarinic receptor subtypes (M1 to M5). Due to their overlapping expression patterns and the lack of receptor subtype-specific ligands, the roles of the individual muscarinic receptors have long remained elusive. During the past decade, studies with knockout mice lacking specific muscarinic receptor subtypes have greatly advanced our knowledge of the physiological roles of the M1–M5 receptors. Recently, new ligands have been developed that can interact with allosteric sites on different muscarinic receptor subtypes, rather than the conventional (orthosteric) acetylcholine binding site. Such agents may lead to the development of novel classes of drugs useful for the treatment of psychosis, drug abuse, and Parkinson’s disease. The present review highlights recent studies carried out using muscarinic receptor knockout mice and new subtype-selective allosteric ligands to assess the roles of M1, M4, and M5 receptors in various central processes that are under strong dopaminergic control. The outcome of these studies opens new perspectives for the use of novel muscarinic drugs for several severe disorders of the central nervous system.



[Drug-induced diabetes].  


A carbohydrate disturbance or diabetogenic effect may occur even in people with normal metabolism as an undesired side effect with a great number of drugs. According to present nomenclature a distinction should be made between a "decrease of glucose tolerance" and the appearance of a (manifest) "diabetes mellitus." Instead the term "borderline diabetes" is often used in American literature. Particularly with already existing glucose tolerance disturbances, or hereditary disposition, a further deterioration can lead to diabetes mellitus that may not always disappear after discontinued use of the drug. In this context, the glucocorticoids, the saluretics and the oral contraceptives have special clinical interest. In a table are listed several drugs having a minor, or only sporadically observed, or questionably unfavorable influence on glucose tolerance. Some contain diabetogenic toxins and chemical substances that are used for experimental diabetes inducement (in animals). Extensive literature concerning the influence of female sexual hormones or oral contraceptives on the carbohydrate metabolism seems contradictory. Several mechanisms are discussed: peripheral insulin resistance, increased secretion of growth hormones and insulin, increased peripheral insulin decomposition, and inhibition of glucose decomposition via the pentose-phosphatic shunt. Glucose tolerance disturbances caused by oral contraceptives are described by some authors as occurring in 25% to 75% of all cases. Other authors found no or only rarely such an effect. The composition of the test group, the kind of ovulatory inhibitor, and the length of usage period evidently play a great role. Earlier, the estrogens, especially for higher dosages, were attributed a diabetogenic effect. However, lately the gestagens have come more to the fore. After many years of pill usage, a greater incidence of pathological glucose tolerance was registered for combination than for sequential preparations. It would appear that for (younger) diabetics (without late complications) that the most suitable contraceptive should consist of a sequential preparation with a low estrogen admixture (below 50 mg). Which gestagen and which dosage would result in the smallest long-term effect on glucose tolerance remains to be clarified. PMID:2894732

Schatz, H



Clinical Features, Pathophysiology, and Treatment of Levodopa-Induced Dyskinesias in Parkinson's Disease  

PubMed Central

Dyskinetic disorders are characterized by excess of motor activity that may interfere with normal movement control. In patients with Parkinson's disease, the chronic levodopa treatment induces dyskinetic movements known as levodopa-induced dyskinesias (LID). This paper analyzed the pathophysiology, clinical manifestations, pharmacological treatments, and surgical procedures to treat hyperkinetic disorders. Surgery is currently the only treatment available for Parkinson's disease that may improve both parkinsonian motor syndrome and LID. However, this paper shows the different mechanisms involved are not well understood.

Guridi, J.; Gonzalez-Redondo, R.; Obeso, J. A.



Wearing off, dyskinesia, and the use of continuous drug delivery in Parkinson's disease.  


Motor fluctuations (wearing off) and motor complications (dyskinesia) are common features of the long-term treatment of Parkinson's disease (PD). The basis of both is considered to be a reflection of the progression of neuronal degeneration, coupled with the nature of drug treatment used to control motor symptoms. The concept of continuous dopaminergic stimulation has been used to explain both the onset of wearing off and dyskinesia and their avoidance through pharmacologic manipulation. This review focuses on using with the transdermal dopamine agonist, rotigotine, for continuous dopaminergic drug delivery in the treatment of PD. PMID:23931952

Jenner, Peter



The Endotoxin-Induced Neuroinflammation Model of Parkinson's Disease  

PubMed Central

Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra. Although the exact cause of the dopaminergic neurodegeneration remains elusive, recent postmortem and experimental studies have revealed an essential role for neuroinflammation that is initiated and driven by activated microglial and infiltrated peripheral immune cells and their neurotoxic products (such as proinflammatory cytokines, reactive oxygen species, and nitric oxide) in the pathogenesis of PD. A bacterial endotoxin-based experimental model of PD has been established, representing a purely inflammation-driven animal model for the induction of nigrostriatal dopaminergic neurodegeneration. This model, by itself or together with genetic and toxin-based animal models, provides an important tool to delineate the precise mechanisms of neuroinflammation-mediated dopaminergic neuron loss. Here, we review the characteristics of this model and the contribution of neuroinflammatory processes, induced by the in vivo administration of bacterial endotoxin, to neurodegeneration. Furthermore, we summarize the recent experimental therapeutic strategies targeting endotoxin-induced neuroinflammation to elicit neuroprotection in the nigrostriatal dopaminergic system. The potential of the endotoxin-based PD model in the development of an early-stage specific diagnostic biomarker is also emphasized.

Tufekci, Kemal Ugur; Genc, Sermin; Genc, Kursad



Effect of centrophenoxine against rotenone-induced oxidative stress in an animal model of Parkinson's disease.  


Oxidative stress has been implicated in the etiology of Parkinson's disease (PD). The important biochemical features of PD, being profound deficit in dopamine (DA) content, reduced glutathione (GSH), and enhanced lipid peroxidation (LPO) in dopaminergic (DA-ergic) neurons resulting in oxidative stress, mitochondrial dysfunction and apoptosis. Rotenone-induced neurotoxicity is a well acknowledged preclinical model for studying PD in rodents as it produces selective DA-ergic neuronal degeneration. In our previous study, we have shown that chronic administration of rotenone to rats is able to produce motor dysfunction, which increases progressively with rotenone treatment and centrophenoxine (CPH) co-treatment is able to attenuate these motor defects. The present study was carried out to evaluate the antioxidant potential of CPH against rotenone-induced oxidative stress. Chronic administration of rotenone to SD rats resulted in marked oxidative damage in the midbrain region compared to other regions of the brain and CPH co-treatment successfully attenuated most of these changes. CPH significantly attenuated rotenone-induced depletion in DA, GSH and increase in LPO levels. In addition, the drug prevented the increase in nitric oxide (NO) and citrulline levels and also enhanced the activity of catalase and superoxide dismutase (SOD). Histological analysis carried out using hematoxylin and eosin staining has indicated severe damage to mid brain in comparison to cortex and cerebellum and this damage is attenuated by CPH co-treatment. Our results strongly indicate the possible therapeutic potential of centrophenoxine as an antioxidant in Parkinson's disease and other movement disorders where oxidative stress is a key player in the disease process. PMID:19375462

Verma, Ranjeet; Nehru, Bimla



Buspirone improves haloperidol-induced Parkinson disease in mice through 5-HT1A recaptors  

PubMed Central

Background and the purpose of the study The available literatures show that 5-HT1A receptors are widely distributed throughout the basal ganglia, and their activation facilitate dopamine release. Neuroleptic drugs such as haloperidol induce Parkinson-like syndrome through blocking brain D2 receptors. This study aimed to investigate effect of buspirone, a partial agonist of 5HT1A receptor, on motor dysfunctions induced by haloperidol and involvement of 5HT1A receptors in this regard. Methods Study was performed on the male mice weighing 25–30 g. Animals were divided randomly to groups of 10 animals. Motor dysfunction was induced by intraperitoneal (i.p.) injection of haloperidol (1 mg/kg). Catalepsy was assayed by bar-test method 5, 60, 120 and 180 minutes after drug administration and motor imbalance was studied by rotarod test. Results and major conclusion Results showed that buspirone (20 mg/kg, i.p.) decreased significantly haloperidol-induced catalepsy and balance disorder in a dose dependent manner. Furthermore, 8-OH-DPAT (10 mg/kg, i.p.), as an agonist of 5-HT1A receptor, decreased haloperidol-induced catalepsy and balance disorder. The effect of buspirone (20 mg/kg, i.p.) on haloperidol-induced motor disorders was abolished by NAN-190 (10 mg/kg, i.p.), as a 5-HT1A receptor antagonist. From the results it may be concluded that buspirone improves haloperidol-induced catalepsy and balance disorder through activation of 5-HT1A receptors.

Mohajjel Nayebi A, A; Sheidaei, H



Drug-induced lupus erythematosus  

Microsoft Academic Search

Drug-induced lupus erythematosus (DILE) is defined as a lupus-like syndrome temporally related to continuous drug exposure\\u000a which resolves after discontinuation of the offending drug. There are currently no standard diagnostic criteria for DILE and\\u000a the pathomechanisms are still unclear. Similarly to idiopathic lupus, DILE can be diveded into systemic (SLE), subacute cutaneous\\u000a (SCLE) and chronic cutaneous lupus (CCLE). Systemic DILE

Camilla Dalle Vedove; Micol Del Giglio; Donatella Schena; Giampiero Girolomoni



Structural brain plasticity in Parkinson's disease induced by balance training.  


We investigated morphometric brain changes in patients with Parkinson's disease (PD) that are associated with balance training. A total of 20 patients and 16 healthy matched controls learned a balance task over a period of 6 weeks. Balance testing and structural magnetic resonance imaging were performed before and after 2, 4, and 6 training weeks. Balance performance was re-evaluated after ?20 months. Balance training resulted in performance improvements in both groups. Voxel-based morphometry revealed learning-dependent gray matter changes in the left hippocampus in healthy controls. In PD patients, performance improvements were correlated with gray matter changes in the right anterior precuneus, left inferior parietal cortex, left ventral premotor cortex, bilateral anterior cingulate cortex, and left middle temporal gyrus. Furthermore, a TIME × GROUP interaction analysis revealed time-dependent gray matter changes in the right cerebellum. Our results highlight training-induced balance improvements in PD patients that may be associated with specific patterns of structural brain plasticity. In summary, we provide novel evidence for the capacity of the human brain to undergo learning-related structural plasticity even in a pathophysiological disease state such as in PD. PMID:23916062

Sehm, Bernhard; Taubert, Marco; Conde, Virginia; Weise, David; Classen, Joseph; Dukart, Juergen; Draganski, Bogdan; Villringer, Arno; Ragert, Patrick



[A case of parkinsonism induced by an oral contraceptive].  


We report a case of parkinsonism induced by long term administration of an oral contraceptive. A 38-year-old woman complained of easily stumbling, démarche ŕ petit pas and fatiguability in her lower extremities since January, 1991. When examined on April 5, 1991, she explained taking an oral contraceptive for 7 years on her doctor's recommendation after two times artificial abortions. Her facial expression was mask-like and body was bent forward with knee joints flexed and arms flexed at elbow joints. She had frozen gait with inactive pendulousness of the arms. We could find her muscle rigidity in both upper and lower extremities, especially in her right side extremities. A brain MRI finding was lacunar infarction which proton density weighted and T2-weighted MR images showed small patches of high-signal intensities in white matter of the bilateral frontal lobes and in left periventricular white matter. Her symptoms improved after stopping administration of the oral contraceptive and starting combination therapy with nicergoline and bromocriptine. She had some leg fatiguability at the onset of her next menstruation in May, but it was much less than her previous condition. When her menstruation terminated, those symptoms disappeared and it was possible to stop the administration of bromocriptine and nicergoline, and her symptoms have improved. PMID:1567736

Yasui, M; Kihira, T; Ota, K; Funahashi, K; Komai, N



Why Do We Need Multifunctional Neuroprotective and Neurorestorative Drugs for Parkinson's and Alzheimer's Disorders?  

PubMed Central

Parkinson’s disease (PD) and Alzheimer’s disease (AD) are severe neurodegenerative disorders, with no drugs that are currently approved to prevent the neuronal cell loss characteristic in brains of patients suffering from PD and AD, and all drug treatments are symptomatic and monomodal in their action. Due to the complex pathophysiology, including a cascade of neurotoxic molecular events that result in neuronal death and predisposition to depression and eventual dementia, and etiology of these disorders, an innovative approach towards neuroprotection or neurorestoration (neurorescue) is the development and use of multifunctional pharmaceuticals which can act at different brain regions and neurons. Such drugs target an array of pathological pathways, each of which is believed to contribute to the cascades that ultimately lead to neuronal cell death. In this short review, we discuss examples of novel multifunctional ligands that may have potential as neuroprotective-neurorestorative therapeutics in PD and AD, some of which are under development. The compounds discussed originate from synthetic chemistry as well as from natural sources.

Youdim, Moussa B. H.



[Drug-induced liver injury].  


Drug-induced liver injury represents the principal cause of acute liver failure and orthotopic liver transplantation in western country. A very large number of different drugs and medicinal herbs has been associated with liver injury but just for few of them we know the process that causes liver disease. All the people which ingest a large number of drugs present a risk of developing liver injury. Diagnosis is very difficult because a specific biomarker of damage is absent and the clinical picture is common to other liver diseases. A therapeutic approach is efficacy only in few cases. When a drug-induced liver injury is suspected, cessation of the drug is the first step in their management. PMID:22430754

Abenavoli, Ludovico; Libri, Emanuela; Bosco, Domenico; Gallo, Dionisio; Luzza, Francesco



Drug-Induced Depression  

Microsoft Academic Search

Background: Certain drugs may contribute to the etiology of depressive symptoms and depressive disorders. The objective of this review is to critically appraise the literature concerned with these potential etiological associations. Method: The review was based on papers uncovered in electronic literature searches using Medline, Psychlit and Psychological Abstracts. Statistical power calculations were used to assist in the interpretation of

Scott B. Patten; Edgar J. Love



Multi target neuroprotective and neurorestorative anti-Parkinson and anti-Alzheimer drugs ladostigil and m30 derived from rasagiline.  


Present anti-PD and -AD drugs have limited symptomatic activity and devoid of neuroprotective and neurorestorative property that is needed for disease modifying action. The complex pathology of PD and AD led us to develop several multi-target neuroprotective and neurorestorative drugs with several CNS targets with the ability for possible disease modifying activity. Employing the pharmacophore of our anti-parkinson drug rasagiline (Azilect, N-propagrgyl-1-R-aminoindan), we have developed a series of novel multi-functional neuroprotective drugs (A) [TV-3326 (N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate)], with both cholinesterase-butyrylesterase and brain selective monoamine-oxidase (MAO) A/B inhibitory activities and (B) the iron chelator-radical scavenging-brain selective monoamine oxidase (MAO) A/B inhibitor and M30 possessing the neuroprotective and neurorescuing propargyl moiety of rasagiline, as potential treatment of AD, DLB and PD with dementia. Another series of multi-target drugs (M30, HLA-20 series) which are brain permeable iron chelators and potent selective brain MAO inhibitors were also developed. These series of drugs have the ability of regulating and processing amyloid precursor protein (APP) since APP and alpha-synuclein are metaloproteins (iron-regulated proteins), with an iron responsive element 5"UTR mRNA similar to transferring and ferritin. Ladostigil inhibits brain acetyl and butyrylcholinesterase in rats after oral doses. After chronic but not acute treatment, it inhibits MAO-A and -B in the brain. Ladostigil acts like an anti-depressant in the forced swim test in rats, indicating a potential for anti-depressant activity. Ladostigil prevents the destruction of nigrostriatal neurons induced by infusion of neurotoxin MPTP in mice. The propargylamine moiety of ladostigil confers neuroprotective activity against cytotoxicity induced by ischemia and peroxynitrite in cultured neuronal cells. The multi-target iron chelator M30 has all the properties of ladostigil and similar neuroprotective activity to ladostigil, but is not a ChE inhibitor. M30 has a neurorestorative activity in post-lesion of nigrostriatal dopamine neurons in MPTP, lacatcystin and 6-hydroxydopamine animal models of PD. The neurorestorative activity is related to the ability of the drug to activate hypoxia inducing factor (HIF) which induces the production of such neurotrophins as brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF) and erythropoietin as well as glia-derived neurotrophic factor (GDNF). The unique multiple actions of ladostigil and M30 make the potentially useful drugs for the treatment of dementia with Parkinsonian-like symptoms and depression. PMID:23585716

Youdim, Moussa B H



Dopamine Induced Neurodegeneration in a PINK1 Model of Parkinson's Disease  

PubMed Central

Background Parkinson's disease is a common neurodegenerative disease characterised by progressive loss of dopaminergic neurons, leading to dopamine depletion in the striatum. Mutations in the PINK1 gene cause an autosomal recessive form of Parkinson's disease. Loss of PINK1 function causes mitochondrial dysfunction, increased reactive oxygen species production and calcium dysregulation, which increases susceptibility to neuronal death in Parkinson's disease. The basis of neuronal vulnerability to dopamine in Parkinson's disease is not well understood. Methodology We investigated the mechanism of dopamine induced cell death in transgenic PINK1 knockout mouse neurons. We show that dopamine results in mitochondrial depolarisation caused by mitochondrial permeability transition pore (mPTP) opening. Dopamine-induced mPTP opening is dependent on a complex of reactive oxygen species production and calcium signalling. Dopamine-induced mPTP opening, and dopamine-induced cell death, could be prevented by inhibition of reactive oxygen species production, by provision of respiratory chain substrates, and by alteration in calcium signalling. Conclusions These data demonstrate the mechanism of dopamine toxicity in PINK1 deficient neurons, and suggest potential therapeutic strategies for neuroprotection in Parkinson's disease.

Yao, Zhi; Duchen, Michael R.; Wood, Nicholas W.; Abramov, Andrey Y.



Drug-induced steatohepatitis.  


Nonalcoholic fatty liver disease (NAFLD) is currently the most common cause of chronic liver disease in the United States. The term NALFD was first used by Ludwig in 1980 to describe the presence of hepatic steatosis and steatohepatitis in a series of patients with no identifiable cause. Since then, our insight into the pathogenesis of NAFLD has expanded significantly. We now know that NAFLD is closely related to metabolic syndrome and chronic low-grade inflammation. In the following review, the authors summarize the current evidence about drugs that lead to hepatic steatosis and steatohepatitis and pathogenic mechanisms thereof. PMID:24099016

Patel, Vaishali; Sanyal, Arun J



[Antiepileptic drug-induced encephalopathy].  


The clinical features of an antiepileptic drug-induced encephalopathy (ADE) are confusion, reduction of vigilance, neurological deficits or an increase of the seizure frequency. In the electroencephalogram a general slowing or epileptic discharges are found. Characteristic are non-toxic blood levels of the antiepileptic drugs. So far an ADE was reported under phenytoin, carbamazepine or valproatic acid (valproate) therapy. More seldom, an ADE has been described after the intake of vigabatrine, lamotrigine und topiramate. Potential pathogenic mechanisms of AED are hyperammonemia, intrinsic effects on cerebral receptors, drug interactions, hepatic enzyme interactions, metabolic reasons or paradoxical proconvulsive effects of antiepileptic drugs. The medicamentous therapy consists of an immediate discontinuation of the antiepileptic drug. PMID:20927690

Hansen, N; Finzel, M; Block, F



Drug Induced Interstitial Lung Disease  

PubMed Central

With an increasing number of therapeutic drugs, the list of drugs that is responsible for severe pulmonary disease also grows. Many drugs have been associated with pulmonary complications of various types, including interstitial inflammation and fibrosis, bronchospasm, pulmonary edema, and pleural effusions. Drug-induced interstitial lung disease (DILD) can be caused by chemotherapeutic agents, antibiotics, antiarrhythmic drugs, and immunosuppressive agents. There are no distinct physiologic, radiographic or pathologic patterns of DILD, and the diagnosis is usually made when a patient with interstitial lung disease (ILD) is exposed to a medication known to result in lung disease. Other causes of ILD must be excluded. Treatment is avoidance of further exposure and systemic corticosteroids in patients with progressive or disabling disease.

Schwaiblmair, Martin; Behr, Werner; Haeckel, Thomas; Markl, Bruno; Foerg, Wolfgang; Berghaus, Thomas



Curcumin reduces ?-synuclein induced cytotoxicity in Parkinson's disease cell model  

Microsoft Academic Search

BACKGROUND: Overexpression and abnormal accumulation of aggregated ?-synuclein (?S) have been linked to Parkinson's disease (PD) and other synucleinopathies. ?S can misfold and adopt a variety of morphologies but recent studies implicate oligomeric forms as the most cytotoxic species. Both genetic mutations and chronic exposure to neurotoxins increase ?S aggregation and intracellular reactive oxygen species (ROS), leading to mitochondrial dysfunction

Min S Wang; Shanta Boddapati; Sharareh Emadi; Michael R Sierks



Drug-Induced Endocrine Autoimmunity  

Microsoft Academic Search

\\u000a Drug-induced autoimmune syndromes have been recognized for a long time and their frequency and complexity have increased in\\u000a recent years. Many of these conditions are associated with autoantibodies that have been classically defined as limited to\\u000a idiopathic disease states. Several medications are known to induce endocrine autoimmunity in genetically predisposed individuals,\\u000a but the mechanisms to which they owe this effect

Paolo Pozzilli; Rocky Strollo; Nicola Napoli


Continuous drug delivery in early- and late-stage Parkinson's disease as a strategy for avoiding dyskinesia induction and expression.  


The treatment of the motor symptoms of Parkinson's disease (PD) is dependent on the use of dopamine replacement therapy in the form of L: -dopa and dopamine agonist drugs. However, the development of dyskinesia (chorea, dystonia, athetosis) can become treatment limiting. The initiation of dyskinesia involves a priming process dependent on the presence of nigral dopaminergic cell loss leading to alterations in basal ganglia function that underlie the expression of involuntary movements following the administration of each drug dose. Once established, dyskinesia is difficult to control and it is even more difficult to reverse the priming process. Dyskinesia is more commonly induced by L: -dopa than by dopamine agonist drugs. This has been associated with the short duration of L: -dopa causing pulsatile stimulation of postsynaptic dopamine receptors compared to the longer acting dopamine agonists that cause more continuous stimulation. As a result, the concept of continuous dopaminergic stimulation (CDS) has arisen and has come to dominate the strategy for treatment of early PD. However, CDS has flaws that have led to the general acceptance that continuous drug delivery (CDD) is key to the successful treatment of PD. Studies in both experimental models of PD and in clinical trials have shown CDD to improve efficacy, but reduce dyskinesia induction, and to reverse established involuntary movements. Two key clinical strategies currently address the concept of CDD: (1) in early-, mid- and late-stage PD, transdermal administration of rotigotine provides 24 h of drug delivery; (2) in late-stage PD, the constant intraduodenal administration of L: -dopa is utilized to improve control of motor symptoms and to diminish established dyskinesia. This review examines the rationale for CDD and explores the clinical benefit of using such a strategy for the treatment of patients with PD. PMID:21881838

Jenner, P; McCreary, A C; Scheller, D K A



Decreased striatal dopamine transporter binding assessed with [ 123 I] FP-CIT in first-episode schizophrenic patients with and without short-term antipsychotic-induced parkinsonism  

Microsoft Academic Search

Rationale  Drug-induced parkinsonism (DIP) is one of the main causes of treatment drop-out in schizophrenic patients causing a high incidence\\u000a of relapse that leads patients to a bad clinical prognosis. The dopaminergic nigrostriatal pathway is involved in the movement\\u000a control, so the study of the dopamine transporter (DAT) could be of great value to determine its implication in the appearance\\u000a of

Jose J. Mateos; Francisco Lomeńa; Eduardo Parellada; Emili Fernandez; Javier Pavia; Alberto Prats; Francisca Pons; Miquel Bernardo



Drugs induced pulmonary arterial hypertension.  


Pulmonary arterial hypertension (PAH) is a rare disorder characterized by progressive obliteration of the pulmonary microvasculature, resulting in elevated pulmonary vascular resistance and premature death. According to the current classification, PAH can be associated with exposure to certain drugs or toxins, particularly appetite suppressant drugs, such as aminorex, fenfluramine derivatives and benfluorex. These drugs have been confirmed to be risk factors for PAH and were withdrawn from the market. The supposed mechanism is an increase in serotonin levels, which was demonstrated to act as a growth factor for the pulmonary arterial smooth muscle cells. Amphetamines, phentermine and mazindol were less frequently used but are also considered as possible risk factors for PAH. Dasatinib, a dual Src/Abl kinase inhibitor, used in the treatment of chronic myelogenous leukaemia was associated with cases of severe PAH, in part reversible after its withdrawal. Recently several studies raised the potential endothelial dysfunction that could be induced by interferon, and few cases of PAH have been reported with interferon therapy. Other possible risk factors for PAH include: nasal decongestants, like phenylpropanolamine, dietary supplement - L-Tryptophan, selective serotonin reuptake inhibitors, pergolide and other drugs that could act on 5HT2B receptors. Interestingly, PAH remains a rare complication of these drugs, suggesting possible individual susceptibility and further studies are needed to identify patients at risk of drugs induced PAH. PMID:23972547

Seferian, Andrei; Chaumais, Marie-Camille; Savale, Laurent; Günther, Sven; Tubert-Bitter, Pascale; Humbert, Marc; Montani, David



Anti-Parkinson botanical Mucuna pruriens prevents levodopa induced plasmid and genomic DNA damage.  


Levodopa is considered the 'gold standard' for the treatment of Parkinson's disease. However, a serious concern is dyskinesia and motor fluctuation that occurs after several years of use. In vitro experiments have shown that in the presence of divalent copper ions, levodopa may induce intense DNA damage. Mucuna pruriens cotyledon powder (MPCP) has shown anti-parkinson and neuroprotective effects in animal models of Parkinson's disease that is superior to synthetic levodopa. In the present study two different doses of MPCP protected both plasmid DNA and genomic DNA against levodopa and divalent copper-induced DNA strand scission and damage. It exhibited chelation of divalent copper ions in a dose-dependent manner. The copper chelating property may be one of the mechanisms by which MPCP exerts its protective effects on DNA. PMID:17622977

Tharakan, Binu; Dhanasekaran, Muralikrishnan; Mize-Berge, Janna; Manyam, Bala V



"Cutaneous adverse drug reactions" are not always drug-induced.  


Cutaneous adverse drug reactions present as many different clinical symptoms which may be induced by triggers other than drugs. This review focuses on the non-drug causes of fixed "drug" eruptions, acute generalized erythematous pustulosis (AGEP), "drug" reactions with eosinophilia and systemic symptoms (DRESS) and Stevens-Johnson syndrome/toxic epidermal necrolysis (TEN), which may be induced by foods, xenobiotics, venoms etc... PMID:24007777

Raison-Peyron, Nadia



Antagonism of haloperidol-induced swim impairment in L-dopa and caffeine treated mice: a pre-clinical model to study Parkinson's disease.  


Parkinson's disease (PD) exhibits symptoms of motor dysfunction such as tremor, akinesia and rigidity. Agents that selectively disrupt or destroy catecholaminergic systems, such as reserpine, methamphetamine, 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine, have been used to develop PD models and to study the animal behavior like catalepsy, akinesia, swim-test, etc. The major apprehension while working with these chemicals is their irreversible neuro-toxic effect. Haloperidol is a classical antipsychotic drug, which produces extra-pyrimidal Parkinson's symptoms (EPS). Measuring catalepsy and akinesia in the treated mice monitored the haloperidol-induced EPS. Alternatively, swimming disability was tested as a new parameter to monitor haloperidol-induced EPS. The results showed that the restoration of swimming disability in haloperidol-induced L-dopa and caffeine pre-treated mice could be used as pre-clinical model to study PD. PMID:19146880

Luthra, Pratibha Mehta; Barodia, Sandeep Kumar; Raghubir, Ram



Pramipexole- and methamphetamine-induced reward-mediated behavior in a rodent model of Parkinson's disease and controls.  


Pramipexole (PPX) is a dopamine agonist that is FDA-approved for treatment of motor dysfunction in Parkinson's disease and restless leg syndrome. In a subpopulation of treated patients, PPX can lead to impulsive-compulsive disorders including behavioral addictions and dopamine dysregulation syndrome, a phenomenon that mirrors drug addiction. Regardless of this clinical picture, the capacity of PPX to regulate reward-mediated behaviors remains unclear and has not been evaluated in an animal model of Parkinson's disease. To fill this gap, we examined the rewarding potential of PPX in parkinsonian-like rats using conditioned place preference (CPP) and also evaluated associated motor behaviors. Methamphetamine (meth) and saline served as positive and negative controls, respectively. To model Parkinson's disease, the neurotoxin 6-OHDA was injected bilaterally into the dorsolateral striatum. The resulting lesions were verified functionally using a forelimb adjusting step and post mortem immunohistochemical staining of striatal tyrosine hydroxylase. Three pairings of meth (1mg/kg, ip), paired with a unique context, induced CPP in both 6-OHDA-treated and sham-operated rats; saline pairings had no effect. Three pairings of (±)PPX at 2mg/kg ip (equal to 1mg/kg of the active racimer) induced CPP in 6-OHDA-treated rats, but a higher dose (4 mg/kg, ip (±)PPX) was needed to induce CPP in sham rats. In all rats, acute administration of 2mg/kg (±)PPX decreased locomotor activity; the behavior was normalized by the third (±)PPX administration. In summary, these findings reveal that (±)PPX has motor and rewarding effects and suggest the parkinsonian brain state may be more sensitive to the rewarding, but not motoric effects. PMID:22727039

Riddle, J L; Rokosik, S L; Napier, T C



Effect of centrophenoxine against rotenone-induced oxidative stress in an animal model of Parkinson's disease  

Microsoft Academic Search

Oxidative stress has been implicated in the etiology of Parkinson's disease (PD). The important biochemical features of PD, being profound deficit in dopamine (DA) content, reduced glutathione (GSH), and enhanced lipid peroxidation (LPO) in dopaminergic (DA-ergic) neurons resulting in oxidative stress, mitochondrial dysfunction and apoptosis. Rotenone-induced neurotoxicity is a well acknowledged preclinical model for studying PD in rodents as it

Ranjeet Verma; Bimla Nehru



Characterization of spontaneous Parkinsonism in drug-naive patients with nonaffective psychotic disorders.  


Spontaneous Parkinsonism (SP) in schizophrenia-related disorders is poorly characterized. The objective of this study was to examine the concordance and clinical validity of alternative definitions of SP in patients with nonaffective psychotic disorders. Two-hundred drug-naive patients with nonaffective psychotic disorders were examined for core parkinsonian signs, including bradykinesia, rigidity, and tremor, and diagnosed of SP according to the Simpson-Angus Scale (SAS) cutoff criterion, the UK Parkinson's disease brain bank (UKPDBB) criteria, the National Institute of Neurological Disorders and Stroke (NINDS) criteria, and criteria requiring the presence of all three core features (full syndrome criteria). Parkinsonian signs and criteria were examined in relation to a number of relevant clinical variables. The most frequent sign was rigidity (33.5%) followed by bradykinesia (16%) and tremor (12%). The prevalence rate of SP according to the SAS cutoff criterion, the UKPDBB criteria, the NINDS criteria for possible and probable SP, and the full syndrome criteria were 20.5, 13, 25.5, 18.5, and 4%, respectively. Bradykinesia was specifically related to negative symptoms, rigidity to neurological soft signs, and tremor to dyskinetic movements. The set of criteria showing more associations with clinical variables were the NINDS criteria for probable SP. Patients fulfilling these criteria had higher ratings for poor premorbid adjustment, negative symptoms, dyskinesia, neurological soft signs, and poor global treatment response than those without that diagnosis. The NINDS criteria for probable SP, i.e., presence of any two of the three core parkinsonian signs, seem to be the most suitable for clinical and research purposes. PMID:21626260

Peralta, Victor; Basterra, Virginia; Campos, Maria S; de Jalón, Elena García; Moreno-Izco, Lucía; Cuesta, Manuel J



Symptomatic Characteristics of Parkinsonism and the Width of Substantia nigra pars compacta on MRI According to Ischemic Changes in the Putamen and Cerebral White Matter: Implications for the Diagnosis of Vascular Parkinsonism  

Microsoft Academic Search

To investigate the significance of vascular lesions as a cause of secondary parkinsonism, we analyzed the symptomatic characteristics, the width of the substantia nigra pars compacta (SNpc) on MRI and the responsiveness to L-dopa in 227 parkinsonian cases, excluding those with drug-induced parkinsonism and neurodegenerative diseases other than idiopathic Parkinson’s disease (IPD). They were classified into those without a significant

Hideo Tohgi; Satoshi Takahashi; Takashi Abe; Kimiaki Utsugisawa



Gender differences in non-motor symptoms in early, drug naďve Parkinson's disease.  


Gender differences in brain structure and function may lead to differences in the clinical expression of neurological diseases, including Parkinson's disease (PD). Few studies reported gender-related differences in the burden of non-motor symptoms (NMS) in treated PD patients, but this matter has not been previously explored in drug-naďve PD patients. This study is to assess gender differences in the prevalence of NMS in a large sample of early, drug-naďve PD patients compared with age and sex-matched healthy controls. Two hundred early, drug-naďve PD patients and ninety-three age and sex-matched healthy controls were included in the study. Frequency of NMS was evaluated by means of the Non-Motor Symptoms Questionnaire. The difference in gender distribution of NMS was evaluated with the ? (2) exact test; multiple comparisons were corrected with the Benjamini-Hochberg method. Male PD patients complained of problems having sex and taste/smelling difficulties significantly more frequently than female PD patients. Furthermore, men with PD complained more frequently of dribbling, sadness/blues, loss of interest, anxiety, acting during dreams, and taste/smelling difficulties as compared to healthy control men, while female PD patients reported more frequently loss of interest and anxiety as compared with healthy control women. This study shows specific sex-related patterns of NMS in drug-naďve PD. In contrast with previous data, female PD patients did not present higher prevalence of mood symptoms as compared to male PD patients. Comparison with healthy controls showed that some NMS classically present in premotor and early stage of disease (i.e., acting out during dreams, taste/smelling difficulties) are more frequent in male than in female patients. PMID:23989344

Picillo, Marina; Amboni, Marianna; Erro, Roberto; Longo, Katia; Vitale, Carmine; Moccia, Marcello; Pierro, Angela; Santangelo, Gabriella; De Rosa, Anna; De Michele, Giuseppe; Santoro, Lucio; Orefice, Giuseppe; Barone, Paolo; Pellecchia, Maria Teresa



Safinamide: from molecular targets to a new anti-Parkinson drug.  


Ideal treatment in Parkinson's disease (PD) aims at relieving symptoms and slowing disease progression. Of all remedies, levodopa remains the most effective for symptomatic relief, but the medical need for neuroprotectant drugs is still unfulfilled. Safinamide, currently in phase III clinical trials for the treatment of PD, is a unique molecule with multiple mechanisms of action and a very high therapeutic index. It combines potent, selective, and reversible inhibition of MAO-B with blockade of voltage-dependent Na+ and Ca2+ channels and inhibition of glutamate release. Safinamide has neuroprotective and neurorescuing effects in MPTP-treated mice, in the rat kainic acid, and in the gerbil ischemia model. Safinamide potentiates levodopa-mediated increase of DA levels in DA-depleted mice and reverses the waning motor response after prolonged levodopa treatment in 6-OHDA-lesioned rats. Safinamide has excellent bioavailability, linear kinetics, and is suitable for once-a-day administration. Therefore, safinamide may be used in PD to reduce l-dopa dosage and also represents a valuable therapeutic drug to test disease-modifying potential. PMID:17030736

Caccia, C; Maj, R; Calabresi, M; Maestroni, S; Faravelli, L; Curatolo, L; Salvati, P; Fariello, R G



Region-Specific Protein Abundance Changes in the Brain of MPTP-induced Parkinson’s Disease Mouse Model  

SciTech Connect

Parkinson’s disease (PD) is characterized by dopaminergic neurodegeneration in the nigrostriatal region of the brain; however, the neurodegeneration extends well beyond dopaminergic neurons. To gain a better understanding of the molecular changes relevant to PD, we applied two-dimensional LC-MS/MS to comparatively analyze the proteome changes in four brain regions (striatum, cerebellum, cortex, and the rest of brain) using a MPTP-induced PD mouse model with the objective to identify nigrostriatal-specific and other region-specific protein abundance changes. The combined analyses resulted in the identification of 4,895 non-redundant proteins with at least two unique peptides per protein. The relative abundance changes in each analyzed brain region were estimated based on the spectral count information. A total of 518 proteins were observed with significant MPTP-induced changes across different brain regions. 270 of these proteins were observed with specific changes occurring either only in the striatum and/or in the rest of the brain region that contains substantia nigra, suggesting that these proteins are associated with the underlying nigrostriatal pathways. Many of the proteins that exhibit significant abundance changes were associated with dopamine signaling, mitochondrial dysfunction, the ubiquitin system, calcium signaling, the oxidative stress response, and apoptosis. A set of proteins with either consistent change across all brain regions or with changes specific to the cortex and cerebellum regions were also detected. One of the interesting proteins is ubiquitin specific protease (USP9X), a deubiquination enzyme involved in the protection of proteins from degradation and promotion of the TGF-? pathway, which exhibited altered abundances in all brain regions. Western blot validation showed similar spatial changes, suggesting that USP9X is potentially associated with neurodegeneration. Together, this study for the first time presents an overall picture of proteome changes underlying both nigrostriatal pathways and other brain regions potentially involved in MPTP-induced neurodegeneration. The observed molecular changes provide a valuable reference resource for future hypothesis-driven functional studies of PD.

Zhang, Xu; Zhou, Jianying; Chin, Mark H.; Schepmoes, Athena A.; Petyuk, Vladislav A.; Weitz, Karl K.; Petritis, Brianne O.; Monroe, Matthew E.; Camp, David G.; Wood, Stephen A.; Melega, William P.; Bigelow, Diana J.; Smith, Desmond J.; Qian, Weijun; Smith, Richard D.



Drug-induced psychiatric disorders and their management.  


Psychiatric disorders induced by drugs are of most concern when they occur in the context of therapeutic use of a drug. Such iatrogenic psychiatric disturbances may interfere considerably with the treatment of the primary illness and may cause concern to patients, their relatives and the medical staff. Because many drugs are often used simultaneously in seriously ill patients, it may be difficult to be sure which drug may have been responsible. The best procedure is to remove those drugs which are most probable causes of the psychiatric disturbances as well as any drugs that are not truly essential for the treatment of the patient. Problems involved in evaluating the relationship between use of drugs and psychiatric disorders are considerable. Many reports are isolated cases and the denominators which might provide some idea of the potential risk are unknown. Many relationships are still controversial, such as the association of depression with sedatives, antihypertensives and oral contraceptives. Areas of uncertainty are great. Psychomotor impairment may be caused by a drug that can alter consciousness, or any drugs that can produce more delineated psychiatric syndromes. Sedative drugs are those most commonly associated with psychomotor impairment, and may include psychotherapeutic drugs, sedative antihistamines, narcotic analgesics and, of course, the widely used social drug, alcohol. Delirious states are most often associated with drugs that possess central anticholinergic actions. These include not only drugs clearly identified as anticholinergics, but also tricyclic antidepressants and anti-Parkinson drugs. Cimetidine, which is often used parenterally in seriously ill patients, is also a prominent cause. Delirium is most often seen in elderly patients and in those who have received rather large doses of drugs. The association of schizophrenic-like psychoses with dopaminomimetic drugs tends to support the prevailing dopamine hypothesis of schizophrenia. Levodopa, the dopamine precursor, and bromocriptine, a direct dopamine agonist, are examples of such relationships. Abuse of social drugs has also been thought to provide a useful model of schizophrenia. Hallucinogens are probably a rather poor model, abuse of amphetamines may provide a better model, and possibly the best is the psychotic state elicited by phencyclidine. Manic reactions are clinically difficult to differentiate from schizophrenic-like psychoses and are often produced by similar drugs. Corticosteroids may produce either manic or schizophrenic-like disorders, as well as occasionally confusion and depression.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:3540520

Hollister, L E


Novel neuroprotective mechanisms of pramipexole, an anti-Parkinson drug, against endogenous dopamine-mediated excitotoxicity  

Microsoft Academic Search

Parkinson disease is characterized by selective degeneration of mesencephalic dopaminergic neurons, and endogenous dopamine may play a pivotal role in the degenerative processes. Using primary cultured mesencephalic neurons, we found that glutamate, an excitotoxin, caused selective dopaminergic neuronal death depending on endogenous dopamine content. Pramipexole, a dopamine D2\\/D3 receptor agonist used clinically in the treatment of Parkinson disease, did not

Yasuhiko Izumi; Hideyuki Sawada; Noriyuki Yamamoto; Toshiaki Kume; Hiroshi Katsuki; Shun Shimohama; Akinori Akaike



Neuroprotective activity of Stereospermum suaveolens DC against 6-OHDA induced Parkinson's disease model  

PubMed Central

Objectives: To evaluate the neuroprotective effect of Stereospermum suaveolens DC on 6-hydroxy dopamine induced Parkinson's disease model. Materials and Methods: The study was conducted on Sprague-Dawley rats where parkinson's disease was induced by producing the striatal 6-hydroxy dopamine lesions. The test animals received methanolic extract of Stereospermum suaveolens at dose of 125, 250 and 500 mg/kg for 42 days. Behavioral assessment, spontaneous locomotor activity and muscular coordination were studied. Antioxidant levels, striatal infraction area were assessed and histopathological studies were carried out. Results: The Stereospermum suaveolens DC methanolic extract showed significant dose dependent increase in behavioral activity, improved muscular coordination. Significant reduction of lipid peroxidation (LPO), increased antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT) and non-enzymatic activity of glutathione (GSH) and total thiol levels in extract treated groups was observed in test groups as compared to control group. Striatal infarction area was significantly reduced in extract treated groups as compared to control group. Conclusion: The methanolic extract of Stereospermum suaveolens DC showed neuroprotective activity against 6-hydroxy dopamine induced Parkinson's disease in rats.

Shalavadi, M. H.; Chandrashekhar, V. M.; Avinash, S. P.; Sowmya, C.; Ramkishan, A.



Dopamine-Induced Nonmotor Symptoms of Parkinson's Disease  

PubMed Central

Nonmotor symptoms of Parkinson's disease (PD) may emerge secondary to the underlying pathogenesis of the disease, while others are recognized side effects of treatment. Inevitably, there is an overlap as the disease advances and patients require higher dosages and more complex medical regimens. The non-motor symptoms that emerge secondary to dopaminergic therapy encompass several domains, including neuropsychiatric, autonomic, and sleep. These are detailed in the paper. Neuropsychiatric complications include hallucinations and psychosis. In addition, compulsive behaviors, such as pathological gambling, hypersexuality, shopping, binge eating, and punding, have been shown to have a clear association with dopaminergic medications. Dopamine dysregulation syndrome (DDS) is a compulsive behavior that is typically viewed through the lens of addiction, with patients needing escalating dosages of dopamine replacement therapy. Treatment side effects on the autonomic system include nausea, orthostatic hypotension, and constipation. Sleep disturbances include fragmented sleep, nighttime sleep problems, daytime sleepiness, and sleep attacks. Recognizing the non-motor symptoms that can arise specifically from dopamine therapy is useful to help optimize treatment regimens for this complex disease.

Park, Ariane; Stacy, Mark



Neuromelanin Activates Microglia and Induces Degeneration of Dopaminergic Neurons: Implications for Progression of Parkinson’s Disease  

Microsoft Academic Search

In Parkinson’s disease (PD), there is a progressive loss of neuromelanin (NM)-containing dopamine neurons in substantia nigra\\u000a (SN) which is associated with microgliosis and presence of extracellular NM. Herein, we have investigated the interplay between\\u000a microglia and human NM on the degeneration of SN dopaminergic neurons. Although NM particles are phagocytized and degraded\\u000a by microglia within minutes in vitro, extracellular

Wei Zhang; Kester Phillips; Albert R. Wielgus; Jie Liu; Alberto Albertini; Fabio A. Zucca; Rudolph Faust; Steven Y. Qian; David S. Miller; Colin F. Chignell; Belinda Wilson; Vernice Jackson-Lewis; Serge Przedborski; Danielle Joset; John Loike; Jau-Shyong Hong; David Sulzer; Luigi Zecca



Effects of exercise induced oxidative stress on glutathione levels in Parkinson’s disease on and off medication  

Microsoft Academic Search

Resting plasma glutathione (GSH) levels are lower in individuals with Parkinson’s disease (PD) than any other neurological\\u000a condition. Medications used to treat PD have also been shown to further decrease this depletion. Acute exercise has been shown\\u000a to be an effective tool to produce oxidative stress in other populations as reflected in lowering levels of GSH. The purpose\\u000a of this

Ahmed Elokda; Joanne DiFrancisco-Donoghue; Eric M. Lamberg; William G. Werner



Drug-induced macular edema.  


Macular edema constitutes a serious pathologic entity of ophthalmology resulting in vision loss with a remarkable impact on the quality of life of patients. It is the final common pathway of various systemic diseases and underlying intraocular conditions, with diabetes mellitus being the most frequent cause. Other causes include venous occlusive disease, intraocular surgery, and inflammatory conditions of the posterior segment of the eye. Macular edema is a recognized side effect of various systemic and local medications and requires special consideration among ophthalmologists and other clinicians. Recently, antidiabetic thiazolidinediones have been implicated in the development of macular edema, and a review of the English literature revealed that other systemically administered drugs like fingolimod, recently approved for relapsing forms of multiple sclerosis, the anticancer agents tamoxifen and the taxanes, as well as niacin and interferons have been reported to cause macular edema. Ophthalmologic pharmaceutical agents, like prostaglandin analogs, epinephrine, timolol, and ophthalmic preparation preservatives have also been reported to cause macular edema as an adverse event. The purpose of this article is to provide a short, balanced overview of the available evidence in this regard. The available data and the possible pathophysiologic mechanisms leading to the development of macular edema are discussed. Possible therapeutic strategies for drug-induced macular edema are also proposed. PMID:23640687

Makri, Olga E; Georgalas, Ilias; Georgakopoulos, Constantine D



Environmental risk factors for Parkinson's disease and parkinsonism: the Geoparkinson study  

PubMed Central

Objective To investigate the associations between Parkinson's disease and other degenerative parkinsonian syndromes and environmental factors in five European countries. Methods A case–control study of 959 prevalent cases of parkinsonism (767 with Parkinson's disease) and 1989 controls in Scotland, Italy, Sweden, Romania and Malta was carried out. Cases were defined using the United Kingdom Parkinson's Disease Society Brain Bank criteria, and those with drug?induced or vascular parkinsonism or dementia were excluded. Subjects completed an interviewer?administered questionnaire about lifetime occupational and hobby exposure to solvents, pesticides, iron, copper and manganese. Lifetime and average annual exposures were estimated blind to disease status using a job?exposure matrix modified by subjective exposure modelling. Results were analysed using multiple logistic regression, adjusting for age, sex, country, tobacco use, ever knocked unconscious and family history of Parkinson's disease. Results Adjusted logistic regression analyses showed significantly increased odds ratios for Parkinson's disease/parkinsonism with an exposure–response relationship for pesticides (low vs no exposure, odds ratio (OR)?=?1.13, 95% CI 0.82 to 1.57, high vs no exposure, OR?=?1.41, 95% CI 1.06 to 1.88) and ever knocked unconscious (once vs never, OR?=?1.35, 95% CI 1.09 to 1.68, more than once vs never, OR?=?2.53, 95% CI 1.78 to 3.59). Hypnotic, anxiolytic or antidepressant drug use for more than 1 year and a family history of Parkinson's disease showed significantly increased odds ratios. Tobacco use was protective (OR?=?0.50, 95% CI 0.42 to 0.60). Analyses confined to subjects with Parkinson's disease gave similar results. Conclusions The association of pesticide exposure with Parkinson's disease suggests a causative role. Repeated traumatic loss of consciousness is associated with increased risk.

Dick, F D; De Palma, G; Ahmadi, A; Scott, N W; Prescott, G J; Bennett, J; Semple, S; Dick, S; Counsell, C; Mozzoni, P; Haites, N; Wettinger, S Bezzina; Mutti, A; Otelea, M; Seaton, A; Soderkvist, P; Felice, A



Current status of safinamide for the drug portfolio of Parkinson's disease therapy.  


