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1

Drug-Induced Parkinsonism  

PubMed Central

Drug-induced parkinsonism (DIP) is the second-most-common etiology of parkinsonism in the elderly after Parkinson's disease (PD). Many patients with DIP may be misdiagnosed with PD because the clinical features of these two conditions are indistinguishable. Moreover, neurological deficits in patients with DIP may be severe enough to affect daily activities and may persist for long periods of time after the cessation of drug taking. In addition to typical antipsychotics, DIP may be caused by gastrointestinal prokinetics, calcium channel blockers, atypical antipsychotics, and antiepileptic drugs. The clinical manifestations of DIP are classically described as bilateral and symmetric parkinsonism without tremor at rest. However, about half of DIP patients show asymmetrical parkinsonism and tremor at rest, making it difficult to differentiate DIP from PD. The pathophysiology of DIP is related to drug-induced changes in the basal ganglia motor circuit secondary to dopaminergic receptor blockade. Since these effects are limited to postsynaptic dopaminergic receptors, it is expected that presynaptic dopaminergic neurons in the striatum will be intact. Dopamine transporter (DAT) imaging is useful for diagnosing presynaptic parkinsonism. DAT uptake in the striatum is significantly decreased even in the early stage of PD, and this characteristic may help in differentiating PD from DIP. DIP may have a significant and longstanding effect on patients' daily lives, and so physicians should be cautious when prescribing dopaminergic receptor blockers and should monitor patients' neurological signs, especially for parkinsonism and other movement disorders. PMID:22523509

Shin, Hae-Won

2012-01-01

2

EXPLORING THE RELATIONSHIP BETWEEN DRUG-INDUCED PARKINSONISM AND TARDIVE DYSKINESIAS  

E-print Network

EXPLORING THE RELATIONSHIP BETWEEN DRUG-INDUCED PARKINSONISM AND TARDIVE DYSKINESIAS L. Giselle Aguilar, MD and William G Ondo, MD Parkinson's Disease Center and Movement Disorders Clinic, Department, haloperidol and thioridazine. Drug-induced parkinsonism (DIP) tends to have an insidious onset, often starting

Lichtarge, Olivier

3

[ą˛łI]FP-CIT single photon emission computed tomography findings in drug-induced Parkinsonism.  

PubMed

Drug-induced parkinsonism (DIP) in patients treated with antipsychotic drugs is considered a form of post-synaptic parkinsonism, caused by D2-receptor blockade. Recent studies, however, carried out on small and heterogeneous patient samples, have shown that DIP may be associated with [(123)I]FP-CIT single photon emission computed tomography (SPECT) abnormalities, which are markers of dopamine nigrostriatal terminal defect. In the present study, outpatients fulfilling the DSM-IV criteria for schizophrenia and treated with antipsychotics for at least 6 months, were enrolled in order to estimate the prevalence of DIP and, among patients with DIP, the prevalence of [(123)I]FP-CIT SPECT abnormalities. Socio-demographic and clinical variables associated with the presence of DIP and SPECT abnormalities were also assessed. DIP was diagnosed in 149 out of 448 patients with schizophrenia (33%). Age, use of long-acting antipsychotics and a positive family history of parkinsonism were the only demographic variables significantly associated with the development of DIP. Neuroimaging abnormalities were found in 41 of 97 patients who agreed to undergo [(123)I]FP-CIT SPECT (42%). Only age differentiated this group of patients from those with normal imaging. These preliminary findings suggest that D2-receptor blockade may coexist with a dopamine nigrostriatal terminal defect, as assessed by [(123)I]FP-CIT SPECT abnormalities, in a relevant proportion of DIP patients. Longitudinal studies should be designed with the aim of improving our understanding of the mechanisms of pre-synaptic abnormalities in DIP patients and identifying specific treatment strategies. PMID:22727453

Tinazzi, Michele; Cipriani, Andrea; Matinella, Angela; Cannas, Antonino; Solla, Paolo; Nicoletti, Alessandra; Zappia, Mario; Morgante, Letterio; Morgante, Francesca; Pacchetti, Claudio; Sciarretta, Massimo; Dallocchio, Carlo; Rossi, Simone; Malentacchi, Maria; Ceravolo, Roberto; Frosini, Daniela; Sestini, Stelvio; Bovi, Tommaso; Barbui, Corrado

2012-08-01

4

Drug interactions in the treatment of Parkinson's disease  

Microsoft Academic Search

In recent years, the antiparkinsonian drug regime has become increasingly complicated. A wide range of antiparkinson agents is meanwhile available. Combination therapies may unfortunately induce interactions up to the point of life-threatening events. The potential of drug-drug interactions must be taken into account before starting a patient on combination treatment. Moreover, the frequent multimorbidity of patients with Parkinson's disease necessitates

W. H. Jost; C. Brück

2002-01-01

5

Parkinson's Drugs May Spur Compulsive Behaviors  

MedlinePLUS

... sharing features on this page, please enable JavaScript. Parkinson's Drugs May Spur Compulsive Behaviors Study estimated a ... 20, 2014 Related MedlinePlus Pages Obsessive-Compulsive Disorder Parkinson's Disease MONDAY, Oct. 20, 2014 (HealthDay News) -- Drugs ...

6

Parkinsonism caused by adverse drug reactions: a case series  

PubMed Central

Introduction Parkinsonism puts a high direct cost burden on both patient and caregiver. Several reports of drug-induced parkinsonism have been published, but to the best of our knowledge, there has not been any report of quinine or halothane inducing parkinsonism. Case presentation We describe two cases of parkinsonism possibly caused by adverse drug reaction to quinine in a 29-year-old black Nigerian woman and to halothane in a 36-year-old black Hausa (Nigerian) man who received it as general anaesthesia for appendicectomy in our teaching hospital. Conclusion These are two unusual cases of parkinsonism caused by adverse drug reactions to high-dose quinine and to halothane as general anaesthesia. We consider that these two cases are important in bringing this potential side-effect to the attention of both pharmacologists and primary care physicians as these are two of the most commonly used medications in our clinics. We conclude that parkinsonism should be included among the adverse drug reactions to high-dose quinine and halothane general anaesthetic. PMID:21410947