Parkinson's disease (PD) is characterized by a slowly ongoing neuronal death. This alters dopaminergic and glutamatergic neurotransmission and causes a wide variety of motor and non-motor features. Safinamide has a unique pharmacological profile, which combines modulation of dopamine metabolism by reversible, highly specific monoamine oxidase-B inhibition, blockage of voltage-dependent sodium channels, modulation of calcium channels and of glutamate release induced by abnormal neuronal activity. Therefore, safinamide represents an ideal candidate for the treatment of PD. This compound asks for one time daily intake only within an optimum dose range between 50 and 100 mg. In clinical trials, safinamide was well tolerated and safe, improved motor behavior even in combination with dopamine agonist only, ameliorated levodopa-associated motor complications. Safinamide has the potential to become an important compound for the therapy of PD, since its symptomatic efficacy appears to be superior to available monoamine oxidase-B inhibitors or N-methyl-d-aspartate receptor antagonists like amantadine, according to available trial outcomes. PMID:24053341

Müller, Thomas



Constant dopaminergic stimulation by transdermal delivery of dopaminergic drugs: a new treatment paradigm in Parkinson's disease.  


Current dopaminergic therapies for the treatment of Parkinson's disease are associated with the development of long-term motor complications. Abnormal pulsatile stimulation of dopamine receptors is thought to underlie the development of motor complications. There is thus a need for therapies that mimic the normal physiological state more closely by resulting in constant dopaminergic stimulation (CDS). Several studies support the hypothesis that CDS can reverse levodopa-induced motor complications. Other potential benefits of CDS include alleviating nocturnal disturbances, minimizing daytime sleepiness, avoiding priming for motor fluctuations and dyskinesia, preventing the development of gastrointestinal dysfunction and reducing the risk of developing psychosis or behavioural disturbances. Continuous infusion of dopaminergic therapies is impractical for the routine treatment of large numbers of patients. Although catechol-O-methyltransferase inhibitors or sustained-release preparations of levodopa may be beneficial, they do not entirely eliminate pulsatile stimulation of dopamine receptors. A new dopamine agonist (rotigotine), delivered over 24 h by a once-daily transdermal patch, has been investigated in several clinical trials. Continuous delivery of rotigotine has been shown to provide 'true' CDS in animal models. The potential of true CDS therapy to prevent or reduce long-term motor and non-motor complications requires investigation in appropriately designed clinical trials. PMID:18042245

Steiger, M



Histopathologic Manifestations of Drug-induced Hepatotoxicity.  


Drug-induced hepatotoxicity is underrecognized but increasingly identified as causing acute and chronic liver disease. Several prescription drugs, over-the-counter medications, dietary and/or supplementary agents, and herbal products are hepatotoxic. Drug-induced liver injury mimics other primary acute and chronic liver diseases and it should be considered in patients with hepatobiliary disease. Certain drugs result in specific histopathologic patterns of liver injury, which may help in sorting out the responsible drug. The diagnosis of drug-induced hepatotoxicity is challenging. It involves excluding other possible causes, careful medication history, the latent period between drug exposure and symptom onset and/or abnormal liver tests, and histopathologic findings. PMID:24099017

Zhang, Xuchen; Ouyang, Jie; Thung, Swan N



Motor and nonmotor complications in Parkinson's disease: an argument for continuous drug delivery?  


The complications of long-term levodopa therapy for Parkinson's disease (PD) include motor fluctuations, dyskinesias, and also nonmotor fluctuations-at least equally common, but less well appreciated-in autonomic, cognitive/psychiatric, and sensory symptoms. In seeking the pathophysiologic mechanisms, the leading hypothesis is that in the parkinsonian brain, intermittent, nonphysiological stimulation of striatal dopamine receptors destabilizes an already unstable system. Accordingly, a major goal of PD treatment in recent years has been the attainment of continuous dopaminergic stimulation (CDS)-or, less theoretically (and more clinically verifiable), continuous drug delivery (CDD). Improvements in the steadiness of the plasma profiles of various dopaminergic therapies may be a signal of progress. However, improvements in plasma profile do not necessarily translate into CDS, or even into CDD to the brain. Still, it is reassuring that clinical studies of approaches to CDD have generally been positive. Head-to-head comparative trials have often failed to uncover evidence favoring such approaches over an intermittent therapy. Nevertheless, the findings among recipients of subcutaneous apomorphine infusion or intrajejunal levodopa/carbidopa intestinal gel suggest that nonmotor PD symptoms or complications may improve in tandem with motor improvement. In vivo receptor binding studies may help to determine the degree of CDS that a dopaminergic therapy can confer. This may be a necessary first step toward establishing whether CDS is, in fact, an important determinant of clinical efficacy. Certainly, the complexities of optimal PD management, and the rationale for an underlying strategy such as CDS or CDD, have not yet been thoroughly elucidated. PMID:23456290

Chaudhuri, K Ray; Rizos, Alexandra; Sethi, Kapil D



Drug-Induced Liver Injury  

Center for Drug Evaluation (CDER)

Text Version... Practicing MDs ACs prestige advice payment Rx care fees taxes votes Page 26. protection drugs purchase Tetrahedron of Interrelationships ... More results from


Psychiatric aspects of Parkinson’s disease  

Microsoft Academic Search

In patients with Parkinson’s disease (PD) disturbances of mental state constitute some of the most difficult treatment challenges of advanced disease, often limiting effective treatment of motor symptoms and leading to increased disability and poor quality of life. This article provides an update on the current knowledge of these complications and the use of old and new drugs in their

Anette Schrag



5-Hydroxy-tryptophan for the treatment of l-DOPA-induced dyskinesia in the rat Parkinson's disease model.  


The serotonin system has recently emerged as an important player in the appearance of l-DOPA-induced dyskinesia (LID) in experimental models of Parkinson's disease, as it provides an unregulated source of l-DOPA-derived dopamine release in the dopamine-depleted striatum. Accordingly, toxin lesion or pharmacological silencing of serotonin neurons suppressed LID in the rat and monkey models of Parkinson's disease. However, 5-HT1 receptor agonists were also found to partially reduce the therapeutic effect of l-DOPA. In this study, we evaluated whether enhancement of the serotonin tone induced by the administration of the serotonin precursor 5-hydroxy-tryptophan (5-HTP) could affect induction and expression of LID, as well as the therapeutic effect of l-DOPA, in 6-OHDA-lesioned rats. Drug naďve and l-DOPA-primed 6-OHDA-lesioned rats were chronically treated with a daily injection of l-DOPA (6mg/kg plus benserazide, s.c.) alone, or in combination with 5-HTP (24-48mg/kg, i.p.). The abnormal involuntary movements (AIMs) test, as well as the stepping and the motor activity tests, were performed during the chronic treatments. Results showed that 5-HTP reduced the appearance of LID of about 50% at both tested doses. A partial reduction of the therapeutic effect of l-DOPA was seen with the higher but not with the lower dose of 5-HTP. 5-HTP 24mg/kg was also able to reduce the expression of dyskinesia in l-DOPA-primed dyskinetic rats, to a similar extent than in l-DOPA-primed rats. Importantly, the antidyskinetic effect of 5-HTP 24mg/kg does not appear to be due to a competition with l-DOPA for crossing the blood-brain barrier; in fact, similar l-DOPA striatal levels were found in l-DOPA only and l-DOPA plus 5-HTP 24mg/kg treated animals. These data further confirm the involvement of the serotonin system in the appearance of LID, and suggest that 5-HTP may be useful to counteract the appearance of dyskinesia in Parkinson's disease patients. PMID:24004632

Tronci, Elisabetta; Lisci, Carlo; Stancampiano, Roberto; Fidalgo, Camino; Collu, Maria; Devoto, Paola; Carta, Manolo



Why Do We Need Multifunctional Neuroprotective and Neurorestorative Drugs for Parkinson's and Alzheimer's Diseases as Disease Modifying Agents  

PubMed Central

Parkinson's disease (PD) and Alzheimer's Disease (AD) are severe neurodegenerative disorders, with no drugs that are currently approved to prevent the neuronal cell loss characteristic in brains of patients suffering from PD and AD and all drug treatment are synptomactic. Due to the complex pathophysiology, including a cascade of neurotoxic molecular events that results in neuronal death and predisposition to depression and eventual dementia and etiology of these disorders, an innovative approach towards neuroprotection or neurorestoration (neurorescue) may be the development and use of multifunctional pharmaceuticals. Such drugs target an array of pathological pathways, each of which is believed to contribute to the cascades that ultimately lead to neuronal cell death. In this short review, we discuss examples of novel multifunctional ligands that may have potential as neuroprotective-neurorestorative therapeutics in PD and AD. The compounds discussed originate from synthetic chemistry as well as from natural sources.



Promise of Neurorestoration and Mitochondrial Biogenesis in Parkinson's Disease with Multi Target Drugs: An Alternative to Stem Cell Therapy  

PubMed Central

There is an unmet need in progressive neurodegenerative diseases such as Parkinson's and Alzheimer's diseases. The present therapeutics for these diseases at best is symptomatic and is not able to delay disease or possess disease modifying activity. Thus an approach to drug design should be made to slow or halt progressive course of a neurological disorder by interfering with a disease-specific pathogenetic process. This would entail the ability of the drug to protect neurons by blocking the common pathway for neuronal injury and cell death and the ability to promote regeneration of neurons and restoration of neuronal function. We have now developed a number of multi target drugs which possess neuroprotective, and neurorestorative activity as well as being able to active PGC-1? (peroxisome proliferator-activated receptor ? coactivator-1?), SIRT1 (NAD-dependent deacetylase protein) and NTF (mitochondrial transcription factor) that are intimately associated with mitochondrial biogenesis.

Oh, Young J.



Preventive effect of antioxidants in MPTP-induced mouse model of Parkinson's disease.  


Oxidative stress to dopaminergic neurons is believed to be one of the causes of neurodegeneration in Parkinson's disease (PD). It was investigated whether N-acetylcysteine (NAC) and l-2-oxothiazolidine-4-carboxylate (OTC) have a preventive effect in an oxidative stress-induced model of PD. We found that NAC and OTC prevent degradation of PARP during auto-oxidized dopamine- or auto-oxidized L-DOPA-induced apoptosis in PC12 cells. In an animal model study, NAC and OTC showed a preventive effect against MPTP-induced loss of tyrosine hydroxylase-positive neurons, and suppressed the nuclear translocation of c-jun N-terminal kinase (JNK), suggesting that NAC and OTC can prevent MPTP-induced apoptosis by suppressing JNK activation. Therefore, these results suggest that NAC and OTC can be used as potential agents to prevent the progression of PD. PMID:15182952

Park, Soon-Won; Kim, Sun-Hee; Park, Kyu-Hyun; Kim, Sang-Doo; Kim, Joo-Young; Baek, Sun-Yong; Chung, Byung-Seon; Kang, Chi-Dug



Valproate for the treatment of medication-induced impulse-control disorders in three patients with Parkinson’s disease  

Microsoft Academic Search

Impulse-control disorders (ICDs) are becoming more commonly recognized in the Parkinson disease (PD) population. To date, there are no definitive methods of treating dopamine dysregulation syndromes in PD patients. We sought to uncover an effective treatment option for future study. We report a series of 3 PD patients with ICDs who were effectively treated with valproate. Based on these encouraging

C. W. Hicks; M. M. Pandya; I. Itin; H. H. Fernandez



Effects of Opioid Antagonists on l -DOPA-Induced Dyskinesia in Parkinson's Disease  

Microsoft Academic Search

\\u000a \\u000a Long-term treatment of Parkinson's disease with the dopamine precursor 3,4-dihydroxyphenylalanine (l-DOPA) is compromised\\u000a by the development of motor complications, including involuntary movements termed dyskinesia. The neural mechanisms underlying\\u000a l-DOPA-induced dyskinesia (LID) involve altered activity of GABAergic striatal output pathways resulting, directly and indirectly,\\u000a in underactivity of the output regions of the basal ganglia. These GABAergic striatal efferents employ, as co-neurotransmitters,

Susan H. Fox; Tom H. Johnston; Jonathan M. Brotchie


Cognitive, motor and tyrosine hydroxylase temporal impairment in a model of parkinsonism induced by reserpine.  


Studies have suggested that cognitive deficits can precede motor alterations in Parkinson's disease (PD). However, in general, classic animal models are based on severe motor impairment after one single administration of neurotoxins, and thereby do not express the progressive nature of the pathology. A previous study showed that the repeated administration with a low dose (0.1mg/kg) of the monoamine depleting agent reserpine induces a gradual appearance of motor signs of pharmacological parkinsonism in rats. Here, we showed this repeated treatment with reserpine induced a memory impairment (evaluated by the novel object recognition task) before the gradual appearance of the motor signs. Additionally, these alterations were accompanied by decreased tyrosine hydroxylase (TH) striatal levels and reduced number of TH+ cells in substantia nigra pars compacta (SNpc). After 30 days without treatment, reserpine-treated animals showed normal levels of striatal TH, partial recovery of TH+ cells in SNpc, recovery of motor function, but not reversal of the memory impairment. Furthermore, the motor alterations were statistically correlated with decreased TH levels (GD, CA1, PFC and DS) and number of TH+ cells (SNpc and VTA) in the brain. Thus, we extended previous results showing that the gradual appearance of motor impairment induced by repeated treatment with a low dose of reserpine is preceded by short-term memory impairment, as well as accompanied by neurochemical alterations compatible with the pathology of PD. PMID:23831411

Santos, José R; Cunha, Joăo A S; Dierschnabel, Aline L; Campęlo, Clarissa L C; Leăo, Anderson H F F; Silva, Anatildes F; Engelberth, Rovena C G J; Izídio, Geison S; Cavalcante, Jeferson S; Abílio, Vanessa C; Ribeiro, Alessandra M; Silva, Regina H



Drug-induced Acute Liver Failure.  


Although acute liver failure caused by drug-induced liver injury comprises a small fraction of overall drug-induced liver injury, these patients require high resource use and have relatively poor outcomes. Drug-induced liver injury caused by idiosyncrasy more often leads to death or transplantation than does acetaminophen acute liver failure, but the number of patients in each category receiving a graft is roughly the same. Efforts in the future to improve outcomes should focus on more effective treatments and better methods to identify those that might experience poor outcomes. PMID:24099019

Lee, William M



Non-steroidal drug-induced glaucoma  

PubMed Central

Numerous systemically used drugs are involved in drug-induced glaucoma. Most reported cases of non-steroidal drug-induced glaucoma are closed-angle glaucoma (CAG). Indeed, many routinely used drugs that have sympathomimetic or parasympatholytic properties can cause pupillary block CAG in individuals with narrow iridocorneal angle. The resulting acute glaucoma occurs much more commonly unilaterally and only rarely bilaterally. CAG secondary to sulfa drugs is a bilateral non-pupillary block type and is due to forward movement of iris–lens diaphragm, which occurs in individuals with narrow or open iridocorneal angle. A few agents, including antineoplastics, may induce open-angle glaucoma. In conclusion, the majority of cases with glaucoma secondary to non-steroidal medications are of the pupillary block closed-angle type and preventable if the at-risk patients are recognized and treated prophylactically.

Razeghinejad, M R; Pro, M J; Katz, L J



Drug-induced liver injury from antiepileptic drugs.  


Drug-induced liver injury is a potential complication of innumerable medications. Most cases do not occur in a predictable, dose-dependent manner, leading to delayed recognition of a drug's hepatotoxic potential until after its release into the market. The estimated occurrence is 1 in 10,000 to 100,000 patients. However, the rates are likely higher because many cases go unrecognized owing to lack of reporting or missed diagnosis. This article reviews the most commonly associated antiepileptic drugs. PMID:24099025

Au, Jennifer S; Pockros, Paul J



Drug-induced photosensitivity: culprit drugs, management and prevention.  


Photo-induced drug eruptions are cutaneous adverse events due to exposure to a drug and either ultraviolet or visible radiation. Based on their pathogenesis, they can be classified as phototoxic or photoallergic drug eruptions, although in many cases it is not possible to determine whether a particular eruption is due to a phototoxic or photoallergic mechanism. In this review, the diagnosis, prevention and management of drug-induced photosensitivity are discussed. Diagnosis is based primarily on the history of drug intake and the clinical appearance of the eruption, primarily affecting sun-exposed areas of the skin. Phototesting and photopatch testing can be useful adjuncts in making a diagnosis. The mainstay of management is prevention, including informing patients of the possibility of increased sun sensitivity and the use of sun protective measures. However, once the eruption has occurred, it may be necessary to discontinue the culprit medication and treat the eruption with a potent topical corticosteroid. Drugs that have been implicated in causing photosensitive eruptions are reviewed. Tetracycline, doxycycline, nalidixic acid, voriconazole, amiodarone, hydrochlorothiazide, naproxen, piroxicam, chlorpromazine and thioridazine are among the most commonly implicated medications. We review the medical literature regarding evidence for the culpability of each drug, including the results of phototesting, photopatch testing and rechallenge testing. PMID:21879777

Drucker, Aaron M; Rosen, Cheryl F



Gait analysis in patients with advanced Parkinson disease: different or additive effects on gait induced by levodopa and chronic STN stimulation  

Microsoft Academic Search

Summary.  The aim of our study was to observe the effects on gait parameters induced by STN stimulation and levodopa medication in patients\\u000a with advanced Parkinson’s disease in order to determine different or additive effects.\\u000a \\u000a Therefore we examined 12 patients with advanced Parkinson disease after bilateral implantation of DBS into the STN. We assessed\\u000a the motor score of the UPDRS and

S. Lubik; W. Fogel; V. Tronnier; M. Krause; J. König; W. H. Jost



Acquired (Drug-Induced) Long QT Syndrome  

Microsoft Academic Search

The most common cause of acquired drug-induced long QT syndrome (ADILQTS) in clinical practice is an exposure of the heart\\u000a to drugs known for their potential to prolong the QT interval. It has long been recognized that most drugs that prolong the\\u000a duration of the QT interval can cause fatal tachyarrhythmias. However, it took decades to sensitize medical and scientific

Jeffrey S. Litwin; Robert B. Kleiman; Ihor Gussak


Mechanisms of Drug-induced Liver Injury.  


Drug-induced liver injury (DILI) represents a broad spectrum of liver manifestations. However, the most common manifestation is hepatocyte death following drug intake. DILI can be predictable and dose dependent with a notable example of acetaminophen toxicity. Idiosyncratic DILI occurs in an unpredictable fashion at low frequencies, implying that environmental and genetic factors alter the susceptibility of individuals to the insult (drugs). PMID:24099014

Yuan, Liyun; Kaplowitz, Neil



Drug-induced disorders of teeth.  


It is essential that every health care professional who is involved with the prescription or recommendation of drugs be fully aware of any resultant disorders that may arise as a side-effect. A range of drugs can affect the teeth. In this review article, drugs that have the potential to induce changes in teeth have been classified as those leading to tooth discoloration (intrinsic and extrinsic), physical damage to tooth structure (enamel, dentin, and cementum), and alteration in tooth sensitivity. PMID:15972585

Tredwin, C J; Scully, C; Bagan-Sebastian, J-V



Pluripotent stem cells as new drugs? The example of Parkinson's disease  

Microsoft Academic Search

Cell replacement therapy is a widely discussed novel concept of medical treatment. The increased knowl- edge in the stem cell field, particularly pluripotent stem cells, potentially provides powerful tools for this therapeutic concept. A large number of disease characterized by the loss of functional cells are potential candidates for cell replacement therapy and, in this regards, Parkinson's disease is of

Olivier Preynat-Seauve; Pierre R. Burkhard; Jean Villard; Walter Zingg; Nathalie Ginovart; Anis Feki; Michel Dubois-Dauphin; Samia A. Hurst; Alex Mauron; Marisa Jaconi



Drosophila modifier screens to identify novel neuropsychiatric drugs including aminergic agents for the possible treatment of Parkinson's disease and depression.  


Small molecules that increase the presynaptic function of aminergic cells may provide neuroprotection in Parkinson's disease (PD) as well as treatments for attention deficit hyperactivity disorder (ADHD) and depression. Model genetic organisms such as Drosophila melanogaster may enhance the detection of new drugs via modifier or 'enhancer/suppressor' screens, but this technique has not been applied to processes relevant to psychiatry. To identify new aminergic drugs in vivo, we used a mutation in the Drosophila vesicular monoamine transporter (dVMAT) as a sensitized genetic background and performed a suppressor screen. We fed dVMAT mutant larvae ?1000 known drugs and quantitated rescue (suppression) of an amine-dependent locomotor deficit in the larva. To determine which drugs might specifically potentiate neurotransmitter release, we performed an additional secondary screen for drugs that require presynaptic amine storage to rescue larval locomotion. Using additional larval locomotion and adult fertility assays, we validated that at least one compound previously used clinically as an antineoplastic agent potentiates the presynaptic function of aminergic circuits. We suggest that structurally similar agents might be used to development treatments for PD, depression and ADHD, and that modifier screens in Drosophila provide a new strategy to screen for neuropsychiatric drugs. More generally, our findings demonstrate the power of physiologically based screens for identifying bioactive agents for select neurotransmitter systems.Molecular Psychiatry advance online publication, 11 December 2012; doi:10.1038/mp.2012.170. PMID:23229049

Lawal, H O; Terrell, A; Lam, H A; Djapri, C; Jang, J; Hadi, R; Roberts, L; Shahi, V; Chou, M-T; Biedermann, T; Huang, B; Lawless, G M; Maidment, N T; Krantz, D E



Forensic aspects of drug-induced violence.  


Violence is unfortunately a part of society. The causes of violence are not completely understood, but it involves sociological, genetic, financial, biological, and environmental factors. Drugs can cause aggression by altering the neurotransmitters dopamine, norepinephrine, gamma-aminobutyric acid (GABA), and serotonin. Specific drugs associated with aggression include alcohol, anabolic steroids, cocaine, amphetamines, sedatives, opiates, and hallucinogens. Aggression can be categorized into impulsive and predatory aggression. Drugs under certain conditions cause impulsive aggression. Sometimes a defense in criminal cases is that the drug caused the violence, that is drug-induced insanity. A case of insanity is more likely to be accepted if the event was unplanned and had no apparent motive. An acceptance of insanity by voluntary intoxication is rarely accepted by the criminal justice system. A more common legal strategy is to seek diminished capacity which aims to obtain a reduction in the severity of the criminal charges. We will discuss some, but not all of the pharmacological and physiological issues relating to drug-induced violence. Then some of the "big picture" forensic issues will be presented. Our goal is to present a primer on the pharmacological and forensic issues relating to drug-induced violence. No attempt was made to provide a comprehensive review of all the literature related to drug-induced violence. PMID:22215647

Anderson, Peter D; Bokor, Gyula



Acute dystonia induced by neuroleptic drugs  

Microsoft Academic Search

About 2.5% of patients treated with neuroleptic drugs develop acute dystonia within 48 h of commencing therapy. The symptoms remit on drug withdrawal or following anticholinergic therapy. Acute dystonia can also be reliably induced in many primate species by neuroleptic treatment with comparable time course, symptomatology and pharmacological characteristics to those observed in man. In general, New World monkeys appear

N. M. J. Rupniak; P. Jenner; C. D. Marsden



Drug-induced mental status changes  

Microsoft Academic Search

Drug-induced mental status changes may include depression, psychosis, confusion, delirium, vivid dreams, nightmares, hallucinations, dementia, and confusion, among others. This review is devoted to a discussion of the major drug classes that may cause alterations in mental function and methods that are useful in detecting and minimizing the risk of this occurring.

Mary Lynn McPherson



Parkinson's Disease Patient-Derived Induced Pluripotent Stem Cells Free of Viral Reprogramming Factors  

PubMed Central

SUMMARY Induced pluripotent stem cells (iPSCs) derived from somatic cells of patients represent a powerful tool for biomedical research and may provide a source for replacement therapies. However, the use of viruses encoding the reprogramming factors represents a major limitation of the current technology since even low vector expression may alter the differentiation potential of the iPSCs or induce malignant transformation. Here, we show that fibroblasts from five patients with idiopathic Parkinson’s disease can be efficiently reprogrammed and subsequently differentiated into dopaminergic neurons. Moreover, we derived hiPSCs free of reprogramming factors using Cre-recombinase excisable viruses. Factor-free hiPSCs maintain a pluripotent state and show a global gene expression profile, more closely related to hESCs than to hiPSCs carrying the transgenes. Our results indicate that residual transgene expression in virus-carrying hiPSCs can affect their molecular characteristics and that factor-free hiPSCs therefore represent a more suitable source of cells for modeling of human disease.

Soldner, Frank; Hockemeyer, Dirk; Beard, Caroline; Gao, Qing; Bell, George W.; Cook, Elizabeth G.; Hargus, Gunnar; Blak, Alexandra; Cooper, Oliver; Mitalipova, Maisam; Isacson, Ole; Jaenisch, Rudolf



Oxidants induce alternative splicing of alpha-synuclein: Implications for Parkinson's disease.  


alpha-Synuclein (alpha-syn) is a presynaptic protein that is widely implicated in the pathophysiology of Parkinson's disease (PD). Emerging evidence indicates a strong correlation between alpha-syn aggregation and proteasomal dysfunction as one of the major pathways responsible for destruction of the dopamine neurons. Using parkinsonism mimetics (MPP(+), rotenone) and related oxidants, we have identified an oxidant-induced alternative splicing of alpha-syn mRNA, generating a shorter isoform of alpha-syn with deleted exon-5 (112-syn). This spliced isoform has an altered localization and profoundly inhibits proteasomal function. The generation of 112-syn was suppressed by constitutively active MEK-1 and enhanced by inhibition of the Erk-MAP kinase pathway. Overexpression of 112-syn exacerbated cell death in a human dopaminergic cell line compared to full-length protein. Expression of 112-syn and proteasomal dysfunction were also evident in the substantia nigra and to a lesser extent in striatum, but not in the cortex of MPTP-treated mice. We conclude that oxidant-induced alternative splicing of alpha-syn plays a crucial role in the mechanism of dopamine neuron cell death and thus contributes to PD. PMID:19857570

Kalivendi, Shasi V; Yedlapudi, Deepthi; Hillard, Cecilia J; Kalyanaraman, B




Center for Drug Evaluation (CDER)

Text Version... can we minimize missing this (study design)? - historical validation? (also false positive and negative “signals”) - when to pull the plug? ... More results from


Drug-induced taste disorders.  


Numerous drugs have the potential to adversely influence a patient's sense of taste, either by decreasing function or producing perceptual distortions or phantom tastes. In some cases, such adverse effects are long lasting and cannot be quickly reversed by drug cessation. In a number of cases, taste-related adverse effects significantly alter the patient's quality of life, dietary choices, emotional state and compliance with medication regimens. In this review, we describe common drug-related taste disturbances and review the major classes of medications associated with them, including antihypertensives, antimicrobials and antidepressants. We point out that there is a dearth of scientific information related to this problem, limiting our understanding of the true nature, incidence and prevalence of drug-related chemosensory disturbances. The limited data available suggest that large differences exist among individuals in terms of their susceptibility to taste-related adverse effects, and that sex, age, body mass and genetic variations in taste sensitivity are likely involved. Aside from altering drug usage, management strategies for patients with taste-related adverse effects are sorely needed. Unfortunately, stopping a medication is not always an easy option, particularly when one is dealing with life-threatening conditions such as seizures, cancer, infection, diabetes mellitus and uncontrolled hypertension. Hopefully, the information contained in this review will sensitize physicians, researchers and drug manufacturers to this problem and will result in much more research on this pressing topic. PMID:18302445

Doty, Richard L; Shah, Muhammad; Bromley, Steven M



Pramipexole in patients with Parkinson's disease and marked drug resistant tremor: a randomised, double blind, placebo controlled multicentre study  

PubMed Central

Objective: To compare the tremorlytic properties of pramipexole, a non-ergoline dopamine agonist to those of placebo as add on medication in patients with Parkinson's disease. Methods: Eighty four patients with early or advanced Parkinson's disease and marked, drug resistant tremor under a stable and optimised antiparkinsonian medication were included in a double blind, randomised, placebo controlled, multicentre study and assigned to add on treatment (7 week dose titration interval, 4 week maintenance period) with either pramipexole (n=44) or placebo (n=40) as adjunct. The primary end point was the absolute change in tremor score, defined as the sum of tremor related items (16, 20, 21) of the unified Parkinson's disease rating scale (UPDRS) in "on" periods. Secondary end points included the percentage change in tremor score, the absolute and percentage changes in long term EMG tremor registration, and the change in tremor self rating scales. Safety and tolerability were assessed on the basis of adverse events, laboratory tests, ECG, and vital signs. Results: Pramipexole was significantly superior to placebo with a difference between treatment groups in the mean absolute change in tremor score of -4.4 (95% confidence interval (95% CI) -6.2 to -2.5) (p<0.0001), corresponding to a difference in the mean percentage change of -34.7% in favour of pramipexole. The secondary end points were consistent with the significant change in tremor score and provided further evidence for the benefit of pramipexole compared with placebo. Long term EMG registration as an objective measure showed a difference in mean absolute change in tremor occurrence of -15.2% (95%CI -21.4 to -9.0) (p<0.0001), and a difference in the mean percentage change of -45.7% in favour of pramipexole. The treatment effects increased during dose titration and remained stable during the 4 week maintenance dose period until the end of the study. The average daily pramipexole dose during maintenance was 4.1 (SD 0.9) mg. Safety analysis showed an increased rate of fatigue, insomnia, nausea, abdominal pain, and headache under pramipexole, comparable with previous studies. Conclusion: Pramipexole proved to be an effective agent for patients with Parkinson's disease and drug resistant tremor.

Pogarell, O; Gasser, T; van Hilten, J J; Spieker, S; Pollentier, S; Meier, D; Oertel, W



Protective Effects of Nicotine Against Aminochrome-Induced Toxicity in Substantia Nigra Derived Cells: Implications for Parkinson's Disease  

PubMed Central

Parkinson’s disease is a debilitating progressive neurodegenerative disorder that results from the loss of or damage to dopaminergic cells containing neuromelanin in the substantia nigra (SN). The underlying neurodegenerative mechanism(s), however, remain elusive. Aminochrome, the precursor of neuromelanin is an endogenous substance capable of inducing selective neurotoxicity to dopaminergic neurons in SN. Nicotine, on the other hand, may offer protective effects against dopaminergic cell damage induced by various neurotoxins including MPTP and salsolinol. In this study, we sought to determine whether nicotine may also protect against aminochrome-induced toxicity in SN derived RCSN-3 cells. Exposure of RCSN-3 cells to a combination of aminochrome (50 ?M) and dicoumarol (50 ?M) for 48 h induced approximately 70 % cell death. Pretreatment with nicotine, dose-dependently blocked this toxicity. The effects of nicotine in turn were dose-dependently blocked by mecamylamine, a non-selective nicotinic receptor antagonist. These results suggest involvement of nicotinic receptors in protective effects of nicotine against aminochrome-induced toxicity and provide further evidence for possible therapeutic effects of nicotine or nicotinic agonists in Parkinson’s disease.

Munoz, Patricia; Huenchuguala, Sandro; Paris, Irmgard; Cuevas, Carlos; Villa, Monica; Caviedes, Pablo; Segura-Aguilar, Juan



Drug metabolite profiling and elucidation of drug-induced hepatotoxicity.  


Drug metabolism studies, together with pathologic and histologic evaluation, provide critical data sets to help understand mechanisms underlying drug-related hepatotoxicity. A common practice is to trace morphologic changes resulting from liver injury back to perturbation of biochemical processes and to identify drug metabolites that affect those processes as possible culprits. This strategy can be illustrated in efforts of elucidating the cause of acetaminophen-, troglitazone- and valproic acid-induced hepatic necrosis, microvesicular steatosis and cholestasis with the aid of information from qualitative and quantitative analysis of metabolites. From a pharmaceutical research perspective, metabolite profiling represents an important function because a structure-activity relationship is essential to rational drug design. In addition, drugs are known to induce idiosyncratic hepatotoxicity, which usually escapes the detection by preclinical safety assessment and clinical trials. This issue is addressed, at present, by eliminating those molecules that are prone to metabolic bioactivation, based on the concept that formation of electrophilic metabolites triggers covalent protein modification and subsequent organ toxicity. Although pragmatic, such an approach has its limitations as a linear correlation does not exist between toxicity and the extent of bioactivation. It may be possible in the future that the advance of proteomics, metabonomics and genomics would pave the way leading to personalized medication in which beneficial effect of a drug is maximized, whereas toxicity risk is minimized. PMID:17539747

Tang, Wei



Dopamine Induced Neurodegeneration in a PINK1 Model of Parkinson's Disease  

Microsoft Academic Search

BackgroundParkinson's disease is a common neurodegenerative disease characterised by progressive loss of dopaminergic neurons, leading to dopamine depletion in the striatum. Mutations in the PINK1 gene cause an autosomal recessive form of Parkinson's disease. Loss of PINK1 function causes mitochondrial dysfunction, increased reactive oxygen species production and calcium dysregulation, which increases susceptibility to neuronal death in Parkinson's disease. The basis

Sonia Gandhi; Annika Vaarmann; Zhi Yao; Michael R. Duchen; Nicholas W. Wood; Andrey Y. Abramov



Drug-induced thrombosis: an update.  


Drugs may play an important role in development of thrombosis, and in recent years there has been increased attention to the importance of this issue. Although drug-induced thrombosis usually causes venous thrombotic events, arterial events are also noted due to drug administration. Here we review the different mechanisms through which drugs can exert thrombosis. Drugs can cause direct endothelial damage and expose the underlying subendothelium thus leading to platelet adherence and subsequent thrombus formation. Such an effect is seen by contrast media and chemotherapeutic cytotoxic drugs. Drugs may also attenuate the secretion of pro- and anticoagulation mediators by the endothelial cells and may have prothrombotic effects on platelets by increasing adhesion and aggregation, as for example seen after heparin administration in an immune-mediated mechanism. Red and white cells can also be affected by drugs, by increasing their aggregation or adhesion to the endothelial wall. Some drugs, such as oral contraceptive pills, may promote thrombosis by altering the balance between the different coagulation factors, and many drugs can lead to decreased blood flow by increasing blood viscosity, as seen for example after intravenous immunoglobulin administration. Better understanding of the mechanisms through which drugs exert thrombosis may facilitate their safe use in patients. Additionally, awareness of the drugs that are known to induce thrombosis is important in order to stop their administration in case of a thrombotic event. This review further emphasizes the fact that drug administration is a risk factor that should always be considered together with additional known thromboembolic risk factors such as genetic predisposition or cancer. PMID:23640658

Ramot, Yuval; Nyska, Abraham; Spectre, Galia




Microsoft Academic Search

Parkinson's disease is not only among the most common neurodegenerative disorders, it is also one of the most famed neurological illnesses with several celebrity figures suffering from Parkinson's disease. Over the past few decades there has been steady increase in the understanding of disease pathophysiology and clinical course, with advances in management choices including new drug therapies, surgical treatment options

Ismail A. Khatri; Umar S. Chaudhry


Parkinson's disease and anxiety  

Microsoft Academic Search

There has been a recent surge of interest in the subject of anxiety in patients with Parkinson's disease. Up to 40% of patients with Parkinson's disease experience clinically significant anxiety. This anxiety may be a psychological reaction to the stress of the illness or may be related to the neurochemical changes of the disease itself. Antiparkinsonian drugs may have a

K Walsh; G Bennett



Movement Disorders Induced by Antipsychotic Drugs: Implications of the CATIE Schizophrenia Trial  

PubMed Central

Synopsis Drug-induced movement disorders have dramatically declined with the widespread use of second generation antipsychotics but remain important in clinical practice and for understanding antipsychotic pharmacology. The diagnosis and management of dystonia, parkinsonism, akathisia, catatonia, neuroleptic malignant syndrome and tardive dyskinesia are reviewed in relation to the decreased liability of the second generation antipsychotics contrasted with evidence from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial. Data from the CATIE trial imply that advantages of second generation antipsychotics in significantly reducing extrapyramidal side effects compared with haloperidol may be diminished when compared with modest doses of lower-potency first generation drugs, that the dichotomy between first and second generation drugs may be oversimplified, and that antipsychotics could be conceptualized as a single drug class with a spectrum of risk for movement disorders depending upon receptor binding affinities and individual patient susceptibility.

Caroff, Stanley N.; Hurford, Irene; Lybrand, Janice; Campbell, E. Cabrina



Drug-Induced Oxidative Stress and Toxicity  

PubMed Central

Reactive oxygen species (ROS) are a byproduct of normal metabolism and have roles in cell signaling and homeostasis. Species include oxygen radicals and reactive nonradicals. Mechanisms exist that regulate cellular levels of ROS, as their reactive nature may otherwise cause damage to key cellular components including DNA, protein, and lipid. When the cellular antioxidant capacity is exceeded, oxidative stress can result. Pleiotropic deleterious effects of oxidative stress are observed in numerous disease states and are also implicated in a variety of drug-induced toxicities. In this paper, we examine the nature of ROS-induced damage on key cellular targets of oxidative stress. We also review evidence implicating ROS in clinically relevant, drug-related side effects including doxorubicin-induced cardiac damage, azidothymidine-induced myopathy, and cisplatin-induced ototoxicity.

Deavall, Damian G.; Martin, Elizabeth A.; Horner, Judith M.; Roberts, Ruth



Fluconazole-induced Fixed Drug Eruption.  


Triazole antifungals are commonly used in the treatment of oral, esophageal, and vaginal candidiasis. Fluconazole is frequently prescribed as the therapy modality for vaginal fungal infections. On rare occasions, fluconazole has been shown to cause fixed drug eruptions. Lesions of fixed drug eruptions vary in size and number, but have the same general appearance and symptoms. The authors report a case of fluconazole-induced fixed drug eruption in a 24-year-old woman with recurrent vaginal candidiasis. The lesion was initially diagnosed as a spider bite. Topical and oral provocation tests with fluconazole were performed. Topical provocation with petroleum/fluconazole and dimethyl sulfoxide/fluonazole were both negative. Oral provocation was positive, thus confirming the diagnosis of fluconazole-induced fixed drug eruption. PMID:23556037

Gaiser, Cory Allen; Sabatino, Dominick



Fluconazole-induced Fixed Drug Eruption  

PubMed Central

Triazole antifungals are commonly used in the treatment of oral, esophageal, and vaginal candidiasis. Fluconazole is frequently prescribed as the therapy modality for vaginal fungal infections. On rare occasions, fluconazole has been shown to cause fixed drug eruptions. Lesions of fixed drug eruptions vary in size and number, but have the same general appearance and symptoms. The authors report a case of fluconazole-induced fixed drug eruption in a 24-year-old woman with recurrent vaginal candidiasis. The lesion was initially diagnosed as a spider bite. Topical and oral provocation tests with fluconazole were performed. Topical provocation with petroleum/fluconazole and dimethyl sulfoxide/fluonazole were both negative. Oral provocation was positive, thus confirming the diagnosis of fluconazole-induced fixed drug eruption.

Sabatino, Dominick



Drug-induced arrhythmia: pharmacogenomic prescribing?  


Drug-induced Torsades de Pointes is a rare, unpredictable, and life-threatening serious adverse event. It can be caused by both cardiac and non-cardiac drugs and has become a major issue in novel drug development and for the regulatory authorities. This review describes the problem, predisposing factors, and the underlying genetic predisposition as it is understood currently. The future potential for pharmacogenomic-guided and personalized prescription to prevent drug-induced Torsades de Pointes is discussed. Database searches utilized reports from up to January 2012, case reports and articles from up to January 2012, and the British National Formulary edition at PMID:23091201

Behr, Elijah R; Roden, Dan



Immune Mechanisms in Drug-Induced Hepatotoxicity  

Microsoft Academic Search

Drug-induced liver injury (DILI) is a common cause of liver disease. It accounts for approximately one-half of cases of acute\\u000a liver failure and significant numbers of deaths in the United States and many other countries (1–5). An estimated 1000 or more drugs have been implicated in causing liver disease on more than one occasion (5). Clinically, DILI mimics all forms

Zhang-Xu Liu; Neil Kaplowitz


Management of drug-induced liver disease  

Microsoft Academic Search

The treatment and prevention of drug-induced liver injury starts with the recognition of hepatotoxicity at the earliest possible\\u000a time so that the suspected drug can be discontinued expeditiously. Both liver enzyme monitoring and vigilance for signs of\\u000a hypersensitivity involving the liver are useful strategies for many agents known to cause hepatocellular necrosis leading\\u000a to liver failure. Specific antidotes to prevent

Gustavo Marino; Hyman J. Zimmerman; James H. Lewis



Drug-Induced Long QT Syndrome  

PubMed Central

The drug-induced long QT syndrome is a distinct clinical entity that has evolved from an electrophysiologic curiosity to a centerpiece in drug regulation and development. This evolution reflects an increasing recognition that a rare adverse drug effect can profoundly upset the balance between benefit and risk that goes into the prescription of a drug by an individual practitioner as well as the approval of a new drug entity by a regulatory agency. This review will outline how defining the central mechanism, block of the cardiac delayed-rectifier potassium current IKr, has contributed to defining risk in patients and in populations. Models for studying risk, and understanding the way in which clinical risk factors modulate cardiac repolarization at the molecular level are discussed. Finally, the role of genetic variants in modulating risk is described.

Kannankeril, Prince; Darbar, Dawood



Drug-induced Sweet's syndrome by aceclofenac.  


Sweet's syndrome (SS) or acute febrile neutrophilic dermatosis is a reactive process that presents in different clinical settings and ranges from classical (idiopathic), malignancy associated or drug induced. The authors describe a 51-year-old Caucasian woman referred to our department with a 3-day history of pseudovesicular reddish papules on her neck, upper trunk and limbs. Two days prior to the eruption, aceclofenac 100 mg every 8 h was initiated for lower back pain. She also complained of high fever (39°C), arthralgias and general malaise. Laboratory evaluation showed an elevation of erythrocyte sedimentation rate and C reactive protein. A biopsy specimen of skin lesions showed throughout the upper reticular dermis a dense infiltrate of mature neutrophils. Aceclofenac was discontinued and oral prednisolone (0.5 mg/kg) was started. Fever resolved within 48 h, whereas cutaneous lesions cleared within the first week. No relapse was noted after a 6-month follow-up period. Drug-induced SS by aceclofenac diagnosis was sustained by the presence of all the five diagnostic criteria for drug-induced SS presented by Walker and Cohen in 1996. Several hundred cases of SS have been reported in the literature. However, drug-induced SS represent overall less than 5% of all cases, mostly as isolated clinical cases. Reports of nonsteroidal anti-inflammatory drug-induced SS include diclofenac, celecoxib and rofecoxib. Our patient represents the first case of aceclofenac-induced SS and illustrates the need to enquire about recent drugs in a patient with suspicion of SS. PMID:21506881

Carvalho, Rodrigo; Fernandes, Cândida; Afonso, Ana; Cardoso, Jorge



Modafinil-induced Fixed Drug Eruption  

PubMed Central

Modafinil is a stimulant drug widely used to promote wakefulness in a variety of psychiatric and neurological conditions. Modafinil-induced severe dermatologic reactions are uncommon but serious side effects. We report a patient who developed fixed drug eruption after exposure to a single dose of tablet modafinil. On assessment using the Naranjo scale, the score was five, which made us conclude that modafinil was the “probable” cause of the patient's adverse drug event. This case report highlights the need to be alert toward the emergence of dermatologic side effects among patients taking modafinil.

Gaikwad, Girish Vasant; Dhuri, Chetali Vijay



Modafinil-induced Fixed Drug Eruption.  


Modafinil is a stimulant drug widely used to promote wakefulness in a variety of psychiatric and neurological conditions. Modafinil-induced severe dermatologic reactions are uncommon but serious side effects. We report a patient who developed fixed drug eruption after exposure to a single dose of tablet modafinil. On assessment using the Naranjo scale, the score was five, which made us conclude that modafinil was the "probable" cause of the patient's adverse drug event. This case report highlights the need to be alert toward the emergence of dermatologic side effects among patients taking modafinil. PMID:23723550

Gaikwad, Girish Vasant; Dhuri, Chetali Vijay



Pharmacodynamics of drug-induced weight gain.  


Body weight gain during treatment with drugs for any kind of disease may represent improvement of the disease itself. However, sometimes these drug-induced alterations of the body's appetite-regulating mechanisms result in excessive weight gain, thus jeopardizing compliance with prescribed medication. A number of drugs are capable of changing body weight as an adverse consequence of their therapeutic effect. Included in this category are the psychotropic drugs such as antipsychotics, antidepressants and mood stabilizers. Antipsychotics are well-known culprits of weight gain. The low-potency (e.g., chlorpromazine and thioridazine) and atypical agents (e.g., clozapine, olanzapine, quetiapine and risperidone) are most often associated with weight gain. Antidepressants such as tricyclic antidepressants and monoamine oxidase (MAO) inhibitors are most often associated with significant weight gain. The tertiary tricyclic antidepressant amitriptyline is thought to induce the most weight gain. Mood stabilizers such as lithium carbonate, valproic acid and carbamazepine also induce weight gain in a considerable number of patients. Treatment with corticosteroids is associated with dose-dependent body weight gain in many patients and corticosteroid-induced obesity aggravates other corticosteroid-associated health risks. Insulin therapy in diabetic patients usually increases body weight. Finally, sulfonylurea derivatives, antineoplastic agents used for the treatment of breast cancer and several drugs used in migraine prophylaxis may cause body weight gain as well. (c) 2001 Prous Science. All rights reserved. PMID:12743638

Kulkarni, S. K.; Kaur, Gurpreet



Anti-apoptotic and anti-inflammatory effect of Piperine on 6-OHDA induced Parkinson's rat model.  


In the present study, we examined the molecular mechanism by which Piperine (bioactive compound of Piper nigrum) inhibits neuronal cell apoptosis. We further investigated the anti-inflammatory effect of Piperine on 6-OHDA induced Parkinson's disease. Consistent with its antioxidant properties, Piperine (10 mg/kg bwt) reduced 6-OHDA-induced lipid peroxidation and stimulated glutathione levels in striatum of rats. Furthermore, Piperine treatment diminished cytochrome-c release from mitochondria and reduced caspase-3 and caspase-9 activation induced by 6-OHDA. Treatment with Piperine markedly inhibited poly(ADP-ribose) polymerase activation, pro-apoptotic Bax levels and elevation of Bcl-2 levels. Piperine reduces contralateral rotations induced by apomorphine. Further narrow beam test and rotarod also showed improvement in motor coordination and balance behavior in rats treated with Piperine. In addition Piperine depletes inflammatory markers, TNF-? and IL-1? in 6-OHDA-induced Parkinson's rats. We propose that, in addition to its antioxidant properties Piperine exerts a protective effect via anti-apoptotic and anti-inflammatory mechanism on 6-OHDA induced Parkinson's disease. PMID:22819561

Shrivastava, Pallavi; Vaibhav, Kumar; Tabassum, Rizwana; Khan, Andleeb; Ishrat, Tauheed; Khan, Mohd Moshahid; Ahmad, Ajmal; Islam, Farah; Safhi, Mohammed M; Islam, Fakhrul



Induced Pluripotent Stem Cells as a Model for Accelerated Patient- and Disease-specific Drug Discovery  

PubMed Central

Human induced pluripotent stem (iPS) cells hold great promise for therapy of a number of degenerative diseases such as ischemic heart failure, Parkinson’s disease, Alzheimer’s disease, diabetes mellitus, sickle cell anemia and Huntington disease. They also have the potential to accelerate drug discovery in 3 ways. The first involves the delineation of chemical components for efficient reprogramming of patient’s blood cells or cells from biopsies, obviating the need for cellular delivery of reprogramming exogenous transgenes, thereby converting hope into reality for patients suffering from degenerative diseases. Patients worldwide stand to benefit from the clinical applicability of iPS cell-based cell replacement therapy for a number of degenerative diseases. The second is the potential for discovering novel drugs in a high throughput manner using patient-specific iPS cell-derived somatic cells possessing the etiology of the specific disease. The third is their suitability for toxicological testing of drugs and environmental factors. This review focuses on these potential applications of iPS cells with special emphasis on recent updates of iPS cell research contributing to the accelerated drug discovery.

Gunaseeli, I.; Doss, M.X.; Antzelevitch, C.; Hescheler, J.; Sachinidis, A.



Subthalamic stimulation modulates self-estimation of patients with Parkinson's disease and induces risk-seeking behaviour.  


Patients with Parkinson's disease with deep brain stimulation in the subthalamic nucleus postoperatively often display higher impulsivity and therefore may experience difficulties in social interactions. Here, we examined social interactions of patients with Parkinson's disease with and without deep brain stimulation in the subthalamic nucleus in competitive situations. We hypothesized altered self-estimation and risk-seeking behaviour in this patient group induced by deep brain stimulation in the subthalamic nucleus. To test the hypothesis, an experimental setting was used in which participants performed a calculation task and chose their preferred compensation. Based on their actual calculation performance, more patients with Parkinson's disease with deep brain stimulation chose a competitive tournament compensation. Assuming rational behaviour, this self-selection pattern reflects increased risk tolerance. Since patients who performed in the lowest quartile chose the tournament option, the data suggest that deep brain stimulation in the subthalamic nucleus results in a loss of the correct reference frame against which patients with Parkinson's disease evaluate their performance. The stimulation-induced combination of overestimation of their own performance, increased risk-taking, and preference for competitive environments despite poor performance is likely to impact considerably on the patients' social and work life. PMID:24071530

Florin, Esther; Müller, Désirée; Pfeifer, Johannes; Barbe, Michael T; Fink, Gereon R; Timmermann, Lars



Initiatives to improve prescribing efficiency for drugs to treat Parkinson's disease in Croatia: influence and future directions.  


Parkinson's disease (PD) is the second most common neurological disease affecting older adults. Consequently, this disease should be a focus among payers, with increasing utilization of newer premium-priced patent-protected add-on therapies to stabilize or even improve motor function over time. However, expenditure can be moderated by reforms. Consequently, there is a need to assess the influence of these reforms on the prescribing efficiency for drugs to treat PD in Croatia before proposing additional measures. Prescribing efficiency is defined as increasing the use of add-on therapies for similar expenditure. An observational retrospective study of the Croatian Institute for Health Insurance database of drugs to treat patients with PD in Croatia from 2000 to 2010 was carried out, with utilization measured in defined daily doses (defined as the average maintenance dose of a drug when used in its major indication in adults). The study years were chosen to reflect recent reforms. Only reimbursed expenditure is measured from a health insurance perspective. Utilization of drugs to treat PD increased by 218% between 2000 and 2010. Reimbursed expenditure increased by 360%, principally driven by increasing utilization of premium-priced patent-protected add-on therapies, including ropinirole and pramipexole. However, following recent reforms, reducing expenditure/defined daily dose for the different drugs, as well as overall expenditure, stabilized reimbursed expenditure between 2005 and 2010. Treatment of PD is complex, and add-on therapies are needed to improve care. Reimbursed expenditure should now fall following stabilization, despite increasing volumes, as successive add-on therapies lose their patents, further increasing prescribing efficiency. PMID:22812560

Brkicic, Ljiljana Sovic; Godman, Brian; Voncina, Luka; Sovic, Slavica; Relja, Maja



Development of Inducible Leucine-rich Repeat Kinase 2 (LRRK2) Cell Lines for Therapeutics Development in Parkinson's Disease.  


The pathogenic mechanism(s) contributing to loss of dopamine neurons in Parkinson's disease (PD) remain obscure. Leucine-rich repeat kinase 2 (LRRK2) mutations are linked, as a causative gene, to PD. LRRK2 mutations are estimated to account for 10 % of familial and between 1 % and 3 % of sporadic PD. LRRK2 proximate single nucleotide polymorphisms have also been significantly associated with idiopathic/sporadic PD by genome-wide association studies. LRRK2 is a multidomain-containing protein and belongs to the protein kinase super-family. We constructed two inducible dopaminergic cell lines expressing either human-LRRK2-wild-type or human-LRRK2-mutant (G2019S). Phenotypes of these LRRK2 cell lines were examined with respect to cell viability, morphology, and protein function with or without induction of LRRK2 gene expression. The overexpression of G2019S gene promoted 1) low cellular metabolic activity without affecting cell viability, 2) blunted neurite extension, and 3) increased phosphorylation at S910 and S935. Our observations are consistent with reported general phenotypes in LRRK2 cell lines by other investigators. We used these cell lines to interrogate the biological function of LRRK2, to evaluate their potential as a drug-screening tool, and to investigate screening for small hairpin RNA-mediated LRRK2 G2019S gene knockdown as a potential therapeutic strategy. A proposed LRRK2 kinase inhibitor (i.e., IN-1) decreased LRRK2 S910 and S935 phosphorylation in our MN9DLRRK2 cell lines in a dose-dependent manner. Lentivirus-mediated transfer of LRRK2 G2019S allele-specific small hairpin RNA reversed the blunting of neurite extension caused by LRRK2 G2019S overexpression. Taken together, these inducible LRRK2 cell lines are suitable reagents for LRRK2 functional studies, and the screening of potential LRRK2 therapeutics. PMID:23963789

Huang, Liang; Shimoji, Mika; Wang, Juan; Shah, Salim; Kamila, Sukanta; Biehl, Edward R; Lim, Seung; Chang, Allison; Maguire-Zeiss, Kathleen A; Su, Xiaomin; Federoff, Howard J



Pesticide-induced gene mutations and Parkinson disease risk: a meta-analysis.  


Aims: Increasing scientific evidence suggests that pesticide-induced gene mutations may contribute to increasing susceptibility to Parkinson disease (PD), but many existing studies have yielded inconclusive results. This meta-analysis aims at assessing the exact roles of pesticide-induced gene mutations in the development of PD. Methods: An extensive literature search for relevant studies was conducted on PubMed, Embase, Web of Science, Cochrane Library, and CBM databases from their inception through May 1st, 2013. This meta-analysis was performed using the STATA 12.0 software. The crude odds ratio with 95% confidence interval was calculated. Results: Ten case-control studies were included with a total of 1248 PD patients and 1831 healthy controls. Our meta-analysis revealed that PD patients with pesticide exposure had higher gene mutation rates than those of healthy controls. Subgroup analysis by gene type indicated that the mutation rates in the GSTP1, SLC6A3, and MDR1 genes of PD patients with pesticide exposure were higher than those of healthy controls. No publication bias was detected in this meta-analysis. Conclusion: The current meta-analysis indicates that pesticide-induced gene mutations may contribute to increasing susceptibility to PD, especially in the GSTP1, SLC6A3, and MDR1 genes. PMID:23987116

Liu, Xiaowei; Ma, Tao; Qu, Bo; Ji, Yan; Liu, Zhi



Reprint of: revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease-resemblance to the effect of amphetamine drugs of abuse.  


Parkinson disease (PD) is a chronic and progressive neurological disease associated with a loss of dopaminergic neurons. In most cases the disease is sporadic but genetically inherited cases also exist. One of the major pathological features of PD is the presence of aggregates that localize in neuronal cytoplasm as Lewy bodies, mainly composed of ?-synuclein (?-syn) and ubiquitin. The selective degeneration of dopaminergic neurons suggests that dopamine itself may contribute to the neurodegenerative process in PD. Furthermore, mitochondrial dysfunction and oxidative stress constitute key pathogenic events of this disorder. Thus, in this review we give an actual perspective to classical pathways involving these two mechanisms of neurodegeneration, including the role of dopamine in sporadic and familial PD, as well as in the case of abuse of amphetamine-type drugs. Mutations in genes related to familial PD causing autosomal dominant or recessive forms may also have crucial effects on mitochondrial morphology, function, and oxidative stress. Environmental factors, such as MPTP and rotenone, have been reported to induce selective degeneration of the nigrostriatal pathways leading to ?-syn-positive inclusions, possibly by inhibiting mitochondrial complex I of the respiratory chain and subsequently increasing oxidative stress. Recently, increased risk for PD was found in amphetamine users. Amphetamine drugs have effects similar to those of other environmental factors for PD, because long-term exposure to these drugs leads to dopamine depletion. Moreover, amphetamine neurotoxicity involves ?-syn aggregation, mitochondrial dysfunction, and oxidative stress. Therefore, dopamine and related oxidative stress, as well as mitochondrial dysfunction, seem to be common links between PD and amphetamine neurotoxicity. PMID:23743292

Perfeito, Rita; Cunha-Oliveira, Teresa; Rego, Ana Cristina



Cationic amphiphilic drug-induced phospholipidosis.  


Phospholipidosis, a phospholipid storage disorder, defines an excessive accumulation of intracellular phospholipids. Phospholipids are structural components of mammalian cytoskeleton and cell membranes. The metabolism of this essential cell component is regulated by the individual cell and may be altered by drugs that interact with phospholipids or the enzymes that affect their metabolism. Xenobiotics or their metabolites that induce phospholipidosis include a wide variety of pharmacologic agents, including antibacterials, antipsychotics, antidepressants, antiarrhythmics, antianginals, antimalarials, anorexic agents, cholesterol-lowering agents, and others. Each of these drugs shares several common physiochemical properties: hydrophobic ring structure on the molecule and a hydrophilic side chain with a charged cationic amine group, hence the class term cationic amphiphilic drugs (CADs). This paper reviews the phospholipid metabolism, physiochemical characteristics of CADs, specificity of phospholipidosis in animals and humans, functional effects of phospholipidosis, interaction of CADs with biologic membranes and lysosome metabolism, influence of CADs on phospholipases and phospholipid synthesis, and a proposed mechanism for induction of phospholipidosis in the lung. In human risk assessment, investigators should consider the many factors in evaluating a drug that induces phospholipidosis in animals. These include: the therapeutic class of drug, presence of active metabolites, tissue or organ selectivity in animals and humans, influence of concurrently administered drugs, reversibility of effect, and other factors that increase or decrease the induction of phospholipidosis. Generalities regarding the etiology, incidence, and effect of the drug on a specific host may not be made. Each drug must be evaluated separately to identify the risk when administered for therapeutic effect in humans. PMID:9061852

Halliwell, W H


Calcium entry induces mitochondrial oxidant stress in vagal neurons at risk in Parkinson's disease  

PubMed Central

Mitochondrial oxidant stress is widely viewed as critical to pathogenesis in Parkinson’s disease. But the origins of this stress are poorly defined. One possibility is that it arises from the metabolic demands associated with regenerative activity. To test this hypothesis, neurons in the dorsal motor nucleus of the vagus (DMV), a population cholinergic neurons that shows signs of pathology in the early stages of Parkinson’s disease, were characterized in mouse brain slices. DMV neurons were slow, autonomous pacemakers with broad spikes, leading to calcium entry that was weakly buffered. Using a novel transgenic mouse expressing a redox-sensitive optical probe targeted to the mitochondrial matrix, it was found that calcium entry during pacemaking created a basal mitochondrial oxidant stress. Knocking out DJ-1 – a gene associated with early-onset Parkinson’s disease – exacerbated this stress. These results point to a common mechanism underlying mitochondrial oxidant stress in Parkinson’s disease and a therapeutic strategy to ameliorate it.

Goldberg, Joshua A.; Guzman, Jaime N.; Estep, Chad M.; Ilijic, Ema; Kondapalli, Jyothisri; Sanchez-Padilla, Javier; Surmeier, D. James



Levodopa-induced local cerebral blood flow changes in Parkinson's disease and related disorders  

Microsoft Academic Search

Local cerebral blood flow (CBF) in the steady state and after intravenous administration of levodopa (1 mg\\/kg) was measured by xenon-enhanced computed tomography in patients with Parkinson's disease (PD, n = 16), progressive supranuclear palsy (PSP, n = 6), olivopontocerebellar atrophy (OPCA, n = 5), and arteriosclerotic parkinsonism (AP, n = 7). Three patterns of local CBF changes following levodopa

Masahiro Kobari; Yasuo Fukuuchi; Tamotsu Shinohara; Katsuyuki Obara; Shigeru Nogawa



A validated chiral liquid chromatographic method for the enantiomeric separation of safinamide mesilate, a new anti-Parkinson drug.  


A enantioselective reversed-phase high performance liquid chromatographic method was developed for the enantiomeric resolution of safinamide mesilate, 2(S)-[4-(3-fluorobenzyloxy)benzylamino] propionamide methanesulfonate, a neuroprotectant with antiparkinsonian and anticonvulsant activity for the treatment of Parkinson disease. The enantiomers of safinamide mesilate were baseline resolved on a Chiralcel OD-RH (150mm×4.6mm, 5?m) column using a mobile phase system containing 300mM sodium di-hydrogen phosphate buffer (pH 3.0):methanol:acetonitrile (65:25:10, v/v/v). The resolution between the enantiomers was not less than 3.0. The pH value of buffer solution in the mobile phase has played a key role in enhancing chromatographic efficiency and resolution between the enantiomers. The developed method was validated and proved to be robust. The limit of detection and limit of quantification of (R)-enantiomer were found to be 15 and 50ng/mL, respectively, for 20?L injection volume. The percentage recovery of (R)-enantiomer was ranged from 94.2 to 103.7 in bulk drug samples of safinamide mesilate. The sample solution and mobile phase were found to be stable at least for 48h. The final optimized method was successfully applied to separate (R)-enantiomer from safinamide mesilate and was proven to be reproducible and accurate for the quantitative determination of (R)-enantiomer in bulk drugs. PMID:21277726

Zhang, Kai; Xue, Na; Shi, Xiaowei; Liu, Weina; Meng, Jing; Du, Yumin



Dopamine D 3 receptor stimulation underlies the development of L-DOPA-induced dyskinesia in animal models of Parkinson's disease  

Microsoft Academic Search

Development of L-DOPA-induced dyskinesia (LID) remains a major problem in the long-term treatment of Parkinson's disease (PD). Sensitization to L-DOPA correlates with ectopic expression of D3 dopamine receptors in the striatum, implicating D3 receptors in development of LID.We demonstrate that the selective D3 antagonist S33084 abolishes development of LID over 30 days in MPTP-lesioned marmosets without effecting the anti-parkinsonian actions of

Naomi P. Visanji; Susan H. Fox; Tom Johnston; Gabriela Reyes; Mark J. Millan; Jonathan M. Brotchie



Parkinson’s disease  


... leads to shaking ( tremors ) and difficulty with walking , movement, and coordination. ... disease occurs in younger adults. It affects both men and women. In ... movement. Parkinson's disease occurs when the nerve cells in ...


Adherence to anti-Parkinson drug therapy in the "REASON" sample of Italian patients with Parkinson's disease: the linguistic validation of the Italian version of the "Morisky Medical Adherence scale-8 items"  


Information about patients' adherence to therapy represents a primary issue in Parkinson's disease (PD) management. To perform the linguistic validation of the Italian version of the self-rated 8-Item Morisky Medical Adherence Scale (MMAS-8) and to describe in a sample of Italian patients affected by PD the adherence to anti-Parkinson drug therapy and the association between adherence and some socio-demographic and clinical features. MMAS-8 was translated into Italian language by two independent Italian mother-tongue translators. The consensus version was then back-translated by an English mother-tongue translator. This translation process was followed by a consensus meeting between the authors of translation and investigators and then by two comprehension tests. The translated version of the MMAS-8 scale was then administered at the baseline visit of the "REASON" study (Italian Study on the Therapy Management in Parkinson's disease: Motor, Non-Motor, Adherence and Quality Of Life Factors) in a large sample of PD patients. The final version of the MMAS-8 was easily understood. Mean ± SD MMAS-8 score was 6.1 ± 1.2. There were no differences in adherence to therapy in relationship to disease severity, gender, educational level or decision to change therapy. The Italian version of MMAS-8, the key tool of the REASON study to assess the adherence to therapy, has shown to be understandable to patients with PD. Patients enrolled in the REASON study showed medium therapy adherence. PMID:23728715

Fabbrini, G; Abbruzzese, G; Barone, P; Antonini, A; Tinazzi, M; Castegnaro, G; Rizzoli, S; Morisky, D E; Lessi, P; Ceravolo, R



Silymarin- and melatonin-mediated changes in the expression of selected genes in pesticides-induced Parkinsonism.  


Parkinson's disease (PD) is the second most unconcealed neurodegenerative disorder labelled with motor impairments. Two pesticides, manganese ethylene-1,2-bisdithiocarbamate (maneb) and 1,1'-dimethyl-4,4'-bipyridinium dichloride (paraquat), together, are reported to increase the incidence of PD in humans and Parkinsonism in mice. Conversely, silymarin and melatonin, two naturally occurring antioxidants, rescue from maneb- and paraquat-induced Parkinsonism. The study examined silymarin- and melatonin-mediated changes in the expression of selected genes in maneb- and paraquat-induced Parkinsonism employing mouse discover chips microarrays. The mice were treated intraperitoneally (i.p.), daily, with silymarin (40 mg/kg) or melatonin (30 mg/kg) for 9 weeks along with vehicles. Subsets of animals were also treated with maneb (30 mg/kg; i.p.) and paraquat (10 mg/kg; i.p.), twice a week, for 9 weeks. Whilst the expression of genes in the striatum was determined by microarray, the expression of randomly selected transcripts was validated by quantitative real-time polymerase chain reaction (qRT-PCR). Combined maneb- and paraquat-treatment altered the expression of several genes associated with apoptosis, inflammation, cell cycle, cell-signalling, etc. pathways. Silymarin and melatonin significantly resisted the changes in the expression of a few genes related to apoptosis, inflammation, cell cycle, cell-signalling, etc. The expression patterns of seven randomly selected genes were analyzed by qRT-PCR, which were found to follow the similar trends, as observed with microarray. The results obtained from the study thus demonstrate that despite resemblances, silymarin and melatonin differentially offset maneb- and paraquat-induced changes in transcriptome. PMID:23963992

Singhal, Naveen Kumar; Chauhan, Amit Kumar; Jain, Swatantra Kumar; Shanker, Rishi; Singh, Chetna; Singh, Mahendra Pratap



Surveillance of drug induced diseases in children  

Microsoft Academic Search

A hospital based prospective study on drug induced diseases (DID) in children below 14 years of age was done for a duration\\u000a of two years. A total number of 20,310 patients were examined in pediatric department during this period, out of which 204\\u000a (1.004%) patients were diagnosed as DID. Children with severe reactions were admitted in pediatric ward, for in

K. P. Kushwaha; R. B. Verma; Y. D. Singh; A. K. Rathi



An update on adenosine A2A receptors as drug target in Parkinson's disease.  


Adenosine receptors are G protein-coupled receptors (GPCRs) that mediate the physiological functions of adenosine. In the central nervous system adenosine A(2A) receptors (A(2A)Rs) are highly enriched in striatopallidal neurons where they form functional oligomeric complexes with other GPCRs such us the dopamine D(2) receptor (D(2)R). Furthermore, it is assumed that the formation of balanced A(2A)R/D(2)R receptor oligomers are essential for correct striatal function as the allosteric receptor-receptor interactions established within the oligomer are needed for properly sensing adenosine and dopamine. Interestingly, A(2A)R activation reduces the affinity of striatal D(2)R for dopamine and the blockade of A(2A)R with specific antagonists facilitates function of the D(2)R. Thus, it may be postulated that A(2A)R antagonists are pro-dopaminergic agents. Therefore, A(2A)R antagonists will potentially reduce the effects associated with dopamine depletion in Parkinson's disease (PD). Accordingly, this class of compounds have recently attracted considerable attention as potential therapeutic agents for PD pharmacotherapy as they have shown potential effectiveness in counteracting motor dysfunctions and also displayed neuroprotective and anti-inflammatory effects in animal models of PD. Overall, we provide here an update of the current state of the art of these A(2A)R-based approaches that are under clinical study as agents devoted to alleviate PD symptoms. PMID:21838670

Vallano, Antoni; Fernandez-Duenas, Victor; Pedros, Consuelo; Arnau, Josep Maria; Ciruela, Francisco



Nicotinic receptor stimulation protects nigral dopaminergic neurons in rotenone-induced Parkinson's disease models.  


Parkinson's disease (PD) is the second most common neurodegenerative disease and is characterized by dopaminergic (DA) neuronal cell loss in the substantia nigra. Although the entire pathogenesis of PD is still unclear, both environmental and genetic factors contribute to neurodegeneration. Epidemiologic studies show that prevalence of PD is lower in smokers than in nonsmokers. Nicotine, a releaser of dopamine from DA neurons, is one of the candidates of antiparkinson agents in tobacco. To assess the protective effect of nicotine against rotenone-induced DA neuronal cell toxicity, we examined the neuroprotective effects of nicotine in rotenone-induced PD models in vivo and in vitro. We observed that simultaneous subcutaneous administration of nicotine inhibited both motor deficits and DA neuronal cell loss in the substantia nigra of rotenone-treated mice. Next, we analyzed the molecular mechanisms of DA neuroprotective effect of nicotine against rotenone-induced toxicity with primary DA neuronal culture. We found that DA neuroprotective effects of nicotine were inhibited by dihydro-beta-erythroidine (DHbetaE), alpha-bungarotoxin (alphaBuTx), and/or PI3K-Akt/PKB (protein serine/threonine kinase B) inhibitors, demonstrating that rotenone-toxicity on DA neurons are inhibited via activation of alpha4beta2 or alpha7 nAChRs-PI3K-Akt/PKB pathway or pathways. These results suggest that the rotenone mouse model may be useful for assessing candidate antiparkinson agents, and that nAChR (nicotinic acetylcholine receptor) stimulation can protect DA neurons against degeneration. PMID:18803299

Takeuchi, Hiroki; Yanagida, Takashi; Inden, Masatoshi; Takata, Kazuyuki; Kitamura, Yoshihisa; Yamakawa, Kentaro; Sawada, Hideyuki; Izumi, Yasuhiko; Yamamoto, Noriyuki; Kihara, Takeshi; Uemura, Kengo; Inoue, Haruhisa; Taniguchi, Takashi; Akaike, Akinori; Takahashi, Ryosuke; Shimohama, Shun



Biomarkers of cell damage induced by oxidative stress in Parkinson's disease and related models.  


One of the common features occurring in several experimental models of neurodegenerative disorders is oxidative/nitrosative stress (OS/NS). This event induces a series of deleterious actions involving the primary formation of reactive oxygen and nitrogen species (ROS/RNS), affecting both the structure and function of different biological molecules, and leading to specific toxic processes that compromise cell redox status. Biomarkers are important indicators of normal and abnormal biological processes. Specific biochemical and genetic changes observed in different pathologies bring us comprehensive information regarding the nature of any particular disorder. Parkinson's disease (PD) is a chronic neurodegenerative disorder difficult to study, given the intricate events occurring in the pathology, and also because the resultant clinical phenotype fluctuates over time. At present, we have no definitive diagnostic test, and thus for clinicians there is still expectation that biomarkers will eventually help to diagnose symptomatic and presymptomatic disease, or provide surrogated end-points to demonstrate clinical efficacy of new treatments and neuroprotective therapies. In this review we explore current information on some potential biomarkers of OS/NS in PD models, with special emphasis on the most-recent findings on this topic. PMID:20868359

Tobón-Velasco, Julio César; Carmona-Aparicio, Liliana; Ali, Syed F; Santamaría, Abel



Neuroprotective role of Withania somnifera root extract in maneb-paraquat induced mouse model of parkinsonism.  


Parkinson's disease (PD) is a neurodegenerative disorder and these days a lot of emphasis is given on the treatment of this disease using herbal medicines. The present study evaluates the neuroprotective effect of Withania somnifera (Ws) root extract on Parkinsonian mice. The mice were divided into three groups; the first group served as control, the second group was given maneb (MB) and paraquat (PQ) and the last group was administered MB-PQ along with Ws root extract for 3, 6 and 9 weeks. The behavioral studies showed a significant improvement in the motor movement patterns and gripping ability of Ws root extract exposed Parkinsonian mice. Tyrosine hydroxylase (TH) immunostaining was reduced in the substantia nigra of MB-PQ exposed mice, while Ws co-exposure restored TH immunostaining significantly. Additionally, our results also demonstrate generation of oxidative stress in the nigrostriatal region of MB-PQ exposed mice. There was a marked decline in the level of catalase and a simultaneous increase in the level of nitrite and lipid peroxidation in Parkinsonian mice. Thus, the Ws root extract have shown to counteract the pro-oxidants and their associated oxidative stress in the PD model studied here. Our results clearly indicate the usefulness of Ws root extract in providing protection against MB-PQ induced nigrostriatal dopaminergic neurodegeneration and marked improvement in the behavioral, anatomical and the biochemical deformities. PMID:23430469

Prakash, Jay; Yadav, Satyndra Kumar; Chouhan, Shikha; Singh, Surya Pratap



Parkinson's disease  

Microsoft Academic Search

Parkinson's disease is a common disabling disease of old age. The diagnosis of idiopathic Parkinson's disease is based on clinical signs and has poor sensitivity, with about 25% of patients confidently diagnosed as having the disease actually having other conditions such as multi-system atrophy and other parkinsonism-plus syndromes. Benign essential tremor and arteriosclerotic pseudo-parkinsonism can easily be confused with Parkinson's

J. R. Playfer



Inhibition of monoamine oxidase-B by the polyphenolic compound, curcumin and its metabolite tetrahydrocurcumin, in a model of Parkinson’s disease induced by MPTP neurodegeneration in mice  

Microsoft Academic Search

.  We investigated the effects of the polyphenolic compound curcumin and its metabolite tetrahydrocurcumin (ThC), in the model\\u000a of Parkinson’s disease induced in mice by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this model depletion of\\u000a dopamine(DA) and DOPAC (3,4-dihydroxy phenyl acetic acid)) occurs with increased monoamine oxidase (MAO-B) activity. We used\\u000a HPLC with electrochemical detection to measure DA and DOPAC respectively while MAO-B was

A. Rajeswari; M. Sabesan



What is the best treatment for fluctuating Parkinson's disease: continuous drug delivery or deep brain stimulation of the subthalamic nucleus?  


Motor complications impair quality of life and cause severe disability in patients with advanced Parkinson's disease (PD). Since they are often refractory to medical therapy, interventional therapies have been developed, which can provide a considerable reduction of daily off-time and dopaminergic dyskinesias. Continuous dopaminergic drug delivery (CDD) is based on the steady stimulation of striatal dopamine receptors by subcutaneous apomorphine or duodenal L: -DOPA infusions via portable minipumps. Advances in the understanding of basal ganglia functioning and in neurosurgical, electrophysiological and neuroimaging techniques have led to a renaissance of neurosurgery for advanced PD. Deep brain stimulation of the subthalamic nucleus (STN-DBS) is the most invasive procedure promising great benefit and the highest level of independency for suitable patients, but is definitely associated with surgical risks and DBS-related side effects. Each of these more or less invasive therapy options has its own profile, and a thorough consideration of its advantages and drawbacks for the individual situation is mandatory. In this paper, we summarize relevant facts for this decision and provide some guidelines for a responsible counseling of eligible patients. PMID:21188435

Hilker, Rüdiger; Antonini, Angelo; Odin, Per



Drug-induced inflammatory responses to the lung.  


A number of drugs can induce lung toxicity. The lung manifestations can range from more acute responses such as an acute ARDS-like reaction, seen occasionally at overdosing of drugs to more insidious reactions, which can occur during conventional drug treatment. In many of these cases inflammation is an important component in the pathophysiology of drug induced lung toxicity. Very little is known about the mechanisms and initial events of drug-induced injury. In this review a couple of mechanistic aspects, related to drug induced lung injury, will be discussed such as reactive oxygen species (ROS)-generation, mediator release and disturbances in lung phospholipid turnover. PMID:10720728

Ryrfeldt, A



Is there room for non-dopaminergic treatment in Parkinson disease?  


Although levodopa and dopaminergic drugs remain the mainstay of therapy for the motor symptoms of Parkinson disease (PD), they fail to address many of the non-motor symptoms of PD including orthostatic hypotension, freezing of gait (FOG) and difficulty with balance, drug-induced paranoia and hallucinations, and drug-induced dyskinesias. Droxidopa, a drug that increases norepinephrine, treats orthostatic hypotension, cholinomimetic drugs sometimes help with FOG and difficulty with balance, pimavanserin, a drug that blocks serotonin receptors, treats paranoia and hallucinations, and anti-glutaminergic drugs treat dyskinesias. Thus, there are ample opportunities for non-dopaminergic drugs in PD. PMID:23242741

Lieberman, Abraham; Krishnamurthi, Narayanan



Bedtime cabergoline in Parkinson’sdisease patients with excessive daytime sleepiness induced bydopamine agonists  

Microsoft Academic Search

Excessive daytime somnolence is a common adverse effect of dopamine-agonist treatment of Parkinson’s disease (PD). Many factors, such as age and sleep disturbances, could be involved in the pathogenesis of this phenomenon. However, pharmacokinetic factors have never been considered. In this open, prospective, pilot study, nine consecutive non-demented PD patients in early disease stages on monotherapy treatment with dopamine agonists

P. Del Dotto; G. Gambaccini; D. Caneparo; C. Berti; S. Bernardini; U. Bonuccelli



Compulsive drumming induced by dopamine agonists treatment in Parkinson's disease: Another aspect of punding.  


We report the case of a man affected by Parkinson's disease who developed an unusual, severe, repetitive behavior characterized by an irrepressible need to drum and beat percussion instruments following to the introduction of pramipexole. This compulsive behavior was not associated to a pattern of chronic inappropriate overuse of dopaminergic medication or other psychiatric symptoms. Sharing many features with other repetitive behaviors, compulsive drumming might be considered a distinct manifestation of punding in Parkinson's disease. PMID:23242361

Vitale, Carmine; Trojano, Luigi; Barone, Paolo; Errico, Domenico; Agosti, Valeria; Sorrentino, Giuseppe; Grossi, Dario; Santangelo, Gabriella



The relationship between motor symptom lateralization and cognitive performance in newly diagnosed drug-naďve patients with Parkinson's disease.  


The side of motor symptom predominance may influence cognitive performance in patients with Parkinson's disease (PD): PD patients with right-side motor symptom predominance typically present difficulties in tasks of language and verbal memory, whereas PD patients with left-side motor symptom predominance typically present difficulties in visuospatial tasks. The current study aimed at investigating the relationship between motor symptom lateralization and cognitive performance in PD patients without the possible confounding effect of dopaminergic drugs, which may enhance or impair cognition on the basis of assessed function and disease stage. From the initial sample of 137 consecutive newly diagnosed drug-naďve (de novo) PD patients, clinical follow-ups and neurological examinations identified 108 right-handed patients with a unilateral motor presentation or a clear motor asymmetry (59 right-PD: 54.6%; 49 left-PD: 45.4%). Any cognitive difference emerged between right-PD patients and left-PD patients at this disease stage. Scores of lateralized motor impairment severity correlated with some cognitive performances: Right motor impairment correlated with a measure of set shifting (Trail Making Test B-A), and left motor impairment correlated with phonemic fluency and tasks with visuospatial material (Colored Progressive Matrices of Raven, Rey-Osterrieth Complex Figure Copy and Immediate Recall). Findings of the current study supported the conclusion that the side of clinical motor predominance scarcely influences cognition in the early untreated stages of PD, suggesting that cognitive differences between subgroups of lateralized PD patients probably may appear in more advanced disease stages. PMID:23216295

Poletti, Michele; Frosini, Daniela; Pagni, Cristina; Baldacci, Filippo; Giuntini, Martina; Mazzucchi, Sonia; Tognoni, Gloria; Lucetti, Claudio; Del Dotto, Paolo; Ceravolo, Roberto; Bonuccelli, Ubaldo



Pramipexole-induced increased probabilistic discounting: comparison between a rodent model of Parkinson's disease and controls.  


The dopamine agonist pramipexole (PPX) can increase impulsiveness, and PPX therapy for neurological diseases (Parkinson's disease (PD) and restless leg syndrome) is associated with impulse control disorders (ICDs) in subpopulations of treated patients. A commonly reported ICD is pathological gambling of which risk taking is a prominent feature. Probability discounting is a measurable aspect of risk taking. We recently developed a probability discounting paradigm wherein intracranial self-stimulation (ICSS) serves as the positive reinforcer. Here we used this paradigm to determine the effects of PPX on discounting. We included assessments of a rodent model of PD, wherein 6-OHDA was injected into the dorsolateral striatum of both hemispheres, which produced persistent PD-like deficits in posture adjustment. Rats were trained to perform ICSS-mediated probability discounting, in which PD-like and control groups exhibited similar profiles. Rats were treated twice daily for 2 weeks with 2?mg/kg (±)PPX (ie, 1?mg/kg of the active form), a dose that improved lesion-induced motor deficits. In both groups, (±)PPX increased discounting; preference for the large reinforcer was enhanced 30-45% at the most uncertain probabilities. Tolerance did not develop with repeated treatments. Increased discounting subsided within 2 weeks of (±)PPX cessation, and re-exposure to (±)PPX reinstated heightened discounting. Such findings emulate the clinical scenario; therefore, ICSS for discounting assessments in rats exhibited high face validity. This model should prove useful in medication development where assessment of the propensity of a putative therapy to induce risk-taking behaviors is of interest. PMID:22257895

Rokosik, Sandra L; Napier, T Celeste



Management of drug-induced liver disease.  


The treatment and prevention of drug-induced liver injury starts with the recognition of hepatotoxicity at the earliest possible time so that the suspected drug can be discontinued expeditiously. Both liver enzyme monitoring and vigilance for signs of hypersensitivity involving the liver are useful strategies for many agents known to cause hepatocellular necrosis leading to liver failure. Specific antidotes to prevent or limit hepatic damage exist for only a few drugs, the most important being N-acetylcysteine for the treatment of acetaminophen hepatotoxicity. Corticosteroids are of unproven benefit in the setting of fulminant failure. Ursodiol may be helpful in instances of cholestatic injury. For other agents, supportive measures and the increasing use of liver-assist devices as well as emergency liver transplantation are available when drug injury evolves into irreversible liver failure. It is hoped that a better understanding of hepatotoxicity mechanisms will lead to the development of more specific and effective forms of therapy in the near future. PMID:11177693

Marino, G; Zimmerman, H J; Lewis, J H



Protective effects of nicotine against aminochrome-induced toxicity in substantia nigra derived cells: implications for Parkinson's disease.  


Parkinson's disease is a debilitating progressive neurodegenerative disorder that results from the loss of or damage to dopaminergic cells containing neuromelanin in the substantia nigra (SN). The underlying neurodegenerative mechanism(s), however, remain elusive. Aminochrome, the precursor of neuromelanin is an endogenous substance capable of inducing selective neurotoxicity to dopaminergic neurons in SN. Nicotine, on the other hand, may offer protective effects against dopaminergic cell damage induced by various neurotoxins including MPTP and salsolinol. In this study, we sought to determine whether nicotine may also protect against aminochrome-induced toxicity in SN derived RCSN-3 cells. Exposure of RCSN-3 cells to a combination of aminochrome (50 ?M) and dicoumarol (50 ?M) for 48 h induced approximately 70 % cell death. Pretreatment with nicotine, dose-dependently blocked this toxicity. The effects of nicotine in turn were dose-dependently blocked by mecamylamine, a non-selective nicotinic receptor antagonist. These results suggest involvement of nicotinic receptors in protective effects of nicotine against aminochrome-induced toxicity and provide further evidence for possible therapeutic effects of nicotine or nicotinic agonists in Parkinson's disease. PMID:22528249

Muńoz, Patricia; Huenchuguala, Sandro; Paris, Irmgard; Cuevas, Carlos; Villa, Monica; Caviedes, Pablo; Segura-Aguilar, Juan; Tizabi, Yousef



Pramipexole (Mirapex) for Parkinson's: Safety News from the FDA  


... Pramipexole (Mirapex®) for Parkinson's: Safety News from the FDA - Sep 20 2012 The Parkinson's Disease Foundation® (PDF®) ... their doctors: The United States Federal Drug Administration (FDA), the governmental agency that monitors prescription drugs, alerted ...


Young-Onset Parkinson's  


... here: Parkinson's Disease > Young-Onset Parkinson's Text Size Young-Onset Parkinson's The diagnosis of Young-Onset Parkinson’s ... Parkinson's Conference . What are the common symptoms of Young-Onset PD? There are some symptoms that are ...


Fatal drug-induced heat stroke.  


In the case reported, fatal hyperpyrexia resulted from massive doses of chlorpromazine combined with benztropine mesylate given to a paranoid schizophrenic admitted for increased psychotic symptoms. Phenothiazines disturb the thermoregulatory mechanism and also exert anticholinergic effects peripherally, including sweating. The goal of treatment of drug-induced hyperpyrexia is to reduce oxygen demand and core temperature. Ice water soaked towels, fanning, thermal blanket, or immersion in an ice bath can be used. Oxygenation will help combat further tissue anoxia. Severe acidosis may be present and must be corrected with sodium bicarbonate after arterial pH determination. Vasoconstrictors should be avoided if shock is present. PMID:661049

Forester, D



Drug-induced deactivation of inhibitory networks predicts pathological gambling in PD (e–Pub ahead of print)  

PubMed Central

Objective: Some patients with Parkinson disease (PD) develop pathological gambling when treated with dopamine agonists (DAs). However, little is known about DA-induced changes in neuronal networks that may underpin this drug-induced change in behavior in vulnerable individuals. In this case-control study, we aimed to investigate DA-induced changes in brain activity that may differentiate patients with PD with DA-induced pathological gambling (gamblers) from patients with PD without such a history (controls). Methods: Following overnight withdrawal of antiparkinsonian medication, patients were studied with H2 15O PET before and after administration of DA (3 mg apomorphine) to measure changes in regional cerebral blood flow as an index of regional brain activity during a card selection game with probabilistic feedback. Results: We observed that the direction of DA-related activity change in brain areas that are implicated in impulse control and response inhibition (lateral orbitofrontal cortex, rostral cingulate zone, amygdala, external pallidum) distinguished gamblers from controls. DA significantly increased activity in these areas in controls, while gamblers showed a significant DA-induced reduction of activity. Conclusions: We propose that in vulnerable patients with PD, DAs produce an abnormal neuronal pattern that resembles those found in nonparkinsonian pathological gambling and drug addiction. DA-induced disruption of inhibitory key functions—outcome monitoring (rostral cingulate zone), acquisition and retention of negative action-outcome associations (amygdala and lateral orbitofrontal cortex)—together with restricted access of those areas to executive control (external pallidum)—may well explain loss of impulse control and response inhibition in vulnerable patients with PD, thereby fostering the development of pathological gambling. GLOSSARY ANOVA = analysis of variance; DA = dopamine agonist; G-SAS = Gambling Symptom Assessment Scale; GPe = external pallidum; MNI = Montréal Neurological Institute; OFC = orbitofrontal cortex; PD = Parkinson disease; rCBF = regional cerebral blood flow; RCZ = rostral cingulated zone; UPDRS = Unified Parkinson's Disease Rating Scale.

van Eimeren, T.; Pellecchia, G.; Cilia, R.; Ballanger, B.; Steeves, T.D.L.; Houle, S.; Miyasaki, J.M.; Zurowski, M.; Lang, A.E.; Strafella, A.P.



Kinematic optimization of deep brain stimulation across multiple motor symptoms in Parkinson's disease  

Microsoft Academic Search

Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor symptoms including tremor and bradykinesia (slowness of movement). Drug treatment, although capable of controlling these symptoms over a number of years, becomes less effective as the disease progresses and leads to motor complications such as drug-induced dyskinesia (involuntary abnormal movements). Deep brain stimulation (DBS) provides an alternative means of controlling

Thomas Mera; Jerrold L. Vitek; Jay L. Alberts; Joseph P. Giuffrida



Drug-induced lipidoses of the cornea and conjunctiva  

Microsoft Academic Search

A variety of lysosomal disorders affect the human cornea and conjunctiva. These disorders may result from inborn abnormalities of a specific intralysosomal enzyme such as the deficit of ceramide trihexosidase in Fabry's disease. Alternately, lysosomal dysfunction may be the result of drug administration with subsequent drug-induced lipidosis. Chloroquine, amiodarone, amodiaquine, benoquin, tilorone, and gentamicin are lipidosis-inducing drugs with proven involvement

Donald J. D'amico; Kenneth R. Kenyon



The pharmacology of L-DOPA-induced dyskinesia in Parkinson's disease.  


L-3,4-Dihydroxyphenylalanine (L-DOPA) remains the most effective symptomatic treatment of Parkinson's disease (PD). However, long-term administration of L-DOPA is marred by the emergence of abnormal involuntary movements, i.e., L-DOPA-induced dyskinesia (LID). Years of intensive research have yielded significant progress in the quest to elucidate the mechanisms leading to the development and expression of dyskinesia and maintenance of the dyskinetic state, but the search for a complete understanding is still ongoing. Herein, we summarize the current knowledge of the pharmacology of LID in PD. Specifically, we review evidence gathered from postmortem and pharmacological studies, both preclinical and clinical, and discuss the involvement of dopaminergic and nondopaminergic systems, including glutamatergic, opioid, serotonergic, ?-aminobutyric acid (GABA)-ergic, adenosine, cannabinoid, adrenergic, histaminergic, and cholinergic systems. Moreover, we discuss changes occurring in transcription factors, intracellular signaling, and gene expression in the dyskinetic phenotype. Inasmuch as a multitude of neurotransmitters and receptors play a role in the etiology of dyskinesia, we propose that to optimally alleviate this motor complication, it may be necessary to develop combined treatment approaches that will target simultaneously more than one neurotransmitter system. This could be achieved via three ways as follows: 1) by developing compounds that will interact simultaneously to a multitude of receptors with the required agonist/antagonist effect at each target, 2) by targeting intracellular signaling cascades where the signals mediated by multiple receptors converge, and/or 3) to regulate gene expression in a manner that has effects on signaling by multiple pathways. PMID:23319549

Huot, Philippe; Johnston, Tom H; Koprich, James B; Fox, Susan H; Brotchie, Jonathan M



Cellular Imaging Predictions of Clinical Drug-Induced Liver Injury  

Microsoft Academic Search

Drug-induced liver injury (DILI) is the most common adverse event causing drug nonapprovals and drug withdrawals. Using drugs as test agents and measuring a panel of cellular phenotypes that are directly linked to key mechanisms of hepatotoxicity, we have developed an in vitro testing strategy that is predictive of many clinical outcomes of DILI. Mitochondrial damage, oxidative stress, and intracellular

Jinghai J. Xu; Peter V. Henstock; Margaret C. Dunn; Arthur R. Smith; Jeffrey R. Chabot; David de Graaf



Drug- induced liver injury: pre-clinical issues in drug ...  

Center for Drug Evaluation (CDER)

Text Version... Page 54. Hepatotoxicity in Drug Development Animal Toxicity Studies (2) ? all animals sacrificed at the end of the study ... More results from


Geraniol Ameliorates the Motor Behavior and Neurotrophic Factors Inadequacy in MPTP-Induced Mice Model of Parkinson's Disease.  


Many experiments affirm the notion that augmentation of neurotrophic factors (NTFs) activity, especially brain-derived neurotrophic factors and glial cell-derived neurotrophic factors, could prevent or halt the progress of neurodegeneration in Parkinson's disease (PD). In this study, we investigated the therapeutic accomplishment of geraniol (GE 100 mg/kg) on 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced mice model of PD. Current investigation proved that pretreatment with GE ameliorates the MPTP-induced alterations in behavioral, biochemical, immunohistochemical, and immunoblotting manifestations in mice. Systematically, the loss of dopaminergic neurons and reduced NTFs mRNA expressions induced by MPTP was ameliorated to a significant extent by pretreatment with GE. We found that GE confers a potent neuroprotective agent against MPTP-induced dopaminergic denervation and may become a potential therapeutic agent for PD and/or its progression. PMID:23943375

Rekha, Karamkolly R; Selvakumar, Govindasamy P; Sethupathy, Subramaniam; Santha, Karunanidhi; Sivakamasundari, Ramu Inmozhi



Parkinson's Disease  


... Parkinson Disease Association 135 Parkinson Avenue Staten Island, NY 10305-1425 http://www.apdaparkinson. ... Central Station P.O. Box 4777 New York, NY 10163 Tel: 212-509- ...


Pathogenesis of Parkinson's disease.  


Parkinson's disease is a common adult-onset neurodegenerative disorder whose pathogenesis remains essentially unknown. Currently, it is believed that the neurodegenerative process in Parkinson's disease is a combination of both cell-autonomous and non-cell-autonomous mechanisms. Proposed cell-autonomous mechanisms include alterations in mitochondrial bioenergetics, dysregulation of calcium homeostasis, and impaired turnover of mitochondria. As for the proposed non-cell-autonomous mechanisms, they involve prion-like behavior of misfolded proteins and neuroinflammation. This suggests that cell death in Parkinson's disease is caused by a multifactorial cascade of pathogenic events and argues that effective neuroprotective therapy for Parkinson's disease may have to rely on multiple drug interventions. PMID:22927094

Hirsch, Etienne C; Jenner, Peter; Przedborski, Serge



Drug-Induced Liver Injury: A National and Global Problem ...  

Center for Drug Evaluation (CDER)

... Drug-Induced Liver Injury: A National and Global Problem, February 2001. Final Program. ... 9:45 AM Final Q and A, discussion of issues. ... More results from


Striatal glutamate induces retrograde excitotoxicity and neuronal degeneration of intralaminar thalamic nuclei: their potential relevance for Parkinson's disease.  


An over-stimulation of nigral glutamate (GLU) receptors has been proposed as a cause of the progression of the dopamine (DA) cell degeneration (excitotoxicity) which characterizes Parkinson's disease. The possible toxic action of striatal GLU (retrograde excitotoxicity) on these cells, and on other neurons which innervate the striatum and which also degenerate in Parkinson's disease (thalamostriatal cells of the intralaminar thalamic nuclei), is still practically unexplored. The retrograde excitotoxicity of striatal GLU on DAergic mesostriatal and GLUergic thalamostriatal cells was tested here by studying these cells 6 weeks after striatal perfusion of GLU by reverse microdialysis. GLU perfusion induced the striatal denervation of thalamic inputs (as revealed by vesicular glutamate transporter 2) and the remote degeneration of intralaminar neurons. In both centres, these effects were accompanied by microglial activation. Similar responses were not observed for nigrostriatal neurons, which showed no dopaminergic striatal denervation, no microglial activation in the substantia nigra and no changes in the number of dopaminergic cells in the substantia nigra. The inhibition of DAergic transmission increased the extrasynaptic GLU levels in the striatum (evaluated by microdialysis), an effect observed after the local administration of agonists and antagonists of DAergic transmission, and after the peripheral administration of levodopa (which increased the DA and decreased the GLU levels in the striatum of rats with an experimental DAergic denervation of this centre). The data presented show that striatal GLU induced a retrograde excitotoxicity which did not affect all striatal inputs in the same way and which could be involved in the cell degeneration of the intralaminar nuclei of the thalamus generally observed in Parkinson's disease. PMID:23565852

Morales, Ingrid; Sabate, Magdalena; Rodriguez, Manuel



Drug-Induced Impulse Control Disorders: A Prospectus for Neuroethical Analysis  

Microsoft Academic Search

There is growing evidence that dopamine replacement therapy (DRT) used to treat Parkinson’s Disease can cause compulsive behaviours\\u000a and impulse control disorders (ICDs), such as pathological gambling, compulsive buying and hypersexuality. Like more familiar\\u000a drug-based forms of addiction, these iatrogenic disorders can cause significant harm and distress for sufferers and their\\u000a families. In some cases, people treated with DRT have

Adrian Carter; Polly Ambermoon; Wayne D. Hall



Calcium entry induces mitochondrial oxidant stress in vagal neurons at risk in Parkinson's disease.  


Mitochondrial oxidant stress is widely viewed as being critical to pathogenesis in Parkinson's disease. But the origins of this stress are poorly defined. One possibility is that it arises from the metabolic demands associated with regenerative activity. To test this hypothesis, we characterized neurons in the dorsal motor nucleus of the vagus (DMV), a population of cholinergic neurons that show signs of pathology in the early stages of Parkinson's disease, in mouse brain slices. DMV neurons were slow, autonomous pacemakers with broad spikes, leading to calcium entry that was weakly buffered. Using a transgenic mouse expressing a redox-sensitive optical probe targeted to the mitochondrial matrix, we found that calcium entry during pacemaking created a basal mitochondrial oxidant stress. Knocking out DJ-1 (also known as PARK7), a gene associated with early-onset Parkinson's disease, exacerbated this stress. These results point to a common mechanism underlying mitochondrial oxidant stress in Parkinson's disease and a therapeutic strategy to ameliorate it. PMID:22941107

Goldberg, Joshua A; Guzman, Jaime N; Estep, Chad M; Ilijic, Ema; Kondapalli, Jyothisri; Sanchez-Padilla, Javier; Surmeier, D James



Pramipexole-Induced Increased Probabilistic Discounting: Comparison Between a Rodent Model of Parkinson's Disease and Controls  

Microsoft Academic Search

The dopamine agonist pramipexole (PPX) can increase impulsiveness, and PPX therapy for neurological diseases (Parkinson's disease (PD) and restless leg syndrome) is associated with impulse control disorders (ICDs) in subpopulations of treated patients. A commonly reported ICD is pathological gambling of which risk taking is a prominent feature. Probability discounting is a measurable aspect of risk taking. We recently developed

Sandra L Rokosik; T Celeste Napier



Increased beta activity in dystonia patients after drug-induced dopamine deficiency.  