2011-01-01

7

Flunarizine and cinnarizine-induced parkinsonism: a historical and clinical analysis  

Microsoft Academic Search

Background. Drug-Induced Parkinsonism (DIP) represents the second leading cause of Parkinsonism (PK) in several countries. Flunarizine and cinnarizine are some of the most common drugs that cause DIP. This paper reviews the first description of Flunarizine and Cinnarizine-Induced Parkinsonism (FCIP), as well as the subsequent literature, emphasizing epidemiological, clinical and diagnostic aspects. Methods. We reviewed the literature on the subject,

Hélio A. G. Teive; André R. Troiano; Francisco M. B. Germiniani; Lineu C. Werneck

2004-01-01

8

Low dose quetiapine for drug induced dyskinesias in Parkinson's disease: a double blind cross over study  

PubMed Central

Methods: Nine patients with PD were enrolled and received 25 mg of quetiapine or placebo at night for two weeks in prerandomised order, with one week of wash out between treatment periods. Assessments were made using on–off diaries, self assessment of dyskinesias, and L-dopa challenges at baseline and after each treatment period. Videotapes were rated blindly by two raters using modified Abnormal Involuntary Movement Scale and Goetz scores. Patients subsequently went on open label quetiapine at 50 mg/day, for a mean duration of 30 days, and completed the same self assessment forms. Results: During the double blind phase, no significant change in dyskinesias was found on either 25 mg of quetiapine or placebo. Duration of off states and Unified PD Rating Scale motor scores also remained unchanged. Moderate tiredness and daytime sleepiness occurred in two patients on quetiapine. One patient dropped out early for unrelated reasons. Eight patients completed the open label phase. On 50 mg/day of quetiapine, a slight reduction in dyskinesias occurred on some scales. Reduction in dyskinesia severity on visual analogue scales was by 50.1%. Off time was not significantly increased. This improvement was not strongly reflected in patients' overall impression of treatment effect. Drowsiness and daytime sleep episodes led to discontinuation in four patients, after completion of the study, and two additional patients stopped treatment after the study because of lack of effect. Conclusion: Our study failed to demonstrate an antidyskinetic effect of low dose (25 mg) quetiapine. The absence of an increase in parkinsonism combined with a possible antidyskinetic effect on higher doses warrants further investigation. PMID:14742609

Katzenschlager, R; Manson, A; Evans, A; Watt, H; Lees, A

2004-01-01

9

Fracture risk associated with parkinsonism and anti-Parkinson drugs.  

PubMed

We studied fracture risk associated with parkinsonism (including Parkinson's disease) and drugs used to treat these conditions in a case-control study. Cases were all subjects with any fracture during the year 2000 (n = 124,655). For each case, three controls (n = 373,962) matched on age and gender were randomly drawn from the background population. Exposure was a diagnosis of parkinsonism or use of anticholinergic drugs, levodopa alone or in combination with carbidopa, and/or catechol-O-methyl transferase (COMT) inhibitors, dopamine agonists, or monoamine oxidase B (MAO-B) inhibitors and a number of other confounders. Parkinsonism was associated with a crude odds ratio (OR) of any fracture of 2.2 (95% confidence interval [95% CI] 2.0-2.5) and an adjusted OR of 1.2 (95% CI 1.0-1.4), the risk being higher especially in males younger than 75 years. Levodopa was associated with an increased overall fracture risk and an increased risk of hip fractures in high doses. Dopamine agonists, anticholinergic drugs, and MAO-B inhibitors were not associated with increased fracture risk except for hip fractures at high doses for MAO-B inhibitors and hip fractures at median doses for dopamine agonists. Neuroleptics were associated with increased risk of fractures in almost all skeletal sites and doses. In conclusion, parkinsonism was associated with increased risk of fractures, especially among males younger than 75 years, and the risk was significantly attenuated upon adjustment for confounders. Use of neuroleptics and, to some degree, levodopa was associated with increased risk of fractures. PMID:17705047

Vestergaard, Peter; Rejnmark, Lars; Mosekilde, Leif

2007-09-01

10

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. PMID:23211041

2012-01-01

11

Continuous drug delivery in Parkinson's disease.  

PubMed

Development of motor and non-motor complications during the course of Parkinson's disease (PD) is a major challenge for therapeutic management. At advanced disease stages, patients frequently fluctuate between PD symptoms-such as bradykinesia-and dyskinesias, in response to fluctuations in drug concentrations. Continuous subcutaneous infusion of the dopamine agonist apomorphine or intestinal infusion of levodopa reduce such fluctuations in both pharmacokinetics and motor function. This is the basis for the concept of continuous drug delivery in PD, and the more theoretical concept of continuous dopaminergic stimulation. These expressions are sometimes used to describe a treatment that is more continuous in its pharmacokinetic profile or that produces more sustained effects, compared with immediate-release levodopa, i.e. not only pump treatments. For example, sustained-release formulations of levodopa or dopamine agonists, transdermal delivery of rotigotine, and addition of catechol-O-methyltransferase inhibitors or monoamine oxidase-B inhibitors have been developed with the aim to provide more continuous drug concentrations, sustained benefits and minimized side effects. Progress has been made, but there are still knowledge gaps regarding how these treatment alternatives can be optimally used. New treatments are currently being developed to provide the continuous drug delivery that is known to successfully alleviate motor and non-motor complications. Hopefully, although not yet proven, these new methods may also prevent or postpone some of the late-stage complications. PMID:24323838

Senek, Marina; Nyholm, Dag

2014-01-01

12

A new approach to disease-modifying drug trials in Parkinson’s disease  

PubMed Central

Translating new findings in the laboratory into therapies for patients is a slow and expensive process. The development of therapies for neurodegenerative diseases is further complicated by the difficulty in determining whether the drug truly retards the slow degenerative process or provides only symptomatic benefit. In this issue, Aviles-Olmos et al. describe a first in Parkinson’s disease (PD) patient study using a drug previously approved for diabetes treatment. In addition to suggesting that the drug may indeed be disease modifying in PD, their innovative approach suggests there may be more rapid and inexpensive avenues for testing novel therapies in PD. PMID:23728166

Barker, Roger A.; Stacy, Mark; Brundin, Patrik

2013-01-01

13

Drugs in development for Parkinson's disease.  

PubMed

Pharmacological treatment of Parkinson's disease (PD) is entering a new and exciting era. Real promise now exists for the clinical application of a large range of molecules in development that will combat different aspects and stages of the condition. These include methyl- and ethyl-esterified forms of L-dopa (etilevodopa and melevodopa), inhibitors of enzymes such as monoamine oxidase type-B (eg, rasagiline), catechol-O-methyl transferase (eg, BIA-3202) and the monoamine re-uptake mechanism (eg, brasofensine). In addition, a range of full and partial dopamine agonists (eg, sumanirole, piribedil and BP-897) and their new formulations, for example, patch delivery systems (eg, rotigotine) are being developed. We also highlight non-dopaminergic treatments that will have wide ranging applications in the treatment of PD and L-dopa-induced dyskinesia. These include alpha2 adrenergic receptor antagonists (eg, fipamezole), adenosine A2A receptor antagonists (eg, istradefylline), AMPA receptor antagonists (eg, talampanel), neuronal synchronization modulators (eg, levetiracetam) and agents that interact with serotonergic systems such as 5-hydroxytryptamine (5-HT)1A agonists (eg, sarizotan) and 5-HT2A antagonists (eg, quetiapine). Lastly, we examine a growing number of neuroprotective agents that seek to halt or even reverse disease progression. These include anti-apoptotic kinase inhibitors (eg, CEP-1347), modulators of mitochondrial function (eg, creatine), growth factors (eg, leteprinim), neuroimmunophilins (eg, V-10367), estrogens (eg, MITO-4509), c-synuclein oligomerization inhibitors (eg, PAN-408) and sonic hedgehog ligands. PMID:15298067

Johnston, Tom H; Brotchie, Jonathan M

2004-07-01

14

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. PMID:23505333

Skibinski, Gaia; Finkbeiner, Steven

2013-01-01

15

?6?2* and ?4?2* Nicotinic Acetylcholine Receptors As Drug Targets for Parkinson's Disease  

PubMed Central

Parkinson's disease is a debilitating movement disorder characterized by a generalized dysfunction of the nervous system, with a particularly prominent decline in the nigrostriatal dopaminergic pathway. Although there is currently no cure, drugs targeting the dopaminergic system provide major symptomatic relief. As well, agents directed to other neurotransmitter systems are of therapeutic benefit. Such drugs may act by directly improving functional deficits in these other systems, or they may restore aberrant motor activity that arises as a result of a dopaminergic imbalance. Recent research attention has focused on a role for drugs targeting the nicotinic cholinergic systems. The rationale for such work stems from basic research findings that there is an extensive overlap in the organization and function of the nicotinic cholinergic and dopaminergic systems in the basal ganglia. In addition, nicotinic acetylcholine receptor (nAChR) drugs could have clinical potential for Parkinson's disease. Evidence for this proposition stems from studies with experimental animal models showing that nicotine protects against neurotoxin-induced nigrostriatal damage and improves motor complications associated with l-DOPA, the “gold standard” for Parkinson's disease treatment. Nicotine interacts with multiple central nervous system receptors to generate therapeutic responses but also produces side effects. It is important therefore to identify the nAChR subtypes most beneficial for treating Parkinson's disease. Here we review nAChRs with particular emphasis on the subtypes that contribute to basal ganglia function. Accumulating evidence suggests that drugs targeting ?6?2* and ?4?2* nAChR may prove useful in the management of Parkinson's disease. PMID:21969327

Wonnacott, Susan

2011-01-01

16

Eye Movements in Ephedrone-Induced Parkinsonism  

PubMed Central

Patients with ephedrone parkinsonism (EP) show a complex, rapidly progressive, irreversible, and levodopa non-responsive parkinsonian and dystonic syndrome due to manganese intoxication. Eye movements may help to differentiate parkinsonian syndromes providing insights into which brain networks are affected in the underlying disease, but they have never been systematically studied in EP. Horizontal and vertical eye movements were recorded in 28 EP and compared to 21 Parkinson's disease (PD) patients, and 27 age- and gender-matched healthy subjects using standardized oculomotor tasks with infrared videooculography. EP patients showed slow and hypometric horizontal saccades, an increased occurrence of square wave jerks, long latencies of vertical antisaccades, a high error rate in the horizontal antisaccade task, and made more errors than controls when pro- and antisaccades were mixed. Based on oculomotor performance, a direct differentiation between EP and PD was possible only by the velocity of horizontal saccades. All remaining metrics were similar between both patient groups. EP patients present extensive oculomotor disturbances probably due to manganese-induced damage to the basal ganglia, reflecting their role in oculomotor system. PMID:25117825

Megrelishvili, Marika; Sieger, Tomas; Matouskova, Olga; Okujava, Michael; Brozova, Hana; Nikolai, Tomas; Hanuska, Jaromir; Kapianidze, Mariam; Mikeladze, Nina; Botchorishvili, Nazi; Khatiashvili, Irine; Janelidze, Marina; Serranova, Tereza; Fiala, Ondrej; Roth, Jan; Bergquist, Jonas; Jech, Robert; Rivaud-Pechoux, Sophie; Gaymard, Bertrand; Ruzicka, Evzen

2014-01-01

17

Eye movements in ephedrone-induced parkinsonism.  