Several studies have confirmed that subthalamic and pallidal local field potential activity in the beta frequency band (13-30 Hz) is exaggerated in untreated patients with Parkinson's disease (PD) and is suppressed by dopaminergic treatment. This particular spectral pattern differs from that in patients with dystonia in whom pallidal activity is prominent at low frequencies (<12 Hz). Here we demonstrate that tetrabenazine induced monoamine depletion and dopamine blockade is associated with increased activity in the low beta band (13-20 Hz) in the internal pallidum of patients with dystonia. Beta activity was elevated in six patients treated with tetrabenazine compared to six patients in whom this drug was not used. Our findings suggest that beta activity is enhanced in the chronically dopamine-depleted and blocked state irrespective of the underlying pathology, consistent with the idea that excessive synchrony in the beta band is directly related to dopaminergic hypofunction, rather than some degenerative disease-specific attribute of Parkinson's disease. PMID:18760276

Kühn, Andrea A; Brücke, Christof; Schneider, Gerd-Helge; Trottenberg, Thomas; Kivi, Anatol; Kupsch, Andreas; Capelle, H Holger; Krauss, Joachim K; Brown, Peter



Cognitive-Enhancing Effect of Quercetin in a Rat Model of Parkinson's Disease Induced by 6-Hydroxydopamine  

PubMed Central

Oxidative stress has been reported to induce cognitive impairment in Parkinson's disease. This paper aimed to determine the effect of quercetin, a substance possessing antioxidant activity, on the cognitive function in a rat model of Parkinson's disease. Male Wistar rats, weighing 200–250?g, were orally given quercetin at doses of 100, 200, 300?mg/kg BW once daily for a period of 14 days before and 14 days after the unilateral lesion of right substantia nigra induced by 6-hydroxydopamine (6-OHDA). Their spatial memory was assessed at 7 and 14 days of treatment and neuron density was determined, malondialdehyde (MDA) level, the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were evaluated at the end of the experiment. In addition, the activity of acetylcholinesterase (AChE) was also measured. It was found that all doses of quercetin enhanced spatial memory. Therefore, it is suggested that the cognitive-enhancing effect of quercetin occurs partly because of decreased oxidative damage resulting in increased neuron density.

Sriraksa, Napatr; Wattanathorn, Jintanaporn; Muchimapura, Supaporn; Tiamkao, Somsak; Brown, Kamoltip; Chaisiwamongkol, Kowit



Levetiracetam for the management of levodopa-induced dyskinesias in Parkinson's disease.  


The efficacy and safety of levetiracetam (LEV), administered for management of levodopa-induced dyskinesias (LID) in Parkinson's disease (PD), was examined using a multicenter, double-blind, placebo-controlled, parallel groups, crossover trial. Because of having a period effect, data after crossover point was excluded from analysis. Levodopa-treated PD participants with LID (n = 38) received LEV 500 mg/day, were assessed, titrated to 1,000 mg/day and reassessed, before and after crossover. The placebo group followed the same routine. Primary efficacy was defined from percent change in "On with LID" time from patient diaries. Secondary efficacy assessment used "On without LID," "Off" time, unified PD rating scale (UPDRS), clinical global impression (CGI), and Goetz dyskinesia scale after levodopa challenge. Safety measures were also performed. On with LID time decreased 37 minutes (95% confidence interval [CI] 0.59, 7.15; P = 0.02) at 500 mg/day, 7.85% 75 minutes (95% CI 3.3, 12.4; P = 0.002) at 1,000 mg/day. On without LID time increased by 46 minutes (95% CI -1.55, -0.03; P = 0.04) at 500 mg/day and 55 minutes (95% CI -10.39, -1.14; P = 0.018) at 1,000 mg/day. UPDRS 32 showed decreased dyskinesia duration mean change 0.35 (95% CI 0.09, 0.5; P = 0.009) at 1,000 mg/day. CGI showed LID decreased by 0.7 (95% CI 0.21, 1.18; P = 0.006) at 1,000 mg/day. Patient diaries and UPDRS show no increase in Off time. This exploratory trial provides evidence that LEV in 1,000 mg/day, slowly titrated, could be useful in improving LID as was assessed with patient diaries, UPDRS, and CGI scales, safely, with minimal side effects. PMID:21412833

Stathis, P; Konitsiotis, S; Tagaris, G; Peterson, D



Drug-induced lupus erythematosus: incidence, management and prevention.  


The generation of autoantibodies and autoimmune diseases such as systemic lupus erythematosus has been associated with the use of certain drugs in humans. Early reports suggested that procainamide and hydralazine were associated with the highest risk of developing lupus, quinidine with a moderate risk and all other drugs were considered low or very low risk. More recently, drug-induced lupus has been associated with the use of the newer biological modulators such as tumour necrosis factor (TNF)-? inhibitors and interferons. The clinical features and laboratory findings of TNF? inhibitor-induced lupus are different from that of traditional drug-induced lupus or idiopathic lupus, and standardized criteria for the diagnosis of drug-induced lupus have not been established. The mechanism(s) responsible for the development of drug-induced lupus may vary depending on the drug or even on the patient. Besides lupus, other autoimmune diseases have been associated with drugs or toxins. Diagnosis of drug-induced lupus requires identification of a temporal relationship between drug administration and symptom development, and in traditional drug-induced lupus there must be no pre-existing lupus. Resolution of symptoms generally occurs after cessation of the drug. In this review, we will discuss those drugs that are more commonly associated with drug-induced lupus, with an emphasis on the new biologicals and the difficulty of making the diagnosis of drug-induced lupus against a backdrop of the autoimmune diseases that these drugs are used to treat. Stimulation of the immune system by these drugs to cause autoimmunity may in fact be associated with an increased effectiveness in treating the pathology for which they are prescribed, leading to the dilemma of deciding which is worse, the original disease or the adverse effect of the drug. Optimistically, one must hope that ongoing research in drug development and in pharmacogenetics will help to treat patients with the maximum effectiveness while minimizing side effects. Vigilance and early diagnosis are critical. The purpose of this review is to summarize the most recent developments in our understanding of the incidence, pathogenesis, diagnosis and treatment of drug-induced lupus. PMID:21513360

Chang, Christopher; Gershwin, M Eric



Parkinsonism: Causes and Coping Strategies  


... muscle stiffness — especially resulting from the loss of dopamine-containing nerve cells (neurons). Possible causes Not everyone ... always taken as a combination drug — replenishes brain dopamine, and brain dopamine loss is fundamental to Parkinson's ...


Parkinson's Disease: Hope through Research  


... What Causes the Disease? Parkinson's disease occurs when nerve cells, or neurons, in an area of the brain ... it is formulated for drug use in patients. Nerve cells can use levodopa to make dopamine and replenish ...


Subthalamic nucleus stimulation-induced regional blood flow responses correlate with improvement of motor signs in Parkinson disease  

PubMed Central

Deep brain stimulation of the subthalamic nucleus (STN DBS) improves motor symptoms in idiopathic Parkinson's disease, yet the mechanism of action remains unclear. Previous studies indicate that STN DBS increases regional cerebral blood flow (rCBF) in immediate downstream targets but does not reveal which brain regions may have functional changes associated with improved motor manifestations. We studied 48 patients with STN DBS who withheld medication overnight and underwent PET scans to measure rCBF responses to bilateral STN DBS. PET scans were performed with bilateral DBS OFF and ON in a counterbalanced order followed by clinical ratings of motor manifestations using Unified Parkinson Disease Rating Scale 3 (UPDRS 3). We investigated whether improvement in UPDRS 3 scores in rigidity, bradykinesia, postural stability and gait correlate with rCBF responses in a priori determined regions. These regions were selected based on a previous study showing significant STN DBS-induced rCBF change in the thalamus, midbrain and supplementary motor area (SMA). We also chose the pedunculopontine nucleus region (PPN) due to mounting evidence of its involvement in locomotion. In the current study, bilateral STN DBS improved rigidity (62%), bradykinesia (44%), gait (49%) and postural stability (56%) (paired t-tests: P < 0.001). As expected, bilateral STN DBS also increased rCBF in the bilateral thalami, right midbrain, and decreased rCBF in the right premotor cortex (P < 0.05, corrected). There were significant correlations between improvement of rigidity and decreased rCBF in the SMA (rs = –0.4, P < 0.02) and between improvement in bradykinesia and increased rCBF in the thalamus (rs = 0.31, P < 0.05). In addition, improved postural reflexes correlated with decreased rCBF in the PPN (rs = –0.38, P < 0.03). These modest correlations between selective motor manifestations and rCBF in specific regions suggest possible regional selectivity for improvement of different motor signs of Parkinson's disease.

Karimi, M.; Golchin, N.; Tabbal, S. D.; Hershey, T.; Videen, T. O.; Wu, J.; Usche, J. W. M.; Revilla, F. J.; Hartlein, J. M.; Wernle, A. R.; Mink, J. W.



Tremorolytic effects of safinamide in animal models of drug-induced parkinsonian tremor.  


Safinamide is an ?-aminoamide derivative that is currently in Phase III clinical trial development as an add-on therapy to levodopa or dopamine agonists for patients with Parkinson's disease. Safinamide is a monoamine oxidase B inhibitor with additional non-dopaminergic actions. The present experiments were performed to evaluate the ability of safinamide to attenuate parkinsonian motor impairments using the tremulous jaw movement model, an animal model of parkinsonian tremor. In rats, tremulous jaw movements can be induced with dopamine (DA) antagonists, DA depletion, and cholinomimetics, and can be reversed by various antiparkinsonian drugs, including L-DOPA, DA agonists, anticholinergics and adenosine A2A antagonists. In these present experiments, tremulous jaw movements were induced with the anticholinesterase galantamine (3.0mg/kg IP), the muscarinic agonist pilocarpine (0.5mg/kg IP), and the dopamine D2 antagonist pimozide (1.0mg/kg IP). Safinamide significantly reduced the number of tremulous jaw movements induced by galantamine, pilocarpine, and pimozide, with consistent effects across all three drugs at a dose range of 5.0-10.0mg/kg. The results of this study support the use of safinamide as a treatment for parkinsonian tremor. PMID:23360954

Podurgiel, Samantha; Collins-Praino, Lyndsey E; Yohn, Samantha; Randall, Patrick A; Roach, Arthur; Lobianco, Christophe; Salamone, John D



Kaurenoic acid from pulp of Annona cherimolia in regard to Annonaceae-induced Parkinsonism.  


Guadeloupean Parkinsonism has been linked epidemiologically to the consumption of Annonaceae fruits. These were proposed to be etiological agents for sporadic atypical Parkinsonism worldwide, because of their content of neurotoxins such as isoquinolinic alkaloids and Annonaceous acetogenins. The pulp of Annona cherimolia Mill. from Spain was screened for these toxic molecules using Matrix-Assisted Laser Desorption Ionisation - Time of Flight mass spectrometry (MALDI-TOF MS) and it was found not to be a source of exposure. However, kaurenoic acid, a diterpene considered to be cytotoxic, was detected in high amounts (66?mg/fresh fruit). Treatment of rat embryonic striatal primary cultures, up to a high concentration (50?µM), did not cause neuronal death nor astrogliosis, suggesting that this molecule is not at risk of implication in human neurodegenerative diseases. PMID:21520310

Guillopé, R; Escobar-Khondiker, M; Guérineau, V; Laprévote, O; Höglinger, G U; Champy, P



Molecular Mechanisms of Pesticide-induced Neurotoxicity: Relevance to Parkinson's Disease  

PubMed Central

Pesticides are widely used in agricultural and other settings, resulting in continued human exposure. Pesticide toxicity has been clearly demonstrated to alter a variety of neurological functions. Particularly, there is strong evidence suggesting that pesticide exposure predisposes to neurodegenerative diseases. Epidemiological data has suggested a relationship between pesticide exposure and brain neurodegeneration. However, an increasing debate has aroused regarding this issue. Paraquat is a highly toxic quaternary nitrogen herbicide which has been largely studied as a model for Parkinson’s disease providing valuable insight into the possible mechanisms involved in the toxic effects of pesticides and their role in the progression of neurodegenerative diseases. In this work, we review the molecular mechanisms involved in the neurotoxic actions of pesticides, with a particular emphasis on the mechanisms associated with the induction neuronal cell death by paraquat as a model for Parkinsonian neurodegeneration.

Franco, Rodrigo; Li, Sumin; Rodriguez-Rocha, Humberto; Burns, Michaela; Panayiotidis, Mihalis I.



Mechanisms of drug-induced proarrhythmia in clinical practice.  


Drug-induced proarrhythmia represents a great challenge for those involved in the development of novel pharmaceuticals and in the regulatory bodies for drug approval as well as for the prescribing clinicians. Our understanding of the mechanisms that underlie drug-induced proarrhythmia has grown dramatically over the last two decades. A growing number of cardiac and non-cardiac agents have been shown to alter cardiac repolarization predisposing to fatal cardiac arrhythmias such as ventricular tachycardia or ventricular fibrillation and sudden cardiac death. These agents may induce the phenotype of long QT syndrome and less commonly of short QT syndrome and Brugada syndrome (BS). Although, genetic susceptibility underlie drug-induced proarrhythmia in certain cases, current data are limited regarding this topic. The present review surveys the current published literature on the mechanisms and the offending medical agents that predispose to drug-induced long QT syndrome, short QT syndrome and BS. Drug-induced proarrhythmia should be considered as a predictor of sudden cardiac death and should prompt critical re-evaluation of the risks and benefits of the suspicious medication. Survivors of drug-induced proarrhythmia and family members require careful examination and possibly genetic testing for the presence of a channelopathy. Treating physicians are advised to follow the lists of agents implicated in drug-induced proarrhythmia in order to minimize the risk of arrhythmia and sudden cardiac death. PMID:23847724

Konstantopoulou, Arkadia; Tsikrikas, Spyros; Asvestas, Dimitrios; Korantzopoulos, Panagiotis; Letsas, Konstantinos P



Mechanisms of drug-induced proarrhythmia in clinical practice  

PubMed Central

Drug-induced proarrhythmia represents a great challenge for those involved in the development of novel pharmaceuticals and in the regulatory bodies for drug approval as well as for the prescribing clinicians. Our understanding of the mechanisms that underlie drug-induced proarrhythmia has grown dramatically over the last two decades. A growing number of cardiac and non-cardiac agents have been shown to alter cardiac repolarization predisposing to fatal cardiac arrhythmias such as ventricular tachycardia or ventricular fibrillation and sudden cardiac death. These agents may induce the phenotype of long QT syndrome and less commonly of short QT syndrome and Brugada syndrome (BS). Although, genetic susceptibility underlie drug-induced proarrhythmia in certain cases, current data are limited regarding this topic. The present review surveys the current published literature on the mechanisms and the offending medical agents that predispose to drug-induced long QT syndrome, short QT syndrome and BS. Drug-induced proarrhythmia should be considered as a predictor of sudden cardiac death and should prompt critical re-evaluation of the risks and benefits of the suspicious medication. Survivors of drug-induced proarrhythmia and family members require careful examination and possibly genetic testing for the presence of a channelopathy. Treating physicians are advised to follow the lists of agents implicated in drug-induced proarrhythmia in order to minimize the risk of arrhythmia and sudden cardiac death.

Konstantopoulou, Arkadia; Tsikrikas, Spyros; Asvestas, Dimitrios; Korantzopoulos, Panagiotis; Letsas, Konstantinos P



Subthalamic nucleus stimulation induces deficits in decoding emotional facial expressions in Parkinson's disease  

PubMed Central

Background: Bilateral subthalamic nucleus (STN) stimulation is recognised as a treatment for parkinsonian patients with severe levodopa related motor complications. Although adverse effects are infrequent, some behavioural disturbances have been reported. Objective: To investigate the consequences of STN stimulation on emotional information processing in Parkinson's disease by assessing the performance of an emotional facial expression (EFE) decoding task in a group of patients before and after surgery. Methods: 12 non-demented patients with Parkinson's disease were studied. They were assessed one month before surgery and three months after. Their ability to decode EFEs was assessed using a standardised quantitative task. Overall cognitive function, executive function, visuospatial perception, depression, and anxiety were also measured. Twelve healthy controls were matched for age, sex, and duration of education. Results: Before surgery, the patients showed no impairment in EFE decoding compared with the controls. Their overall cognitive status was preserved but they had a moderate dysexecutive syndrome. Three months after surgery, they had significant impairment of EFE decoding. This was not related to their overall cognitive status or to depression/anxiety scores. Visuospatial perception was not impaired. There was no change in the extent of the dysexecutive syndrome except for a reduction in phonemic word fluency. Conclusions: Bilateral STN stimulation disturbs negative emotional information processing in Parkinson's disease. The impairment appears specific and unrelated to certain secondary variables. This behavioural complication of STN may have implications for the patient's social life.

Dujardin, K; Blairy, S; Defebvre, L; Krystkowiak, P; Hess, U; Blond, S; Destee, A



Bromocriptine in Parkinsonism  

Microsoft Academic Search

Bromocriptine, a drug acting directly upon dopaminergic receptors, has been found to have a significant therapeutic action in a double-blind study of 20 patients with idiopathic Parkinsonism who were already receiving conventional therapy, including levodopa. Neurological deficits improved by almost 20% in severely disabled patients; amelioration of mildly affected patients was about 10%. Adverse reactions were similar to those encountered

D. B. Calne; P. F. Teychenne; L. E. Claveria; R. Eastman; J. K. Greenacre; A. Petrie



Translating Clinical Findings into Knowledge in Drug Safety Evaluation - Drug Induced Liver Injury Prediction System (DILIps)  

Microsoft Academic Search

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side

Zhichao Liu; Qiang Shi; Don Ding; Reagan Kelly; Hong Fang; Weida Tong



Therapeutic Effect of Hydrogen Sulfide-Releasing L-Dopa Derivative ACS84 on 6-OHDA-Induced Parkinson's Disease Rat Model  

PubMed Central

Parkinson’s disease (PD), characterized by loss of dopaminergic neurons in the substantia nigra, is a neurodegenerative disorder of central nervous system. The present study was designed to investigate the therapeutic effect of ACS84, a hydrogen sulfide-releasing-L-Dopa derivative compound, in a 6-hydroxydopamine (6-OHDA)-induced PD model. ACS84 protected the SH-SY5Y cells against 6-OHDA-induced cell injury and oxidative stress. The protective effect resulted from stimulation of Nrf-2 nuclear translocation and promotion of anti-oxidant enzymes expression. In the 6-OHDA-induced PD rat model, intragastric administration of ACS84 relieved the movement dysfunction of the model animals. Immunofluorescence staining and High-performance liquid chromatography analysis showed that ACS84 alleviated the loss of tyrosine-hydroxylase positive neurons in the substantia nigra and the declined dopamine concentration in the injured striatums of the 6-OHDA-induced PD model. Moreover, ACS84 reversed the elevated malondialdehyde level and the decreased glutathione level in vivo. In conclusion, ACS84 may prevent neurodegeneration via the anti-oxidative mechanism and has potential therapeutic values for Parkinson’s disease.

Teo, Xing Qi; Tiong, Chi Xin; Tazzari, Valerio; Sparatore, Anna; Soldato, Piero Del; Dawe, Gavin Stewart; Bian, Jin-Song



Glial cell-line derived neurotrophic factor is essential for electroconvulsive shock-induced neuroprotection in an animal model of Parkinson's disease  

Microsoft Academic Search

Sustained motor improvement in human patients with idiopathic Parkinson's disease has been described following electroconvulsive shock (ECS) treatment. In rats, ECS stimulates the expression of various trophic factors (TFs), some of which have been proposed to exert neuroprotective actions. We previously reported that ECS protects the integrity of the rat nigrostriatal dopaminergic system against 6-hydroxydopamine (6-OHDA)-induced toxicity; in order to

A. Anastasía; J. Wojnacki; G. A. de Erausquin; D. H. Mascó



FceRII\\/CD23 Is Expressed in Parkinson's Disease and Induces, In Vitro, Production of Nitric Oxide and Tumor Necrosis Factor-a in Glial Cells  

Microsoft Academic Search

Oxidative stress is thought to be involved in the mechanism of nerve cell death in Parkinson's disease (PD). Among several toxic oxidative species, nitric oxide (NO) has been proposed as a key element on the basis of the increased density of glial cells expressing inducible nitric oxide synthase (iNOS) in the sub- stantia nigra (SN) of patients with PD. However,

Stephane Hunot; Nathalie Dugas; Baptiste Faucheux; Andreas Hartmann; Marc Tardieu; Patrice Debre; Yves Agid; Bernard Dugas; Etienne C. Hirsch



Diagnosis, management and prevention of drug-induced liver injury  

Microsoft Academic Search

Drug-induced liver injury (DILI) is increasingly being recognised as a significant cause of both acute and chronic liver disease. The most commonly implicated agents are paracetamol, antimicrobials, non-steroidal anti-inflammatory drugs, statins, isoniazid and herbal remedies. Drug-induced hepatotoxicity is generally idiosyncratic in nature. The pathogenesis of DILI remains enigmatic, but involves exposure to the toxic agent, mitochondrial injury, failure of adaptation,

S Verma; N Kaplowitz



Curcumin protects against A53T alpha-synuclein-induced toxicity in a PC12 inducible cell model for Parkinsonism  

Microsoft Academic Search

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder characterized by selective loss of dopaminergic neurons and the presence of Lewy bodies. The pathogenesis of PD remains incompletely understood, but it appears to involve both genetic susceptibility and environmental factors. Treatment for PD that prevents neuronal death in the dopaminergic system and abnormal protein deposition in the brain is not

Zhaohui Liu; Yi Yu; Xueping Li; Christopher A. Ross; Wanli W. Smith



Leucine-Rich Repeat Kinase 2 Regulates the Progression of Neuropathology Induced by Parkinson's Disease-related Mutant ?-synuclein  

PubMed Central

Summary Mutations in ?-synuclein and Leucine-rich repeat kinase 2 (LRRK2) are linked to autosomal dominant forms of Parkinson’s disease (PD). However, little is known about any potential pathophysiological interplay between these two PD-related genes. Here we show in transgenic mice that although over-expression of LRRK2 alone did not cause neurodegeneration, the presence of excess LRRK2 greatly accelerated the progression of neuropathological abnormalities developed in PD-related A53T ?-synuclein transgenic mice. Moreover, we found that LRRK2 promoted the abnormal aggregation and somatic accumulation of ?-synuclein in A53T mice, likely resulted from the impairment of microtubule dynamics, Golgi organization, and ubiquitin-proteasome pathway. Conversely, genetic ablation of LRRK2 preserved the Golgi structure, suppressed the aggregation and somatic accumulation of ?-synuclein, and thereby delayed the progression of neuropathology in A53T mice. These findings demonstrate that over-expression of LRRK2 enhances ?-synuclein-mediated cytotoxicity and suggest inhibition of LRRK2 expression as a potential therapeutic option for ameliorating ?-synuclein-induced neurodegeneration.

Lin, Xian; Parisiadou, Loukia; Gu, Xing-Long; Wang, Lizhen; Shim, Hoon; Sun, Lixin; Xie, Chengsong; Long, Cai-Xia; Yang, Wan-Jou; Ding, Jinhui; Chen, Zsu Zsu; Gallant, Paul E.; Tao-Cheng, Jung-Hwa; Rudow, Gay; Troncoso, Juan C.; Liu, Zhihua; Li, Zheng; Cai, Huaibin



Drug-induced pathology of the upper gastrointestinal tract  

Microsoft Academic Search

Drugs can produce a wide range of pathology in the upper gastrointestinal tract. Often, the injury pattern is non-specific. Pill-induced oesophagitis usually affects the mid oesophagus. In the stomach, many drugs, particularly non-steroid anti-inflammatory drugs (NSAIDs), can cause ulcers, erosions or reactive gastropathy. Some drugs produce specific injury patterns that can be recognized by pathologists. Proton pump inhibitors cause parietal

Joseph Misdraji



Interstitial Lung Disease Induced by Drugs and Radiation  

Microsoft Academic Search

An ever-increasing number of drugs can reproduce variegated patterns of naturally occurring interstitial lung disease (ILD), including most forms of interstitial pneumonias, alveolar involvement and, rarely, vasculitis. Drugs in one therapeutic class may collectively produce the same pattern of involvement. A few drugs can produce more than one pattern of ILD. The diagnosis of drug-induced ILD (DI-ILD) essentially rests on

Philippe Camus; Annlyse Fanton; Philippe Bonniaud; Clio Camus; Pascal Foucher



Emerging drugs for chemotherapy-induced emesis.  


Chemotherapy-induced nausea and vomiting (CINV) is associated with a significant deterioration in quality of life. The emetogenicity of the chemotherapeutic agents, repeated chemotherapy cycles and patient risk factors (female gender, younger age, no alcohol consumption, history of motion sickness) are the major risk factors for CINV. The use of 5-hydroxytryptamine-3 (5-HT3) receptor antagonists plus dexamethasone has significantly improved the control of acute CINV, but delayed nausea and vomiting remains a significant clinical problem. Two new agents, palonosetron and aprepitant, have recently been approved for the prevention of both acute and delayed CINV. Palonosetron is a 5-HT3 receptor antagonist with a longer half-life and a higher binding affinity than first-generation 5-HT3 receptor antagonists. Aprepitant is the first agent available in the new drug class of neurokinin-1 receptor (NK-1) antagonists. There are a number of 5-HT3 receptor antagonists and NK-1 receptor antagonists currently in Phase II and III clinical trials. Revised antiemetic guidelines for the prevention of CINV are reviewed. Future studies may consider the use of palonosetron and aprepitant with current and other new agents (olanzapine, gabapentin) in moderately and highly emetogenic chemotherapy, as well as in the clinical settings of multiple-day chemotherapy and bone marrow transplantation. PMID:16503832

Navari, Rudolph M; Province, Paula S



Identification of Drugs Inducing Phospholipidosis by Novel in vitro Data.  


Drug-induced phospholipidosis (PLD) is a lysosomal storage disorder characterized by the accumulation of phospholipids within the lysosome. This adverse drug effect can occur in various tissues and is suspected to impact cellular viability. Therefore, it is important to test chemical compounds for their potential to induce PLD during the drug design process. PLD has been reported to be a side effect of many commonly used drugs, especially those with cationic amphiphilic properties. To predict drug-induced PLD in silico, we established a high-throughput cell-culture-based method to quantitatively determine the induction of PLD by chemical compounds. Using this assay, we tested 297 drug-like compounds at two different concentrations (2.5??M and 5.0??M). We were able to identify 28 previously unknown PLD-inducing agents. Furthermore, our experimental results enabled the development of a binary classification model to predict PLD-inducing agents based on their molecular properties. This random forest prediction system yields a bootstrapped validated accuracy of 86?%. PLD-inducing agents overlap with those that target similar biological processes; a high degree of concordance with PLD-inducing agents was identified for cationic amphiphilic compounds, small molecules that inhibit acid sphingomyelinase, compounds that cross the blood-brain barrier, and compounds that violate Lipinski's rule of five. Furthermore, we were able to show that PLD-inducing compounds applied in combination additively induce PLD. PMID:22945602

Muehlbacher, Markus; Tripal, Philipp; Roas, Florian; Kornhuber, Johannes



Drug-Induced Hypothermia as Beneficial Treatment before and after Cerebral Ischemia.  


Objectives: Hypothermia is still unproven as beneficial treatment in human stroke, although in animal models, conditioning the brain with hypothermia has induced tolerance to insults. Here, we delineate the feasibility of drug-induced mild hypothermia in reducing ischemic brain damage when conditioning before (preconditioning) and after (postconditioning) experimental stroke. Methods: Hypothermia was induced in rats with a bolus of 6 mg/kg talipexole followed by 20 h continuous talipexole infusion of 6 mg/kg in total. Controls received similar treatment with saline. The core body temperature was continuously monitored. In preconditioning, hypothermia was terminated before either reversible occlusion of the middle cerebral artery (MCAO) for 60 min or global ischemia for 10 min with 2-vessel occlusion and hypotension. In postconditioning, rats experienced 60 min of MCAO before hypothermia was induced either immediately or with 3 h delay. Rats survived ischemia for 2, 7 or 90 days. Infarct volumes were quantified by stereology. Additional experiments of methodological relevance were included in the study. Results: Talipexole induced mild hypothermia (35.1 ± 1.1 to 36.0 ± 0.5°C) for <20 h. Hypothermic pre- and postconditioning reduced infarct sizes by more than 60% as monitored during the first 90 days after experimental stroke (p < 0.05). Conclusion: Talipexole is registered for use as a dopamine substitute in humans with Parkinson's disease. Although dosages cannot be directly translated to patients, our study exemplifies in an animal model that drug-induced hypothermia in a clinical setting might reduce cerebral ischemic damage before neuro- and cardiac surgical procedures and after stroke. PMID:23989388

Johansen, Flemming F; Hasseldam, Henrik; Rasmussen, Rune S; Bisgaard, Anne Sofie; Bonfils, Peter K; Poulsen, Steen S; Hansen-Schwartz, Jacob



Dopaminergic neurotoxicant 6-OHDA induces oxidative damage through proteolytic activation of PKC? in cell culture and animal models of Parkinson's disease  

Microsoft Academic Search

The neurotoxicant 6-hydroxydopamine (6-OHDA) is used to investigate the cellular and molecular mechanisms underlying selective degeneration of dopaminergic neurons in Parkinson's disease (PD). Oxidative stress and caspase activation contribute to the 6-OHDA-induced apoptotic cell death of dopaminergic neurons. In the present study, we sought to systematically characterize the key downstream signaling molecule involved in 6-OHDA-induced dopaminergic degeneration in cell culture

Calivarathan Latchoumycandane; Vellareddy Anantharam; Huajun Jin; Anumantha Kanthasamy; Arthi Kanthasamy



Drug-induced skin, nail and hair disorders.  


Drug eruptions are among the most common adverse drug reactions, affecting approximately 3% of hospitalised patients. Although the rate of severe cutaneous adverse reactions to medications is low, these reactions can affect anyone who takes medication, and can result in death or disability. Two general patterns can be distinguished, depending on the type of onset of these cutaneous adverse drug reactions: acute or chronic. Acute-onset events are usually rather specific cutaneous 'syndromes' that constitute emergencies and should therefore be promptly recognised and treated, while chronic-onset events often present as dermatological diseases. The challenge is therefore to recognise the drug aetiology in front of a 'classical' dermatosis such as acne, lichen or pemphigus. Therefore, clinicians should carefully evaluate the signs or symptoms of all adverse reactions thought to be drug related, and discontinue the offending agent when feasible. Erythematous drug eruptions are the most frequent and less severe acute immune drug-induced rashes, and are sometimes difficult to differentiate from viral eruptions. On the other hand, acute urticaria and angioedema are sometimes life-threatening eruptions for which a drug aetiology must be investigated. Photosensitivity, vasculitis and skin necrosis belong to the acute onset reactions, which are not always drug-induced, in contrast to fixed drug eruptions. The early recognition of acute generalised exanthematous pustulosis, DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome, Stevens-Johnson syndrome and toxic epidermal necrolysis are of high importance because of the specific mechanisms involved and the different prognosis of each of these diseases. Chronic onset drug-induced disorders include pigmentary changes, drug-induced autoimmune bullous diseases, lupus, pseudo lymphoma and acneiform eruptions; these are discussed, along with specific data on drug-induced hair and nail disorders. As the disorders are numerous, the mechanisms and the drugs involved in the development of these various reactions are multiple. The list of drugs discussed in relation to the different disorders are as accurate as possible at the time of preparation of this review, but will need updating as new drugs emerge onto the market. We emphasize the clinical recognition, pathophysiology and treatment of skin, hair and nail adverse drug reactions, and the role of each doctor involved in the management of these patients in the notification of the adverse drug reaction to health authorities, using the minimal requirement for notification proposed. PMID:17973540

Valeyrie-Allanore, Laurence; Sassolas, Bruno; Roujeau, Jean-Claude



Increased Drug Effect Induced by Surgery  

Microsoft Academic Search

1 A thyrotoxic patient receiving a constant dose of propranolol and digoxin developed marked bradycardia postoperatively.2 Compared to preoperative levels there was a considerable rise postoperatively in both plasma propranolol and serum digoxin steady-state concentrations.3 Surgery by effecting drug disposition and disease processes may significantly alter drug handling in the perioperative period.

John Feely



Mechanisms of Drug-Induced Allergy  

PubMed Central

We identified English-language publications on hypersensitivity reactions to xenobiotics through the PubMed database, using the search terms drug and/or xenobiotic, hypersensitivity reaction, mechanism, and immune mediated. We analyzed articles pertaining to the mechanism and the role of T cells. Immune hypersensitivity reactions to drugs are mediated predominantly by IgE antibodies or T cells. The mechanism of IgE-mediated reactions is well investigated, but the mechanisms of T-cell-mediated drug hypersensitivity are not well understood. The literature describes 2 concepts: the hapten/prohapten concept and the concept of pharmacological interactions of drugs with immune receptors. In T-cell-mediated allergic drug reactions, the specificity of the T-cell receptor that is stimulated by the drug may often be directed to a cross-reactive major histocompatibility complex-peptide compound. Thus, previous contact with the causative drug is not obligatory, and an immune mechanism should be considered as the cause of hypersensitivity, even in reactions that occur on primary exposure. Indeed, immune-mediated reactions to xenobiotics in patients without prior exposure to the agent have been described recently for radiocontrast media and neuromuscular blocking agents. Thus, the “allergenic” potential of a drug under development should be evaluated not only by screening its haptenlike characteristics but also by assessing its direct immunostimulatory potential.

Schnyder, Benno; Pichler, Werner J.



TOM40 Mediates Mitochondrial Dysfunction Induced by ?-Synuclein Accumulation in Parkinson's Disease  

PubMed Central

Alpha-synuclein (?-Syn) accumulation/aggregation and mitochondrial dysfunction play prominent roles in the pathology of Parkinson’s disease. We have previously shown that postmortem human dopaminergic neurons from PD brains accumulate high levels of mitochondrial DNA (mtDNA) deletions. We now addressed the question, whether alterations in a component of the mitochondrial import machinery -TOM40- might contribute to the mitochondrial dysfunction and damage in PD. For this purpose, we studied levels of TOM40, mtDNA deletions, oxidative damage, energy production, and complexes of the respiratory chain in brain homogenates as well as in single neurons, using laser-capture-microdissection in transgenic mice overexpressing human wildtype ?-Syn. Additionally, we used lentivirus-mediated stereotactic delivery of a component of this import machinery into mouse brain as a novel therapeutic strategy. We report here that TOM40 is significantly reduced in the brain of PD patients and in ?-Syn transgenic mice. TOM40 deficits were associated with increased mtDNA deletions and oxidative DNA damage, and with decreased energy production and altered levels of complex I proteins in ?-Syn transgenic mice. Lentiviral-mediated overexpression of Tom40 in ?-Syn-transgenic mice brains ameliorated energy deficits as well as oxidative burden. Our results suggest that alterations in the mitochondrial protein transport machinery might contribute to mitochondrial impairment in ?-Synucleinopathies.

Rockenstein, Edward; Adame, Anthony; Elstner, Matthias; Laub, Christoph; Mueller, Sarina; Koob, Andrew O.; Mante, Michael; Pham, Emily; Klopstock, Thomas; Masliah, Eliezer



An approach to drug induced delirium in the elderly  

PubMed Central

Drugs have been associated with the development of delirium in the elderly. Successful treatment of delirium depends on identifying the reversible contributing factors, and drugs are the most common reversible cause of delirium. Anticholinergic medications, benzodiazepines, and narcotics in high doses are common causes of drug induced delirium. This article provides an approach for clinicians to prevent, recognise, and manage drug induced delirium. It also reviews the mechanisms for this condition, especially the neurotransmitter imbalances involving acetylcholine, dopamine, and gamma aminobutyric acid and discusses the age related changes that may contribute to altered pharmacological effects which have a role in delirium. Specific interventions for high risk elderly with the goal of preventing drug induced delirium are discussed.

Alagiakrishnan, K; Wiens, C



[Drug-induced malignant arrhythmias. IT prevents lethal drug mixtures].  


We report a case of nearly fatal ventricular tachyarrhythmia type Torsade de pointes caused by medication-induced prolongation of QTc duration (methadone, ondansetron, escitalopram). The etiology, pathophysiology, and trigger mechanisms of such malignant arrhythmias are discussed. In order to prevent similar iatrogenic complications in the future, we networked the qtdrug database with our medication interaction control program and installed an automatic electronic warning system for the physicians in charge in case of a digitally recorded prolonged QTc duration. PMID:23460391

Thaler, S; Neumeier, C; Flury, G



Drug-Induced Discoloration of Teeth: An Updated Review  

Microsoft Academic Search

The problem of tooth discoloration is emerging in our society because of the poor oral hygiene, physical agents, environmental chemicals, mouth rinses, some dental procedures, general systemic conditions, and drugs. Other common causes of tooth discoloration include excessive use of tea, coffee, tobacco smoking and chewing, chewing of betel morsel (piper betel, paan), and so on. Drug-induced tooth discoloration can

Arun Kumar; Vijay Kumar; Janardhan Singh; Anita Hooda; Samir Dutta



Drug-Induced Nephrotoxicity in Inflammatory Bowel Disease  

Microsoft Academic Search

Conservative management of inflammatory bowel disease (IBD) is based on a combination of drugs, including aminosalicylates (ASAs), steroids, antibiotics, immunosuppressives and biologic agents. Although various side effects have been related to treatment regimens, drug-induced nephrotoxicity is rather uncommon. Furthermore, it is often underestimated since renal function deterioration may be attributed to the underlying disease. The nephrotoxicity of ASAs and cyclosporine

Konstantinos A. Oikonomou; Andreas N. Kapsoritakis; Ioannis Stefanidis; Spyros P. Potamianos



Mechanisms in cancer-chemotherapeutic drugs-induced peripheral neuropathy  

Microsoft Academic Search

Anti-cancer drugs such as vincristine, paclitaxel, oxaliplatin, cisplatin and bortezomib are well reported to exert direct and indirect effects on sensory nerves to alter the amplitude of action potential, conduction velocity and induce pain. It results in patient suffering and also limits the treatment with potentially useful anticancer drugs. The different scientists have worked in this area to explore the

Amteshwar Singh Jaggi; Nirmal Singh


Gefitinib-associated vitiligo: report in a man with parotid squamous cell carcinoma and review of drug-induced hypopigmentation.  


Gefitinib is a tyrosine kinase inhibitor that targets and inhibits epidermal growth factor receptors. It was initially used to treat non-small cell lung cancer but has increasingly been used for other solid tumors such as those in the breast, colorectal sites, and head and neck, as in our patient. Vitiligo is an autoimmune disorder that results in the destruction of melanocytes and subsequent skin depigmentation and hypopigmentation. Previously described mucocutanous side effects of gefitinib at 250-500 mg/day include alopecia, asteatotic dermatitis, desquamation, hyperpigmentation, papulopustular acneiform eruption, pruritus, seborrheic dermatitis, and skin fragility. A 54-year-old man with metastatic squamous cell carcinoma to the parotid gland developed vitiligo within 1 month of starting gefitinib therapy. We retrospectively reviewed the medical literature using PubMed, searching: (1) gefitinib side effects, (2) drugs and (3) vitiligo. The patient with gefitinib-induced vitiligo continued to receive treatment with the drug during which time areas of skin hypopigmentation persisted and progressed. Etiology of drug-induced vitiligo includes alopecia areata therapies, anticonvulsants, antimalarials, antineoplastics, anti-Parkinson medications, and other miscellaneous drugs. No other individuals have been described with gefitinib-induced vitiligo. Albeit rare, gefitinib may be associated with the development of vitiligo. PMID:24139363

Jalalat, Sheila Z; Cohen, Philip R



The need for regulatable vectors for gene therapy for Parkinson's disease  

Microsoft Academic Search

Gene therapy is now a very promising approach for the treatment of Parkinson's disease, for which there are currently few treatment options. However, gene therapy is invasive and irreversible, and its long-term effects are not yet known. Regulatable vectors allow the expression of the introduced gene to be adjusted or stopped by changing the dose of an oral inducer drug,

Dean E. Cress



Drug-induced dystonia in neuronal ceroid-lipofuscinosis.  


Neuroleptic-induced tardive dystonia is frequently refractory to therapy. We describe a 13-year-old girl with neuronal ceroid-lipofuscinosis who developed dystonia after beginning treatment with thioridazine for acute psychosis. Although anticholinergic drugs and benzodiazepines were ineffective, the patient improved with baclofen. Patients with certain degenerative diseases of the central nervous system may be at increased risk for the development of drug-induced dystonia, and we caution against the use of neuroleptics in these patients. PMID:3508694

Gospe, S M; Jankovic, J


Emerging restorative treatments for Parkinson's disease: manipulation and inducement of dopaminergic neurons from adult stem cells.  


Parkinson's disease (PD) is a common neurodegenerative disease, characterized by a selective loss of midbrain Dopaminergic (DA) neurons. To address this problem, various types of stem cells that have potential to differentiate into DA neurons are being investigated as cellular therapies for PD, including cells derived from embryonic or adult donor tissue, and embryonic stem cells. These cell sources, however, have raised certain questions with regard to ethical and rejection issues. Recent progress in adult stems has further proved that the cells derived from adult tissue could be expanded and differentiated into DA precursor cells in vitro, and cell therapy with adult stem cells could produce a clear improvement for PD models. Using adult stem cells for clinic application may not only overcome the ethical problem inherent in using human fetal tissue or embryonic stem cells, but also open the possibility for autologous transplantation. The patient-specific adult stem cell is therefore a potential and prospective candidate for PD treatment. PMID:21495964

Zhao, Junpeng; Xu, Qunyuan



Extrapontine Myelinolysis-Induced Parkinsonism in a Patient with Adrenal Crisis  

PubMed Central

Background. Extrapontine myelinolysis (EPM) has been well described in the presence of rapid correction of hyponatremia. It is seldom reported with adrenal insufficiency. We report a unique case where a patient developed EPM as a result of adrenal insufficiency where the brain MRI revealed symmetrical lesion in the basal ganglia with pallidal sparing. Case Report. A 30-year-old gentleman with panhypopituitarism developed adrenal crisis, hyponatremia, and hyponatremic encephalopathy. Seven days after the rapid correction of hyponatremia, he developed parkinsonism and neuropsychiatric symptoms. MRI showed extrapontine myelinolysis without central pontine myelinolysis. Conclusion. Extrapontine myelinolysis without central pontine myelinolysis is rare and should raise a concern of associated adrenal insufficiency in the right clinical setting. Rapid correction of hyponatremia particularly in steroid-deficient states should be avoided as it can predispose to extrapontine myelinolysis. Magnetic resonance imaging is very helpful in supporting the diagnosis of EPM.

Imam, Yahia Z.; Saqqur, Maher; Alhail, Hassan



Sodium butyrate improves locomotor impairment and early mortality in a rotenone-induced Drosophila model of Parkinson's disease.  


Parkinson's disease (PD) is a neurodegenerative disorder primarily affecting the dopaminergic neurons in the nigrastriatal pathway resulting in debilitating motor impairment in both familial and sporadic cases. Histone deacetylase (HDAC) inhibitors have been recently implicated as a therapeutic candidate because of their ability to correct the disrupted HDAC activity in PD and other neurodegenerative diseases. Sodium butyrate (SB), an HDAC inhibitor, reduces degeneration of dopaminergic neurons in a mutant alpha-synuclein Drosophila transgenic model of familial PD. Chronic exposure to the pesticide rotenone also causes selective degeneration of dopaminergic neurons and causes locomotor impairment and early mortality in a Drosophila model of chemically induced PD. This study investigated the effects of sodium butyrate on locomotor impairment and early mortality in a rotenone-induced PD model. We show that treatment with 10mM SB-supplemented food rescued the rotenone-induced locomotor impairment and early mortality in flies. Additionally, flies with the genetic knockdown of HDAC activity through Sin3A loss-of-function mutation (Sin3A(lof)) were resistant to rotenone-induced locomotor impairment and early mortality. Furthermore, SB-supplemented Sin3A(lof) flies had a modest additive effect for improving locomotor impairment. We also show SB-mediated improvement of rotenone-induced locomotor impairment was associated with elevated dopamine levels in the brain. However, the possibility of SB-mediated protective role through mechanisms independent from dopamine system is also discussed. These findings demonstrate that HDAC inhibitors like SB can ameliorate locomotor impairment in a rotenone-induced PD model. PMID:23623990

St Laurent, R; O'Brien, L M; Ahmad, S T



Parkinson's disease - discharge  


Your doctor has told you that you have Parkinson’s disease . This disease affects the brain and leads to ( ... place you on different medicines to treat your Parkinson’s disease and many of the problems that may come ...


Molecular Docking and Prediction of Pharmacokinetic Properties of Dual Mechanism Drugs that Block MAO-B and Adenosine A2A Receptors for the Treatment of Parkinson's Disease  

PubMed Central

Monoamine oxidase B (MAO-B) inhibitory potential of adenosine A2A receptor (AA2AR) antagonists has raised the possibility of designing dual-target–directed drugs that may provide enhanced symptomatic relief and that may also slow the progression of Parkinson's disease (PD) by protecting against further neurodegeneration. To explain the dual inhibition of MAO-B and AA2AR at the molecular level, molecular docking technique was employed. Lamarckian genetic algorithm methodology was used for flexible ligand docking studies. A good correlation (R2= 0.524 and 0.627 for MAO-B and AA2AR, respectively) was established between docking predicted and experimental Ki values, which confirms that the molecular docking approach is reliable to study the mechanism of dual interaction of caffeinyl analogs with MAO-B and AA2AR. Parameters for Lipinski's “Rule-of-Five” were also calculated to estimate the pharmacokinetic properties of dual-target–directed drugs where both MAO-B inhibition and AA2AR antagonism exhibited a positive correlation with calculated LogP having a correlation coefficient R2 of 0.535 and 0.607, respectively. These results provide some beneficial clues in structural modification for designing new inhibitors as dual-target–directed drugs with desired pharmacokinetic properties for the treatment of PD.

Azam, Faizul; Madi, Arwa M.; Ali, Hamed I.



Further evidence for association of the RGS2 gene with antipsychotic-induced parkinsonism: protective role of a functional polymorphism in the 3'-untranslated region.  


RGS2 (regulator of G-protein signaling 2) modulates dopamine receptor signal transduction. Functional variants in the gene may influence susceptibility to extrapyramidal symptoms (EPS) induced by antipsychotic drugs. To further investigate our previous report of association of the RGS2 gene with susceptibility to antipsychotic-induced EPS, we performed a replication study. EPS were rated in 184 US patients with schizophrenia (115 African Americans, 69 Caucasian) treated for at least a month with typical antipsychotic drugs (n=45), risperidone (n=46), olanzapine (n=50) or clozapine (n=43). Six single nucleotide polymorphisms (SNPs) within or flanking RGS2 were genotyped (rs1933695, rs2179652, rs2746073, rs4606, rs1819741 and rs1152746). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression. Our results indicate association of SNP rs4606 with antipsychotic-induced parkinsonism (AIP), as measured by the Simpson Angus scale, in the overall sample and in the African-American subsample, the G (minor) allele having a protective effect. ORs for AIP among rs4606 G-allele carriers were 0.23 (95% CI 0.10-0.54, P=0.001) in the overall sample, and 0.20 (0.07-0.57, P=0.003) in the African-American subsample. In the previously studied Israeli sample the OR was 0.31 (0.11-0.84, P=0.02). We completely sequenced the RGS2 gene in nine patients with AIP and nine patients without, from the Israeli sample. No common coding polymorphisms or additional regulatory variants were revealed, suggesting that association of the rs4606 C/G polymorphism with AIP is biologically meaningful and not a consequence of linkage disequilibrium with another functional variant. Taken together, the findings of the current study support the association of RGS2 with AIP and focus on a possible protective effect of the minor G allele of SNP rs4606. This SNP is located in the 3'-regulatory region of the gene, and is known to influence RGS2 mRNA levels and protein expression. PMID:18347610

Greenbaum, L; Smith, R C; Rigbi, A; Strous, R; Teltsh, O; Kanyas, K; Korner, M; Lancet, D; Ben-Asher, E; Lerer, B



Drug-induced discoloration of teeth: an updated review.  