PubMed

Patients with ephedrone parkinsonism (EP) show a complex, rapidly progressive, irreversible, and levodopa non-responsive parkinsonian and dystonic syndrome due to manganese intoxication. Eye movements may help to differentiate parkinsonian syndromes providing insights into which brain networks are affected in the underlying disease, but they have never been systematically studied in EP. Horizontal and vertical eye movements were recorded in 28 EP and compared to 21 Parkinson's disease (PD) patients, and 27 age- and gender-matched healthy subjects using standardized oculomotor tasks with infrared videooculography. EP patients showed slow and hypometric horizontal saccades, an increased occurrence of square wave jerks, long latencies of vertical antisaccades, a high error rate in the horizontal antisaccade task, and made more errors than controls when pro- and antisaccades were mixed. Based on oculomotor performance, a direct differentiation between EP and PD was possible only by the velocity of horizontal saccades. All remaining metrics were similar between both patient groups. EP patients present extensive oculomotor disturbances probably due to manganese-induced damage to the basal ganglia, reflecting their role in oculomotor system. PMID:25117825

Bonnet, Cecilia; Rusz, Jan; Megrelishvili, Marika; Sieger, Tomáš; Matoušková, Olga; Okujava, Michael; Brožová, Hana; Nikolai, Tomáš; Hanuška, Jaromír; Kapianidze, Mariam; Mikeladze, Nina; Botchorishvili, Nazi; Khatiashvili, Irine; Janelidze, Marina; Serranová, Tereza; Fiala, Ond?ej; Roth, Jan; Bergquist, Jonas; Jech, Robert; Rivaud-Péchoux, Sophie; Gaymard, Bertrand; R?ži?ka, Evžen

2014-01-01

18

Drug-induced hepatitis  

MedlinePLUS

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 ...

19

Advances in drug development for Parkinson's disease: present status.  

PubMed

The major hallmark of Parkinson's disease (PD) is the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, leading to the characteristic motor symptoms of resting tremors, bradykinesia and rigidity. Research in the field of PD therapy has been partly successful in terms of developing symptomatic treatments, but it also experienced several failures with regard to developing disease-modifying therapies. According to the definition of the Committee to Identify Neuroprotective Agents for Parkinson's, neuroprotection would be any intervention that favorably influences the disease process or underlying pathogenesis to produce enduring benefits for patients. A development of effective neuroprotective therapies resulting in clinically meaningful results is hampered by several factors in all research stages. Novel solutions might be offered by an evaluation of new targets throughout clinical studies, therapies emerging from drug repositioning approaches, multitarget approaches and network pharmacology. Several promising randomized controlled trials are in progress, and the increased collaboration between pharmaceutical companies and basic and clinical researchers has the potential to bring us closer to developing an optimum pharmaceutical approach for the treatment of PD. The aim of the present review is to give an overview of the neuroprotective agents and their targets currently investigated for the treatment of PD in phase I-III clinical trials. PMID:25096413

Harikrishna Reddy, Dibbanti; Misra, Shubham; Medhi, Bikash

2014-01-01

20

Drug-Induced Diarrhea  

Microsoft Academic Search

\\u000a Drug-induced diarrhea (DID) is common, but our understanding of the underlying mechanisms may vary from solid understanding\\u000a to reasonable hypothesis to considerable conjecture. Drug-induced diarrhea is rarely an allergy, i.e., with an underlying\\u000a immune mechanism, but may well be an inherent component of the pharmacologic effect of the drug, may be due to variable pharmacogenomics\\u000a or be an appropriate physiologic

Bincy P. Abraham; Joseph H. Sellin

21

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

PubMed Central

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

2013-01-01

22

Vitiligo, drug induced (image)  

MedlinePLUS

... 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 ...

23

Drug induced pancreatitis.  

PubMed

525 different drugs that can, as an adverse reaction, induce acute pancreatitis are listed in a WHO database. Compared to other causes drugs represent a relatively rare cause of pancreatitis. They should be considered as a triggering event in patients with no other identifiable cause of the disease, who takes medications that have been shown to induce pancreatitis. The prevalence of drug-induced pancreatitis is still unclear because most incidences have been documented only as isolated case reports. The overall incidence probably ranges from between 0.1 and 2% of pancreatitis cases. For only very few substances evidence from controlled trials has been obtained. Epidemiologic data suggest the risk of pancreatitis is highest for mesalazine (HR 3.5,) azathioprine (HR 2,5) and simvastatine (HR 1,8). Even when a definite association has been demonstrated it is often impossible to determine whether the drug, or the underlying condition for which the drug was taken has conferred the risk of pancreatitis (e.g. azathioprine and Crohns disease or pentamidine and HIV). Knowledge about the underlying pathophysiologic mechanisms as well as evidence for a direct causality often remains sparse. For only 31 drugs a definite causality has been established. The most frequently reported are mesalazine (nine cases in total, three cases with re-exposure), azathioprine (five cases in total, two cases with re-exposure) and simvastatin (one case in total, this one with re-exposure). As cause-effect relationship is generally accepted when symptoms re-occur upon re-challenge. Available data from case control studies suggest that even drugs with solid evidence for an association with pancreatitis only rarely cause the disease. Even when pancreatitis is induced as an adverse drug event the disease course is usually mild or even subclinical. PMID:20227028

Nitsche, Claudia J; Jamieson, Nigel; Lerch, Markus M; Mayerle, Julia V

2010-04-01

24

Piribedil-induced sleep attacks in Parkinson's disease.  

PubMed

'Sleep attacks', episodes of sudden onset of sleep without any prodromal symptoms, were initially described in patients with Parkinson's disease (PD) taking the newer dopamine agonists pramipexole and ropinirole. Piribedil, a nonergot agonist with both D2 and D3 agonist action, is an effective antiparkinsonian medication. However, there are very few reports of Piribedil-induced sleep attacks in PD. Among 50 PD patients seen at our Movement Disorder Clinic who had recently taken Piribedil, we identified three (6%) who satisfied the clinical description of sleep attacks. Here we provide details of the clinical characteristics of Piribedil-induced sleep attacks in these PD patients. PMID:12588638

Tan, E K

2003-02-01

25

Drug-Induced Cholestasis  

Microsoft Academic Search

Medications and herbal supplements can induce a variety of hepatic, acute, and chronic cholestatic syndromes including bland\\u000a cholestasis, cholestasis with concurrent hepatitis, bile duct injury, and extrahepatic biliary strictures and stones. Most\\u000a cases of drug- and herbal-induced cholestasis are benign, but progression to chronic liver disease, cirrhosis, and death is\\u000a well described. We discuss the different types of cholestasis that

James P. Hamilton; Jacqueline M. Laurin

26

Targeting GTPases in Parkinson's disease: comparison to the historic path of kinase drug discovery and perspectives  

PubMed Central

Neurological diseases have placed heavy social and financial burdens on modern society. As the life expectancy of humans is extended, neurological diseases, such as Parkinson’s disease, have become increasingly common among senior populations. Although the enigmas of Parkinson’s diseases await resolution, more vivid pictures on the cause, progression, and control of the illness are emerging after years of research. On the molecular level, GTPases are implicated in the etiology of Parkinson’s disease and are rational pharmaceutical targets for their control. However, targeting individual GTPases, which belong to a superfamily of proteins containing multiple members with a conserved guanine nucleotide binding domain, has proven to be challenging. In contrast, pharmaceutical pursuit of inhibition of kinases, which constitute another superfamily of proteins with more than 500 members, has been fairly successful. We reviewed the breakthroughs in the history of kinase drug discovery to provide guidance for the GTPase field. We summarize recent progress made in the regulation of GTPase activity. We also present an efficient and cost effective approach to drug screening, which uses multiplex flow cytometry and mixture-based positional scanning libraries. These methods allow simultaneous measurements of both the activity and the selectivity of the screened library. Several GTPase activator clusters were identified which showed selectivity against different GTPase subfamilies. While the clusters need to be further deconvoluted to identify individual active compounds, the method described here and the structure information gathered create a foundation for further developments to build upon. PMID:24926233

Hong, Lin; Sklar, Larry A.

2014-01-01

27

Parkinson's Disease: Diagnosis and Treatment  

Microsoft Academic Search

Parkinson's disease is a common neurodegenerative disorder that can cause significant disability and decreased quality of life. The cardinal physical signs of the disease are distal resting tremor, rigidity, bradykinesia, and asym- metric onset. Levodopa is the primary treatment for Parkinson's disease; however, its long-term use is limited by motor complications and drug-induced dyskinesia. Dopamine agonists are options for initial

SHOBHA S. RAO; LAURA A. HOFMANN; AMER SHAKIL

2006-01-01

28

Drug-induced tremor  

MedlinePLUS

... Cigarette smoking Hyperthyroidism Parkinson's disease Pheochromocytoma Too much caffeine Wilson's disease Blood tests and imaging studies (such as a CT scan of the head, brain MRI , and x-rays) are usually normal.

29

Castration Induces Parkinson Disease Pathologies in Young Male Mice via Inducible Nitric-oxide Synthase*  

PubMed Central

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

2013-01-01

30

Drug-induced pulmonary disease  

MedlinePLUS

Drug-induced pulmonary disease is lung disease brought on by a bad reaction to a medicine. ... Maldonado F, Limper AH. Drug-induced pulmonary disease. In: Mason RJ, ... of Respiratory Medicine . 5th ed. Philadelphia, PA: Elsevier ...

31

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

PubMed Central

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 age alone or by age and scores for confounders (comorbidity and indicators of NSAID use). Up to five controls were matched to each of 616 cases by age and 565 cases by age and confounder scores. Setting United States. Main outcome measures Odds of having been exposed to prior non-aspirin NSAID or aspirin use by participants with Parkinson’s disease and by their controls in each case-control set. Results Participants who had ever used non-aspirin NSAIDs had an increased risk of Parkinson’s disease (odds ratio 1.28 (95% CI 1.05 to 1.56) in the age matched group but not in the group also matched on confounder scores (odds ratio 1.17 (0.94 to 1.46)). There was an increased risk of Parkinson’s disease in men who had 1–2 years of regular non-aspirin NSAID use (odds ratio 1.35 (1.07 to 1.70)), a finding that remained significant after matching for confounder scores as well (odds ratio 1.35 (1.05 to 1.75)). In contrast, the significant association of use of non-aspirin NSAIDs for ?5 years (odds ratio 1.48 (1.05 to 2.09)) in the age matched group was entirely attenuated in the group also matched on confounder scores (1.03 (0.70 to 1.53)). There was also a suggestion that men who regularly used aspirin had an increased risk of Parkinson’s disease. Positive associations between non-aspirin NSAID or aspirin and risk of Parkinson’s disease tended to disappear when analyses were limited to drug use ?5 years before the disease diagnosis. Conclusions This case-control study did not find evidence that NSAID use reduces Parkinson’s disease risk. The positive associations observed between NSAID use and Parkinson’s disease might have been due to confounding by indication as the use was clustered in the few years before disease diagnosis. PMID:21252104

2011-01-01

32

Heptachlor induced nigral dopaminergic neuronal loss and Parkinsonism-like movement deficits in mice.  

PubMed

Epidemiological studies have suggested an association between pesticide exposure and Parkinson's disease. In this study, we examined the neurotoxicity of an organochlorine pesticide, heptachlor, in vitro and in vivo. In cultured SH-SY5Y cells, heptachlor induced mitochondria-mediated apoptosis. When injected into mice intraperitoneally on a subchronic schedule, heptachlor induced selective loss of dopaminergic neurons in the substantia nigra pars compacta. In addition, the heptachlor injection induced gliosis of microglia and astrocytes selectively in the ventral midbrain area. When the general locomotor activities were monitored by open field test, the heptachlor injection did not induce any gross motor dysfunction. However, the compound induced Parkinsonism-like movement deficits when assessed by a gait and a pole test. These results suggest that heptachlor can induce Parkinson's disease-related neurotoxicities in vivo. PMID:24577234

Hong, Seokheon; Hwang, Joohyun; Kim, Joo Yeon; Shin, Ki Soon; Kang, Shin Jung

2014-01-01

33

Human alkaloid biosynthesis : chemical inducers of Parkinson's disease?  

E-print Network

The occurrence of certain alkaloids in the human brain appears to be associated with the onset of Parkinson's disease (PD). Recently, a human protein bearing homology to an alkaloid synthase in plants was identified. This ...

Hatzios, Stavroula K. (Stavroula-Artemis K.)

2005-01-01

34

The path from anti Parkinson drug selegiline and rasagiline to multifunctional neuroprotective anti Alzheimer drugs ladostigil and m30.  