The problem of tooth discoloration is emerging in our society because of the poor oral hygiene, physical agents, environmental chemicals, mouth rinses, some dental procedures, general systemic conditions, and drugs. Other common causes of tooth discoloration include excessive use of tea, coffee, tobacco smoking and chewing, chewing of betel morsel (piper betel, paan), and so on. Drug-induced tooth discoloration can be prevented by avoiding prescriptions of well-known offender drugs known to cause tooth discoloration during pregnancy and in young children. This review describes some important groups of drugs that cause tooth discoloration. PMID:21917545

Kumar, Arun; Kumar, Vijay; Singh, Janardhan; Hooda, Anita; Dutta, Samir



Vanadium Induces Dopaminergic Neurotoxicity Via Protein Kinase C-Delta Dependent Oxidative Signaling Mechanisms: Relevance to Etiopathogenesis of Parkinson's Disease  

PubMed Central

Environmental exposure to neurotoxic metals through various sources including exposure to welding fumes has been linked to an increased incidence of Parkinson's disease (PD). Welding fumes contain many different metals including vanadium typically present as particulates containing vanadium pentoxide (V2O5). However, possible neurotoxic effects of this metal oxide on dopaminergic neuronal cells are not well studied. In the present study, we characterized vanadium-induced oxidative stress-dependent cellular events in cell culture models of PD. V2O5 was neurotoxic to dopaminergic neuronal cells including primary nigral dopaminergic neurons and the EC50 was determined to be 37 ?M in N27 dopaminergic neuronal cell model. The neurotoxic effect was accompanied by a time-dependent uptake of vanadium and upregulation of metal transporter proteins Tf and DMT1 in N27 cells. Additionally, vanadium resulted in a threefold increase in reactive oxygen species generation, followed by release of mitochondrial cytochrome c into cytoplasm and subsequent activation of caspase-9 (>fourfold) and caspase-3 (>ninefold). Interestingly, vanadium exposure induced proteolytic cleavage of native protein kinase Cdelta (PKC?, 72-74 kDa) to yield a 41 kDa catalytically active fragment resulting in a persistent increase in PKC? kinase activity. Co-treatment with pan-caspase inhibitor ZVAD-FMK significantly blocked vanadium-induced PKC? proteolytic activation, indicating that caspases mediate PKC? cleavage. Also, co-treatment with Z-VAD-FMK almost completely inhibited V2O5-induced DNA fragmentation. Furthermore, PKC? knockdown using siRNA protected N27 cells from V2O5-induced apoptotic cell death. Collectively, these results demonstrate vanadium can exert neurotoxic effects in dopaminergic neuronal cells via caspase-3-dependent PKC? cleavage, suggesting that metal exposure may promote nigral dopaminergic degeneration.

Afeseh Ngwa, Hilary; Kanthasamy, Arthi; Anantharam, Vellareddy; Song, Chunjuan; Witte, Travis; Houk, R. S.; Kanthasamy, Anumantha G.



Vanadium induces dopaminergic neurotoxicity via protein kinase Cdelta dependent oxidative signaling mechanisms: Relevance to etiopathogenesis of Parkinson's disease  

SciTech Connect

Environmental exposure to neurotoxic metals through various sources including exposure to welding fumes has been linked to an increased incidence of Parkinson's disease (PD). Welding fumes contain many different metals including vanadium typically present as particulates containing vanadium pentoxide (V{sub 2}O{sub 5}). However, possible neurotoxic effects of this metal oxide on dopaminergic neuronal cells are not well studied. In the present study, we characterized vanadium-induced oxidative stress-dependent cellular events in cell culture models of PD. V{sub 2}O{sub 5} was neurotoxic to dopaminergic neuronal cells including primary nigral dopaminergic neurons and the EC{sub 50} was determined to be 37 {mu}M in N27 dopaminergic neuronal cell model. The neurotoxic effect was accompanied by a time-dependent uptake of vanadium and upregulation of metal transporter proteins Tf and DMT1 in N27 cells. Additionally, vanadium resulted in a threefold increase in reactive oxygen species generation, followed by release of mitochondrial cytochrome c into cytoplasm and subsequent activation of caspase-9 (> fourfold) and caspase-3 (> ninefold). Interestingly, vanadium exposure induced proteolytic cleavage of native protein kinase Cdelta (PKC{delta}, 72-74 kDa) to yield a 41 kDa catalytically active fragment resulting in a persistent increase in PKC{delta} kinase activity. Co-treatment with pan-caspase inhibitor Z-VAD-FMK significantly blocked vanadium-induced PKC{delta} proteolytic activation, indicating that caspases mediate PKC{delta} cleavage. Also, co-treatment with Z-VAD-FMK almost completely inhibited V{sub 2}O{sub 5}-induced DNA fragmentation. Furthermore, PKC{delta} knockdown using siRNA protected N27 cells from V{sub 2}O{sub 5}-induced apoptotic cell death. Collectively, these results demonstrate that vanadium can exert neurotoxic effects in dopaminergic neuronal cells via caspase-3-dependent PKC{delta} cleavage, suggesting that metal exposure may promote nigral dopaminergic degeneration.

Afeseh Ngwa, Hilary; Kanthasamy, Arthi; Anantharam, Vellareddy; Song, Chunjuan [Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA 50011 (United States); Witte, Travis; Houk, Robert [Ames Laboratory, U. S. Department of Energy, Ames, IA 50011 (United States); Department of Chemistry, Iowa State University, Ames, IA 50011 (United States); Kanthasamy, Anumantha G. [Department of Biomedical Sciences, Iowa Center for Advanced Neurotoxicology, Iowa State University, Ames, IA 50011 (United States)], E-mail:



S-Allylcysteine, a garlic compound, protects against oxidative stress in 1-methyl-4-phenylpyridinium-induced parkinsonism in mice.  


S-Allylcysteine (SAC), the most abundant organosulfur compound in aged garlic extract, has multifunctional activity via different mechanisms and neuroprotective effects that are exerted probably via its antioxidant or free radical scavenger action. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mouse has been the most widely used model for assessing neuroprotective agents for Parkinson's disease. 1-Methyl-4-phenylpyridinium (MPP(+)) is the stable metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and it causes nigrostriatal dopaminergic neurotoxicity. Previous studies suggest that oxidative stress, via free radical production, is involved in MPP(+)-induced neurotoxicity. Here, we report on the neuroprotective effect of SAC against oxidative stress induced by MPP(+) in the striatum of C57BL/6J mice. Mice were pretreated with SAC (125 mg/kg ip) daily for 17 days, followed by administration of MPP(+) (0.72 mg/kg icv), and were sacrificed 24 h later to evaluate lipid peroxidation, different antioxidant enzyme activities, spontaneous locomotor activity and dopamine (DA) content. MPP(+) administration resulted in a significant decrease in DA levels in the striatum. Mice receiving SAC (125 mg/kg ip) had significantly attenuated MPP(+)-induced loss of striatal DA levels (32%). The neuroprotective effect of SAC against MPP(+) neurotoxicity was associated with blocked (100% of protection) of lipid peroxidation and reduction of superoxide radical production - indicated by an up-regulation of Cu-Zn-superoxide dismutase activity - both of which are indices of oxidative stress. Behavioral analyses showed that SAC improved MPP(+)-induced impairment of locomotion (35%). These findings suggest that in mice, SAC attenuates MPP(+)-induced neurotoxicity in the striatum and that an antioxidant effect against oxidative stress may be partly responsible for its observed neuroprotective effects. PMID:21190833

Rojas, Patricia; Serrano-García, Norma; Medina-Campos, Omar N; Pedraza-Chaverri, José; Maldonado, Perla D; Ruiz-Sánchez, Elizabeth



Parkinson's Disease  


... of the brain, there is a collection of nerve cells that help control movement, known as the basal ... ah). In a person with Parkinson's disease, these nerve cells are damaged and do not work as well ...


Parkinson's Disease  


Parkinson's disease (PD) is a type of movement disorder. It happens when nerve cells in the brain don't produce enough ... or speaking. There is no lab test for PD, so it can be difficult to diagnose. Doctors ...


The 5-HT1A-receptor agonist flibanserin reduces drug-induced dyskinesia in RGS9-deficient mice.  


Drug-induced dyskinesia is a major complication of dopamine replacement therapy in advanced Parkinson's disease consisting of dystonia, chorea and athetosis. Agonists at 5-HT1A-receptors attenuate levodopa-induced motor complications in non-human primates. Mice with increased dopamine D2 receptor (DRD2) signalling due to the lack of expression of the regulator of G-protein signalling 9 (RGS9) also develop dyskinesia following levodopa treatment. We investigated whether the 5-HT1A-receptor agonist flibanserin compared with buspirone reduces motor abnormalities induced by levodopa or quinelorane, a selective dopamine D2-receptor agonist. Following dopamine depletion via reserpine, 40 mice (20 wild-type and 20 RGS9 knock-out) were treated with flibanserin or buspirone in combination with levodopa or quinelorane. Motor behaviour was analysed using open field analysis. RGS9 knock-out mice displayed significantly more drug-induced dystonia (p < 0.04; t test) than wild type. In quinelorane-treated wild-type mice flibanserin as well as buspirone significantly reduced dystonia (p < 0.05). In RGS9 knock-out animals again both reduced quinelorane-induced dystonia. However, flibanserin was significantly more effective (p = 0.003). Following reserpine pretreatment and administration of levodopa wild-type and RGS 9 knock-out mice showed mild to moderate dystonia. Surprisingly, 10 mg/kg buspirone increased dystonia in both animal groups, whereas it was decreased by 10 mg/kg flibanserin. However, compared with levodopa alone only the increase of dystonia by buspirone was significant (p < 0.04). Flibanserin showed promising antidyskinetic effects in a model of drug-induced dyskinesia. Our data underline the possible benefit of 5-HT1A agonists in drug-induced dyskinesia. PMID:22569849

Strecker, Karl; Adamaszek, Michael; Ohm, Sven; Wegner, Florian; Beck, Jürgen; Schwarz, Johannes



Pulmonary and generalized lysosomal storage induced by amphiphilic drugs.  


Administration of amphiphilic drugs to experimental animals causes formation of myelinoid bodies in many cell types, accumulation of foamy macrophages in pulmonary alveoli and pulmonary alveolar proteinosis. These changes are the result of an interaction between the drugs and phospholipids which leads to an alteration in physicochemical properties of the phospholipids. Impairment of the digestion of altered pulmonary secretions in phagosomes of macrophages results in accumulation of foam cells in pulmonary alveoli. Impairment of the metabolism of altered phospholipids removed by autophagy induces an accumulation of myelinoid bodies. The administration of amphiphilic compounds thus causes pulmonary intra-alveolar histiocytosis which is a part of a drug-induced lysosomal storage or generalized lipidosis. The accumulation of drug-lipid complexes in myelinoid bodies and in pulmonary foam cells may lead to alteration of cellular functioning and to clinical disease. Currently over 50 amphiphilic drugs are known. Unique pharmacological properties necessitate clinical use of some of these drugs. The occurrence and severity of potential clinical side effects depend on the nature of each drug, dosage and duration of treatment, simultaneous administration of other drugs and foods, individual metabolic pattern of the patient and other factors. Further studies on factors preventing and potentiating adverse effects of amphiphilic drugs are indicated. PMID:6376111

Hruban, Z



Histological patterns in drug-induced liver disease.  


The diagnosis of drug-induced liver injury (DILI) is a challenging problem, often confounded by incomplete clinical information and the difficulty of eliciting exposure to herbal products, over-the-counter agents and toxins. The task is further rendered difficult on biopsy, as drugs can mimic all the patterns found in primary liver disease. Acute hepatitis, with or without cholestasis, is the most common histological pattern of DILI, and drugs such as acetaminophen are the leading causes of acute liver failure. Most cases of DILI resolve on discontinuation of the drug, but recovery can take months or rarely the disease can progress despite drug withdrawal. Drugs such as methotrexate can lead to chronic hepatitis and cirrhosis, while others such as minocycline, nitrofurantoin and methyldopa are implicated in autoimmune hepatitis. Prolonged cholestasis and ductopenia resembling primary chronic biliary disease can occur. Drug-induced steatohepatitis is also an uncommon pattern, but is well described with drugs such as amiodarone and irinotecan. In the presence of risk factors such as obesity and diabetes, some drugs such as tamoxifen, oestrogens and nifedipine can precipitate or exacerbate steatohepatitis. Other observed patterns include granulomatous hepatitis, vascular injury (eg, sinusoidal obstruction syndrome), Ito cell lipidosis and neoplasms (eg, adenomas). PMID:19474352

Ramachandran, R; Kakar, S



The Expression and Release of Hsp60 in 6-OHDA Induced In Vivo and In Vitro Models of Parkinson's Disease.  


In Parkinson's disease, dopaminergic neuron damage/death causes the release of soluble substances that are selectively toxic to neighboring/additional dopaminergic neurons through the activation of microglia. Hsp60 can be released from injured cells of central nervous system to activate microglia. However, its expression and role in Parkinson's disease has not been well understood. Here, we performed a 6-OHDA treated Parkinson's disease model in adult rats. Western blot analysis showed a time-course expression of Hsp60, which decreased gradually and then rose back. Immunofluorescence staining showed that Hsp60 was decreased in dopaminergic neuron, and most Hsp60 located on the surface of activated microglia. Furthermore, in cellular Parkinson's disease model, Hsp60 was obviously detected in the culture supernatants after 6-OHDA treatment, and a concomitant decrease in cell extracts. Taken together, our results suggested that Hsp60 could be released extracellularly to activate microglia in Parkinson's disease model. PMID:23943523

Feng, Mei Jiang; Zhang, Ling; Liu, Zhengxia; Zhou, Ping; Lu, Xiang



Elucidating mechanisms of drug-induced toxicity  

Microsoft Academic Search

The early and high-throughput application of assays for non-genetic toxicity is of great interest to the pharmaceutical industry, although few systems have been validated as being of good predictive value. New technologies could enable toxicity to be studied in the context of systems biology. An important factor to be considered is the metabolism of drugs to reactive intermediates. Chemical reactions

Daniel C. Liebler; F. Peter Guengerich



Parkinson's Onboard: Traveling with PD  


... NPF Center of Excellence Parkinson’s Onboard: Traveling with PD Travel is accessible for many people with Parkinson’s ... NPF Center of Excellence Parkinson’s Onboard: Traveling with PD Air Travel Specifics: • Airline carriers must provide meet- ...


Effects of D-cycloserine on MPTP-induced behavioral and neurological changes: potential for treatment of Parkinson's disease dementia.  


Glutamatergic dysfunction has been implicated in the neurodegeneration seen in Parkinson's disease (PD). Sub-chronic intraperitoneal injection with D-cycloserine (DCS), a partial agonist at the glycine binding site of the N-methyl-D-aspartate (NMDA) receptor, at dosages of 30, 100, or 200 mg/kg/day, was used to evaluate the role of NMDA receptors in neuronal and behavioral changes in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. Starting one day after intra-nigral infusion of MPTP, transient disturbance of motor function in the rotarod test was observed. This impairment spontaneously recovered to control levels 6 days after MPTP lesioning and DCS treatment facilitated recovery. MPTP lesioning also caused deficits in working memory and anxiety-like behavior in the T-maze and elevated plus-maze tests, respectively. Further, object recognition was disrupted in MPTP-lesioned rats, and interleukin-2 levels in the striatum, amygdala, and non-prefrontal cortex were increased, both changes being restored by DCS treatment. Furthermore, MPTP lesion-induced dopaminergic degeneration, microglial activation, and cell loss in the hippocampal CA1 area were all improved by DCS treatment. These results suggest that NMDA receptors are involved in PD-related neuronal and behavioral dysfunctions and that DCS may have clinical potential in the treatment of dementia associated with PD. PMID:21262271

Ho, Ying-Jui; Ho, Shih-Chun; Pawlak, Cornelius Rainer; Yeh, Kuei-Ying



A tribute to charlie chaplin: induced positive affect improves reward-based decision-learning in Parkinson's disease.  


Reward-based decision-learning refers to the process of learning to select those actions that lead to rewards while avoiding actions that lead to punishments. This process, known to rely on dopaminergic activity in striatal brain regions, is compromised in Parkinson's disease (PD). We hypothesized that such decision-learning deficits are alleviated by induced positive affect, which is thought to incur transient boosts in midbrain and striatal dopaminergic activity. Computational measures of probabilistic reward-based decision-learning were determined for 51 patients diagnosed with PD. Previous work has shown these measures to rely on the nucleus caudatus (outcome evaluation during the early phases of learning) and the putamen (reward prediction during later phases of learning). We observed that induced positive affect facilitated learning, through its effects on reward prediction rather than outcome evaluation. Viewing a few minutes of comedy clips served to remedy dopamine-related problems associated with frontostriatal circuitry and, consequently, learning to predict which actions will yield reward. PMID:22707944

Ridderinkhof, K Richard; van Wouwe, Nelleke C; Band, Guido P H; Wylie, Scott A; Van der Stigchel, Stefan; van Hees, Pieter; Buitenweg, Jessika; van de Vijver, Irene; van den Wildenberg, Wery P M



Drug-induced esophageal injury with an occult vascular ring  

PubMed Central

Drug-induced esophageal injury is an under-recognized clinical problem, and is associated with antibiotic use in more than 50% of cases. The current report describes a teenage girl who presented with symptoms of pill-induced esophagitis following doxycycline use. Subsequent investigations identified a previously undiagnosed vascular ring. Although most patients who experience drug-induced esophageal injury have no underlying anatomical or functional disorder of the esophagus, the condition is more common in areas of esophageal narrowing. The present case illustrates the possibility of an occult esophageal obstruction representing a risk factor for pill esophagitis. The etiologies, mechanisms and management of drug-induced esophageal injury are reviewed, and aspects of vascular rings that are relevant to paediatricians are discussed.

Guttman, Orlee R; Zachos, Mary



Protective effect of lycopene on oxidative stress and cognitive decline in rotenone induced model of Parkinson's disease.  


Evidence from clinical and experimental studies indicate that oxidative stress is involved in pathogenesis of Parkinson's disease. The present study was designed to investigate the neuroprotective potential of lycopene on oxidative stress and neurobehavioral abnormalities in rotenone induced PD. Rats were treated with rotenone (3 mg/kg body weight, intraperitoneally) for 30 days. NADH dehydrogenase a marker of rotenone action was observed to be significantly inhibited (35%) in striatum of treated animals. However, lycopene administration (10 mg/kg, orally) to the rotenone treated animals for 30 days increased the activity by 39% when compared to rotenone treated animals. Rotenone administration increased the MDA levels (75.15%) in striatum, whereas, lycopene administration to rotenone treated animals decreased the levels by 24.33%. Along with this, significant decrease in GSH levels (42.69%) was observed in rotenone treated animals. Lycopene supplementation on the other hand, increased the levels of GSH by 75.35% when compared with rotenone treated group. The activity of SOD was inhibited by 69% in rotenone treated animals and on lycopene supplementation; the activity increased by 12% when compared to controls. This was accompanied by cognitive and motor deficits in rotenone administered animals, which were reversed on lycopene treatment. Lycopene treatment also prevented release of cytochrome c from mitochondria. Collectively, these observations suggest that lycopene supplementation along with rotenone for 30 days prevented rotenone-induced alterations in antioxidants along with the prevention of rotenone induced oxidative stress and neurobehavioral deficits. The results provide an evidence for beneficial effect of lycopene supplementation in rotenone-induced PD and suggest therapeutic potential in neurodegenerative diseases involving accentuated oxidative stress. PMID:21484267

Kaur, Harpreet; Chauhan, Shaveta; Sandhir, Rajat



Drug-induced cognitive impairment in the elderly.  


Elderly people are more likely than younger patients to develop cognitive impairment as a result of taking medications. This reflects age- and disease-associated changes in brain neurochemistry and drug handling. Delirium (acute confusional state) is the cognitive disturbance most clearly associated with drug toxicity, but dementia has also been reported. The aetiology of cognitive impairment is commonly multifactorial, and it may be difficult to firmly establish a causal role for an individual medication. In studies of elderly hospital patients, drugs have been reported as the cause of delirium in 11 to 30% of cases. Medication toxicity occurs in 2 to 12% of patients presenting with suspected dementia. In some cases CNS toxicity occurs in a dose-dependent manner, often as a result of interference with neurotransmitter function. Drug-induced delirium can also occur as an idiosyncratic complication. Finally, delirium may occur secondary to iatrogenic complications of drug use. Almost any drug can cause delirium, especially in a vulnerable patient. Impaired cholinergic neurotransmission has been implicated in the pathogenesis of delirium and of Alzheimer's disease. Anticholinergic medications are important causes of acute and chronic confusional states. Nevertheless, polypharmacy with anticholinergic compounds is common, especially in nursing home residents. Recent studies have suggested that the total burden of anticholinergic drugs may determine development of delirium rather than any single agent. Also, anticholinergic effects have been identified in many drugs other than those classically thought of as having major anticholinergic effects. Psychoactive drugs are important causes of delirium. Narcotic agents are among the most important causes of delirium in postoperative patients. Long-acting benzodiazepines are the commonest drugs to cause or exacerbate dementia. Delirium was a major complication of treatment with tricyclic antidepressants but seems less common with newer agents. Anticonvulsants can cause delirium and dementia. Drug-induced confusion with nonpsychoactive drugs is often idiosyncratic in nature, and the diagnosis is easily missed unless clinicians maintain a high index of suspicion. Histamine H2 receptor antagonists, cardiac medications such as digoxin and beta-blockers, corticosteroids, non-steroidal anti-inflammatory agents and antibiotics can all cause acute, and, less commonly, chronic confusion. Drug-induced confusion can be prevented by avoiding polypharmacy and adhering to the saying 'start low and go slow'. Special care is needed when prescribing for people with cognitive impairment. Early diagnosis of drug-induced confusion, and withdrawal of the offending agent or agents is essential. PMID:10459729

Moore, A R; O'Keeffe, S T



Treatment of Parkinson's disease: nanostructured sol-gel silica-dopamine reservoirs for controlled drug release in the central nervous system  

PubMed Central

Introduction We have evaluated the use of silica–dopamine reservoirs synthesized by the sol–gel approach with the aim of using them in the treatment of Parkinson’s disease, specifically as a device for the controlled release of dopamine in the striatum. Theoretical calculations illustrate that dopamine is expected to assume a planar structure and exhibit weak interactions with the silica surface. Methods Several samples were prepared by varying the wt% of dopamine added during the hydrolysis of tetraethyl orthosilicate. The silica–dopamine reservoirs were characterized by N2 adsorption, scanning and transmission electron microscopy, and Fourier transform infrared spectroscopy. The in vitro release profiles were determined using ultraviolet visible absorbance spectroscopy. The textural analyses showed a maximum value for the surface area of 620 m2/g nanostructured silica materials. The stability of dopamine in the silica network was confirmed by infrared and 13C-nuclear magnetic resonance spectroscopy. The reservoirs were evaluated by means of apomorphine-induced rotation behavior in hemiparkisonian rats. Results The in vitro dopamine delivery profiles indicate two regimes of release, a fast and sustained dopamine delivery was observed up to 24 hours, and after this time the rate of delivery became constant. Histologic analysis of formalin-fixed brains performed 24–32 weeks after reservoir implantation revealed that silica–dopamine implants had a reddish-brown color, suggesting the presence of oxidized dopamine, likely caused by the fixation procedure, while implants without dopamine were always translucent. Conclusion The major finding of the study was that intrastriatal silica–dopamine implants reversed the rotational asymmetry induced by apomorphine, a dopamine agonist, in hemiparkinsonian rats. No dyskinesias or other motor abnormalities were observed in animals implanted with silica or silica–dopamine.

Lopez, Tessy; Bata-Garcia, Jose L; Esquivel, Dulce; Ortiz-Islas, Emma; Gonzalez, Richard; Ascencio, Jorge; Quintana, Patricia; Oskam, Gerko; Alvarez-Cervera, Fernando J; Heredia-Lopez, Francisco J; Gongora-Alfaro, Jose L



Nondipping in Parkinson's Disease  

PubMed Central

Objective. The aim of this study was to identify patients with Parkinson's disease who showed loss or decrease of nocturnal blood pressure fall (nondipper patients) as a marker of autonomic dysfunction. Presence or absence of orthostatic hypotension was considered to investigate whether alterations in circadian blood pressure pattern are associated with posture-related dysregulation of blood pressure. Methods. 40 patients with Parkinson's disease underwent 24-hour blood pressure monitoring. 21 patients were diagnosed with arterial hypertension and received anti-hypertensive drugs. Nondipper patients were defined as having nocturnal decrease of mean systolic and diastolic blood pressure less than 10%. Presence or absence of orthostatic hypotension was determined by Schellong's test. Results. We identified 35 nondipper patients (88%). Nondipping was detected in 20 patients with orthostatic hypotension (95%) and in 15 patients without orthostatic hypotension (79%). 18 patients with hypertensive and 22 patients with normal blood pressure values were detected. Conclusions. In conclusion 24-hour blood pressure monitoring showed a high prevalence of nondipping in 40 patients with Parkinson's disease with and without orthostatic hypotension independent of coexisting arterial hypertension and antihypertensive treatment. 24-hour blood pressure monitoring may be useful to identify non-dipping as a marker of autonomic dysfunction in patients with Parkinson's disease.

Sommer, Sita; Aral-Becher, Billur; Jost, Wolfgang



Parkinson Hastal›¤›nda Depresyonun Tedavisi  

Microsoft Academic Search

Depression is the most frequent psychiatric disorder in patients with Parkinson's disease. The rate of depression as published in a number of studies varies from 4% to 75%. There are several pos- sible approaches for the treatment of depression in Parkinson's disease. Drug treatment (TCAs, SSRIs, MAOIs and SNRI) is often, but not always necessary. Although antidepressant medications commonly used

Kemal Bayülkem; Fuat Torun


Adrenal Medulla Graft Induced Recovery of Function in an Animal Model of Parkinson's Disease: Possible Mechanisms of Action  

Microsoft Academic Search

Following unilateral dopamine (DA) denervation of the striatum in animals, there is an asymmetry in the striatal DA system. Animals with such denervations will rotate vigorously when given dopaminergic drugs. Adrenal medulla grafts placed in the lateral ventricle adjacent to a DA-denervated striatum decrease rotational behaviour induced by DA receptor agonists or DA-releasing agents. This discussion reviews research on the

Jill B. Becker; Eileen J. Curran; William J. Freed



Cyclooxygenase and Neuroinflammation in Parkinson's Disease Neurodegeneration  

PubMed Central

Cyclooxygenase (COX) expression in the brain is associated with pro-inflammatory activities, which are instrumental in neurodegenerative processes such as Parkinson’s disease (PD). It is discussed that drugs with the capacity to rescue dopaminergic neurons from microglia toxicity and neuroinflammatory processes may result in an amelioration of parkinsonian symptoms by delaying the onset or slowing progression. This article reviews the involvement of COX in neuroinflammation, specifically focussing at the role of selective COX-2 inhibition in neuroinflammation and neurodegeneration in Parkinson’s disease.

Bartels, Anna L; Leenders, Klaus L



Nonsteroidal anti-inflammatory drug-induced hepatoxicity.  


Nonsteroidal anti-inflammatory drugs are among the most prescribed medications worldwide. After antibiotics and anticonvulsants they are considered the most common medications associated with drug-induced liver injury mainly through an idiosyncratic form of hepatotoxicity. In rare cases severe hepatotoxicity has been described with significant morbidity and mortality. Genetic risk factors have been reported with diclofenac and lumiracoxib. Postmarketing surveillance and monitoring is crucial to identify severe cases of hepatotoxicity. PMID:24099022

Unzueta, Alberto; Vargas, Hugo E



Risk Factors for Complications of Drug-Induced Seizures  

Microsoft Academic Search

The purpose of this study is to determine clinical factors associated with complications of drug-induced seizures. This prospective\\u000a observational study was conducted at an American Association of Poison Control Centers-certified regional poison control center\\u000a (PCC) over a 1-year period. All consecutive cases reported to a PCC involving seizures were forwarded to investigators, who\\u000a obtained standardized information including the specific drug

Josef G. Thundiyil; Freda Rowley; Linda Papa; Kent R. Olson; Thomas E. Kearney



Calpain upregulation and neuron death in spinal cord of MPTP-induced parkinsonism in mice.  


Parkinson's disease (PD) is a neurodegenerative disorder resulting in slowness, tremors, and imbalance. Treatment of mice with 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) is one of several models used to mimic PD in humans. Administration of MPTP leads to the production of 1-methyl-4-phenyl-2,3 dihydropyridinium (MPP(+)). MPP(+) is taken up by dopaminergic neurons, causing mitochondrial dysfunction and cell death. Because calpain is involved in neuronal cell death and mitochondrial dysfunction, we examined the level of calpain in neurons in the substantia nigra (SN) and hippocampus of MPTP-treated C57BL/6 mice. Because of the interconnections between spinal cord and upper central nervous system neurons, we examined morphology, calpain activity, and calpain expression in neurons by double immunofluorescence using calpain and neuron marker (NeuN) antibodies. In controls, calpain expression was low in SN, hippocampus, and spinal cord NeuN(+) cells, and the NeuN stain was concentrated around the nucleus. In mice sacrificed 24 h after administration of three 20 mg/kg doses of MPTP, calpain expression was slightly increased in SN and hippocampal neurons and moderately increased in spinal cord neurons. In these animals, the NeuN stain was less concentrated around the nuclear membrane. One week after MPTP treatment, calpain content in NeuN(+) cells was greatly increased in SN, hippocampus, and spinal cord. Morphologically, SN and spinal cord neurons, treated for one week, were necrotic with a granular cytoplasmic NeuN content. Also, MPTP treatment upregulated calpain activity and mRNA level in spinal cord. These data suggest that following MPTP treatment, calpain causes neuronal death in SN as well as in spinal cord. PMID:12105103

Chera, Bhisham; Schaecher, Kurt E; Rocchini, Anne; Imam, Syed Z; Ray, Swapan K; Ali, Syed F; Banik, Naren L



Translating Clinical Findings into Knowledge in Drug Safety Evaluation - Drug Induced Liver Injury Prediction System (DILIps)  

PubMed Central

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60–70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the “Rule of Three” was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.

Liu, Zhichao; Shi, Qiang; Ding, Don; Kelly, Reagan; Fang, Hong; Tong, Weida



A strategy for risk management of drug-induced phospholipidosis.  


Drug-induced phospholipidosis (PL) is an excessive accumulation of phospholipids and drug in lysosomes. Phospholipidosis signals a change in cell membrane integrity and accumulation of intracellular drug or metabolite in tissues. The sensitivity and susceptibility of preclinical models to detect PL vary with therapeutic agents, and PL is expected to be reversible after discontinuation of drug treatment. The prevailing scientific opinion is that PL by itself is not adverse; however, some regulatory authorities consider PL to be adverse because a small number of chemicals are able to cause PL and concurrent organ toxicity. Until a greater understanding of PL emerges, a well-thought-out risk management strategy for PL will increase confidence in safety and improve selection and development of new drugs. This paper provides a tiered approach to risk management of drug-induced PL. It begins with use of in silico and in vitro tools to design and select compounds with reduced potential to produce PL. Early in vivo studies in two species are used to better characterize potential for toxicity and PL. Finally, routine risk management tools (i.e., translational biomarkers, assessment of reversibility) are used to support confidence in safety of compounds that induce PL in animals. PMID:20008549

Chatman, Linda A; Morton, Daniel; Johnson, Theodore O; Anway, Susan D



Impact of dopamine versus serotonin cell transplantation for the development of graft-induced dyskinesia in a rat Parkinson model.  


Graft-induced dyskinesia (GID), covering a range of dystonic and choreiform involuntary movements, has been observed in some patients with Parkinson's disease (PD) after intracerebral cell transplantation. These dyskinesias have been severe in a number of patients and represent one of the main obstacles for further development of the cell therapy in PD. Serotonin neurons, included into the dopaminergic cell suspension due to the nature of the dissection process, have been suggested as a key factor for the development of GID, since the administration of the serotonin (5-HT)(1A)-receptor agonist buspirone reduced dyskinesia in transplanted PD patients. In the present study, we characterized GID in the rat PD model after transplantation of dopaminergic grafts containing different amounts of serotonin neurons. The severity of GID was significantly correlated with the amount of grafted dopamine and serotonin neurons, but the r-values were low. However, neither the innervation density of dopamine and serotonin fibers in the grafted striatum nor the dopamine-to-serotonin cell ratio correlated significantly with the severity of GID. The results extend prior knowledge of the role of dopaminergic grafts in the development of GID and show that, in the animal model, serotonin neurons within the graft suspension might be involved, but given sufficient dopamine cells, their impact on GID may be minor. PMID:22759908

García, Joanna; Carlsson, Thomas; Döbrössy, Máté; Nikkhah, Guido; Winkler, Christian



Mutations in PTEN-induced putative kinase 1 associated with recessive parkinsonism have differential effects on protein stability.  


Several mutations in PTEN-induced putative kinase 1 (PINK1) gene have been reported to be associated with recessive parkinsonism. The encoded protein is predicted to be a Ser/Thr protein kinase targeted to mitochondria. In this study, we have investigated the effects of mutations on PINK1 kinase activity in vitro and on expression levels and localization in mammalian cells. We chose to examine two point mutations: G309D, which was originally reported to be stable and properly localized in cells and L347P, which is of interest because it is present at an appreciable carrier frequency in the Philippines. We were able to confirm kinase activity and produce artificial "kinase-dead" mutants that are stable but lack activity. The L347P mutation grossly destabilizes PINK1 and drastically reduces kinase activity, whereas G309D has much more modest effects on these parameters in vitro. This finding is in line with predictions based on homology modeling. We also examined the localization of PINK1 in transfected mammalian cells by using constructs that were tagged with myc or GFP at either end of the protein. These results show that PINK1 is processed at the N terminus in a manner consistent with mitochondrial import, but the mature protein also exists in the cytosol. The physiological relevance of this observation is not yet clear, but it implies that a portion of PINK1 may be exported after processing in the mitochondria. PMID:15824318

Beilina, Alexandra; Van Der Brug, Marcel; Ahmad, Rili; Kesavapany, Sashi; Miller, David W; Petsko, Gregory A; Cookson, Mark R



Anti-parkinsonian effects of Nurr1 activator in ubiquitin-proteasome system impairment induced animal model of Parkinson's disease.  


Nurr1 is a member of the nuclear receptor superfamily and is a potential susceptibility gene for Parkinson's disease (PD). Several lines of studies in vitro and in vivo reported that defects in the Nurr1 gene cause nigrostriatal neuronal deficiency as seen in PD. In the present study, we used a a synthetic low molecular weight Nurr1 activator which increases the transcription of Nurr1 to investigate whether it has anti-parkinsonian effects against nigrostriatal neuronal degeneration induced by proteasome inhibitor lactacystin. Adult C57BL/6 mice were treated orally with the Nurr1 activator and an inactive structural analog as a control at a dose of 10mg/kg per day, starting 3 days before microinjection of proteasome inhibitor lactacystin into the medial forebrain bundle and the treatment continued for a total of 4 weeks. Animal behavior tests, and pathological and biochemical examinations were performed to determine the anti-parkinsonian effects of the Nurr1 activator. We found that treatment with the Nurr1 activator significantly improved rotarod performance, attenuated dopamine neuron loss and nigrostriatal dopamine reduction, increased expression of Nurr1, dopamine transporter and vesicular monoamine transporter 2, and alleviated microglial activation in the substantia nigra of lactacystin-lesioned mice. These results suggest that the Nurr1 activator may become an innovative strategy for the treatment of PD. PMID:22483304

Zhang, Zhen; Li, Xuping; Xie, Wen-jie; Tuo, Houzhen; Hintermann, Samuel; Jankovic, Joseph; Le, Weidong



Drug-induced liver injury after allogeneic bone marrow transplantation.  


A 23-year-old woman developed acute severe hepatitis and jaundice on day 183 after bone marrow transplantation from HLA-B antigen mismatched-related donor. The administration of prednisolone and cessation of the prescribed drugs resolved the liver injury. Drug lymphocyte stimulation test was positive for acyclovir, and liver biopsy indicated the characteristics of drug-induced liver injury (DILI) rather than graft-versus-host disease. Physicians should keep DILI in mind when considering differential diagnosis for liver complications after allogeneic cell transplantation. PMID:24037455

Tachibana, Takayoshi; Nozaki, Akito; Enaka, Makiko; Yamamoto, Eri; Kawasaki, Rika; Koharazawa, Hideyuki; Hagihara, Maki; Ishibashi, Daisuke; Nakajima, Yuki; Kuwabara, Hideyuki; Tomita, Naoto; Ishigatsubo, Yoshiaki; Fujisawa, Shin



In silico modeling to predict drug-induced phospholipidosis.  


Drug-induced phospholipidosis (DIPL) is a preclinical finding during pharmaceutical drug development that has implications on the course of drug development and regulatory safety review. A principal characteristic of drugs inducing DIPL is known to be a cationic amphiphilic structure. This provides evidence for a structure-based explanation and opportunity to analyze properties and structures of drugs with the histopathologic findings for DIPL. In previous work from the FDA, in silico quantitative structure-activity relationship (QSAR) modeling using machine learning approaches has shown promise with a large dataset of drugs but included unconfirmed data as well. In this study, we report the construction and validation of a battery of complementary in silico QSAR models using the FDA's updated database on phospholipidosis, new algorithms and predictive technologies, and in particular, we address high performance with a high-confidence dataset. The results of our modeling for DIPL include rigorous external validation tests showing 80-81% concordance. Furthermore, the predictive performance characteristics include models with high sensitivity and specificity, in most cases above ?80% leading to desired high negative and positive predictivity. These models are intended to be utilized for regulatory toxicology applied science needs in screening new drugs for DIPL. PMID:23541745

Choi, Sydney S; Kim, Jae S; Valerio, Luis G; Sadrieh, Nakissa



Biomarkers to monitor drug-induced phospholipidosis  

SciTech Connect

Di-docosahexaenoyl (C22:6)-bis(monoacylglycerol) phosphate (BMP) was identified as a promising phospholipidosis (PL) biomarker in rats treated with either amiodarone, gentamicin, or azithromycin. Sprague-Dawley rats received either amiodarone (150 mg/kg), gentamicin (100 mg/kg) or azithromycin (30 mg/kg) once daily for ten consecutive days. Histopathological examination of tissues by transmission electron microscopy (TEM) indicated different degrees of accumulation of phospholipidosis in liver, lung, mesenteric lymph node, and kidney of drug-treated rats but not controls. Liquid chromatography coupled to mass spectrometry (LC/MS) was used to identify levels of endogenous biochemical profiles in rat urine. Urinary levels of di-docosahexaenoyl (C22:6)-bis(monoacylglycerol) phosphate (BMP) correlated with induction of phospholipidosis for amiodarone, gentamicin and azithromycin. Rats treated with gentamicin also had increased urinary levels of several phosphatidylinositol (PI), phosphatidylcholine (PC), and phosphatidylethanolamine (PE) species.

Baronas, Elizabeth Tengstrand [Nextcea, Inc., 3 Goffe Road, Lexington, MA 02421 (United States); Lee, Ju-Whei [Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115 (United States); Alden, Carl [Drug Safety and Disposition, Millennium Pharmaceuticals, Inc. 75 Sidney Street, Cambridge, MA 02139 (United States); Hsieh, Frank Y. [Nextcea, Inc., 3 Goffe Road, Lexington, MA 02421 (United States)]. E-mail:



Biomarkers to monitor drug-induced phospholipidosis.  


Di-docosahexaenoyl (C22:6)-bis(monoacylglycerol) phosphate (BMP) was identified as a promising phospholipidosis (PL) biomarker in rats treated with either amiodarone, gentamicin, or azithromycin. Sprague-Dawley rats received either amiodarone (150 mg/kg), gentamicin (100 mg/kg) or azithromycin (30 mg/kg) once daily for ten consecutive days. Histopathological examination of tissues by transmission electron microscopy (TEM) indicated different degrees of accumulation of phospholipidosis in liver, lung, mesenteric lymph node, and kidney of drug-treated rats but not controls. Liquid chromatography coupled to mass spectrometry (LC/MS) was used to identify levels of endogenous biochemical profiles in rat urine. Urinary levels of di-docosahexaenoyl (C22:6)-bis(monoacylglycerol) phosphate (BMP) correlated with induction of phospholipidosis for amiodarone, gentamicin and azithromycin. Rats treated with gentamicin also had increased urinary levels of several phosphatidylinositol (PI), phosphatidylcholine (PC), and phosphatidylethanolamine (PE) species. PMID:17156806

Baronas, Elizabeth Tengstrand; Lee, Ju-Whei; Alden, Carl; Hsieh, Frank Y



Stimulation of basal and l-DOPA-induced motor activity by glutamate antagonists in animal models of Parkinson's disease  

Microsoft Academic Search

In parkinsonism, glutamate pathways within the basal ganglia become overactive, leading to the suggestion that glutamate antagonists might possess antiparkinsonian qualities. This report examines the motor properties of antagonists of NMDA and AMPA-type glutamate receptors, as well as some inhibitors of glutamate release, in animal models of idiopathic Parkinson's disease. High affinity NMDA open-channel blockers (e.g. MK 801, phencyclidine), are

Michael S. Starr; Beryl S. Starr; Simranjt Kaur



Parkinson-like syndrome induced by continuous MPTP infusion: Convergent roles of the ubiquitin-proteasome system and -synuclein  

Microsoft Academic Search

In animals, sporadic injections of the mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) selectively damage dopaminergic neurons but do not fully reproduce the features of human Parkinson's disease. We have now developed a mouse Parkinson's disease model that is based on continuous MPTP administration with an osmotic minipump and mimics many features of the human disease. Although both sporadic and continuous MPTP administration

Francesco Fornai; Oliver M. Schlüter; Paola Lenzi; Marco Gesi; Riccardo Ruffoli; Michela Ferrucci; Gloria Lazzeri; Carla L. Busceti; Fabrizio Pontarelli; Giuseppe Battaglia; Antonio Pellegrini; Ferdinando Nicoletti; Stefano Ruggieri; Antonio Paparelli; Thomas C. Südhof



Glycogen Synthase Kinase 3? and Its Phosphorylated Form (Y216) in the Paraquat-Induced Model of Parkinsonism  

Microsoft Academic Search

Parkinson’s disease is a slowly progressing disease, due to a lesion of dopaminergic neurons in the substantia nigra and a\\u000a dramatic loss of dopamine in the striatum. It is now accepted that several environmental agents including the herbicide paraquat\\u000a (PQ) may contribute to its pathogenesis. However, till now nothing is known about the role of glycogen synthase kinase-3?\\u000a (GSK-3?) in

Martyna Songin; Joanna B. Strosznajder; Magdalena Fita?; Katarzyna Kuter; Wac?aw Kolasiewicz; Przemys?aw Nowak; Krystyna Ossowska



Drug-induced hyperhidrosis and hypohidrosis: incidence, prevention and management.  


The human sweating response is subject to the influence of diverse classes of drugs. Some act centrally at the hypothalamus or at spinal thermoregulatory centres, while others act at sympathetic ganglia or at the eccrine-neuroeffector junction. Pharmacological disturbances of sweating have broad clinical implications. Drugs that induce hyperhidrosis, or sweating in excess of that needed to maintain thermoregulation, can cause patient discomfort and embarrassment, and include cholinesterase inhibitors, selective serotonin reuptake inhibitors, opioids and tricyclic antidepressants. Drugs that induce hypohidrosis, or deficient sweating, can increase the risk of heat exhaustion or heat stroke and include antimuscarinic anticholinergic agents, carbonic anhydrase inhibitors and tricyclic antidepressants. As acetylcholine is the principal neuroeccrine mediator, anhidrosis is one of the clinical hallmarks by which acute anticholinergic toxicity may be recognized. The symptom of dry mouth often accompanies the less apparent symptom of hypohidrosis because the muscarinic M(3) acetylcholine receptor type predominates at both sweat and salivary glands. Management options include dose reduction, drug substitution or discontinuation. When compelling medical indications require continuation of a drug causing hyperhidrosis, the addition of a pharmacological agent to suppress sweating can help to reduce symptoms. When hypohidrotic drugs must be continued, deficient sweating can be managed by avoiding situations of heat stress and cooling the skin with externally applied water. The availability of clinical tests for the assessment of sudomotor dysfunction in neurological disease has enhanced recognition of the complex effects of drugs on sweating. Advances in the understanding of drug-induced anhidrosis have also enlarged the therapeutic repertoire of effective treatments for hyperhidrosis. PMID:18217788

Cheshire, William P; Fealey, Robert D



Drug-induced liver injury: past, present and future.  


Drug-induced liver injury (DILI) is a rare but potentially serious idiosyncratic reaction. By using candidate gene and genome-wide association studies, replicated associations for DILI susceptibility with HLA genes and genes relevant to drug metabolism have been detected, mainly since 2000. The HLA associations include a strong association between flucloxacillin-induced injury and the class I allele B*5701 and weaker associations for co-amoxiclav and ximelagatran DILI with the class II genotype. These associations suggest an injury mechanism involving an immune response, possibly to a complex of drug or metabolite and protein. For genes relevant to drug metabolism, the best replicated association is between isoniazid DILI and NAT2 slow acetylation. Homozygosity for GSTM1 null and/or GSTT1 null alleles also seems to be a risk factor for DILI, with associations described independently for several drugs. Other not-yet-replicated associations have been described for genes relevant to drug metabolism and oxidative stress and cytokine genes. PMID:20415545

Daly, Ann K



Doença de Parkinson - Diagnóstico  

Microsoft Academic Search

SUMMARY The diagnosis of Parkinson's disease is made by evaluation of the patient's history, neurological examination and response to dopamine replacement therapy. There is no biological marker that makes the diagnosis, and CT and MRI are typically unrevealing. Causes of secondary parkinsonism are excluded before a diagnosis of Parkinson's disease is made. Atypical parkinsonism, or parkinsonism-plus, is a term coined

Egberto Reis Barbosa; Flávio Augusto; Sekeff Sallem



[Etiological studies of secondary hypertension. e. Drug-induced hypertension].  


The findings of etiological studies show a relationship between secondary hypertension and various chemical agents. The subject populations included males, females, infants, adults (including people of advanced age), and healthy and unhealthy individuals, e.g., those with allergies or liver or digestive deficiencies. Results are presented in a table which shows that effects of drug-induced hypertension include expansion of extracellular fluid volume induced by sodium, antacids, and glycyrrhiza; disturbances of the autonomic nervous system caused by direct or indirect sympathomimetics;mixed or unknown mechanisms caused by poisons and various diagnostic and therapeutic agents, paradoxical response to antihypertensive agents caused by labetalol and saralasin acetate; and rebound hypertension induced by clonidine hydrochloride and methyldopa. Other drugs or chemical agents whose effects were examined include: glycyrrhizic acid, jintan, sulindac, thiazide, indo-methacin, and oral contraceptives. Based on these findings, drug-induced hypertension is observed quite frequently, a fact that has been the basis of considerable study. However, some cases indicate that even when hypertension is observed at experimental stages, insignificant hypertension is found at the clinical stage because of such factors a drug metabolism and patient sensitivity. PMID:6716694

Kato, E



Drug-induced liver injury: Is it somehow foreseeable?  

PubMed Central

The classic view on the pathogenesis of drug-induced liver injury is that the so-called parent compounds are made hepatotoxic by metabolism (formation of neo-substances that react abnormally), mainly by cytochromes P-450 (CYP), with further pathways, such as mitochondrial dysfunction and apoptosis, also playing a role. Risk factors for drug-induced liver injury include concomitant hepatic diseases, age and genetic polymorphisms of CYP. However, some susceptibility can today be predicted before drug administration, working on the common substrate, by phenotyping and genotyping studies and by taking in consideration patients’ health status. Physicians should always think of this adverse effect in the absence of other clear hepatic disease. Ethical and legal problems towards operators in the health care system are always matters to consider.

Tarantino, Giovanni; Di Minno, Matteo Nicola Dario; Capone, Domenico



Non-Steroidal Anti-Inflammatory Drug-Induced Enteropathy  

PubMed Central

Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly prescribed drugs in the world. NSAID-induced lower gastrointestinal (GI) complications are increasing while upper GI complications are decreasing. Lower GI events accounted for 40% of all serious GI events in patients on NSAIDs. Capsule endoscopy and device assisted enteroscopy are available for detection of small intestinal lesions. Capsule endoscopy studies have demonstrated that NSAIDs use in healthy volunteers raised the incidence (55% to 75%) of intestinal damage. It appears that selective cyclooxygenase-2 inhibitors (coxibs) improved upper and lower GI safety based on results of clinical trials. Selective coxibs are still capable of triggering GI adverse events and cardiovascular toxicity issues were the main focus of concerns. Unfortunately, definite strategies are not available to prevent or heal NSAID-induced intestinal injuries. Thus, there is still a strong clinical need for effective drugs with improved safety profiles than the existing NSAIDs.