PubMed

The therapeutic use of enzyme inhibitors in treatment of neurodegenerative diseases has its origin in the anti Parkinson action of the selective monoamine oxidase (MAO) B inhibitor, l-deprenyl (selegiline ), a failed anti depressant in 1975. This led to further development of MAO- A and B, catechol-O-methyltansferase and cholinestrerase inhibitors as anti Parkinson and Alzheimer drugs. One of the main reasons for the cognitive deficit in dementia of the Alzheimer' type (AD) and in dementia with Lewy bodies (DLB) is degeneration of cholinergic cortical neurones and synaptic plasticity. This led to a correlation that similar to Parkinson's Disease (PD), cholinesterase inhibitors (ChEI) may also have therapeutic activity in AD. Significant percentage of AD and DLB subjects also nigrostriatal dopaminergic, locus ceruleous noradrenergic and raphe nucleus serotoninergic neurones. The present ChEI anti AD drugs have limited symptomatic activity and devoid of neuroprotective property that is needed for disease modifying action. It is becoming clear that there are no magic bullets for neurodegenerative disorders and shut gun approach is needed either as polypharmacology or drugs with multiple activity at different target sites in the CNS. The complex pathology of AD as well as cascade of events that leads to the neurodegenerative process has led us to develop several multifunctional neuroprotective drugs with several CNS targets with possible disease modifying activity. Employing the pharamcophore of our antiparkinson drug rasagiline (Azilect, Agilect, N-propagrgyl-1R-aminoindan) we have developed a novel multifunctional neuroprotective drug, ladostigil [TV-3326 (N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate)], with both cholinesterase-butyrylesterase (Ch-BuE) and brain selective monoamine-oxidase (MAO) AB inhibitory activities possessing the neuroprotective-neurescue propargyl moiety, as potential treatment of AD and DLB and PD with dementias. Since brain MAO and iron increase in AD, PD and ageing, that could lead to iron dependent oxidative stress neurodegeneration, we have developed another series of multifunctional drugs (M30 HLA-20 series) which are brain permeable iron chelators- brain selective MAO inhibitors and possess the propargyl neuroprotective moiety. These series of drugs have the ability of regulating and processing APP (amyloid precursor protein) and reducing Abeta peptide, since APP is a metaloprotein, with an iron responsive element 5d'UTR similar to transferring and ferritin. PMID:17168653

Youdim, Moussa B H

2006-12-01

35

Does Dopamine Still Have a Leading Role in Advanced Parkinson’s Disease after Subthalamic Stimulation?  

Microsoft Academic Search

The role of endogenous dopamine in severe Parkinson’s disease is often underestimated. We report on a case of acute general motor worsening induced by the ingestion of fluphenazine in a parkinsonian patient successfully treated with STN DBS. Other etiologies were ruled out. Clinical improvement was gradual and fully reversible 4 days after discontinuation of the antidopaminergic drug. We suggest that

Mazen Jabre; George Nohra; Philippe Damier; Boulos-Paul Bejjani

2008-01-01

36

Drug-induced hepatic steatosis.  

PubMed

Several drugs have been associated with the potential for drug-induced hepatic steatosis (DIHS) and/or phospholipidosis (DIPL), a lysosomal storage disorder. Drug-induced hepatic steatosis is generally a chronic but reversible affliction and may involve drug accumulation in the liver. Fat accumulation may be either macrovesicular or microvesicular in nature. Commonly used medications associated with DIHS include amiodarone, valproate, tamoxifen, methotrexate, and some chemotherapeutic and antiretroviral agents. Two recently approved medications for the treatment of hereditary homozygous hypercholesterolemia have also been noted to cause hepatic steatosis. For some compounds such as methotrexate and tamoxifen, the underlying metabolic risk factors such as obesity and metabolic syndrome may exacerbate their potential to cause DIHS and its progression. In this article, the authors discuss the preclinical screening and mechanisms of DIHS and DIPL, and review specific examples of drugs commonly used in clinical practice that are known to cause DIHS. PMID:24879984

Amacher, David E; Chalasani, Naga

2014-05-01

37

A novel therapeutic approach to 6-OHDA-induced Parkinson’s disease in rats via supplementation of PTD-conjugated tyrosine hydroxylase  

Microsoft Academic Search

The present study aimed to evaluate whether the protein transduction domain (PTD)-conjugated human tyrosine hydroxylase (TH) fusion protein was effective on the 6-hydroxydopamine (6-OHDA)-induced Parkinson’s disease (PD) model rats. An expression vector pET-PTD-TH harbouring the PTD-TH gene was constructed and transformed to the Escherichia coli BL21 cells for expression. The expressed recombinant PTD-TH with a molecular weight of 61kD was

Shao Ping Wu; Ai Ling Fu; Yu Xia Wang; Lei Ping Yu; Pei Yuan Jia; Qian Li; Guo Zhang Jin; Man Ji Sun

2006-01-01

38

Drug-Induced Blood Dyscrasias  

PubMed Central

Categories of undesirable effects of drugs are described. Recent experiments on the production of hypersensitization (1) by the use of ECT solution to enhance skin sensitization to penicillin, (2) through the activity of common metabolites of different drugs, and (3) to a non-sensitizing drug by pretreatment with a sensitizing agent are reviewed. The mechanism of hemolytic anemia due to an inherited enzymatic defect and that of drug-induced purpura and the agranulocytic agents is discussed. The three groups of drugs—(1) rarely toxic, e.g. quinine; (2) always toxic in sufficient amounts, e.g. nitrogen mustard; (3) intermediate, e.g. chloramphenicol—are presented, with special consideration of chloramphenicol. It is the responsibility of the pharmacologist to develop and adopt newer methods for toxicity detection, and of the clinician to practise caution in prescribing drugs and to attempt the early recognition of any disorder they may induce. The incidence, diagnosis, prevention, treatment and prognosis of the drug-induced dyscrasias are discussed. PMID:14005657

Weil, Paul G.

1962-01-01

39

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

PubMed Central

Small molecules that increase the presynaptic function of aminergic cells may provide neuroprotection in Parkinson’s disease 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 Parkinson’s disease, 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. PMID:23229049

Lawal, Hakeem O.; Terrell, Ashley; Lam, Hoa A.; Djapri, Christine; Jang, Jennifer; Hadi, Richard; Roberts, Logan; Shahi, Varun; Chou, Man-Ting; Biedermann, Traci; Huang, Brian; Lawless, George M.; Maidment, Nigel T.; Krantz, David E.

2012-01-01

40

Lentiviral Overexpression of GRK6 Alleviates L-Dopa-Induced Dyskinesia in Experimental Parkinson's Disease  

PubMed Central

Parkinson’s disease is caused primarily by degeneration of brain dopaminergic neurons in the substantia nigra and the consequent deficit of dopamine in the striatum. Dopamine replacement therapy with the dopamine precursor L-dopa is the mainstay of current treatment. After several years, however, the patients develop L-dopa–induced dyskinesia, or abnormal involuntary movements, thought to be due to excessive signaling via dopamine receptors. G protein–coupled receptor kinases (GRKs) control desensitization of dopamine receptors. We found that dyskinesia is attenuated by lentivirus-mediated overexpression of GRK6 in the striatum in rodent and primate models of Parkinson’s disease. Conversely, reduction of GRK6 concentration by microRNA delivered with lentiviral vector exacerbated dyskinesia in parkinsonian rats. GRK6 suppressed dyskinesia in monkeys without compromising the anti-parkinsonian effects of L-dopa and even prolonged the antiparkinsonian effect of a lower dose of L-dopa. Our finding that increased availability of GRK6 ameliorates dyskinesia and increases duration of the antiparkinsonian action of L-dopa suggests a promising approach for controlling both dyskinesia and motor fluctuations in Parkinson’s disease. PMID:20410529

Ahmed, Mohamed R.; Berthet, Amandine; Bychkov, Evgeny; Porras, Gregory; Li, Qin; Bioulac, Bernard H.; Carl, Yonatan T.; Bloch, Bertrand; Kook, Seunghyi; Aubert, Incarnation; Dovero, Sandra; Doudnikoff, Evelyne; Gurevich, Vsevolod V.; Gurevich, Eugenia V.; Bezard, Erwan

2010-01-01

41

Drug-induced Liver Injury  

PubMed Central

Drug-induced liver injury (DILI) is common and nearly all classes of medications can cause liver disease. Most cases of DILI are benign, and improve after drug withdrawal. It is important to recognize and remove the offending agent as quickly as possible to prevent the progression to chronic liver disease and/or acute liver failure. There are no definite risk factors for DILI, but pre-existing liver disease and genetic susceptibility may predispose certain individuals. Although most patients have clinical symptoms that are identical to other liver diseases, some patients may present with symptoms of systemic hypersensitivity. Treatment of drug and herbal-induced liver injury consists of rapid drug discontinuation and supportive care targeted to alleviate unwanted symptoms. PMID:21874146

David, Stefan; Hamilton, James P

2011-01-01

42

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. PMID:23125942

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

2012-01-01

43

Asiaticoside, a trisaccaride triterpene induces biochemical and molecular variations in brain of mice with parkinsonism  

PubMed Central

Background Parkinson’s disease characterized by oxidative stress and mitochondrial damage in the pars compacta of substantia nigra remains a challenge to manage with an added disadvantage of side effects of L-levo dopa, the standard drug used for therapy. Thus, an alternative approach of utilizing natural components would be beneficial in the management of the disease. The present study was aimed to investigate the potential role of asiaticoside (As), a trisaccaride triterpene against1 – methyl 4 – phenyl 1,2,3,6 tetrahydropyridine (MPTP)-induced neurotoxicity in experimental mice. Methods Mice were divided into 4 groups: Group I received vehicle saline, group II was treated with 20 mg/kg of body weight of MPTP (2 doses with 2 h intervals), group III received MPTP along with 50 mg/kg body weight of As for the 21 consecutive days starting from the day of MPTP intoxication. Group IV received 50 mg/kg body weight of asiaticoside for the same period serving as drug control. Animals were sacrificed at the end of experimental period and the striatum and midbrain samples were analyzed for enzyme assays, transmission electron microscopic (TEM) analysis. Immunofluorescent assay was performed to study the expression of GFAP to detect astrocyte, which are activated due to neuronal damage. Imunohistochemical studies were carried out to quantify the expression of Bax and Bcl2, the molecular signatures that would provide clues of the extent of neurodegeneration. Results The activities of enzymes were increased on As administration when compared with those of group II animals. Expressions of Bax and Bcl2 along with GFAP did show significant variations (p?drug control IV) did not show significant variation from that of the control mice. Conclusion The observations suggest that asiaticoside may be efficacious in protecting neurons from the oxidative damage caused by the insult of MPTP. PMID:24262283

2013-01-01

44

Oxidative stress-induced signaling pathways implicated in the pathogenesis of Parkinson's disease.  

PubMed

Parkinson's disease is the second most common neurodegenerative movement disorder; however, its etiology remains elusive. Nevertheless, in vivo observations have concluded that oxidative stress is one of the most common causes in the pathogenesis of Parkinson's disease. It is known that mitochondria play a crucial role in reactive oxygen species-mediated pathways, and several gene products that associate with mitochondrial function are the subject of Parkinson's disease research. The PTEN-induced kinase 1 (PINK1) protects cells from mitochondrial dysfunction and is linked to the autosomal recessive familial form of the disease. PINK1 is a key player in many signaling pathways engaged in mitophagy, apoptosis, or microglial inflammatory response and is induced by oxidative stress. Several proteins participate in mitochondrial networks, and they are associated with PINK1. The E3 ubiquitin ligase Parkin, the protease presenilin-associated rhomboid-like serine protease, the tyrosine kinase c-Abl, the protein kinase MARK2, the protease HtrA2, and the tumor necrosis factor receptor-associated protein 1 (TRAP1) provide different steps of control in protection against oxidative stress. Furthermore, environmental toxins, such as 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, have been identified as contributors to parkinsonism by increasing oxidative stress in dopaminergic neurons. The present review discusses the mechanisms and effects of oxidative stress, the emerging concept of the impact of environmental toxins, and a possible neuroprotective role of the antioxidant astaxanthin in various neurodegenerative disorders with particular emphasis in Parkinson's disease. PMID:24522549

Gaki, Georgia S; Papavassiliou, Athanasios G

2014-06-01

45

Drug-induced ocular disorders.  