Lim, Yun Jeong




PubMed Central

Acetaminophen is a widely used analgesic drug. Its adverse reactions are rare but severe. An 89-year-old man developed an indurated edematous and erythematous plaque on his left arm 1 day after acetaminophen ingestion. Cellulitis was suspected and antibiotictherapy was started but there was no improvement of the rash; there was a spectacular extension of the lesion with occurrence of flaccid vesicles and blisters in the affected sites. The diagnosis of generalized-bullous-fixed drug eruption induced by acetaminophen was considered especially with a reported history of a previous milder reaction occurring in the same site. Acetaminophen was withdrawn and the rash improved significantly. According to the Naranjo probability scale, the eruption experienced by the patient was probably due to acetaminophen. Clinicians should be aware of the ability of acetaminophen to induce fixed drug eruption that may clinically take several aspects and may be misdiagnosed.

Fathallah, Neila; Salem, Chaker Ben; Slim, Raoudha; Boussofara, Lobna; Ghariani, Najet; Bouraoui, Kamel



Therapeutic effect of hydrogen sulfide-releasing L-Dopa derivative ACS84 on 6-OHDA-induced Parkinson's disease rat model.  


Parkinson's disease (PD), characterized by loss of dopaminergic neurons in the substantia nigra, is a neurodegenerative disorder of central nervous system. The present study was designed to investigate the therapeutic effect of ACS84, a hydrogen sulfide-releasing-L-Dopa derivative compound, in a 6-hydroxydopamine (6-OHDA)-induced PD model. ACS84 protected the SH-SY5Y cells against 6-OHDA-induced cell injury and oxidative stress. The protective effect resulted from stimulation of Nrf-2 nuclear translocation and promotion of anti-oxidant enzymes expression. In the 6-OHDA-induced PD rat model, intragastric administration of ACS84 relieved the movement dysfunction of the model animals. Immunofluorescence staining and High-performance liquid chromatography analysis showed that ACS84 alleviated the loss of tyrosine-hydroxylase positive neurons in the substantia nigra and the declined dopamine concentration in the injured striatums of the 6-OHDA-induced PD model. Moreover, ACS84 reversed the elevated malondialdehyde level and the decreased glutathione level in vivo. In conclusion, ACS84 may prevent neurodegeneration via the anti-oxidative mechanism and has potential therapeutic values for Parkinson's disease. PMID:23573240

Xie, Li; Hu, Li-Fang; Teo, Xing Qi; Tiong, Chi Xin; Tazzari, Valerio; Sparatore, Anna; Del Soldato, Piero; Dawe, Gavin Stewart; Bian, Jin-Song



Behavioral and Neurochemical Effects of Alpha-Lipoic Acid in the Model of Parkinson's Disease Induced by Unilateral Stereotaxic Injection of 6-Ohda in Rat  

PubMed Central

This study aimed to investigate behavioral and neurochemical effects of ?-lipoic acid (100?mg/kg or 200?mg/kg) alone or associated with L-DOPA using an animal model of Parkinson's disease induced by stereotaxic injection of 6-hydroxydopamine (6-OHDA) in rat striatum. Motor behavior was assessed by monitoring body rotations induced by apomorphine, open field test and cylinder test. Oxidative stress was accessed by determination of lipid peroxidation using the TBARS method, concentration of nitrite and evaluation of catalase activity. ?-Lipoic acid decreased body rotations induced by apomorphine, as well as caused an improvement in motor performance by increasing locomotor activity in the open field test and use of contralateral paw (in the opposite side of the lesion produced by 6-OHDA) at cylinder test. ?-lipoic acid showed antioxidant effects, decreasing lipid peroxidation and nitrite levels and interacting with antioxidant system by decreasing of endogenous catalase activity. Therefore, ?-lipoic acid prevented the damage induced by 6-OHDA or by chronic use of L-DOPA in dopaminergic neurons, suggesting that ?-lipoic could be a new therapeutic target for Parkinson's disease prevention and treatment.

de Araujo, Dayane Pessoa; De Sousa, Caren Nadia Soares; Araujo, Paulo Victor Pontes; Menezes, Carlos Eduardo de Souza; Sousa Rodrigues, Francisca Taciana; Escudeiro, Sarah Souza; Lima, Nicole Brito Cortez; Patrocinio, Manoel Claudio Azevedo; Aguiar, Lissiana Magna Vasconcelos; Viana, Glauce Socorro de Barros; Vasconcelos, Silvania Maria Mendes



Targeting striatal cholinergic interneurons in Parkinson’s disease: Focus on metabotropic glutamate receptors  

Microsoft Academic Search

In the early sixties, anticholinergic drugs were introduced in the pharmacological treatment of Parkinson’s disease (PD). The rationale behind their utilisation in the treatment of the disease was based on the evidence of an imbalance between the dopaminergic inputs and the intrinsic cholinergic innervation within the striatum. Metabotropic glutamate (mGlu) receptors have been shown to play a key role in

A. Pisani; P. Bonsi; D. Centonze; P. Gubellini; G. Bernardi; P. Calabresi



Drug-induced phospholipidosis: are there functional consequences?  


Phospholipidosis induced by drugs with a cationic amphiphilic structure is a generalized condition in humans and animals that is characterized by an intracellular accumulation of phospholipids and the concurrent development of concentric lamellar bodies. The primary mechanism responsible for the development of phospholipidosis is an inhibition of lysosomal phospholipase activity by the drugs. While the biochemical and ultrastructural features of the condition have been well characterized, much less effort has been directed toward understanding whether the condition has adverse effects on the organism. While there are a few cationic amphiphilic drugs that have been reported to cause phospholipidosis in humans, the principal concern with this condition is in the pharmaceutical industry during preclinical testing. While this class of drugs should technically be referred to as cationic lipophilic, the term cationic amphiphilic is widely used and recognized in this field, and for this reason, the terminology cationic amphiphilic drugs (CADs) will be employed in this Minireview. The aim of this Minireview is to provide an evaluation of the state of knowledge on the functional consequences of CAD-induced phospholipidosis. PMID:11568304

Reasor, M J; Kacew, S



Drug-induced pulmonary arterial hypertension: a recent outbreak.  


Pulmonary arterial hypertension (PAH) is a rare disorder characterised by progressive obliteration of the pulmonary microvasculature resulting in elevated pulmonary vascular resistance and premature death. According to the current classification PAH can be associated with exposure to certain drugs or toxins, particularly to appetite suppressant intake drugs, such as aminorex, fenfluramine derivatives and benfluorex. These drugs have been confirmed to be risk factors for PAH and were withdrawn from the market. The supposed mechanism is an increase in serotonin levels, which was demonstrated to act as a growth factor for the pulmonary artery smooth muscle cells. Amphetamines, phentermine and mazindol were less frequently used, but are considered possible risk factors, for PAH. Dasatinib, dual Src/Abl kinase inhibitor, used in the treatment of chronic myelogenous leukaemia was associated with cases of severe PAH, potentially in part reversible after dasatinib withdrawal. Recently, several studies have raised the issue of potential endothelial dysfunction that could be induced by interferon, and a few cases of PAH have been reported with interferon therapy. PAH remains a rare complication of these drugs, suggesting possible individual susceptibility, and further studies are needed to identify patients at risk of drug-induced PAH. PMID:23997051

Montani, David; Seferian, Andrei; Savale, Laurent; Simonneau, Gérald; Humbert, Marc



In vitro validation of drug-induced phospholipidosis.  


Intracellular accumulation of phospholipids with lamellar bodies is a hallmark of drug-induced phospholipidosis (PLD) which is caused by impaired phospholipid metabolism of the lysosome. Although it remains uncertain whether PLD is associated with the adverse effects, sponsors generally terminate the development of a candidate drug when PLD is observed in an organ. For drugs that are used without serious adverse events, there should be labels indicating that the drug can induce PLD. We conducted LipidTox and NBD-PE assays for detecting PLD to compare and validate the methods. In the case of contrary results in both assays, electron microscopy was performed to confirm the data. We selected 12 chemicals and divided them into 4 categories: P+S+, PLD and steatosis positive; P+/S-, PLD positive and steatosis negative; P-S+, PLD negative and steatosis positive; P-/S-, PLD and steatosis negative. In general, results showed very good agreement with the known information with some minor discrepancies. LipidTox assay is proven to be a very sensitive method. Considering the contrary results of acetaminophen and menadione in LipidTox and the NBD-PE assay, the combination of two methods using different phospholipids is advantageous to reduce false positives. The finding that acetaminophen was positive in LipidTos assay and increased the frequency of lamellar body implies that acetaminophen is a weak inducer of PLD. PMID:22467016

Park, Sora; Choi, You-Jin; Lee, Byung-Hoon



Disease-specific induced pluripotent stem cells: a platform for human disease modeling and drug discovery  

PubMed Central

The generation of disease-specific induced pluripotent stem cell (iPSC) lines from patients with incurable diseases is a promising approach for studying disease mechanisms and drug screening. Such innovation enables to obtain autologous cell sources in regenerative medicine. Herein, we report the generation and characterization of iPSCs from fibroblasts of patients with sporadic or familial diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), juvenile-onset, type I diabetes mellitus (JDM), and Duchenne type muscular dystrophy (DMD), as well as from normal human fibroblasts (WT). As an example to modeling disease using disease-specific iPSCs, we also discuss the previously established childhood cerebral adrenoleukodystrophy (CCALD)- and adrenomyeloneuropathy (AMN)-iPSCs by our group. Through DNA fingerprinting analysis, the origins of generated disease-specific iPSC lines were identified. Each iPSC line exhibited an intense alkaline phosphatase activity, expression of pluripotent markers, and the potential to differentiate into all three embryonic germ layers: the ectoderm, endoderm, and mesoderm. Expression of endogenous pluripotent markers and downregulation of retrovirus-delivered transgenes [OCT4 (POU5F1), SOX2, KLF4, and c-MYC] were observed in the generated iPSCs. Collectively, our results demonstrated that disease-specific iPSC lines characteristically resembled hESC lines. Furthermore, we were able to differentiate PD-iPSCs, one of the disease-specific-iPSC lines we generated, into dopaminergic (DA) neurons, the cell type mostly affected by PD. These PD-specific DA neurons along with other examples of cell models derived from disease-specific iPSCs would provide a powerful platform for examining the pathophysiology of relevant diseases at the cellular and molecular levels and for developing new drugs and therapeutic regimens.

Jang, Jiho; Yoo, Jeong-Eun; Lee, Jeong-Ah; Lee, Dongjin R.; Kim, Ji Young; Huh, Yong Jun; Kim, Dae-Sung; Park, Chul-Yong; Hwang, Dong-Youn; Kim, Han-Soo



Nicotine and caffeine-mediated modulation in the expression of toxicant responsive genes and vesicular monoamine transporter-2 in 1-methyl 4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease phenotype in mouse  

Microsoft Academic Search

Epidemiological evidence revealed that cigarette smokers and coffee drinkers have lower risk of Parkinson's disease (PD). Nicotine inhibits monoamine oxidase activity, and induces expression of neurotrophic factors and nicotinic acetylcholinergic receptors. However, caffeine is capable of antagonizing adenosine A2A receptor. Toxicant responsive enzymes and vesicular monoamine transporter-2 (VMAT-2) play critical roles in chemically induced PD. Despite some known functions, the

Seema Singh; Kavita Singh; Suman Patel; Devendra Kumar Patel; Chetna Singh; Chandishwar Nath; Mahendra Pratap Singh



Drug-induced gingival overgrowth: a case report.  


A variety of systemic drugs can lead to adverse effects in the oral environment. This article reports the case of a 61-year-old man who had a severe drug-induced gingival overgrowth (DIGO) caused by nifedipine. DIGO is relevant due to severe gingival enlargement, which causes disfigurement and blocks physiological and social functions such as mastication and speaking. Management of DIGO is always a challenge due to the patient's systemic condition. This article shows, step-by-step, how the treatment was executed and how the DIGO was reversed. PMID:22782043

Alandia-Roman, Carla Cecilia; Tirapelli, Camila; Ribas, Paulo; Panzeri, Heitor


Metabolic activation in drug-induced liver injury.  


It is generally believed that metabolic bioactivation of drug molecules to form reactive metabolites, followed by their covalent binding to endogenous macromolecules, is one of the mechanisms that can lead to hepatotoxicity or idiosyncratic adverse drug reactions (IADRs). Although the role of bioactivation in drug-induced liver injury has been reasonably well established and accepted, and methodologies (e.g., structural alerts, reactive metabolite trapping, and covalent binding) continue to emerge in an attempt to detect the occurrence of bioactivation, the challenge remains to accurately predict the likelihood for idiosyncratic liver toxicity. Recent advances in risk-assessment methodologies, such as by the estimate of total body burden of covalent binding or by zone classification, taking the clinical dose into consideration, are positive steps toward improving risk assessment. The ability to better predict the potential of a drug candidate to cause IADRs will further be dependent upon a better understanding of the pathophysiological mechanisms of such reactions. Until a thorough understanding of the relationship between liver toxicity and the formation of reactive metabolites is achieved, it appears, at present, that the most practical strategy in drug discovery and development to reduce the likelihood of idiosyncratic liver toxicity via metabolic activation is to minimize or eliminate the occurrence of bioactivation and, at the same time, to maximize the pharmacological potency (to minimze the clinical dose) of the drug of interest. PMID:21939431

Leung, Louis; Kalgutkar, Amit S; Obach, R Scott



Drug-induced hypertension: an unappreciated cause of secondary hypertension.  


A myriad variety of therapeutic agents or chemical substances can induce either a transient or persistent increase in blood pressure, or interfere with the blood pressure-lowering effects of antihypertensive drugs. Some agents cause either sodium retention or extracellular volume expansion, or activate directly or indirectly the sympathetic nervous system. Other substances act directly on arteriolar smooth muscle or do not have a defined mechanism of action. Some medications that usually lower blood pressure may paradoxically increase blood pressure, or an increase in pressure may be encountered after their discontinuation. In general, drug-induced pressure increases are small and transient: however, severe hypertension involving encephalopathy, stroke, and irreversible renal failure have been reported. The deleterious effect of therapeutic agents is more pronounced in patients with preexisting hypertension, in those with renal failure, and in the elderly. Careful evaluation of a patient's drug regimen may identify chemically induced hypertension and obviate unnecessary evaluation and facilitate antihypertensive therapy. Once chemical-induced hypertension has been identified, discontinuation of the causative agent is recommended, although hypertension can often be managed by specific therapy and dose adjustment if continued use of the offending agent is mandatory. The present review summarizes the therapeutic agents or chemical substances that elevate blood pressure and their mechanisms of action. PMID:22195528

Grossman, Ehud; Messerli, Franz H



Influence of Age and Gender on Cytokine Expression in a Murine Model of Parkinson’s Disease  

Microsoft Academic Search

Objective: The neuroinflammatory reaction has been linked with Parkinson’s disease. One of the hypotheses to explain the significance of age and gender (male predominance) effects on neurodegeneration in Parkinson’s disease may result from a link between these risk factors and the inflammatory processes. Here, we investigated the expression of inflammatory mediators in relation to 1-methyl-4-phenyl-1,2,3,6-tetrahydropiridine (MPTP)-induced neurodegenerative processes in nigrostriatal

Agnieszka Ciesielska; Ilona Joniec



Recognizing and Managing Antipsychotic Drug Treatment Side Effects in the Elderly  

Microsoft Academic Search

Although atypical antipsychotics differ from conventional antipsychotics in their decreased ability to cause reversible drug-induced movement disorders\\/motor side effects such as dystonia, drug- induced parkinsonism, and akathisia and potentially persistent drug-induced movement disorders\\/ motor side effects such as tardive dyskinesia, no antipsychotic agent completely eradicates this risk. Antipsychotic agents are frequently used in facilities for the elderly and in general

Bruce L. Saltz; Delbert G. Robinson; Margaret G. Woerner


Acute oxcarbazepine-induced hepatotoxicity in a patient susceptible to developing drug-induced liver injury.  


Oxcarbazepine (OXC) is generally accepted as a drug without risk of severe drug-induced hepatotoxicity, but according to recently reported pharmacovigilance data this statement has been challenged. However, in the literature there have been no reports of acute OXC-induced hepatotoxicity without systemic manifestations of Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome. We present a female with seizures one month after delivery who had borderline elevated liver enzymes prior to the initiation of OXC treatment. Two weeks after introducing OXC, highly elevated liver enzymes were found. After discontinuation of OXC the enzymes continued to rise for another week, and afterward gradually decreased. The causal relationship with OXC intake was determined to be highly probable. Two years later, the transitory elevation of liver enzymes was observed during the treatment of acute tonsilopharingitis with amoxicillin + clavulanic acid. The repeated elevation of liver enzymes related to use of different drugs might indicate patients susceptibility for drug induced liver injuries. We suggest that monitoring of liver function tests would be clinically rational for early detection of acute OXC-induced liver hepatotoxicity in the patients with clinical and/or laboratory features which might be interpreted as possible risk factors of the increased susceptibility to drug induced liver injuries. PMID:23697284

Planjar-Prvan, Miljenka; Bielen, Ana; Sruk, Ana; Marusi?, Marinko; Bielen, Ivan



Drug-induced loss of unstably amplified genes.  


Methotrexate-resistant R500 cells slowly lose amplified dihydrofolate reductase (dhrf) genes with biphasic kinetics when grown in the absence of methotrexate. Both phases of gene loss were markedly accelerated by subcytotoxic drug treatments. R500 cells were passed in low concentrations of cytotoxic drugs (inhibitors of ribonucleotide reductase, type I and type II topoisomerases, and polyamine synthesis). At each passage, relative dhfr gene copy number was determined by slot blot analysis. All of these drugs were able to induce rapid loss of dhfr gene dosage in the R500 cell population. The ability of these treatments to cause the rapid emergence of a cell population with substantially reduced dhfr gene dosage indicates that either the amplified genes or those cells with the highest levels of gene amplification are selectively targeted by low-level cytotoxic stress. The complex kinetics of amplified gene loss are suggestive of differential targeting of resistant cell subpopulations. PMID:2292052

Wani, M A; Snapka, R M



In vitro assays and biomarkers for drug-induced phospholipidosis.  


Drug-induced phospholipidosis is the cytoplasmic accumulation of phospholipids as a result of xenobiotic exposure. This accumulation results in a unique histological effect in cells noted as electron-dense lamellar inclusions or whorls in the cytoplasm when observed with transmission electron microscopy. Electron microscopy has been the widely accepted standard for classification of the phospholipidosis effect. Molecules that have been prone to induce such an effect are made up of a lipophilic region and a positively charged region. Phospholipidosis has most commonly been associated with drugs that are cationic, amphiphilic drugs and can occur in a variety of tissues. Although phospholipidosis is not considered adverse in isolation, depending on the tissue affected or the occasional circumstance of concurrent toxicity, phospholipidosis can be perplexing if identified in early drug development. In most circumstances, characterisation of the effect with in vivo studies allows for determination of exposure and the magnitude of the effect. On occasion in drug development, there may be an interest to screen early stage compounds to minimise phospholipidosis. In such circumstances, in silico and in vitro assays can be employed in a strategy with in vivo assessments. In addition, there may be an interest to monitor for the potential development of phospholipidosis in longer-term animal studies. In such cases, biomarker approaches could be used. The challenge in the overall assessment of phospholipidosis remains the question of the possible relevance to any toxicity, and, therefore, any screening approach, while assessing the potential to induce phospholipidosis, must be considered in relation to prediction of findings in vivo. The status of current assays and biomarkers is presented with strategies for screening. PMID:17014389

Monteith, David K; Morgan, Ryan E; Halstead, Bartley



Drug target validation: Lethal infection blocked by inducible peptide  

NASA Astrophysics Data System (ADS)

Genome projects are generating large numbers of potential new targets for drug discovery. One challenge is target validation, proving the usefulness of a specific target in an animal model. In this paper, we demonstrate a new approach to validation and assay development. We selected in vitro specific peptide binders to a potential pathogen target. By inducing the expression of a selected peptide in pathogen cells causing a lethal infection in mice, the animals were rescued. Thus, by combining in vitro selection methods for peptide binders with inducible expression in animals, the target's validity was rigorously tested and demonstrated. This approach to validation can be generalized and has the potential to become a valuable tool in the drug discovery process.

Tao, Jianshi; Wendler, Philip; Connelly, Gene; Lim, Audrey; Zhang, Jiansu; King, Megan; Li, Tongchuan; Silverman, Jared A.; Schimmel, Paul R.; Tally, Francis P.



Alternative splicing of AMPA receptor subunits in the 6-OHDA-lesioned rat model of Parkinson's disease and L-DOPA-induced dyskinesia.  


Abnormal corticostriatal plasticity is a key mechanism of L-DOPA-induced dyskinesia (LID) in Parkinson's disease (PD). Antagonists at glutamatergic ?-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, such as IEM 1460, reduce induction and expression of dyskinesia in rat and non-human primate models of PD. AMPA receptor function is regulated by post-transcriptional splicing of subunit mRNA to produce flip and flop isoforms, which may therefore influence corticostriatal plasticity. The aim of this work was to evaluate alterations in alternative splicing of striatal AMPA receptor subunits in the unilateral 6-hydroxydopamine (6-OHDA)-lesioned rat model of LID and PD. Male Sprague-Dawley rats received 12.5?g 6-OHDA injections into the right medial forebrain bundle. In experiment 1, to assess acute dyskinesia, rats received L-DOPA/benserazide (6/15mg/kg, i.p.) or vehicle for 21days. In experiment 2, to assess dyskinesia priming, rats received vehicle, L-DOPA+vehicle or L-DOPA+IEM 1460 (3mg/kg, i.p.) for 21days. Animals were humanely killed 1h following final treatment in experiment 1, and 48h following final treatment in experiment 2. Coronal sections of rostral striatum were processed for in situ hybridisation histochemistry, using oligonucleotide probes specific for the GluR1 and GluR2 subunits and their flip and flop isoforms. L-DOPA treatment increased GluR2-flip mRNA expression in the lesioned striatum of both groups; this was blocked by the Ca(2+)-permeable AMPA receptor antagonist IEM 1460. GluR1-flip expression was increased after 48h drug washout but not in acute LID. There were no changes in expression of flop isoforms. Alternative splicing of AMPAR subunits contributes to abnormal striatal plasticity in the induction and expression of LID. Increases in GluR2-flip expression depend on activation of Ca(2+)-permeable AMPA receptors, which are a potential target of anti-dyskinetic therapies. PMID:23360800

Kobylecki, Christopher; Crossman, Alan R; Ravenscroft, Paula



[Chronic myelogenous leukemia complicated by drug-induced agranulocytosis].  


We describe a patient with chronic myelogenous leukemia (CML) who developed drug-induced agranulocytosis. A 75-year-old female was diagnosed with CML in December 2001. She had been receiving imatinib therapy for more than five years. In August 2007, she was hospitalized due to a severe neutropenia 10 days after colonoscopy. She was diagnosed as having agranulocytosis induced by colonoscopy premedication including scopolamine butylbromide and flumazenil. Severe neutropenia was resolved by G-CSF treatment without CML progression. Agranulocytosis in patients with CML is rare, but potentially lethal. Here, we report the clinical course in this patient. PMID:21646773

Nakao, Takafumi; Yoshida, Noriko; Nakane, Takahiko; Terada, Yoshiki; Nakamae, Hirohisa; Koh, Ki-Ryang; Yamane, Takahisa; Hino, Masayuki



The role of metabolic activation in drug-induced hepatotoxicity.  


The importance of reactive metabolites in the pathogenesis of drug-induced toxicity has been a focus of research interest since pioneering investigations in the 1950s revealed the link between toxic metabolites and chemical carcinogenesis. There is now a great deal of evidence that shows that reactive metabolites are formed from drugs known to cause hepatotoxicity, but how these toxic species initiate and propagate tissue damage is still poorly understood. This review summarizes the evidence for reactive metabolite formation from hepatotoxic drugs, such as acetaminophen, tamoxifen, diclofenac, and troglitazone, and the current hypotheses of how this leads to liver injury. Several hepatic proteins can be modified by reactive metabolites, but this in general equates poorly with the extent of toxicity. Much more important may be the identification of the critical proteins modified by these toxic species and how this alters their function. It is also important to note that the toxicity of reactive metabolites may be mediated by noncovalent binding mechanisms, which may also have profound effects on normal liver physiology. Technological developments in the wake of the genomic revolution now provide unprecedented power to characterize and quantify covalent modification of individual target proteins and their functional consequences; such information should dramatically improve our understanding of drug-induced hepatotoxic reactions. PMID:15822174

Park, B Kevin; Kitteringham, Neil R; Maggs, James L; Pirmohamed, Munir; Williams, Dominic P



Domperidone induced galactorrhea: An unusual presentation of a common drug  

PubMed Central

Domperidone is a prokinetic drug used for diabetic gastro paresis, hiccoughs, and vomiting. It is a peripheral D2 receptor antagonist with selective peripheral activity restricted to the upper gastro intestinal tract. It is not known to cross the blood brain barrier and hence, lacks neurological side effects. We would like to report a case of domperidone induced galactorrhea in a young female who presented with galactorrhea and other symptoms suggestive of prolactinoma.

Poovathingal, Mary Anne; Bhat, Rama; Ramamoorthi



Drug-induced immune thrombocytopenia due to moxifloxacin.  


A 39-year-old woman with 1 day of oral petechiae, leg ecchymoses and epistaxis was found to have isolated thrombocytopenia. She had recently completed a 10-day course of moxifloxacin for an upper respiratory infection. On further questioning, she had developed thrombocytopenia 2 years earlier after a treatment course with moxifloxacin. After ruling out other causes, drug-induced immune thrombocytopenia due to moxifloxacin was diagnosed. Her platelets returned to normal range 15 days after finishing the medication. PMID:23329709

Coker, Timothy J



Prolonged drug-induced hypothermia in experimental stroke  

Microsoft Academic Search

In experimental and human stroke, hypothermia is strongly related to a favorable outcome. Previous attempts to manipulate the core temperature in focal cerebral ischemia have been based on mechanical cooling. The purpose of the study is to establish a model for long-term drug-induced hypothermia in focal ischemia by pharmacological alteration of the central thermoregulatory set-point. We tested the hypothesis that

Flemming Fryd Jhansen; Henrik Stig Jřrgensen; Jakob Reith



Current approaches to the treatment of Parkinson's disease  

PubMed Central

Enormous progress has been made in the treatment of Parkinson’s disease (PD). As a result of advances in experimental therapeutics, many promising therapies for PD are emerging. Levodopa remains the most potent drug for controlling PD symptoms, yet is associated with significant complications such as the “wearing off” effect, levodopa-induced dyskinesias and other motor complications. Catechol-o-methyl-transferase inhibitors, dopamine agonists and nondopaminergic therapy are alternative modalities in the management of PD and may be used concomitantly with levodopa or one another. The neurosurgical treatment, focusing on deep brain stimulation, is reviewed briefly. Although this review has attempted to highlight the most recent advances in the treatment of PD, it is important to note that new treatments are not necessarily better than the established conventional therapy and that the treatment options must be individualized and tailored to the needs of each individual patient.

Jankovic, Joseph; Aguilar, L Giselle



Amiloride is neuroprotective in an MPTP model of Parkinson's disease.  


The diuretic amiloride has recently proven neuroprotective in models of cerebral ischemia, a property attributable to the drug's inhibition of central acid-sensing ion channels (ASICs). Given that Parkinson's disease (PD), like ischemia, is associated with cerebral lactic acidosis, we tested amiloride in the MPTP-treated mouse, a model of PD also manifesting lactic acidosis. Amiloride was found to protect substantia nigra (SNc) neurons from MPTP-induced degeneration, as determined by attenuated reductions in striatal tyrosine hydroxylase (TH) and dopamine transporter (DAT) immunohistochemistry, as well as smaller declines in striatal DAT radioligand binding and dopamine levels. More significantly, amiloride also preserved dopaminergic cell bodies in the SNc. Administration of psalmotoxin venom (PcTX), an ASIC1a blocker, resulted in a much more modest effect, attenuating only the deficits in striatal DAT binding and dopamine. These findings represent the first experimental evidence of a potential role for ASICs in the pathogenesis of Parkinson's disease. PMID:18606547

Arias, Robert L; Sung, Mei-Li A; Vasylyev, Dmytro; Zhang, Mei-Yi; Albinson, Kristin; Kubek, Katie; Kagan, Natasha; Beyer, Chad; Lin, Qian; Dwyer, Jason M; Zaleska, Margaret M; Bowlby, Mark R; Dunlop, John; Monaghan, Michael



Dropped head associated with amantadine in Parkinson disease.  


The antiviral agent amantadine has been used to manage Parkinson's disease or levodopa-induced dyskinesias for nearly 5 decades. Amantadine is often associated with hallucinations as an adverse effect, but a long-term study reported no serious motor complications. We describe an unusual patient who had Parkinson's disease with dropped head syndrome (DHS) caused by amantadine. When the patient, who had DHS while receiving only 2 kinds of antiparkinsonian drugs, was rechallenged with amantadine, DHS developed, accompanied by increased muscle tone in the neck muscles on surface electromyogram. The DHS resolved after the withdrawal of amantadine. Moreover, an intravenous infusion of levodopa did not alter the DHS. These findings collectively suggest that the DHS in our patient was most likely caused directly by amantadine. Our findings suggest that amantadine may carry the risk of augmenting dystonic syndrome in humans. PMID:21242745

Kataoka, Hiroshi; Ueno, Satoshi


[A case of drug-induced pneumonitis associated with chinese herbal drugs and valsartan].  


A 70-year-old man was admitted with a chief complaint of dyspnea. Chest X-ray images showed diffuse infiltrative shadows in both lungs. A chest CT scan showed diffuse non-segmental consolidation with an air bronchogram, ground-glass opacity, and possible traction bronchiectasis. The number of lymphocytes was abnormally high in the bronchoalveolar lavage fluid (BALF), and examination of a transbronchial lung biopsy specimen revealed Masson's body and bronchiolitis. Microorganisms were not present in the BALF. Drug-induced pneumonitis, caused by the Chinese herbal drug saiko-ka-ryukotsu-borei-to or valsartan or both, which he had been taking for about 3 months, was diagnosed. The patient's symptoms and the pulmonary infiltrates seen on chest radiograph diminished after these drugs were discontinued and oral prednisolone was administered. PMID:16050466

Tokunaga, Takanari



Mechanism of the neuroprotective role of coenzyme Q10 with or without L-dopa in rotenone-induced parkinsonism  

Microsoft Academic Search

Current treatment options for parkinsonism as a neurodegenerative disease are limited and still mainly symptomatic and lack significant disease-modifying effect. Understanding its molecular pathology and finding the cause of dopaminergic cell loss will lead to exploring therapies that could prevent and cure the disease. Mitochondrial dysfunction was found to stimulate releasing of reactive oxygen species (ROS) with subsequent induction of

Amany A. Abdin; Hala E. Hamouda



Contrasting changes in cortical activation induced by acute high-frequency stimulation within the globus pallidus in Parkinson's disease  

Microsoft Academic Search

Continuous stimulation of the globus pallidus (GP) has been shown to be an effective treatment for Parkinson's disease (PD). We used the fact that the implanted quadripolar leads contain electrodes within the GPi and GPe to investigate the clinical effects of acute high-frequency stimulation applied in these nuclei and changes in regional cerebral blood flow (rCBF) as an index of

Pierre Payoux; Philippe Remy; Malika Miloudi; Jean-Luc Houeto; Claudio Stadler; Boulos-Paul Bejjani; Jérome Yelnik; Yves Samson; Olivier Rascol; Yves Agid; Philippe Damier



Manganese: A transition metal protects nigrostriatal neurons from oxidative stress in the iron-induced animal model of Parkinsonism  

Microsoft Academic Search

It has been suggested that transition metals such as iron and manganese produce oxidative injury to the dopaminergic nigrostriatal system, which may play a critical role in the pathogenesis of Parkinson's disease. Intranigral infusion of ferrous citrate (0 to 8.4 nmol, i.n.) acutely increased lipid peroxidation in the substantia nigra and dopamine turnover in the caudate nucleus. Subsequently, it caused

I. Sziráki; K. P. Mohanakumar; P. Rauhala; H. G. Kim; K. J. Yeh; C. C. Chiueh



The Possible Potential Therapeutic Targets for Drug Induced Gingival Overgrowth  

PubMed Central

Gingival overgrowth is a side effect of certain medications. The most fibrotic drug-induced lesions develop in response to therapy with phenytoin, the least fibrotic lesions are caused by cyclosporin A, and the intermediate fibrosis occurs in nifedipine-induced gingival overgrowth. Fibrosis is one of the largest groups of diseases for which there is no therapy but is believed to occur because of a persistent tissue repair program. During connective tissue repair, activated gingival fibroblasts synthesize and remodel newly created extracellular matrix. Proteins such as transforming growth factor (TGF), endothelin-1 (ET-1), angiotensin II (Ang II), connective tissue growth factor (CCN2/CTGF), insulin-like growth factor (IGF), and platelet-derived growth factor (PDGF) appear to act in a network that contributes to the development of gingival fibrosis. Since inflammation is the prerequisite for gingival overgrowth, mast cells and its protease enzymes also play a vital role in the pathogenesis of gingival fibrosis. Drugs targeting these proteins are currently under consideration as antifibrotic treatments. This review summarizes recent observations concerning the contribution of TGF-?, CTGF, IGF, PDGF, ET-1, Ang II, and mast cell chymase and tryptase enzymes to fibroblast activation in gingival fibrosis and the potential utility of agents blocking these proteins in affecting the outcome of drug-induced gingival overgrowth.

Alitheen, Noorjahan Banu



Serotonergic and dopaminergic mechanisms in graft-induced dyskinesia in a rat model of Parkinson's disease.  


Dyskinesia seen in the off-state, referred as graft-induced dyskinesia (GID), has emerged as a serious complication induced by dopamine (DA) cell transplantation in parkinsonian patients. Although the mechanism underlying the appearance of GID is unknown, in a recent clinical study the partial 5-HT(1A) agonist buspirone was found to markedly reduce GID in three grafted patients, who showed significant serotonin (5-HT) hyperinnervation in the grafted striatum in positron emission tomography scanning (Politis et al., 2010, 2011). Prompted by these findings, this study was performed to investigate the involvement of serotonin neurons in the appearance of GID in the rat 6-hydroxydopamine model. L-DOPA-primed rats received transplants of DA neurons only, DA plus 5-HT neurons or 5-HT neurons only into the lesioned striatum. In DA cell-grafted rats, with or without 5-HT neurons, but not in 5-HT grafts, GID was observed consistently after administration of amphetamine (1.5mg/kg, i.p.) indicating that grafted DA neurons are required to induce GID. Strikingly, a low dose of buspirone produced a complete suppression of GID. In addition, activation of 5-HT(1A) and 5-HT(1B) receptors by 8-OH-DPAT and CP 94253, known to inhibit the activity of 5-HT neurons, significantly reduced GID, whereas induction of neurotransmitter release by fenfluramine administration significantly increased GID, indicating an involvement of the 5-HT system in the modulation of GID. To investigate the involvement of the host 5-HT system in GID, the endogenous 5-HT terminals were removed by intracerebral injection of 5,7-dihydroxytryptamine, but this treatment did not affect GID expression. However, 5-HT terminal destruction suppressed the anti-GID effect of 5-HT(1A) and 5-HT(1B) agonists, demonstrating that the 5-HT(1) agonist combination exerted its anti-GID effect through the activation of pre-synaptic host-derived receptors. By contrast, removal of the host 5-HT innervation or pre-treatment with a 5-HT(1A) antagonist did not abolish the anti-GID effect of buspirone, showing that its effect is independent from activation of either pre- or post-synaptic 5-HT(1A) receptors. Since buspirone is known to also act as a DA D(2) receptor antagonist, the selective D(2) receptor antagonist eticlopride was administered to test whether blockade of D(2) receptors could account for the anti-dyskinetic effect of buspirone. In fact, eticlopride produced complete suppression of GID in grafted animals already at very low dose. Together, these results point to a critical role of both 5-HT(1) and D(2) receptors in the modulation of GID, and suggest that 5-HT neurons exert a modulatory role in the development of this side effect of neuronal transplantation. PMID:22579773

Shin, Eunju; Garcia, Joanna; Winkler, Christian; Björklund, Anders; Carta, Manolo



Sleep disturbances in Parkinson’s disease  

Microsoft Academic Search

Disorders of sleep and daytime alertness are frequent in Parkinson’s disease patients and arise from a number of diverse factors.\\u000a The most common complaint of night-time sleep disturbance in Parkinson’s disease is sleep fragmentation. Sleep fragmentation\\u000a can be associated with recurrent parkinsonian symptoms, the effect of medications, concomitant medical disorders such as nocturia,\\u000a or psychiatric disorders such as depression or

Cynthia L. Comella



Drug-induced DNA Hypermethylation and Drug Resistance in Human Tumors  

Microsoft Academic Search

Drug-induced DNA hypermethylation was observed to constitute one component of the response of human tumor cells to toxic concentrations of commonly used cancer chemotherapy agents. In both human lung adenocarcinoma cells (HTB-54) and human rhabdomyosarcoma cells (CC1-136), pulse exposures to the topoisomerase II inhibitors etoposide and nalidixic acid; to the antibiotic doxorubicin; to the microtubule inhibitors vincristine, vinblastine, and colchicine;

Jonathan Nyce


The parkinsonism-hyperpyrexia syndrome.  


The parkinsonism-hyperpyrexia syndrome (PHS) is a rare but potentially fatal complication seen in Parkinson's disease (PD) patients, most commonly following reduction or cessation of antiparkinson medications. Clinically it resembles neuroleptic malignant syndrome with rigidity, pyrexia, and reduced conscious level. There may be features of autonomic instability, and serum creatine kinase (CK) may be elevated. Complications of PHS include acute renal failure, aspiration pneumonia, deep venous thrombosis/pulmonary embolism, and disseminated intravascular coagulation (DIC). Management consists of dopaminergic drug replacement, supportive measures, and treatment of complications. The prognosis is improved with early recognition and management. Mortality of up to 4% has been reported, but an additional one-third of patients have permanent sequelae. Patients and physicians should be warned against sudden reduction in antiparkinson medications. PHS should always be considered in a patient with parkinsonism who presents with an acute deterioration in symptoms. PMID:18712508

Newman, Edward J; Grosset, Donald G; Kennedy, Peter G E



Pharmacology of Rasagiline, a New MAO-B Inhibitor Drug for the Treatment of Parkinson's Disease with Neuroprotective Potential.  


Rasagiline (Azilect) is a highly selective and potent propargylamine inhibitor of monoamine oxidase (MAO) type B. Like other similar propargylamine inhibitors, rasagiline binds covalently to the N5 nitrogen of the flavin residue of MAO, resulting in irreversible inactivation of the enzyme. Therapeutic doses of the drug which inhibit brain MAO-B by 95% or more cause minimal inhibition of MAO-A, and do not potentiate the pressor or other pharmacological effects of tyramine. Metabolic conversion of the compound in vivo is by hepatic cytochrome P450-1A2, with generation of 1-aminoindan as the major metabolite. Rasagiline possesses no amphetamine-like properties, by contrast with the related compound selegiline (Deprenyl, Jumex, Eldepryl). Although the exact distribution of MAO isoforms in different neurons and tissues is not known, dopamine behaves largely as a MAO-A substrate in vivo, but following loss of dopaminergic axonal varicosities from the striatum, metabolism by glial MAO-B becomes increasingly important. Following subchronic administration to normal rats, rasagiline increases levels of dopamine in striatal microdialysate, possibly by the build-up of ?-phenylethylamine, which is an excellent substrate for MAO-B, and is an effective inhibitor of the plasma membrane dopamine transporter (DAT). Both of these mechanisms may participate in the anti-Parkinsonian effect of rasagiline in humans. Rasagiline possesses neuroprotective properties in a variety of primary neuronal preparations and neuron-like cell lines, which is not due to MAO inhibition. Recent clinical studies have also demonstrated possible neuroprotective properties of the drug in human Parkinsonian patients, as shown by a reduced rate of decline of symptoms over time. PMID:23908775

Finberg, John P M



Pharmacology of Rasagiline, a New MAO-B Inhibitor Drug for the Treatment of Parkinson's Disease with Neuroprotective Potential  

PubMed Central

Rasagiline (Azilect) is a highly selective and potent propargylamine inhibitor of monoamine oxidase (MAO) type B. Like other similar propargylamine inhibitors, rasagiline binds covalently to the N5 nitrogen of the flavin residue of MAO, resulting in irreversible inactivation of the enzyme. Therapeutic doses of the drug which inhibit brain MAO-B by 95% or more cause minimal inhibition of MAO-A, and do not potentiate the pressor or other pharmacological effects of tyramine. Metabolic conversion of the compound in vivo is by hepatic cytochrome P450-1A2, with generation of 1-aminoindan as the major metabolite. Rasagiline possesses no amphetamine-like properties, by contrast with the related compound selegiline (Deprenyl, Jumex, Eldepryl). Although the exact distribution of MAO isoforms in different neurons and tissues is not known, dopamine behaves largely as a MAO-A substrate in vivo, but following loss of dopaminergic axonal varicosities from the striatum, metabolism by glial MAO-B becomes increasingly important. Following subchronic administration to normal rats, rasagiline increases levels of dopamine in striatal microdialysate, possibly by the build-up of ?-phenylethylamine, which is an excellent substrate for MAO-B, and is an effective inhibitor of the plasma membrane dopamine transporter (DAT). Both of these mechanisms may participate in the anti-Parkinsonian effect of rasagiline in humans. Rasagiline possesses neuroprotective properties in a variety of primary neuronal preparations and neuron-like cell lines, which is not due to MAO inhibition. Recent clinical studies have also demonstrated possible neuroprotective properties of the drug in human Parkinsonian patients, as shown by a reduced rate of decline of symptoms over time.

Finberg, John P.M.



Calreticulin Binds to Gentamicin and Reduces Drug-Induced Ototoxicity  

PubMed Central

Aminoglycosides like gentamicin are among the most commonly used antibiotics in clinical practice and are essential for treating life-threatening tuberculosis and Gram-negative bacterial infections. However, aminoglycosides are also nephrotoxic and ototoxic. Although a number of mechanisms have been proposed, it is still unclear how aminoglycosides induce cell death in auditory sensory epithelia and subsequent deafness. Aminoglycosides bind to various intracellular molecules, such as RNA and phosphoinositides. We hypothesized that aminoglycosides, based on their tissue-specific susceptibility, also bind to intracellular proteins that play a role in drug-induced ototoxicity. By conjugating an aminoglycoside, gentamicin, to agarose beads and conducting a gentamicin-agarose pull-down assay, we have isolated gentamicin-binding proteins (GBPs) from immortalized cells of mouse organ of Corti, HEI-OC1. Mass spectrometry identified calreticulin (CRT) as a GBP. Immunofluorescence revealed that CRT expression is concentrated in strial marginal cells and hair cell stereocilia, primary locations of drug uptake and cytotoxicity in the cochlea. In HEI-OC1 cells treated with gentamicin, reduction of CRT expression using small interfering RNA (siRNA) reduced intracellular drug levels. CRT-deficient mouse embryonic fibroblast (MEF) cells as well as CRT siRNA-transfected wild-type MEFs also had reduced cell viability after gentamicin treatment. A pull-down assay using deletion mutants of CRT determined that the carboxyl C-domain of CRT binds to gentamicin. HeLa cells transfected with CRT C-domain deletion mutant construct were more susceptible to gentamicin-induced cytotoxicity compared with cells transfected with full-length CRT or other deletion mutants. Therefore, we conclude that CRT binding to gentamicin is protective against gentamicin-induced cytotoxicity.

Karasawa, Takatoshi; Wang, Qi; David, Larry L.; Steyger, Peter S.



Drug-induced liver injury: present and future.  


Liver injury due to prescription and nonprescription medications is a growing medical, scientific, and public health problem. Worldwide, the estimated annual incidence rate of drug-induced liver injury (DILI) is 13.9-24.0 per 100,000 inhabitants. DILI is one of the leading causes of acute liver failure in the US. In Korea, the annual extrapolated incidence of cases hospitalized at university hospital is 12/100,000 persons/year. Most cases of DILI are the result of idiosyncratic metabolic responses or unexpected reactions to medication. There is marked geographic variation in relevant agents; antibiotics, anticonvulsants, and psychotropic drugs are the most common offending agents in the West, whereas in Asia, 'herbs' and 'health foods or dietary supplements' are more common. Different medical circumstances also cause discrepancy in definition and classification of DILI between West and Asia. In the concern of causality assessment, the application of the Roussel Uclaf Causality Assessment Method (RUCAM) scale frequently undercounts the cases caused by 'herbs' due to a lack of previous information and incompatible time criteria. Therefore, a more objective and reproducible tool that could be used for the diagnosis of DILI caused by 'herbs' is needed in Asia. In addition, a reporting system similar to the Drug-Induced Liver Injury Network (DILIN) in the US should be established as soon as possible in Asia. PMID:23091804

Suk, Ki Tae; Kim, Dong Joon



Drug-induced liver injury: present and future  

PubMed Central

Liver injury due to prescription and nonprescription medications is a growing medical, scientific, and public health problem. Worldwide, the estimated annual incidence rate of drug-induced liver injury (DILI) is 13.9-24.0 per 100,000 inhabitants. DILI is one of the leading causes of acute liver failure in the US. In Korea, the annual extrapolated incidence of cases hospitalized at university hospital is 12/100,000 persons/year. Most cases of DILI are the result of idiosyncratic metabolic responses or unexpected reactions to medication. There is marked geographic variation in relevant agents; antibiotics, anticonvulsants, and psychotropic drugs are the most common offending agents in the West, whereas in Asia, 'herbs' and 'health foods or dietary supplements' are more common. Different medical circumstances also cause discrepancy in definition and classification of DILI between West and Asia. In the concern of causality assessment, the application of the Roussel Uclaf Causality Assessment Method (RUCAM) scale frequently undercounts the cases caused by 'herbs' due to a lack of previous information and incompatible time criteria. Therefore, a more objective and reproducible tool that could be used for the diagnosis of DILI caused by 'herbs' is needed in Asia. In addition, a reporting system similar to the Drug-Induced Liver Injury Network (DILIN) in the US should be established as soon as possible in Asia.

Suk, Ki Tae



Drug-induced hypersensitivity syndrome with human herpesvirus-6 reactivation.  


A 45-year-old man, on carbamazepine for the past 3 months, was referred as a case of atypical measles. On examination, he had high-grade fever, generalized itchy rash, cough, vomiting and jaundice. A provisional diagnosis of drug hypersensitivity syndrome to carbamazepine was made with a differential diagnosis of viral exanthema with systemic complications. Laboratory investigations revealed leukocytosis with eosnophilia and elevated liver enzymes. Real-time multiplex polymerase chain reaction (PCR) on throat swab and blood was suggestive of human herpesvirus-6 (HHV-6). Measles was ruled out by PCR and serology. The diagnosis of drug-induced hypersensitivity syndrome (DIHS) was confirmed, which could explain all the features manifested by the patient. HHV-6 infects almost all humans by age 2 years. It infects and replicates in CD4 T lymphocytes and establishes latency in human peripheral blood monocytes or macrophages and early bone marrow progenitors. In DIHS, allergic reaction to the causative drug stimulates T cells, which leads to reactivation of the herpesvirus genome. DIHS is treated by withdrawal of the culprit drug and administration of systemic steroids. Our patient responded well to steroids and HHV-6 was negative on repeat real-time multiplex PCR at the end of treatment. PMID:22421649

Riyaz, Najeeba; Sarita, S; Arunkumar, G; Sabeena, S; Manikoth, Neeraj; Sivakumar, C P


Social Odor Recognition: A Novel Behavioral Model for Cognitive Dysfunction in Parkinson’s Disease  

Microsoft Academic Search

Background: Parkinson’s disease (PD) is a progressive neurodegenerative condition characterized by an increasing loss of dopaminergic neurons resulting in motor dysfunction. However, cognitive impairments in PD patients are a common clinical feature that has gained increased attention. Objective: The purpose of the current study was to evaluate the effects of an MPTP-induced dopaminergic lesion in mice on social odor recognition

Michael M. Monaghan; Lauren Leddy; Mei-Li Amy Sung; Kristin Albinson; Katie Kubek; Menelas N. Pangalos; Peter H. Reinhart; Margaret M. Zaleska; Thomas A. Comery



Stem-Cell-Based Strategies for the Treatment of Parkinson’s Disease  

Microsoft Academic Search

Background: Cell transplantation to replace lost neurons in neurodegenerative diseases such as Parkinson’s disease (PD) offers a hopeful prospect for many patients. Previously, fetal grafts have been shown to survive, integrate and induce functional recovery in PD patients. However, limited tissue availability has haltered the widespread use of this therapy and begs the demand for alternative tissue sources. In this

Clare L. Parish; Ernest Arenas



Effects of Enzyme Inducers in Therapeutic Efficacy of Rosiglitazone: An Antidiabetic Drug in Albino Rats  

Microsoft Academic Search

The effect of enzyme inducers on therapeutic efficacy of Rosiglitazone (an antidiabetic drug) was evaluated by using alloxan induced diabetic rats. The results exhibit the combined adminstration of enzyme inducers like rifampicin, phenobarbitone and phenytoin with Rosiglitazone was contraindicated. The purpose of the study reveals that if Rosiglitazone drug combined with said enzyme inducers then therapeutic efficacy of Rosiglitazone being

Anand Chaurasia; P. K. Karar; A. S. Mann; M. D. Kharya


Influence of Mast Cells in Drug-Induced Gingival Overgrowth  

PubMed Central

Mast cells (MCs) are multifunctional effector cells that were originally thought to be involved in allergic disorders. Now it is known that they contain an array of mediators with a multitude of effects on many other cells. MCs have become a recent concern in drug-induced gingival overgrowth (DIGO), an unwanted outcome of systemic medication. Most of the studies have confirmed the significant presence of inflammation as a prerequisite for the overgrowth to occur. The inflammatory changes within the gingival tissue appear to influence the interaction between the inducing drug and the fibroblast activity. The development of antibodies to MC-specific enzymes, tryptase and chymase, has facilitated the study of mast cells in DIGO. Many immunohistochemical studies involving MCs have been conducted; as a result, DIGO tissues are found to have increased the number of MCs in the gingiva, especially in the area of fibrosis. At the cellular level, gingival fibrogenesis is initiated by several mediators which induce the recruitment of a large number of inflammatory cells, including MCs. The purpose of this paper is to access the roles played by MCs in gingival overgrowth to hypothesize a relationship between these highly specialized cells in the pathogenesis of DIGO.

Yeap, Swee Keong; Alitheen, Noorjahan Banu



Valproate for the treatment of medication-induced impulse-control disorders in three patients with Parkinson's disease.  


Impulse-control disorders (ICDs) are becoming more commonly recognized in the Parkinson disease (PD) population. To date, there are no definitive methods of treating dopamine dysregulation syndromes in PD patients. We sought to uncover an effective treatment option for future study. We report a series of 3 PD patients with ICDs who were effectively treated with valproate. Based on these encouraging preliminary observations, future controlled clinical trials investigating the efficacy of valproate for ICDs in PD are recommended. PMID:21459656

Hicks, C W; Pandya, M M; Itin, I; Fernandez, H H



Polychlorinated Biphenyl-Induced Reduction of Dopamine Transporter Expression as a Precursor to Parkinson's Disease-Associated Dopamine Toxicity  

Microsoft Academic Search

Epidemiological and laboratory studies have suggested that exposure to polychlorinated biphenyls (PCBs) may be a risk factor for Parkinson's disease. The purpose of this study was to examine the potential mechanisms by which PCBs may disrupt normal functioning of the nigrostriatal dopamine (DA) system. We utilized an environmentally relevant exposure of PCBs (7.5 or 15 mg\\/kg\\/day Aroclor 1254:1260 for 30

W. Michael Caudle; Jason R. Richardson; Kristin C. Delea; Thomas S. Guillot; Minzheng Wang; Kurt D. Pennell; Gary W. Miller



Small RNA sequencing-microarray analyses in Parkinson leukocytes reveal deep brain stimulation-induced splicing changes that classify brain region transcriptomes.  


MicroRNAs (miRNAs) are key post transcriptional regulators of their multiple target genes. However, the detailed profile of miRNA expression in Parkinson's disease, the second most common neurodegenerative disease worldwide and the first motor disorder has not been charted yet. Here, we report comprehensive miRNA profiling by next-generation small-RNA sequencing, combined with targets inspection by splice-junction and exon arrays interrogating leukocyte RNA in Parkinson's disease patients before and after deep brain stimulation (DBS) treatment and of matched healthy control volunteers (HC). RNA-Seq analysis identified 254 miRNAs and 79 passenger strand forms as expressed in blood leukocytes, 16 of which were modified in patients pre-treatment as compared to HC. 11 miRNAs were modified following brain stimulation 5 of which were changed inversely to the disease induced changes. Stimulation cessation further induced changes in 11 miRNAs. Transcript isoform abundance analysis yielded 332 changed isoforms in patients compared to HC, which classified brain transcriptomes of 47 PD and control independent microarrays. Functional enrichment analysis highlighted mitochondrion organization. DBS induced 155 splice changes, enriched in ubiquitin homeostasis. Cellular composition analysis revealed immune cell activity pre and post treatment. Overall, 217 disease and 74 treatment alternative isoforms were predictably targeted by modified miRNAs within both 3' and 5' untranslated ends and coding sequence sites. The stimulation-induced network sustained 4 miRNAs and 7 transcripts of the disease network. We believe that the presented dynamic networks provide a novel avenue for identifying disease and treatment-related therapeutic targets. Furthermore, the identification of these networks is a major step forward in the road for understanding the molecular basis for neurological and neurodegenerative diseases and assessment of the impact of brain stimulation on human diseases. PMID:23717260

Soreq, Lilach; Salomonis, Nathan; Bronstein, Michal; Greenberg, David S; Israel, Zvi; Bergman, Hagai; Soreq, Hermona



Parkinson's disease and anaesthesia  

PubMed Central

Parkinson's disease (PD), one of the most common disabling neurological diseases, affects about 1% of the population over 60 years of age. It is a degenerative disease of the central nervous system caused by the loss of dopaminergic fibers in basal ganglia of the brain. PD is an important cause of perioperative morbidity and with an increasingly elderly population, it is being encountered with greater frequency in surgical patients. Particular anaesthetic problems in PD include old age, antiparkinsonian drug interaction with anaesthetic drugs and various alterations in the respiratory, cardiovascular, autonomic, and neurological systems. This brief review focuses on the preoperative, intraoperative, and postoperative anesthetic management of PD and gives a brief account of intraoperative exacerbation of PDs and anesthetic management of stereotactic pallidotomy.

Shaikh, Safiya I; Verma, Himanshu



Parkinson disease psychosis: Update.  


Psychotic symptoms are common in drug treated patients with Parkinson's disease (PD). Visual hallucinations occur in about 30% typically paranoid in nature, occur in about 5% particularly the delusions, cause great distress for patient and caregivers, and are among the most important precipitants for nursing home placement. Psychotic symptoms carry a poor prognosis. They often herald dementia, and are associated with increased mortality. These symptoms often abate with medication reductions, but this may not be tolerated due to worsened motor function. Only clozapine has level A evidence to support its use in PD patients with psychosis (PDP), whether demented or not. While quetiapine has been recommended by the American Academy of Neurology for "consideration," double blind placebo controlled trials have demonstrated safety but not efficacy. Other antipsychotic drugs have been reported to worsen motor function and data on the effectiveness of cholinesterase inhibitors is limited. PDP remains a serious problem with limited treatment options. PMID:23242358

Friedman, J H



Preladenant, a novel adenosine A(2A) receptor antagonist for the potential treatment of parkinsonism and other disorders.  


Adenosine A(2A) receptor antagonists exert antiparkinsonian effects in animal models and several drugs in this class are currently being assessed in clinical trials. Preladenant (SCH-420814) is an adenosine A(2A) receptor antagonist with a high affinity and very high selectivity for adenosine A(2A) receptors, which is being developed by Merck & Co Inc (following its acquisition of Schering-Plough Corp) for the potential treatment of Parkinson's disease. Preclinical studies in rodent and primate models of parkinsonism demonstrated that preladenant can reverse the motor impairments induced by dopamine depletion or antagonism. Phase I and II clinical trials indicated that preladenant was well tolerated. Moreover, preladenant met its major endpoints by reducing OFF time and increasing ON time in l-DOPA-treated patients with Parkinson's disease, without worsening dyskinesias. Therefore, preladenant may have considerable utility for the treatment of Parkinson's disease, as well as the parkinsonian side effects of dopamine D2 receptor antagonists. As research has suggested that adenosine A(2A) receptor antagonists are active in animal models of effort-based decision making, it is possible that preladenant could also be useful for treating energy-related symptoms, such as fatigue, psychomotor retardation and anergia in patients with parkinsonism or depression. At the time of publication, phase III clinical trials were recruiting patients with Parkinson's disease. PMID:20878595

Salamone, John D



Predicting drug-induced hepatotoxicity using QSAR and toxicogenomics approaches.  


Quantitative structure-activity relationship (QSAR) modeling and toxicogenomics are typically used independently as predictive tools in toxicology. In this study, we evaluated the power of several statistical models for predicting drug hepatotoxicity in rats using different descriptors of drug molecules, namely, their chemical descriptors and toxicogenomics profiles. The records were taken from the Toxicogenomics Project rat liver microarray database containing information on 127 drugs ( ). The model end point was hepatotoxicity in the rat following 28 days of continuous exposure, established by liver histopathology and serum chemistry. First, we developed multiple conventional QSAR classification models using a comprehensive set of chemical descriptors and several classification methods (k nearest neighbor, support vector machines, random forests, and distance weighted discrimination). With chemical descriptors alone, external predictivity (correct classification rate, CCR) from 5-fold external cross-validation was 61%. Next, the same classification methods were employed to build models using only toxicogenomics data (24 h after a single exposure) treated as biological descriptors. The optimized models used only 85 selected toxicogenomics descriptors and had CCR as high as 76%. Finally, hybrid models combining both chemical descriptors and transcripts were developed; their CCRs were between 68 and 77%. Although the accuracy of hybrid models did not exceed that of the models based on toxicogenomics data alone, the use of both chemical and biological descriptors enriched the interpretation of the models. In addition to finding 85 transcripts that were predictive and highly relevant to the mechanisms of drug-induced liver injury, chemical structural alerts for hepatotoxicity were identified. These results suggest that concurrent exploration of the chemical features and acute treatment-induced changes in transcript levels will both enrich the mechanistic understanding of subchronic liver injury and afford models capable of accurate prediction of hepatotoxicity from chemical structure and short-term assay results. PMID:21699217

Low, Yen; Uehara, Takeki; Minowa, Yohsuke; Yamada, Hiroshi; Ohno, Yasuo; Urushidani, Tetsuro; Sedykh, Alexander; Muratov, Eugene; Kuz'min, Viktor; Fourches, Denis; Zhu, Hao; Rusyn, Ivan; Tropsha, Alexander



[Morphological reaction patterns of the liver induced by drugs].  


Drugs are exogenous substances often requiring metabolic transformation to be therapeutically effective. This occurs primarily in the liver, the most important metabolic organ and a structure able to adapt to this burden. Should its adaptive potential be exceeded, damage can occur, affecting principally the liver parenchyma. Such damage manifests itself as disturbed secretory function and as reversible or irreversible structural alteration of the liver cells. The constellation of toxic-degenerative lesions is referred to as hepatosis (toxic hepatosis, toxic hepatopathy). A variety of patterns of damage (lipidosis, necrosis, cholestasis etc.) occur alone or in combination. Depending on the severity and extent of these alterations a secondary inflammatory reaction may result. These changes are manifest as cellular infiltration and proliferation with formation of reticulo-histiocytic nodules or minifocal epitheloid cell reactions and non-caseous epitheloid cell granulomas. The eosinophilic component is striking. In the face of continued toxic exposures, changes resembling those of chronic aggressive hepatitis may develop following the acute changes. Other drug-related liver damage may present as vascular lesions the afferent or efferent venous systems as well as in the sinusoids (i.e. peliosis hepatis, Budd-Chiari syndrome). Moreover there may be neoplastic alterations such as focal nodular hyperplasia or liver cell adenomas. Pathognomonic histologic criteria for drug-induced liver damage have as yet to be recognized, particularly in the case of facultative toxins. Morphologic indications can only suggest that a prior pharmaceutical agent was the likely cause of the damage. Histologic changes must however be viewed in the context of the medical history, clinical and laboratory findings, as well as results of other studies before the conclusion is drawn that the observed liver changes represent drug-induced injury. PMID:3834709

Machnik, G



Immunophilin ligands can prevent progressive dopaminergic degeneration in animal models of Parkinson's disease  

Microsoft Academic Search

Slowing or halting the progressive dopaminergic (DA) degeneration in Parkinson's disease (PD) would delay the onset and development of motor symptoms, prolong the efficacy of pharmacotherapies and decrease drug-induced side-effects. We tested the potential of two orally administered novel immunophilin ligands to protect against DA degeneration in two animal models of PD. First, in an MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model, we

Lauren C. Costantini; Douglas Cole; Ole Isacson



Clinical Manifestations and Treatment of Drug-induced Hepatotoxicity.  


With an increase of prescription medication and herbal supplement use, drug-induced liver injury (DILI) has become an increasingly important entity. Because DILI is a usually readily treatable condition, it is essential for providers to reach a diagnosis in a timely fashion. Unfortunately, varied clinical presentations, difficulties in establishing causality, and lack of a gold standard diagnostic criterion may make early diagnosis difficult. This article seeks to define commonly used terminology, describe common clinical presentations of DILI, provide an overview of current diagnostic criteria, and provide management guidelines. PMID:24099018

Giordano, Christin M; Zervos, Xaralambos B



Parkinson's Disease: A Pharmacological Update  

PubMed Central

The primary biochemical defect in Parkinsonism is dopamine depletion. Anticholinergics (except in the elderly) and amantadine are useful in treating early symptomatic disease. L-dopa remains the most effective drug, but experience has led to more modest use due to its late complications, particularly dyskinesias. Bromocriptine, a dopamine agonist, is relatively effective, but when it should be used is undecided. Beta-blockers may control tremor. Treatment should be tailored to each patient, and focus on functional motor ability. Dyskinesias and neuropsychiatric complications are the major limiting factors with most of these drugs. Several drugs are under investigation.

Chater, Susan; Montgomery, Pat



Drug-induced injury in the gastrointestinal tract: clinical and pathologic considerations  

Microsoft Academic Search

Drug toxicity in the gastrointestinal tract is a common and serious medical problem; the number of drugs that can harm the gastrointestinal tract is impressive. The morbidity, mortality, and medical costs associated with drug toxicity, even when restricted to the gastrointestinal tract, are probably underestimated. Drug-induced gastrointestinal tract pathology is very diverse and can mimic many non-drug-related conditions. Drug toxicity,

Marc P Pusztaszeri; Byron L Cryer; Robert M Genta



Antimicrobial drug-induced thrombocytopenia: a review of the literature.  


The incidence of drug-induced thrombocytopenia (DIT) is not well-defined, but is estimated to occur at a minimum of 10 cases per million per year. This review will focus on the potential DIT associated with specific antibacterial, antifungal, antiviral, and antiparasitic agents. Case reports, cohort studies, and clinical trials were identified using PubMed search terms for each antimicrobial along with the Boolean combiner AND to match with the following outcomes: thrombocytopenia and bleed. Thrombocytopenia was defined as a platelet count of < 100 × 10(9)/L or a decrease in platelet count of at least 50% from baseline. A majority of the data supporting antimicrobial-induced thrombocytopenia consist of case reports and small studies. However, clinicians should be vigilant in monitoring patient platelet counts, as an immune-mediated mechanism is frequently responsible for this hematologic adverse effect and is therefore unpredictable. PMID:23081819

Loo, Angela S; Gerzenshtein, Lana; Ison, Michael G



Circulating microRNAs, potential biomarkers for drug-induced liver injury  

Microsoft Academic Search

Drug-induced liver injury is a frequent side effect of many drugs, constitutes a significant threat to patient health and has an enormous economic impact on health care expenditures. Numerous efforts have been made to identify reliable and predictive markers to detect the early signs of drug-induced injury to the liver, one of the most vulnerable organs in the body. These

Kai Wang; Shile Zhang; Bruz Marzolf; Pamela Troisch; Amy Brightman; Zhiyuan Hu; Leroy E. Hood; David J. Galas



Drug-induced liver steatosis and phospholipidosis: cell-based assays for early screening of drug candidates.  


The liver plays a key role in fat metabolism, and excessive lipid accumulation in liver cells is characterised by a large spectrum of lesions, e.g., steatosis and phospholipidosis. Steatosis is increased lipid accumulation, mainly as triglycerides, in the liver, while phospholipidosis is a lysosomal storage disorder characterised by intracellular accumulation of phospholipids. These alterations can be induced by several factors, including exposure to certain drugs. Drug-induced steatosis is often reversible, and prolonged exposure to certain drugs can cause macrovacuolar steatosis, a benign hepatic lesion, that can evolve into steatohepatitis and cirrhosis in some patients. Some drugs may acutely induce microvesicular steatosis which, despite having a good short-term prognosis, can lead to chronic lipid peroxidation and to the development of steatohepatitis lesions with time. Over 50 marketed drugs have been reported to induce phospholipidosis in different tissues, including the liver. Although drug-induced phospholipidosis is often reversible and there is no definitive evidence for its toxicological implications, it is considered an adverse side finding by regulatory agencies. As developing new drugs is a complex, lengthy and expensive process that aims to identify pharmacologically active, low-toxicity drug candidates among closely related compounds, it could be advantageous to determine which drugs are able to induce lipid metabolic disorders in early developmental stages. To this end, in vitro predictive screening assays, particularly cell-based approaches in which many drug candidates are evaluated, have been developed to identify and rule out compounds with a strong liver steatosis and/or phospholipidosis-inducing potential. PMID:22746303

Donato, M Teresa; Gómez-Lechón, M José



Transplantation of Deprenyl-Induced Tyrosine Hydroxylase-Positive Cells Improves 6-OHDA-Lesion Rat Model of Parkinson's Disease: Behavioral and Immunohistochemical Evaluation  

PubMed Central

Objective: There is longstanding experimental and clinical evidence that supports the idea that replacement of dopaminergic (DAergic) neurons can ameliorate functional disabilities of Parkinson’s disease (PD). The purpose of the present study is to examine the efficacy of transplantation of rat bone marrow stromal cell (BMSCs)-derived tyrosine hydroxylase-positive (TH+) cells induced by deprenyl into 6-hydroxydopamine (6-OHDA)-lesioned rat models, using behavioral tests and immunohistochemical evaluations. Materials and Methods: In this experimental study, undifferentiated BrdU-labeled BMSCs were incubated in serum-free medium that contained 10-8 M deprenyl for 24 hours. Afterwards, BMSCs were cultured for 48 hours in ?-minimal essential medium (?-MEM) supplemented with 10% FBS, then differentiated into TH+ neurons. We randomly divided 24 hemiparkinsonian rats as follows: group 1 (control) received only medium, while groups 2 and 3 were injected with 2×105 BMSCs and deprenyl-treated cells in 4 µl medium. Injections were made into the injured strata of the rats. Rotational behavior in response to apomorphine was tested before transplantation and at 2, 4, and 6 weeks post-graft. Animals were then sacrificed, and the brains were extracted for immunohistochemical and electron microscopic studies. Results: Apomorphine-induced rotation analysis indicated that animals with grafted cells in groups 2 and 3 exhibited significantly less rotational behavior than those in the control group at 2, 4, and 6 weeks after transplantation. Immunohistochemical analysis demonstrated that BrdU-labeled cells expressed specific neuronal markers, such as NF 200 and TH, at the implantation site. The presence of TH+ cells in conjunction with the reduction in rotation might show the capacity of grafted cells to release dopamine. Ultrastructural analysis revealed the presence of immature neurons and astrocyte-like cells at the graft site. Conclusion: TH+ neurons induced by deprenyl can be considered as a cell source for PD autograft therapy.

Haji Ghasem Kashani, Maryam; Ghorbanian, Mohammad Taghi; Hosseinpour, Leili



Quantitative determination and pharmacokinetic study of the novel anti-Parkinson's disease candidate drug FLZ in rat brain by high performance liquid chromatography-tandem mass spectrometry.  


FLZ (N-[2-(4-hydroxy-phenyl)-ethyl]-2-(2,5-dimethoxy-phenyl)-3-(3-methoxy-4-hydroxyphenyl)-acrylamide) is a novel anti-Parkinson's disease candidate drug. A sensitive and specific high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method was developed and validated for the quantification of FLZ in rat brain. Carbamazepine was selected as the internal standard. Sample preparation involved double liquid-liquid extraction by n-hexane and ethyl acetate with high extraction efficiency. The chromatographic separation was achieved on a Zorbax SB-C(18) column (100 mm × 2.1 mm, 3.5 ?m) with an isocratic elution system comprised of acetonitrile and 0.3% aqueous acetic acid at a flow rate of 0.3 ml/min. The elutes were detected under positive electrospray ionization (ESI) and the target analytes were quantified by multiple reaction monitoring (MRM) mode. The method was sensitive with the lowest limit of quantification (LLOQ) at 1.0 ng/g brain tissue. Good linearity (r>0.99) was obtained over the range of 1.0-400 ng/g. The intra- and inter-day precision ranged from 0.68% to 12%, while the accuracy between 92.7% and 111%. In addition, the stability, recovery and matrix effect involved in this method were also validated. The method was used to investigate the pharmacokinetics of FLZ in rat brain successfully after intravenous administration. The brain distribution studies showed that the brain distribution of FLZ was limited with the penetration ratio less than 0.1 in rats, with no target effect in the seven collected regions. Inhibition of P-glycoprotein (P-gp) by zosuquidar·3HCl ((2R)-1-{4-[(1aR,10bS)-1,1-difluoro-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropa[c][7]annulen-6-yl]-1-piperazinyl}-3-(5-quinolinyloxy)-2-propanol trihydrochloride) resulted in a significant increase in brain-to-plasma ratio, while no significant increase by inhibition of breast cancer resistance protein (BCRP) by ko143 (2-methyl-2-propanyl 3-[(3S,6S,12aS)-6-isobutyl-9-methoxy-1,4-dioxo-1,2,3,4,6,7,12,12a-octahydropyrazino[1',2':1,6]pyrido[3,4-b]indol-3-yl]propanoate). The results indicated that FLZ had poor penetration to the brain due to the P-gp transport system. PMID:22472186

Hou, Jinfeng; Qu, Feng; Wu, Caisheng; Ren, Qiang; Zhang, Jinlan



Neuroprotective Effect of CNB-001, a Novel Pyrazole Derivative of Curcumin on Biochemical and Apoptotic Markers Against Rotenone-Induced SK-N-SH Cellular Model of Parkinson's Disease.  


Oxidative stress and mitochondrial dysfunction are underpinned for initiating a cascade of toxic events leading to dopaminergic neuronal death in Parkinson's disease (PD) and identified as vital target for therapeutic intervention. Curcumin, a potent antioxidant has been reported to display diverse neuroprotective properties against various neurodegenerative diseases including PD. In this present study, we investigated the protective effect of CNB-001, a pyrazole derivative of curcumin on rotenone-induced toxicity and its possible mechanisms in neuroblastoma SK-N-SH cells. Rotenone insult significantly reduced cell viability (MTT assay) and resulted in 78 % apoptosis (dual staining) by altering Bcl-2, Bax, caspase-3, and cytochrome C expression. Moreover, rotenone enhanced ROS production and disrupts mitochondrial membrane potential. These resultant phenotypes were distinctly alleviated by CNB-001. Pretreatment with CNB-001(2 ?M) 2 h before rotenone exposure (100 nM) increased cell viability, decreased ROS formation, maintained normal physiological mitochondrial membrane potential, and reduced apoptosis. Furthermore, CNB-001 inhibited downstream apoptotic cascade by increasing the expression of vital antiapoptotic protein Bcl-2 and decreased the expression of Bax, caspase-3, and cytochrome C. Collectively, the results suggest that CNB-001 protects neuronal cell against toxicity through antioxidant and antiapoptotic properties through its action on mitochondria. Therefore, it may be concluded that CNB-001 can be further developed as a promising drug for treatment of PD. PMID:23900721

Jayaraj, Richard L; Tamilselvam, Kuppusamy; Manivasagam, Thamilarasan; Elangovan, Namasivayam



Pharmacologic safety concerns in Parkinson's disease: facts and insights.  


Knowledge and insight of pharmacologic safety issues and drug interactions are important for medical management of Parkinson's disease (PD). This review will discuss several topics, including apomorphine safety and interactions, impulsivity and excessive daytime somnolence associated with dopamine agonists (DAs), tolcapone hepatotoxicity, and monoamine oxidase type-B (MAO-B) inhibitor drug interactions. Initiation of apomorphine requires antiemetic prophylaxis to minimize nausea and orthostatic hypotension. Centrally acting antidopaminergic antiemetics will worsen parkinsonism and block the therapeutic effects of apomorphine and should be avoided. Additionally, serotonin 5-HT(3) receptor antagonist antiemetics should be avoided on the basis of limited clinical data suggesting lack of efficacy for apomorphine-induced nausea. Dopamine-agonist-induced impulsivity and daytime somnolence are not uncommon. When severe, these effects can be disabling and unsafe. Tolcapone-induced hepatotoxicity has been significantly minimized with routine monitoring of liver enzymes, especially during the initial 6 months of therapy. Early detection of abnormal results will allow tolcapone discontinuation before progression to fulminant hepatotoxicity. In patients treated with selective MAO-B inhibitors, the risk of serotonin toxicity (ST) due to a concomitant serotonergic agent (e.g., antidepressants, dextromethorphan, serotonergic analgesics) or hypertensive crisis due to dietary tyramine or sympathomimetic amines appears to be minimal and is based on isolated case reports and overgeneralizations from nonselective MAO inhibitor pharmacology. Concerns about ST or hypertensive crisis should not preclude or restrict clinicians from using MAO-B inhibitors in patients with PD. PMID:22035029

Chen, Jack J



The association between Parkinson's disease and anti-epilepsy drug carbamazepine: a case-control study using the UK General Practice Research Database.  


AIM: To investigate whether the use of carbamazepine is associated with reduced risk of Parkinson's disease. METHODS: We conducted a population-based matched case-control study of patients randomly selected from the UK General Research Practice Database (GPRD). We identified 8,549 patients with Parkinson's disease using diagnosis criteria with a positive predictive value of 90%. These patients were compared with 42,160 controls matched for age, sex, and general practice. RESULTS: Overall, 3.0% of cases (257/8,549) had at least one recorded prescription for carbamazepine compared to 2.5% (1,050/42,160) of controls. The crude odds ratio (OR) for the association between Parkinson's disease and carbamazepine was 1.22 (95% confidence interval [CI]: 1.06-1.40), but this reduced to 0.93 (95%CI: 0.81-1.08, p=0.34) after adjusting for annual consultation rate. Further adjustment for body mass index, smoking status, alcohol consumption, or use of calcium channel blockers did not affect results. There was no evidence that risk decreased with higher doses or longer duration of carbamazepine use. CONCLUSIONS: There was little to no evidence that use of carbamazepine is associated with reduced risk of Parkinson's disease. Although the study was underpowered, it does indicate that any effect of carbamazepine is likely to be small. PMID:23432592

Skow, Aine; Douglas, Ian; Smeeth, Liam



Initial treatment of parkinson’s disease  

Microsoft Academic Search

Opinion statement  Initial treatment of early idiopathic Parkinson’s disease (PD) begins with diagnosis based on clinical evaluation supplemented\\u000a by laboratory studies and brain imaging to exclude causes of secondary parkinsonism. In most cases, testing is normal and\\u000a the diagnosis of PD rests on clinical criteria. In patients with mild symptoms and signs, the diagnosis of PD may not initially\\u000a be apparent,

Daniel Tarsy



Structural Plasticity in Parkinson’s Disease  

Microsoft Academic Search

\\u000a It has been shown that dendritic spine density of medium sized spiny neurons in the neostriatum is reduced by about 19% in\\u000a an animal model of Parkinson’s disease (unilateral 6-hydroxydopamine lesion in rats) (Ingham et al., 1993). Recent results show an even greater reduction of spines (>20%) in the caudate and putamen on these neurons in Parkinson’s\\u000a disease patients. The

C. A. Ingham; B. Stephens; G. W. Arbuthnott


dl-3-n-Butylphthalide prevents oxidative damage and reduces mitochondrial dysfunction in an MPP(+)-induced cellular model of Parkinson's disease.  


The aim of the present study was to explore the neuroprotective effects and mechanisms of action of dl-3-n-butylphthalide (NBP) in a 1-methyl-4-phenylpyridiniumion (MPP(+))-induced cellular model of Parkinson's disease (PD). NBP was extracted from seeds of Apium graveolens Linn. (Chinese celery). MPP(+) treatment of PC12 cells caused reduced viability, formation of reactive oxygen, and disruption of mitochondrial membrane potential. Our results indicated that NBP reduced the cytotoxicity of MPP(+) by suppressing the mitochondrial permeability transition, reducing oxidative stress, and increasing the cellular GSH content. NBP also reduced the accumulation of alpha-synuclein, the main component of Lewy bodies. Given that NBP is safe and currently used in clinical trials for stroke patients, NBP will likely be a promising chemical for the treatment of PD. PMID:20347933

Huang, Jin-Zhong; Chen, Ying-Zhu; Su, Min; Zheng, Hui-Fen; Yang, Ya-Ping; Chen, Jing; Liu, Chun-Feng



Genetic polymorphisms for identifying individuals at risk for drug-induced vestibular dysfunction  

US Patent & Trademark Office Database

In this application is described the identification of genetic variants that contribute to susceptibility to drug-induced vestibular dysfunction, more particularly, GM-induced vestibular dysfunction. Methods, compositions and kits for determining whether an individual has susceptibility for drug-induced vestibular dysfunction are disclosed.



The Parkinson disease-related protein DJ-1 counteracts mitochondrial impairment induced by the tumour suppressor protein p53 by enhancing endoplasmic reticulum-mitochondria tethering.  


DJ-1 was first identified as an oncogene. More recently, mutations in its gene have been found causative for autosomal recessive familial Parkinson disease. Numerous studies support the DJ-1 role in the protection against oxidative stress and maintenance of mitochondria structure; however, the mechanism of its protective function remains largely unknown. We investigated whether mitochondrial Ca(2+) homeostasis, a key parameter in cell physiology, could be a target for DJ-1 action. Here, we show that DJ-1 modulates mitochondrial Ca(2+) transients induced upon cell stimulation with an 1,4,5-inositol-tris-phosphate agonist by favouring the endoplasmic reticulum (ER)-mitochondria tethering. A reduction of DJ-1 levels results in mitochondria fragmentation and decreased mitochondrial Ca(2+) uptake in stimulated cells. To functionally couple these effects with the well-recognized cytoprotective role of DJ-1, we investigated its action in respect to the tumour suppressor p53. p53 overexpression in HeLa cells impairs their ability to accumulate Ca(2+) in the mitochondrial matrix, causes alteration of the mitochondrial morphology and reduces ER-mitochondria contact sites. Mitochondrial impairments are independent from Drp1 activation, since the co-expression of the dominant negative mutant of Drp1 failed to abolish them. DJ-1 overexpression prevents these alterations by re-establishing the ER-mitochondria tethering. Similarly, the co-expression of the pro-fusion protein Mitofusin 2 blocks the effects induced by p53 on mitochondria, confirming that the modulation of the ER-mitochondria contact sites is critical to mitochondria integrity. Thus, the impairment of ER-mitochondria communication, as a consequence of DJ-1 loss-of-function, may be detrimental for mitochondria-related processes and be at the basis of mitochondrial dysfunction observed in Parkinson disease. PMID:23418303

Ottolini, Denis; Calě, Tito; Negro, Alessandro; Brini, Marisa



Changes in the mRNA levels of ?2A and ?2C adrenergic receptors in rat models of Parkinson's disease and L-DOPA-induced dyskinesia.  


The changes in the mRNA levels of ?(2A) and ?(2C) adrenoceptors were investigated in unilateral 6-OHDA-lesioned rat model of Parkinson's disease and L: -DOPA-induced dyskinesia using in situ hybridization. In the untreated 6-OHDA-lesioned rats, ?(2A) expression was elevated in the locus coeruleus (160?±?8% and 142?±?8% in lesioned and unlesioned sides compared to the comparable side in sham-operated rats). Following long-term (21 days, twice daily) treatment with L: -DOPA (25 mg/kg L: -DOPA methyl ester plus benserazide 6.25 mg/kg) in 6-OHDA-lesioned rats, levels of ?(2A) adrenoceptor mRNA in the locus coeruleus were decreased, compared to the 6-OHDA-lesioned rats, returning to the levels of ?(2A) mRNA in the sham-operated rats. ?(2A) adrenoceptor expression was not changed in other brain regions in any treatment group. There was no change in ?(2C) expression in the rostral or caudal striatum in which the highest density of ?(2C) mRNA is present. In conclusion, the data presented in this study demonstrate an increase in ?(2A) adrenoceptor mRNA in the locus coeruleus in the 6-OHDA-lesioned rat model of Parkinson's disease. In addition, the data show that repeated treatment with L: -DOPA in 6-OHDA-lesioned rats, which induces dyskinesia, restores ?(2A) mRNA levels. These changes of ?(2A) mRNA expression, observed in the locus coeruleus, might be of importance to basal ganglia transmission and motor function. PMID:21562737

Alachkar, Amal; Brotchie, Jonathan M; Jones, Owen T



Clinical analysis of 275 cases of acute drug-induced liver disease  

Microsoft Academic Search

In order to analyze the causative drugs, clinical manifestation and pathological characteristics of the patients with acute\\u000a drug-induced liver disease, from January 2000 to December 2005, 275 cases diagnosed as acute drug-induced liver diseases according\\u000a to Maria Criterion and hospitalized in Zhongshan Hospital of Fudan University were retrospectively reviewed. Each was determined\\u000a by drug history, clinical symptoms and signs, laboratory

Lei Li; Wei Jiang; Jiyao Wang



Abnormal Bidirectional Plasticity-Like Effects in Parkinson's Disease  

ERIC Educational Resources Information Center

|Levodopa-induced dyskinesia is a major complication of long-term dopamine replacement therapy for Parkinson's disease that becomes increasingly problematic in advanced Parkinson's disease. Although the cause of levodopa-induced dyskinesias is still unclear, recent work in animal models of the corticostriatal system has suggested that…

Huang, Ying-Zu; Rothwell, John C.; Lu, Chin-Song; Chuang, Wen-Li; Chen, Rou-Shayn



"PINK1"-Linked Parkinsonism Is Associated with Lewy Body Pathology  

ERIC Educational Resources Information Center

|Phosphatase and tensin homolog-induced putative kinase 1 gene mutations have been associated with autosomal recessive early-onset Parkinson's disease. To date, no neuropathological reports have been published from patients with Parkinson's disease with both phosphatase and tensin homolog-induced putative kinase 1 gene copies mutated. We analysed…

Samaranch, Lluis; Lorenzo-Betancor, Oswaldo; Arbelo, Jose M.; Ferrer, Isidre; Lorenzo, Elena; Irigoyen, Jaione; Pastor, Maria A.; Marrero, Carmen; Isla, Concepcion; Herrera-Henriquez, Joanna; Pastor, Pau



Abnormal Bidirectional Plasticity-Like Effects in Parkinson's Disease  

ERIC Educational Resources Information Center

Levodopa-induced dyskinesia is a major complication of long-term dopamine replacement therapy for Parkinson's disease that becomes increasingly problematic in advanced Parkinson's disease. Although the cause of levodopa-induced dyskinesias is still unclear, recent work in animal models of the corticostriatal system has suggested that…

Huang, Ying-Zu; Rothwell, John C.; Lu, Chin-Song; Chuang, Wen-Li; Chen, Rou-Shayn



Novel pharmacological targets for the treatment of Parkinson's disease  

Microsoft Academic Search

Dopamine deficiency, caused by the degeneration of nigrostriatal dopaminergic neurons, is the cause of the major clinical motor symptoms of Parkinson's disease. These symptoms can be treated successfully with a range of drugs that include levodopa, inhibitors of the enzymatic breakdown of levodopa and dopamine agonists delivered by oral, subcutaneous, transcutaneous, intravenous or intra-duodenal routes. However, Parkinson's disease involves degeneration

Erwan Bezard; Jonathan Brotchie; Frédéric Calon; Graham L. Collingridge; Borris Ferger; Bastian Hengerer; Etienne Hirsch; Peter Jenner; Nicolas Le Novčre; José A. Obeso; Michael A. Schwarzschild; Umberto Spampinato; Giora Davidai; Anthony H. V. Schapira



Learning about Parkinson's Disease  


... know about heredity and Parkinson's disease? Parkinson's disease (PD) is a neurological condition that typically causes tremor ... of 60 years and the chance of developing PD increases as we age. Most people affected with ...


Parkinson's Disease Foundation  


... 2:00 PM - 3:15 PM Dance for PD (NY) Monday, October 7, 2013 - Tuesday, October 8, ... protect the dopamine neurons involved in Parkinson’s disease (PD) and reverse the effects of a rare genetic ...


?-Synuclein Induces Alterations in Adult Neurogenesis in Parkinson Disease Models via p53-mediated Repression of Notch1*  

PubMed Central

Parkinson disease is characterized by the loss of dopaminergic neurons mainly in the substantia nigra. Accumulation of ?-synuclein and cell loss has been also reported in many other brain regions including the hippocampus, where it might impair adult neurogenesis, contributing to nonmotor symptoms. However, the molecular mechanisms of these alterations are still unknown. In this report we show that ?-synuclein-accumulating adult rat hippocampus neural progenitors present aberrant neuronal differentiation, with reduction of Notch1 expression and downstream signaling targets. We characterized a Notch1 proximal promoter that contains p53 canonical response elements. In vivo binding of p53 represses the transcription of Notch1 in neurons. Moreover, we demonstrated that ?-synuclein directly binds to the DNA at Notch1 promoter vicinity and also interacts with p53 protein, facilitating or increasing Notch1 signaling repression, which interferes with maturation and survival of neural progenitors cells. This study provides a molecular basis for ?-synuclein-mediated disruption of adult neurogenesis in Parkinson disease.

Desplats, Paula; Spencer, Brian; Crews, Leslie; Pathel, Pruthul; Morvinski-Friedmann, Dinorah; Kosberg, Kori; Roberts, Scott; Patrick, Christina; Winner, Beate; Winkler, Juergen; Masliah, Eliezer



The puzzle of drug-induced conditioned taste aversion: Comparative studies with cathinone and amphetamine  

Microsoft Academic Search

The potency of dl-cathinone (the active constituent of the Khat plant) was compared with that of d-amphetamine in the conditioned taste aversion (C. T. A.) procedure and in a test of drug-induced adipsia in rats. Both drugs induced C.T.A., the potency ratio being 1:17 (amphetamine was more potent). Both drugs induced adipsia in deprived rats given access to water for

A. J. Goudie; T. Newton



Autosomal recessive juvenile parkinsonism  

Microsoft Academic Search

Autosomal recessive juvenile parkinsonism (AR-JP) is a hereditary neurodegenerative disorder characterized by levodopa-responsive parkinsonism with onset before age 40 years and a slowly progressive course. Families with this condition have been described predominantly in Japanese population, occasionally under different names including an autosomal recessive early-onset parkinsonism with diurnal fluctuation (AR-EPDF) or a familial form of juvenile parkinsonism. Recently, the causative

Masaaki Saito; Mieko Maruyama; Ken Ikeuchi; Hiroshi Kondo; Atsushi Ishikawa; Tatsuhiko Yuasa; Shoji Tsuji



Drug induced phospholipidosis: an acquired lysosomal storage disorder.  


There is a strong association between lysosome enzyme deficiencies and monogenic disorders resulting in lysosomal storage disease. Of the more than 75 characterized lysosomal proteins, two thirds are directly linked to inherited diseases of metabolism. Only one lysosomal storage disease, Niemann-Pick disease, is associated with impaired phospholipid metabolism. However, other phospholipases are found in the lysosome but remain poorly characterized. A recent exception is lysosomal phospholipase A2 (group XV phospholipase A2). Although no inherited disorder of lysosomal phospholipid metabolism has yet been associated with a loss of function of this lipase, this enzyme may be a target for an acquired form of lysosomal storage, drug induced phospholipidosis. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism. PMID:22960355

Shayman, James A; Abe, Akira



Possible mechanisms of drug-induced aspirin and clopidogrel resistance.  


Aspirin (ASA) and clopidogrel have been identified as standard of care in the prevention of major cardiovascular events. Aspirin irreversibly inhibits the cyclooxygenase-1 (COX-1) enzyme, whereas non-steroidal anti-inflammatory drugs (NSAIDs) reversibly inhibit the COX-1 enzyme. An analysis of the literature revealed a statistically significant decrease in clinical benefit of ASA with concomitant administration of ibuprofen. Another NSAID, diclofenac, showed minimal effect on the inhibition of platelet aggregation when administered with ASA. Furthermore, the selective COX-2 inhibitor, rofecoxib, was not shown to influence the effect of ASA. Clopidogrel is metabolized to an active thiol metabolite by the CYP 3A4 enzyme. Some HMG CoA reductase inhibitors have the ability to inhibit the CYP 3A4 enzyme, which can result in a possible interaction if administered concomitantly with clopidogrel. Studies have demonstrated clopidogrel's platelet inhibition being significantly attenuated by atorvastatin. However in a post-hoc analysis, it was demonstrated that there was no difference in clinical outcomes between patients taking clopidogrel and HMG-CoA reductase inhibitors metabolized by and not metabolized by CYP 3A4. Data suggest that the interaction observed involving clopidogrel and HMG-CoA reductase inhibitors appears to be significant in-vitro. Therefore, practitioners should advise patients receiving chronic aspirin therapy to limit the use of ibuprofen and may consider concomitant administration of clopidogrel with HMG-CoA reductase inhibitors without regard for the drug interaction. The intent of this paper is to review the literature discussing possible mechanisms of drug-induced aspirin and clopidogrel resistance and discuss whether the interactions translate into clinical effects. PMID:17008981

Schroeder, Walter S; Ghobrial, Linda; Gandhi, Pritesh J



Drug-Induced Long QT Syndrome in Women.  


Congenital long QT syndromes (LQTS) are inherited heart diseases that can present as palpitations, syncope (fainting), seizures, cardiac arrest, and sudden death. Acquired LQTS mostly occurs as a result of exposure to an environmental stressor that is responsible for the excessive prolongation of the QT interval. The most common environmental stressor is adverse drug reactions, which can lead to drug-induced LQTS (di-LQTS). Female gender has been increasingly recognized as an independent risk factor for di-LQTS, which in females is influenced by other factors, including age, menstrual cycle, and hormone replacement therapy. The estrogen-mediated reduced repolarization reserve in women is believed to be responsible for their higher susceptibility to di-LQTS. More studies, especially randomized trials, should be carried out to confirm these findings, and elucidate the clinical impact of gender disparity in modifying the risk of di-LQTS in women, with the ultimate goal of promoting the clinical safety of medication. In this article, we review current knowledge about di-LQTS, specifically in women, and discuss methods for the prevention of di-LQTS in females. PMID:24085659

Li, Guoliang; Cheng, Gong; Wu, Jine; Zhou, Xin; Liu, Ping; Sun, Chaofeng



Drug-induced phospholipidosis: issues and future directions.  


Numerous drugs containing a cationic amphiphilic structure are capable of inducing phospholipidosis in cells under conditions of in vivo administration or ex vivo incubation. The principal characteristics of this condition include the reversible accumulation of polar phospholipids in association with the development of unicentric or multicentric lamellated bodies within cells. There is an abundance of data providing an understanding of potential mechanisms for the induction of phospholipidosis; however, the process is likely to be complex and may differ from one drug to another. The functional consequences of the presence of this condition on cellular or tissue function are not well understood. The general consensus is that the condition is an adaptive response rather than a toxicological manifestation; however, additional studies to examine this question are needed. Until this issue is resolved, concerns about phospholipidosis will continue to exist at regulatory agencies. Procedures for the screening of potential phospholipogenic candidate compounds are available. In contrast, a clear need exists for the identification of valid biomarkers to assess the development of phospholipidosis in preclinical and clinical studies. PMID:16774494

Reasor, Mark J; Hastings, Kenneth L; Ulrich, Roger G



Drug-sensing hydrogels for the inducible release of biopharmaceuticals  

NASA Astrophysics Data System (ADS)

Drug-dependent dissociation or association of cellular receptors represents a potent pharmacologic mode of action for regulating cell fate and function. Transferring the knowledge of pharmacologically triggered protein-protein interactions to materials science will enable novel design concepts for stimuli-sensing smart hydrogels. Here, we show the design and validation of an antibiotic-sensing hydrogel for the trigger-inducible release of human vascular endothelial growth factor. Genetically engineered bacterial gyrase subunit B (GyrB) (ref. 4) coupled to polyacrylamide was dimerized by the addition of the aminocoumarin antibiotic coumermycin, resulting in hydrogel formation. Addition of increasing concentrations of clinically validated novobiocin (Albamycin) dissociated the GyrB subunits, thereby resulting in dissociation of the hydrogel and dose- and time-dependent liberation of the entrapped protein pharmaceutical VEGF121 for triggering proliferation of human umbilical vein endothelial cells. Pharmacologically controlled hydrogels have the potential to fulfil the promises of stimuli-sensing materials as smart devices for spatiotemporally controlled delivery of drugs within the patient.

Ehrbar, Martin; Schoenmakers, Ronald; Christen, Erik H.; Fussenegger, Martin; Weber, Wilfried



Paracetamol-induced fixed drug eruption at an unusual site.  


Background: Paracetamol (acetaminophen) is a widely used analgesic/antipyretic drug for which hypersensitivity reactions appear to be increasingly frequent. Objective: We report the case of a woman who experienced several delayed selective reactions induced by paracetamol: fixed drug eruptions (FDEs) with typical features but an unusual distribution (hard palate and a maculopapular rash. Methods: Skin tests: prick, intradermal and patch tests as well as a single-blind oral challenge test (OCT) were performed. Results: Skin tests were negative. The OCT was necessary to confirm the diagnosis. Interestingly, the challenge test elicited an FDE-type lesion instead of a maculopapular rash. Conclusions: Our findings could reflect 2 different clinical patterns of delayed allergic reactions, or, more probably, the initial phase of a unique clinical entity that was stopped by the corticosteroids prescribed during the challenge. However, we were unable to confirm these hypotheses. The uncommon anatomical site of the lesions (hard palate) is noteworthy. Some relevant patents are also summarized in this paper. PMID:23889091

Gómez-Traseira, Carmen; Rojas-Pérez-Ezquerra, Patricia; Sánchez-Morillas, Leticia; González-Mendiola, Rosario; Rubio-Pérez, María; Moral-Morales, Alicia; Juliolaguna-Martinez, José



Stem Cell Transplantation: A Promising Therapy for Parkinson’s Disease  

Microsoft Academic Search

Parkinson’s disease is one of the most common neurodegenerative diseases caused by the loss of dopaminergic neurons in the\\u000a substantia nigra pars compacta. Pharmacological therapies are valuable but suffer from two main drawbacks: side effects and\\u000a loss of efficacy with disease progression. Surgical treatment is no better than drugs. Transplantation of embryonic mesencephalic\\u000a tissue has emerged as a therapeutic alternative,

Yi Wang; Sheng Chen; Dehua Yang; Wei-dong Le



Dopamine agonists suppress cholinomimetic-induced tremulous jaw movements in an animal model of Parkinsonism: tremorolytic effects of pergolide, ropinirole and CY 208–243  

Microsoft Academic Search

Considerable evidence indicates that cholinomimetic-induced tremulous jaw movements in rats share many characteristics with human Parkinsonian tremor, and several antiparkinsonian drugs suppress cholinomimetic-induced tremulous jaw movements. The present study investigated three different types of dopamine agonists, which have known antiparkinsonian characteristics, for their ability to suppress the tremulous jaw movements induced by tacrine (5.0mg\\/kg). The non-selective dopamine agonist pergolide, a

John D. Salamone; Brian B. Carlson; Clifford Rios; Elizabeth Lentini; Merce Correa; Ania Wisniecki; Adrienne Betz



Nonmotor Disturbances in Parkinson’s Disease  

Microsoft Academic Search

Nonmotor disturbances (NMDs) affect most patients with Parkinson’s disease (PD) and often have a profound impact on their quality of life. NMDs such as depression, anxiety, fatigue, REM sleep behavior disorder, constipation, delayed gastric emptying, altered olfaction and pain can precede the onset of motor symptoms. Other NMDs, including hallucinations, dementia, excessive daytime sleepiness, insomnia, orthostatic hypotension and bladder disturbances,

Claudio L. Bassetti



Drug-Induced Liver Injury Network (DILIN) Prospective Study  

PubMed Central

Background Drug-induced liver injury (DILI) is an uncommon adverse drug reaction of increasing importance to the medical community, pharmaceutical industry, regulatory agencies and the general public. Objectives The Drug-Induced Liver Injury Network (DILIN) was established to advance understanding and research into DILI by initiating a prospective registry of patients with bona fide DILI for future studies of host clinical, genetic, environmental and immunological risk factors. The DILIN was also charged with developing standardized nomenclature, terminology and causality assessment instruments. Methods Five clinical sites, a data coordinating centre and senior scientists from the National Institute of Diabetes and Digestive and Kidney Diseases initiated the DILIN prospective study in September 2004. Eligible patients are required to meet minimal laboratory or histological criteria within 6 months of DILI onset and have other competing causes of liver injury excluded. Patients in the general community setting with pre-existing HIV, hepatitis B virus or hepatitis C virus infections and/or abnormal baseline liver biochemistries are eligible for enrolment. In addition, subjects with liver injury due to herbal products are eligible to participate. Control patients without DILI are also to be recruited in the future. Results All referred subjects undergo an extensive review of available laboratory, pathology and imaging studies. Subjects who meet pre-defined eligibility criteria at the 6-month study visit are followed for 2 years to better define the natural history of chronic DILI. Causality assessment is determined by a panel of three hepatologists who independently assign a causality score ranging from 1 (definite) to 5 (unlikely) as well as a severity score ranging from 1 (mild) to 5 (fatal). During the first 3 years, 367 subjects were enrolled into the DILIN prospective study. Conclusion DILIN is a multicentre research network charged with improving our understanding of the aetiologies, risk factors and outcomes of DILI in the US. The network is meeting the targeted enrolment of ten patients per month and is developing a repository of clinical data and biological samples for future studies of DILI pathogenesis and outcome.

Fontana, Robert J.; Watkins, Paul B.; Bonkovsky, Herbert L.; Chalasani, Naga; Davern, Timothy; Serrano, Jose; Rochon, James



Parkinson's Disease  


... that the symptoms of PD reflect loss of nerve cells that normally release the neurotransmitter dopamine. Recognition of ... led to development of the drug levodopa, which nerve cells turn into dopamine. Levodopa dramatically reversed symptoms of ...


Polymorphism in the P-glycoprotein drug transporter MDR1 gene: a possible link between environmental and genetic factors in Parkinson's disease  

Microsoft Academic Search

P-glycoprotein is a membrane protein encoded by the MDR1 gene, which demonstrates functional polymorphism. It is present in endothelial cells of the blood-brain barrier, thus limiting accumulation of its substrates in the central nervous system. Many epidemiological studies suggest an association between pesticides, which are substrates for P-glycoprotein, and Parkinson's disease. It was hypothesized that polymorphism of the MDR1 gene

Krystyna Honczarenko; Jan Stankiewicz; Zbigniew Sych



Fosinopril as a possible pemphigus-inducing drug.  


Fosinopril has recently been added to the angiotensin-converting enzyme inhibitors inducing pemphigus. The observation of a patient in whom pemphigus vulgaris (PV) worsened after taking fosinopril prompted us to study an experimental way to assess its responsibility. Slices of normal human skin (NHS) were simultaneously incubated for 2, 6, 12 and 24 h at 4 degrees C with progressively diluted fosinopril and captopril solutions and used as indirect immunofluorescence (IIF) substrates for 2 sera containing anti-desmoglein-3 (anti-Dsg3) antibodies at a dilution of 1/160. With captopril, IIF was negative, irrespective of dilution and time of incubation. Only at 1/40,000 dilution was IIF positive. With fosinopril, IIF was negative for the 2- and 6-hour-long incubations but turned positive after 12 h and so remained with all other solutions and incubation times. IIF negativity with captopril suggests that anti-Dsg3 antibodies contained in the PV sera were unable to find molecules in NHS to bind to. Captopril would therefore induce acantholysis by blocking the adhesion molecules. With fosinopril, instead, a partial block of the adhesion molecules was seen only with the very concentrated solution, unlikely to occur in vivo. Fosinopril, therefore, is probably unable to block the adhesion molecules in vivo. Our method might be used to verify the acantholytic properties of a drug. PMID:11937741

Parodi, A; Cozzani, E; Milesi, G; Drosera, M; Rebora, A



The Cortical and Striatal Gene Expression Profile of 100 Hz Electroacupuncture Treatment in 6-Hydroxydopamine-Induced Parkinson's Disease Model  

PubMed Central

Electroacupuncture (EA), especially high-frequency EA, has frequently been used as an alternative therapy for Parkinson disease (PD) and is reportedly effective for alleviating motor symptoms in patients and PD models. However, the molecular mechanism underlying its effectiveness is not completely understood. To implement a full-scale search for the targets of 100?Hz EA, we selected rat models treated with 6-hydroxydopamine into the unilateral MFB, which mimic end-stage PD. High-throughput microarray analysis was then used to uncover the regulated targets in the cortex and striatum after 4-week EA treatment. In the differentially regulated transcripts, the proportion of recovered expression profiles in the genes, the functional categories of targets in different profiles, and the affected pathways were analyzed. Our results suggested that the recovery of homeostasis in the transcript network and many regulated functional clusters in the cortex and striatum after EA treatment may contribute to the behavioral improvement of PD rats.

Huo, Li-Rong; Liang, Xi-Bin; Li, Bo; Liang, Jian-Tao; He, Yi; Jia, Yan-Jun; Jia, Jun; Gong, Xiao-Li; Yu, Fen; Wang, Xiao-Min



Functionalized nanoparticles for AMF-induced gene and drug delivery  

NASA Astrophysics Data System (ADS)

The properties and broad applications of nano-magnetic colloids have generated much interest in recent years. Specially, Fe3O4 nanoparticles have attracted a great deal of attention since their magnetic properties can be used for hyperthermia treatment or drug targeting. For example, enhanced levels of intracellular gene delivery can be achieved using Fe3O4 nano-vectors in the presence of an external magnetic field, a process known as 'magnetofection'. The low cytotoxicity, tunable particle size, ease of surface functionalization, and ability to generate thermal energy using an external alternating magnetic field (AMF) are properties have propelled Fe3O4 research to the forefront of nanoparticle research. The strategy of nanoparticle-mediated, AMF-induced heat generation has been used to effect intracellular hyperthermia. One application of this 'magnetic hyperthermia' is heat activated local delivery of a therapeutic effector (e.g.; drug or polynucleotide). This thesis describes the development of a magnetic nano-vector for AMF-induced, heat-activated pDNA and small molecule delivery. The use of heat-inducible vectors, such as heat shock protein ( hsp) genes, is a promising mode of gene therapy that would restrict gene expression to a local region by focusing a heat stimulus only at a target region. We thus aimed to design an Fe3O4 nanoparticle-mediated gene transfer vehicle for AMF-induced localized gene expression. We opted to use 'click' oximation techniques to assemble the magnetic gene transfer vector. Chapter 2 describes the synthesis, characterization, and transfection studies of the oxime ether lipid-based nano-magnetic vectors MLP and dMLP. The synthesis and characterization of a novel series of quaternary ammonium aminooxy reagents (2.1--2.4) is described. These cationic aminooxy compounds were loaded onto nanoparticles for ligation with carbonyl groups and also to impart a net positive charge on the nanoparticle surface. Our studies indicated that the non-toxic magnetoplexes (magnetic nanoparticle + pDNA complex) derived from dMLP deliver pDNA into mammalian cells even without external magnetic assistance. To date, dMLP is the only polymer-free magnetic gene delivery system that can deliver pDNA without any magnetic assistance. Chapter 3 of this thesis outlines the synthesis and characterization of other oxime ether lipids and details studies using derived-lipoplexes. These lipids were evaluated in pDNA and siRNA transfection studies in various mammalian cell lines. This work constitutes the first use of an oxime ether as the linking domain in cationic transfection lipids. These biocompatible oxime ether lipids can be readily assembled by click chemistry through ligation of hydrophobic aldehydes with quaternary ammonium aminooxy salts. Our studies showed that the oxime ether lipids transfected pDNA and siRNA efficiently in MCF-7, H 1792, and in PAR C10 cells comparable to and in some cases better than commercial transfection lipids. Chapter 4 describes the design and characterization of a nano-magnetic delivery system for AMF-induced drug (doxorubicin) release. In efforts to develop a magnetic formulation free from thermosensitive materials, such as hydrogels, we synthesized three nanoparticle-based doxorubicin formulations using charge interactions as the key associative force. To do so, we synthesized and characterized a novel cationic oxime ether conjugate at C-13 of doxorubicin. Our investigation indicated that the positive charge of the oxime ether drug conjugate tended to bind better to the negatively charged nanoparticle than did the other formulations prepared in stepwise manner. Our findings show that the nano-magnetic formulations remained essestially inactive at body temperature (37.5 °C) and released a majority of the cargo only when exposed to an external AMF. Our designed magnetic drug delivery platform is the first example of an AMF-inducible system that does not depend on the inclusion of thermosensitive materials. Finally, we have developed a bioanalytical application of the highly chemosele

Biswas, Souvik


Drug-Induced Hepatotoxicity in a Tertiary Care Hospital in Rural South India  

PubMed Central

Background: Liver is the main organ for metabolism of drugs and hepatotoxicity is a potential adverse effect for most drugs. Aims: This study was to study the frequency of drug-induced hepatotoxicity and to find the common drugs causing hepatotoxicity. Materials and Methods: The study was conducted at a tertiary care hospital in rural India. It is a study based on case series analysis. All patients with an abnormal liver function report, between July 2006 and July 2007, were included in the study Results: The study included 411 patients. Among them 141 patients were females and 270 males. The common cause for abnormal liver function was alcoholic liver disease (30.4%) followed by drug-induced hepatotoxicity (15.8%) and malaria (15.3%). Drug-induced hepatotoxicity was seen in 65 patients. It was common in males (55%) compared to females (44%). The mean age of the patients with drug-induced hepatotoxicity was 43±15.9. Antitubercular drugs were the commonly encountered drugs (44%) causing hepatotoxicity followed by lipid lowering agents (41%). The others drugs included antiretroviral drugs (6%),steroids (5%) and chlorpromazine (2%). Conclusion: A thorough history of drug intake must be taken in all patients presenting with abnormal hepatic function.

Jaiprakash, Heethal; Narayana, Sarala; Mohanraj, Jaiprakash



Apoptosis in mesangial cells induced by ionizing radiation and cytotoxic drugs  

Microsoft Academic Search

Apoptosis in mesangial cells induced by ionizing radiation and cytotoxic drugs. Mesangial proliferation contributes to the pathogenesis of many forms of glomerulonephritis. To evaluate the role of apoptosis on the pharmacologic effects of cytotoxic drugs and ionizing radiation, we studied their effects on cultured rat mesangial cells (MC), whose apoptotic response to these drugs is unknown. Mesangial cells were cultured

Dae Ryong Cha; Stella M Feld; Cynthia Nast; Janine LaPage; Sharon G Adler



Team management of Parkinson's disease.  


This report describes a multidisciplinary approach to the treatment of Parkinson's disease. By using published sources, the disease process, clinical findings, and medical management of Parkinson's disease are reviewed. The continual change in the clinical picture as well as the therapeutic needs require that clinicians have a full understanding of the disease and drugs used. This is followed by a description of a group program, including the evaluation process, treatment goals, and individual and group activities employed. Rehabilitation services are needed as medical management alone is not sufficient to maintain patient's daily living skills. The occupational therapist is skilled in assessment and training of activities for daily living. As a result, occupational therapy can be an integral part of the treatment program. PMID:860744

Davis, J C


Drug-Induced Pulmonary Vascular Disease--Mechanisms and Clinical Patterns  

PubMed Central

An extensive vascular surface area places the lungs at risk for damage by blood-borne drugs. Drug-induced pulmonary vascular disease may present clinically as acute pulmonary edema, pulmonary edema followed by diffuse interstitial lung disease, pulmonary vascular occlusion, pulmonary hypertension or hemorrhage. It is important to recognize these reactions as drug-related because many are reversible with discontinuation of the drug and supportive therapy. Failure to recognize drug-induced pulmonary vascular disease can lead to significant morbidity and, in some cases, death. ImagesFigure 1.Figure 2.Figure 2.Figure 3.

Kumar, Kusum; Holden, William E.



S100B is increased in Parkinson's disease and ablation protects against MPTP-induced toxicity through the RAGE and TNF-? pathway  

PubMed Central

Parkinson’s disease is a neurodegenerative disorder that can, at least partly, be mimicked by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. S100B is a calcium-binding protein expressed in, and secreted by, astrocytes. There is increasing evidence that S100B acts as a cytokine or damage-associated molecular pattern protein not only in inflammatory but also in neurodegenerative diseases. In this study, we show that S100B protein levels were higher in post-mortem substantia nigra of patients with Parkinson’s disease compared with control tissue, and cerebrospinal fluid S100B levels were higher in a large cohort of patients with Parkinson’s disease compared with controls. Correspondingly, mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine showed upregulated S100B messenger RNA and protein levels. In turn, ablation of S100B resulted in neuroprotection, reduced microgliosis and reduced expression of both the receptor for advanced glycation endproducts and tumour necrosis factor-?. Our results demonstrate a role of S100B in the pathophysiology of Parkinson’s disease. Targeting S100B may emerge as a potential treatment strategy in this disorder.

Maetzler, Walter; Lang, Johannes D.; Mounsey, Ross B.; Fleckenstein, Corina; Martin, Heather L.; Schulte, Claudia; Mustafa, Sarah; Synofzik, Matthis; Vukovic, Zvonimir; Itohara, Shigeyoshi; Berg, Daniela



A Drug-induced Cerebrospinal Lipodystrophy in the Domestic Chicken (Gallus domesticus)  

PubMed Central

A drug-induced lipidosis of the central nervous system of chickens is reported. Membranous cytoplastic neuronal inclusions similar to those seen in Tay-sach's disease in man and in spontaneous or drug-induced disease in swine were seen by electron microscopy. Fat was demonstrated in frozen sections. ImagesFig. 1.Fig. 2.Fig. 3.Fig. 4.

Dukes, T. W.; Read, W. K.; Bay, W. W.; Gleiser, C. A.



A role for lysosomal phospholipase A2 in drug induced phospholipidosis.  


Many therapeutic drugs currently in use are cationic amphiphiles. These cationic amphiphilic drugs (CADs) induce phospholipidosis in humans and experimental animals. The recent study shows that CAD-induced cellular phospholipidosis is linked to the impairment of phospholipid catabolism by inhibition of lysosomal phospholipase A2 activity. PMID:19356018

Abe, Akira; Hiraoka, Miki; Shayman, James A



Decision-making, impulsivity and addictions: Do Parkinson's disease patients jump to conclusions?  

PubMed Central

Links between impulsive compulsive behaviors in treated Parkinson’s disease, behavioral addictions and substance abuse have been postulated, but no direct comparisons have been carried out so far. We directly compared patients with Parkinson’s disease with and without impulsive compulsive behaviors with illicit drug abusers, pathological gamblers and age-matched healthy controls using the beads task, a test of reflection impulsivity and a working memory task. We found that all patients with Parkinson’s disease made more impulsive and irrational choices than the control group. Parkinson’s disease patients who had an impulsive compulsive behavior showed similar behavior to illicit substance abusers whereas patients without impulsive compulsive behaviors more closely resembled pathological gamblers. In contrast we found no difference in working memory performance within the Parkinson’s disease groups. However Parkinson’s disease patients without impulsive compulsive behaviors remembered distractors significantly less than all other patients during working memory tests. We were able to correctly classify 96% of the Parkinson’s disease patients with respect to whether or not they had an impulsive compulsive behavior by analyzing 3 trials of the 80/20 loss condition of the beads task with a negative prediction value of 92.3% and we propose that this task may prove to be a powerful screening tool to detect an impulsive compulsive behavior in Parkinson’s disease. Our results also suggest that intact cortical processing and less distractibility in Parkinson’s disease patients without impulsive compulsive behaviors may protect them from developing behavioral addictions.

Djamshidian, Atbin; O'Sullivan, Sean S.; Sanotsky, Yanosh; Sharman, Stephen; Matviyenko, Yuriy; Foltynie, Thomas; Michalczuk, Rosanna; Aviles-Olmos, Iciar; Fedoryshyn, Ludmyla; Doherty, Karen M.; Filts, Yuriy; Selikhova, Marianna; Bowden-Jones, Henrietta; Joyce, Eileen; Lees, Andrew J.; Averbeck, Bruno B.



[Efficacy of prostaglandin derivatives and mucoprotective drugs in treatment and prevention for NSAIDs-induced ulcer].  


Deficiency of prostaglandins (PGs) by non-steroidal anti-inflammatory drugs (NSAIDs) causes a loss of gastroduodenal mucosal integrity, leading to development of ulceration. PG derivatives such as misoprostol and enprostil have been proven effective in prevention and treatment of NSAIDs-induced gastroduodenal ulcers. Although side effects such as diarrhea limit the use of PG derivatives, the efficacy of these drugs in NSAIDs-induced injuries is approximately equal to that of proton pump inhibitors. Mucoprotective drugs such as rebamipide also have been reported to be effective for prevention of NSAIDs-induced ulcers. Since misoprostol and some mucoprotective drugs can prevent NSAIDs-induced small intestinal injuries, these drugs, especially misoprostol, should be used as first-line therapy for NSAIDs-induced gastrointestinal injuries with attention paid to the side effects. PMID:21688624

Fujikawa, Yoshiko; Watanabe, Toshio; Tominaga, Kazunari; Fujiwara, Yasuhiro; Sato, Hiroyuki; Arakawa, Tetsuo



Neurodegenerative Shielding by Curcumin and Its Derivatives on Brain Lesions Induced by 6-OHDA Model of Parkinson's Disease in Albino Wistar Rats  

PubMed Central

Study was undertaken to evaluate the neurodegenerative defending potential of curcumin (CUR), demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC) on 6-hydroxydopamine-(6-OHDA) induced Parkinsonism model in rats. Curcuminoids were administered (60?mg/kg, body weight, per oral) for three weeks followed by unilateral injection of 6-OHDA on 22nd day (10??g/2??L) into the right striatum leading to extensive loss of dopaminergic cells. The behavioral observations, biochemical markers, quantification of dopamine (DA), DOPAC, and HVA followed by dopamine (D2) receptor binding assay and tyrosine hydroxylase (TH, using immunohistochemistry) were evaluated using HPLC after three weeks of lesion. Pretreated animals showed significant protection against neuronal degeneration compared to lesion animals by normalizing the deranged levels of biomarkers and showed the potency in the order CUR > DMC > BDMC. The same order of effectiveness was observed in D2 receptors binding assay and TH immunohistochemistry study. We conclude that curcuminoids appear to shield progressive neuronal degeneration from increased oxidative attack in 6-OHDA-lesioned rats through its free radical scavenging mechanism, and DA, DOPAC, and HVA enhancing capabilities in the sequence of efficacy CUR > DMC > BDMC. Further, curcuminoids may have potential utility in treatment of many more oxidative stress-induced neurodegenerative disorders.

Agrawal, Shyam Sunder; Gullaiya, Sumeet; Dubey, Vishal; Singh, Varun; Kumar, Ashok; Nagar, Ashish; Tiwari, Poonam



Inflammatory Animal Model for Parkinson's Disease: The Intranigral Injection of LPS Induced the Inflammatory Process along with the Selective Degeneration of Nigrostriatal Dopaminergic Neurons  

PubMed Central

We have developed an animal model of degeneration of the nigrostriatal dopaminergic neurons, the neuronal system involved in Parkinson's disease (PD). The implication of neuroinflammation on this disease was originally established in 1988, when the presence of activated microglia in the substantia nigra (SN) of parkinsonians was reported by McGeer et al. Neuroinflammation could be involved in the progression of the disease or even has more direct implications. We injected 2??g of the potent proinflammatory compound lipopolysaccharide (LPS) in different areas of the CNS, finding that SN displayed the highest inflammatory response and that dopaminergic (body) neurons showed a special and specific sensitivity to this process with the induction of selective dopaminergic degeneration. Neurodegeneration is induced by inflammation since it is prevented by anti-inflammatory compounds. The special sensitivity of dopaminergic neurons seems to be related to the endogenous dopaminergic content, since it is overcome by dopamine depletion. Compounds that activate microglia or induce inflammation have similar effects to LPS. This model suggest that inflammation is an important component of the degeneration of the nigrostriatal dopaminergic system, probably also in PD. Anti-inflammatory treatments could be useful to prevent or slow down the rate of dopaminergic degeneration in this disease.

Machado, A.; Herrera, A. J.; Venero, J. L.; Santiago, M.; de Pablos, R. M.; Villaran, R. F.; Espinosa-Oliva, A. M.; Arguelles, S.; Sarmiento, M.; Delgado-Cortes, M. J.; Maurino, R.; Cano, J.



Regulation of Brain-Derived Neurotrophic Factor (BDNF) and Cerebral Dopamine Neurotrophic Factor (CDNF) by Anti-Parkinsonian Drug Therapy In Vivo  

Microsoft Academic Search

Available treatment for Parkinson’s disease (PD) is mainly symptomatic instead of halting or reversing degenerative processes\\u000a affecting the disease. Research on the molecular pathogenesis of PD has suggested reduced trophic support as a possible cause\\u000a or mediator of neurodegeneration. In animal models of the disease, neurotrophic factors prevent neurodegeneration and induce\\u000a behavioral recovery. Some anti-Parkinsonian drugs show neuroprotective activity, but

Tobias Gyárfás; Juha Knuuttila; Päivi Lindholm; Tomi Rantamäki; Eero Castrén



The Protective Effect of Minocycline in a Paraquat-Induced Parkinson's Disease Model in Drosophila is Modified in Altered Genetic Backgrounds  

PubMed Central

Epidemiological studies link the herbicide paraquat to increased incidence of Parkinson's disease (PD). We previously reported that Drosophila exposed to paraquat recapitulate PD symptoms, including region-specific degeneration of dopaminergic neurons. Minocycline, a tetracycline derivative, exerts ameliorative effects in neurodegenerative disease models, including Drosophila. We investigated whether our environmental toxin-based PD model could contribute to an understanding of cellular and genetic mechanisms of minocycline action and whether we could assess potential interference with these drug effects in altered genetic backgrounds. Cofeeding of minocycline with paraquat prolonged survival, rescued mobility defects, blocked generation of reactive oxygen species, and extended dopaminergic neuron survival, as has been reported previously for a genetic model of PD in Drosophila. We then extended this study to identify potential interactions of minocycline with genes regulating dopamine homeostasis that might modify protection against paraquat and found that deficits in GTP cyclohydrolase adversely affect minocycline rescue. We further performed genetic studies to identify signaling pathways that are necessary for minocycline protection against paraquat toxicity and found that mutations in the Drosophila genes that encode c-Jun N-terminal kinase (JNK) and Akt/Protein kinase B block minocycline rescue.

Inamdar, Arati A.; Chaudhuri, Anathbandhu; O'Donnell, Janis



Drug-Induced Respiratory Disease in Cardiac Patients  

Microsoft Academic Search

\\u000a By definition, adverse reactions to drugs develop unpredictably in patients exposed to therapeutic doses of ‘drugs,’ which\\u000a include such respiratory gases as dioxygen (O2) and nitric oxide (NO). Accordingly, misuse, disuse, drug interactions, deliberate or accidental overdoses, illicit drugs,\\u000a and radiation therapy are outside the province of this chapter. Notwithstanding that, it is difficult to cover this topic\\u000a without mentioning

Philippe Camus; Clio Camus; Pascal Foucher


The history of Parkinson's disease: early clinical descriptions and neurological therapies.  


Although components of possible Parkinson's disease can be found in very early documents, the first clear medical description was written in 1817 by James Parkinson. In the mid-1800s, Jean-Martin Charcot was particularly influential in refining and expanding this early description and in disseminating information internationally about Parkinson's disease. He separated Parkinson's disease from multiple sclerosis and other disorders characterized by tremor, and he recognized cases that later would likely be classified among the Parkinsonism-plus syndromes. Early treatments of Parkinson's disease were based on empirical observation, and anticholinergic drugs were used as early as the nineteenth century. The discovery of dopaminergic deficits in Parkinson's disease and the synthetic pathway of dopamine led to the first human trials of levodopa. Further historically important anatomical, biochemical, and physiological studies identified additional pharmacological and neurosurgical targets for Parkinson's disease and allow modern clinicians to offer an array of therapies aimed at improving function in this still incurable disease. PMID:22229124

Goetz, Christopher G



The History of Parkinson's Disease: Early Clinical Descriptions and Neurological Therapies  

PubMed Central

Although components of possible Parkinson's disease can be found in very early documents, the first clear medical description was written in 1817 by James Parkinson. In the mid-1800s, Jean-Martin Charcot was particularly influential in refining and expanding this early description and in disseminating information internationally about Parkinson's disease. He separated Parkinson's disease from multiple sclerosis and other disorders characterized by tremor, and he recognized cases that later would likely be classified among the Parkinsonism-plus syndromes. Early treatments of Parkinson's disease were based on empirical observation, and anticholinergic drugs were used as early as the nineteenth century. The discovery of dopaminergic deficits in Parkinson's disease and the synthetic pathway of dopamine led to the first human trials of levodopa. Further historically important anatomical, biochemical, and physiological studies identified additional pharmacological and neurosurgical targets for Parkinson's disease and allow modern clinicians to offer an array of therapies aimed at improving function in this still incurable disease.

Goetz, Christopher G.



Drug-induced lipidosis and the alveolar macrophage.  


The alveolar macrophage is the principal component of the defense mechanisms of the lung. As a result, alterations in its function can predispose the host organism to pulmonary disease or damage. This cell shows toxic responses to a wide variety of chemicals which are delivered to the lungs by either inhalation or via the systemic circulation. In this regard, this review will focus on the effects of a group of cationic amphiphilic drugs which when administered to humans and animals causes a lysosomal storage disorder of lipids, principally phospholipids, in alveolar macrophages. The susceptibility to the disorder is species-dependent and can be induced in fetal, neonatal and adult animals. Evidence exists that the accumulation of lipids within the cells occurs as a result of an impairment in lipid catabolism, however, not all of the available data are consistent with this theory. In light of this, other mechanisms to explain the etiology of this lipidosis are discussed. Associated with the increase in lipid content within the cell, striking morphological, biochemical and functional changes occur to the alveolar macrophage. Available data indicate that afflicted cells have an increased phagocytic activity and exhibit enhanced killing of one strain of bacteria. While these data suggest an enhancement in certain cellular functions, inadequate information presently exists to allow conclusions to be drawn concerning the consequences of this disorder. PMID:7022749

Reasor, M J



Drug-induced TINU syndrome and genetic characterization.  


Tubulointerstitial nephritis and uveitis (TINU) syndrome is due to a disregulation of cell-mediated immunity and genetical predisposition due a particular molecular characterization. We report the case of a 50-year-old woman who was admitted for acute renal failure. She had recently taken flurbiprofen for 10 d for recurrent bronchitis. A renal biopsy revealed acute tubulointerstitial nephritis. Prednisone was started and prognosis was favorable. Three months later the patient developed transitory blurred vision. The diagnosis was bilateral uveitis and she received topic and systemic corticosteroid therapy, with resolution of ocular symptoms. Recurrent episodes of uveitis experienced during the next 12 months were treated with same therapy. Genomic haplotype in our patients was HLA A*0278/2631,-B*1517/3802,- Cw*0701/1202, -DRB1*0101/1359 (DRB3* 52), -DQA1*0102/0102, DQB1*0603/0603. TINU syndrome is characterized by tubulointerstitial nephritis that tends to be selflimiting, whereas uveitis tends to relapse. HLA-DQA1*01 and -DQB1*06 haplotypes are strongly associated with TINU syndrome. This is the first report of TINU syndrome induced by flubiprofen intake. Our case emphasizes the importance of the association between drug exposure and strong susceptibility to TINU syndrome giving the molecular characterization. PMID:22874112

Santoro, Domenico; Vita, Giuseppe; Rovito, Stefania; Venuto, Lucia; Cavallari, Vittorio; Vita, Roberto; Savica, Vincenzo; Bellinghieri, Guido; Gangemi, Sebastiano



Fatigue-inducing stimulation resolves myotonia in a drug-induced model  

PubMed Central

Background Slowed muscle relaxation is the contractile hallmark of myotonia congenita, a disease caused by genetic CLC-1 chloride channel deficiency, which improves with antecedent brief contractions ("warm-up phenomenon"). It is unclear to what extent the myotonia continues to dissipate during continued repetitive contractions and how this relates temporally to muscle fatigue. Diaphragm, EDL, and soleus muscles were examined in vitro during repetitive 20 Hz and 50 Hz train stimulation in a drug-induced (9-AC) rat myotonia model. Results At the onset of stimulation, 9-AC treated diaphragm and EDL muscle had markedly prolonged half relaxation and late relaxation times (range 147 to 884 ms, 894 to 1324 ms). Half relaxation and late relaxation times reached near-normal values over the 5-10 and 10-40 subsequent contractions, respectively. In both muscles myotonia declined faster during repetitive 50 Hz than 20 Hz stimulation, and much faster than the rate of force loss during fatigue at both frequencies. Soleus muscle was resistant to the myotonic effects of 9-AC. Conclusions In a drug-induced model of mechanical myotonia, fatigue-inducing stimulation resolves the myotonia, which furthermore appears to be independent from the development of muscle fatigue.



Acetaldehyde and parkinsonism: role of CYP450 2E1  

PubMed Central

The present review update the relationship between acetaldehyde (ACE) and parkinsonism with a specific focus on the role of P450 system and CYP 2E1 isozyme particularly. We have indicated that ACE is able to enhance the parkinsonism induced in mice by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a neurotoxin able to damage the nigrostriatal dopaminergic pathway. Similarly diethyldithiocarbamate, the main metabolite of disulfiram, a drug widely used to control alcoholism, diallylsulfide (DAS) and phenylisothiocyanate also markedly enhance the toxin-related parkinsonism. All these compounds are substrate/inhibitors of CYP450 2E1 isozyme. The presence of CYP 2E1 has been detected in the dopamine (DA) neurons of rodent Substantia Nigra (SN), but a precise function of the enzyme has not been elucidated yet. By treating CYP 2E1 knockout (KO) mice with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, the SN induced lesion was significantly reduced when compared with the lesion observed in wild-type animals. Several in vivo and in vitro studies led to the conclusion that CYP 2E1 may enhance the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in mice by increasing free radical production inside the dopaminergic neurons. ACE is a good substrate for CYP 2E1 enzyme as the other substrate-inhibitors and by this way may facilitate the susceptibility of dopaminergic neurons to toxic events. The literature suggests that ethanol and/or disulfiram may be responsible for toxic parkinsonism in human and it indicates that basal ganglia are the major targets of disulfiram toxicity. A very recent study reports that there are a decreased methylation of the CYP 2E1 gene and increased expression of CYP 2E1 mRNA in Parkinson's disease (PD) patient brains. This study suggests that epigenetic variants of this cytochrome contribute to the susceptibility, thus confirming multiples lines of evidence which indicate a link between environmental toxins and PD.

Vaglini, Francesca; Viaggi, Cristina; Piro, Valentina; Pardini, Carla; Gerace, Claudio; Scarselli, Marco; Corsini, Giovanni Umberto



Reversible transvestic fetishism in a man with Parkinson's disease treated with selegiline.  


Dopaminergic therapy in patients with Parkinson's disease may change the quality as well as the quantity of sexual interest and behavior. This 72-year-old man had a 37-year history of Parkinson's disease treated with a right thalamotomy and was later treated with levodopa for more than 20 years. Selegiline (5 mg twice daily) was added for motor fluctuations. He developed a frequent impulse to wear women's clothing but did not act on this impulse until his wife died over a year later. He then began to dress in women's clothing an average of once per week. He stated he had never thought of cross-dressing previously. The selegiline was stopped, and his urge to wear women's clothing ceased. Paraphilias are a rare behavioral complication of Parkinson's disease treatment. Other paraphilias have been attributed to dopamine agonists, suggesting that the action of the monoamine oxidase inhibitor responsible for the patient's transvestism in this case was dopamine potentiation. Drug-induced paraphilias and hypersexuality may represent a reversal of the putative premorbid Parkinson's disease personality traits of introversion, cautious behavior, and lack of "novelty-seeking." A biologic basis for transvestism, and paraphilias in general, is not known. Rare clues emerge from cases similar to this one. PMID:12151912

Riley, David E


Alpha-lipoic acid protects against 6-hydroxydopamine-induced neurotoxicity in a rat model of hemi-parkinsonism.  


Parkinson's disease (PD) is a progressive and debilitating neurodegenerative disorder for which current treatments afford symptomatic relief with no prevention of disease progression. Due to the neuroprotective and anti-apoptotic potential of alpha lipoic acid (LA), this study was undertaken to evaluate whether LA could improve behavioral and cellular abnormalities and markers of oxidative stress in an experimental model of early PD in rat. Unilateral intrastriatal 6-hydroxydopamine (6-OHDA)-lesioned rats were pretreated p.o. with LA at doses of 50 and/or 100mg/kg twice at an interval of 24h. After 1 week, apomorphine caused significant contralateral rotations, a significant reduction in the number of neurons was observed on the left side of the substantia nigra pars compacta (SNC), and malondialdehyde (MDA) and nitrite levels in midbrain homogenate significantly increased and activity of superoxide dismutase significantly reduced in the 6-OHDA group. LA pretreatment at a dose of 100mg/kg significantly attenuated rotations, prevented loss of SNC neurons, and lowered levels of MDA and nitrite. These results suggest that LA could partially afford neuroprotection against 6-OHDA neurotoxicity that is in part due to the attenuation of oxidative stress burden and this may provide benefits, along with other therapies, in neurodegenerative disorders including PD. PMID:23415934

Jalali-Nadoushan, Mohammadreza; Roghani, Mehrdad



Contrasting changes in cortical activation induced by acute high-frequency stimulation within the globus pallidus in Parkinson's disease.  


Continuous stimulation of the globus pallidus (GP) has been shown to be an effective treatment for Parkinson's disease (PD). We used the fact that the implanted quadripolar leads contain electrodes within the GPi and GPe to investigate the clinical effects of acute high-frequency stimulation applied in these nuclei and changes in regional cerebral blood flow (rCBF) as an index of synaptic activity. In five patients treated by chronic GP stimulation, we compared the effects on PD symptoms and the changes in rCBF at rest and during paced right-hand movements, with and without left GPe or GPi stimulation. Although improving contralateral rigidity and akinesia, left GPe stimulation decreased rCBF in the left cerebellum and lateral premotor cortex at rest and significantly increased it in the left primary sensorimotor cortex (SM1) during movement. In contrast, left ventral GPi stimulation, which improved rigidity and worsened akinesia, decreased rCBF in the left SM1, premotor area, anterior cingulum, and supplementary motor area but did not modify the movement-related activation. GPe stimulation seems to result in a reduced activity of motor-related areas and the facilitation of motor cortex activation during movement, the latter component being absent during GPi stimulation, and this may explain the observed worsening of akinesia. PMID:18781162

Payoux, Pierre; Remy, Philippe; Miloudi, Malika; Houeto, Jean-Luc; Stadler, Claudio; Bejjani, Boulos-Paul; Yelnik, Jérome; Samson, Yves; Rascol, Olivier; Agid, Yves; Damier, Philippe



Treatment of Early Parkinson’s Disease  

Microsoft Academic Search

The management of early Parkinson’s disease (PD) involves the treatment of motor symptoms and, increasingly, non-motor symptoms. Given the fast pace of clinical research in PD, clinicians are faced with the challenge of integrating the latest findings into the ongoing care of individual PD patients. Part 1 of this 2-part article reviews motor symptom efficacy data for the newest PD

Tanya Simuni; Kelly E. Lyons; Rajesh Pahwa; Robert A. Hauser; Cynthia Comella; Lawrence Elmer; Daniel Weintraub



Parkinson’s Disease and Motor Fluctuations  

Microsoft Academic Search

Opinion statement  Many important advances for the treatment of Parkinson’s disease (PD) have been made over the past decade, and quality of\\u000a life has improved for most patients. Nonetheless, motor fluctuations in the form of wearing off with the re-emergence of parkinsonian\\u000a symptoms and hyperkinetic movements (dyskinesias) often arise as a complication of long-term dopaminergic therapy and can\\u000a be disabling. Because

Vanessa K. Hinson



Cell Therapy in Parkinson’s Disease  

Microsoft Academic Search

\\u000a Parkinson’s disease (PD) is a common neurodegenerative disorder, characterized by the progressive loss of dopaminergic neurons\\u000a in the substantia nigra. It is typically treated symptomatically by dopamine replacement using either levodopa or dopamine\\u000a agonists, however, cell therapies that aim to repair and replace these lost neurons and their projections to the striatum\\u000a represent a very promising strategy to help cure

R. Laguna Goya; R. A. Barker


Psychiatric symptoms in Parkinson’s disease  

Microsoft Academic Search

Parkinson’s disease (PD) is a neurodegenerative disorder which is often reduced to a mere dysfunction of motor performance.\\u000a Non-motor symptoms, however, are frequent impairments in PD and result in a major impact on the patients and their caregivers.\\u000a The major neuropsychiatric comorbidities depression, anxiety, and psychotic symptoms are briefly discussed. Additionally,\\u000a a brief outlook on deep brain stimulation and its

Frank Schneider; Astrid Althaus; Volker Backes; Richard Dodel



Parkinson’s disease: Motor fluctuations  

Microsoft Academic Search

Opinion statement  Motor fluctuations represent important late complications of Parkinson’s disease treated with levodopa. Although treatment\\u000a of these problems has improved with the emergence of numerous pharmacologic and surgical therapies, the various options can\\u000a make it confusing. Pharmacologic treatment is the first step. Polytherapy is often the rule in this case with a variety of\\u000a agents available as adjunctive therapy with

Stewart A. Factor



Sleep disorders in Parkinson’s disease  

Microsoft Academic Search

Opinion statement  Sleep disorders in Parkinson’s disease (PD) are frequent and have numerous etiologies. Both nighttime sleep disturbances and\\u000a daytime sleepiness can occur. The key to effective treatment is appropriate diagnosis. A careful interview of the patient\\u000a and his or her bed partner provides direction for additional evaluations. Referral to a sleep specialist for quantitative\\u000a studies is necessary to evaluate for

Cynthia L. Comella



?-Synuclein Aggregation and Parkinson’s Disease  

Microsoft Academic Search

Parkinson’s disease (PD) is a multifactorial movement disorder in which both genetic and especially environmental factors\\u000a play important roles. Substantial evidence implicates the aggregation of ?-synuclein, an abundant and conservative presynaptic\\u000a brain protein with unknown function, as a critical factor in PD. Rare familial cases of PD are associated with the mutations\\u000a A30P (Ala to Pro substitution at position 30),

Vladimir N. Uversky


HLA Typing and Parkinson’s Disease  

Microsoft Academic Search

Idiopathic Parkinson’s disease (IPD) is a neurodegenerative disorder of unknown aetiology. Several antigens have been associated with IPD using serological methods. We systematically analysed HLA class I and II alleles in 45 German Caucasian IPD patients using sequence-specific oligonucleotides and sequence-specific primer technology. Applying Bonferroni adjusted p values, we demonstrate a statistically significant increase of the DQB1*06 allele (p =

J. B. Lampe; G. Gossrau; B. Herting; A. Kempe; U. Sommer; M. Füssel; M. Weber; R. Koch; H. Reichmann



Drug bioactivation and protein adduct formation in the pathogenesis of drug-induced toxicity.  


Adverse drug reactions (ADRs) remain a major complication of drug therapy and can be classified as 'on-target' or 'off-target' (idiosyncratic) reactions. On-target reactions can be predicted from the known primary or secondary pharmacology of the drug and often represent an exaggeration of the pharmacological effect of the drug. In contrast, off-target adverse reactions cannot be predicted from knowledge of the basic pharmacology of the drug. The exact mechanisms of idiosyncratic drug reactions are still unclear; however it is believed that they can be initiated by chemically reactive drug metabolites. It is well known that xenobiotics can undergo metabolic bioactivation reactions which have the potential to cause cellular stress and damage. Bioactivation of drugs is thought to have the potential of initiating covalent linkages between cellular protein and drugs which can be recognised by the adaptive immune system in the absence of detectable cellular stress. This process cannot yet be predicted in pre-clinical models or discovered in clinical trials. Because of this hazard perception, the formation of chemically reactive metabolites in early drug discovery remains a serious impediment to the development of new medicines and can lead to withdrawal of an otherwise effective therapeutic agent. The fear of such reactions occurring at the post-licensing stage - when such problems first become evident - is a major contribution to drug attrition. The first step towards such methodology has been the development of chemically reactive metabolite screens. The chemical basis of drug bioactivation can usually be rationalised and synthetic strategies put in place to prevent such bioactivation. However, there is no simple correlation between drug bioactivation in vitro and adverse drug reactions in the clinic. Such a chemical approach is clearly limited by the facts that (a) not all drugs that can undergo bioactivation by human drug-metabolising enzymes are associated with hypersensitivity in the clinic and (b) drug bioactivation may not always be a mandatory step in drug hypersensitivity. To predict such reactions in early drug development, it will require an integrated understanding of the chemical, immunological and genetic basis of adverse drug reactions in patients, which in turn will depend on the development of novel in vitro experimental systems. PMID:20846520

Park, B K; Laverty, H; Srivastava, A; Antoine, D J; Naisbitt, D; Williams, D P



Parkinsonism Plus Syndromes  

Microsoft Academic Search

\\u000a Parkinson’s plus syndrome is a term that refers to disorders of movement and cognition that are often confused with Parkinson’s\\u000a disease. The three main disorders are progressive supranuclear palsy (PSP), multisystem atrophy (MSA), and corticobasal degeneration\\u000a (CBD). These syndromes are pathologically diverse encompassing a number of distinct proteinopathies but have in common clinical\\u000a features of movement abnormality, cognitive decline, a

Fiona M. Molloy; Daniel G. Healy


Adenosine A 2A receptor antagonists: Potential therapeutic and neuroprotective effects in parkinson’s disease  

Microsoft Academic Search

The most effective treatment of Parkinson’s disease (PD) is, at present, the dopamine precursor L-3,4-dihydroxyphenyl-alanine\\u000a (L-DOPA), however a number of disadvantages such as a loss of drug efficacy and severe side-effects (psychoses, dyskinesias\\u000a and on-off phenomena) limit long-term, effective utilisation of this drug. Recent experimental studies in which selective\\u000a antagonists of adenosine A2A receptors were used, have shown an improvement

M. Morelli; J. Wardas



A fatal case of cutaneous adverse drug-induced toxic epidermal necrolysis associated with severe rhabdomyolysis.  


Toxic epidermal necrolysis represents an immunologic reaction to a foreign antigen and is most often caused by drugs. Atorvastatin, a blood cholesterol-lowering agent, is a recognized cause of rhabdomyolysis; while naproxen, a widely used nonsteroidal anti-inflammatory drug, is a known cause of photo-induced skin lesions. We report the first fatal case of drug-induced toxic epidermal necrolysis associated with severe muscle necrosis due to the use of a nonsteroidal anti-inflammatory drug and a statin with very high levels of creatine phosphokinase leading to acute kidney injury, disseminated intravascular coagulation, and complete skin necrosis leading to death. PMID:22588445

Noordally, Sheik Oaleed; Sohawon, Schoeb; Vanderhulst, Julien; Duttmann, Ruth; Corazza, Francis; Devriendt, Jacques


Objective motion sensor assessment highly correlated with scores of global levodopa-induced dyskinesia in Parkinson's disease.  


Background: Chronic use of medication for treating Parkinson's disease (PD) can give rise to peak-dose dyskinesia. Adjustments in medication often sacrifice control of motor symptoms, and thus balancing this trade-off poses a significant challenge for disease management. Objective: To determine whether a wrist-worn motion sensor unit could be used to ascertain global dyskinesia severity over a levodopa dose cycle and to develop a severity scoring algorithm highly correlated with clinician ratings. Methods: Fifteen individuals with PD were instrumented with a wrist-worn motion sensor unit, and data were collected with arms in resting and extended positions once every hour for three hours after taking a levodopa dose. Two neurologists blinded to treatment status viewed subject videos and rated global and upper extremity dyskinesia severity based on the modified Abnormal Involuntary Movement Scale (mAIMS). Linear regression models were developed using kinematic features extracted from motion sensor data and extremity, global, or combined (average of extremity and global) mAIMS scores. Results: Dyskinesia occurring during a levodopa dose cycle was successfully measured using a wrist-worn sensor. The logarithm of the power spectrum area between 0.3-3 Hz and the combined clinician scores resulted in the best model performance, with a correlation coefficient between clinician and model scores of 0.81 and root mean square error of 0.55, both averaged across the arms resting and extended postures. Conclusions: One sensor unit worn on either hand can effectively predict global dyskinesia severity during the arms resting or extended positions. PMID:23948993

Mera, Thomas O; Burack, Michelle A; Giuffrida, Joseph P



Rotenone-induced parkinsonism elicits behavioral impairments and differential expression of parkin, heat shock proteins and caspases in the rat.  


Rotenone is a pesticide that inhibits mitochondrial complex I activity, thus creating an environment of oxidative stress in the cell. Many studies have employed rotenone to generate an experimental animal model of Parkinson's disease (PD) that mimics and elicits PD-like symptoms, such as motor and cognitive decline. Cytoprotective proteins including parkin and heat shock proteins (HSPs) play major roles in slowing PD progression. Moreover, evidence suggests that mitochondrial dysfunction and oxidative stress-dependent apoptotic pathways contribute to dopaminergic neuron degeneration in PD. Here, rats were chronically exposed to rotenone to confirm that it causes a debilitating phenotype and various behavioral defects. We also performed histopathological examinations of nigrostriatal, cortical and cerebellar regions of rotenone-treated brain to elucidate a plausible neurodegenerative mechanism. The results of silver, tyrosine hydroxylase (TH), parkin, ubiquitin and caspase staining of brain tissue sections further validated our findings. The stress response is known to trigger HSP in response to pharmacological insult. These protective proteins help maintain cellular homeostasis and may be capable of rescuing cells from death. Therefore, we assessed the levels of different HSPs in the rotenone-treated animals. Collectively, our studies indicated the following findings in the striatum and substantia nigra following chronic rotenone exposure in an experimental PD model: (i) behavioral deficit that correlated with histopathological changes and down regulation of TH signaling, (ii) decreased levels of the cytoprotective proteins parkin, DJ1 and Hsp70 and robust expression of mitochondrial chaperone Hsp60 according to Western blot, (iii) increased immunoreactivity for caspase 9, caspase 3 and ubiquitin and decreased parkin immunoreactivity. PMID:22710069

Sonia Angeline, M; Chaterjee, P; Anand, K; Ambasta, R K; Kumar, P



Prime-, stress-, and cue-induced reinstatement of extinguished drug-reinforced responding in rats: cocaine as the prototypical drug of abuse.  


This unit describes the testing of rats in prime-, footshock-, and cue-induced reinstatement procedures. Evaluating rats in these procedures enables the assessment of treatments on behavior thought to model drug relapse precipitated by re-contact with an abused drug (prime-induced), induced by stress (footshock-induced), or by stimuli previously associated with drug administration (cue-induced). For instance, levels of reinstatement under the effects of test compound administration could be compared to levels under vehicle administration to help identify potential treatments for drug relapse, or reinstatement levels of different rat strains could be compared to identify potential genetic determinants of perseverative drug-seeking behavior. Cocaine is used as a prototypical drug of abuse, and relapse to its use serves as the model in this unit, but other self-administered drugs could readily be substituted with little modification to the procedures. PMID:23093352

Beardsley, Patrick M; Shelton, Keith L



Prime-, Stress- and Cue-Induced Reinstatement of Extinguished Drug-Reinforced Responding in Rats: Cocaine as the Prototypical Drug of Abuse  

PubMed Central

This unit describes the testing of rats in prime-, footshock- and cue-induced reinstatement procedures. Evaluating rats in these procedures enables the assessment of treatments on behavior thought to model drug relapse precipitated by re-contact with an abused drug (prime-induced), induced by stress (footshock-induced), or by stimuli previously associated with drug administration (cue-induced). For instance, levels of reinstatement under the effects of test compound administration could be compared to levels under vehicle administration to help identify potential treatments for drug relapse, or reinstatement levels of different rat strains could be compared to identify potential genetic determinants of perseverative drug-seeking behavior. Cocaine is used as a prototypical drug of abuse, and relapse to its use serves as the model in this unit, but ot