PubMed

While beneficial therapeutically, almost all medications have untoward effects on various body tissues and functions, including the eye in which organ toxic reactions are readily detectable. Every part of the eye and all ocular functions could be affected adversely. In this review, we describe the most commonly recognized drug-induced ocular disorders, their specific clinical features, the medications that can cause the problem, the differential diagnosis and possible mechanisms of action, as well as guidelines for the management of the adverse reactions. The eyelids are most frequently involved in drug toxicity that commonly manifests as inflammation, hypersensitivity reaction or dermatitis. Drug-induced keratoconjunctival disorders present mainly as conjunctival hyperaemia (red eye), with or without superficial corneal involvement. Frequently, drug preservatives in topical ocular medications induce these adverse effects. Treatment of blepharospasm with Botox may lead to drooping of the eyelids and corneal exposure. Intraoperative floppy iris syndrome is a drug-induced reaction in patients treated with tamsulosin and who undergo cataract surgery. Certain sulfa-based drugs can cause swelling of the ciliary body and lead to the development of angle-closure glaucoma. In addition, adrenergic agents, certain beta(2)-adrenergic agonists and anticholinergic agents may induce pupillary dilation and precipitate angle-closure glaucoma in susceptible patients. Glucocorticoids administered systemically, topically or intravitreally are known to increase intraocular pressure, which can lead to the development of open-angle glaucoma in susceptible patients. This painless form of glaucoma has also been associated with the use of the anticancer agents docetaxel and paclitaxel. The toxic effects of systemic and topically applied drugs may manifest as cloudiness of the lens. Long-term use of glucocorticoids produces a characteristic posterior subcapsular cataract and, although the opacities may remain stationary or progress, they rarely regress upon drug withdrawal. Systemic administration of phenothiazines or busulfan induce cataractous changes in the anterior or posterior cortex, respectively. Many systemic drugs reach the retina through the vascular supply. Aminoquinolines induce a characteristic bull's eye maculopathy. Phenothiazines bind to melanin granules and can cause a severe phototoxic retinopathy. Typical tamoxifen retinopathy manifests as crystalline deposits in the inner retina. Some patients treated with retinoids have decreased night vision and abnormal dark-adaptation. Patients on long-term treatment with linezolid may develop an optic neuropathy (swollen or pale optic disc), symmetric painless decrease of visual acuity and colour vision, and bilateral visual field defects. A probable link exists between amiodarone and a bilateral optic neuropathy that is very similar to nonarteritic ischaemic optic neuropathy (NAION). The most common adverse effects of cGMP-specific phosphodiesterase type 5 inhibitors (erectile dysfunction drugs) are changes in colour perception, blurry vision and increased light sensitivity; recently these drugs have been also implicated in the development of NAION. A bilateral, retrobulbar optic neuropathy that manifests as loss of visual acuity or colour vision and visual field defect is associated with the use of ethambutol. Many different kinds of medications can cause similar ocular adverse reactions. Conversely, a single medication may affect more than one ocular structure and cause multiple, clinically recognizable disorders. Clinicians should be mindful of drug-induced ocular disorders, whether or not listed in product package inserts, and, if in doubt, consult with an ophthalmologist. PMID:18217789

Li, Junping; Tripathi, Ramesh C; Tripathi, Brenda J

2008-01-01

46

Drug-induced visceral angioedema  

PubMed Central

Angioedema associated with angiotensin converting enzyme inhibitors (ACEIs) is due to the accumulation of bradykinin and its metabolites. Angiotensin receptor blockers (ARBs) produce anti-hypertensive effects by blocking the angiotensin II AT1 receptor action; hence bradykinin-related side effects are not expected. However, we notice the occurrence of ARB-induced angioedema as not a very rare side effect. Visceral drug-induced angioedema has been reported with ACEIs, not with ARBs. This underlying review will help educate readers on the pathophysiology and recent guidelines pertaining to ACEI- and ARB-induced visceral angioedema. PMID:25317271

Thalanayar, Prashanth M.; Ghobrial, Ibrahim; Lubin, Fritz; Karnik, Reena; Bhasin, Robin

2014-01-01

47

On the discovery and development of pimavanserin: a novel drug candidate for Parkinson's psychosis.  

PubMed

Parkinson's disease psychosis (PDP) is a condition that may develop in up to 60 % of Parkinson's patients, and is a major reason for nursing home placement for those affected. There are no FDA approved drugs for PDP but low doses of atypical anti-psychotic drugs (APDs) are commonly prescribed off-label. Only low-dose clozapine has shown efficacy in randomized controlled trials, but all APDs have black box warnings related to the increased mortality and morbidity when used in elderly demented patients. Using molecular pharmacological profiling of a large collection of marketed drugs, we discovered that potent inverse agonist activity against 5-HT2A serotonin receptors was a common feature of atypical APDs, especially the atypical APDs used to treat PDP. Since low-dose clozapine therapy selectively blocks this receptor, it was hypothesized that a highly selective 5-HT2A receptor inverse agonist might provide good symptom control in patients suffering from PDP, with a greatly improved safety and tolerability profile. A high throughput screening and subsequent chemical lead optimization campaign to develop potent, selective 5-HT2A receptor inverse agonists was launched, eventually resulting in the discovery of pimavanserin. Pimavanserin displays nanomolar potency as a 5-HT2A receptor inverse agonist, selectivity for 5-HT2A over 5-HT2C receptors, and no meaningful activity at any other G-protein coupled receptor. It demonstrated robust activity in preclinical models of schizophrenia and PDP, and did not worsen motoric symptoms, in contrast to the APDs tested. In a Phase III clinical trial, pimavanserin showed highly significant benefits in the primary endpoint, the scale for assessment of positive symptoms-PD, a scale adapted for use in PDP. In addition, improvements in all other efficacy endpoints, including physician's clinical global impression, caregiver burden, night-time sleep quality and daytime wakefulness, were seen. Pimavanserin demonstrated good safety and tolerability and did not worsen motoric symptoms as assessed by the unified Parkinson's disease rating scale parts II and III. An open-label extension study has further demonstrated that pimavanserin is safe and well-tolerated with long-term use. Pimavanserin may therefore offer a viable treatment option for patients suffering from PDP. PMID:24682754

Hacksell, Uli; Burstein, Ethan S; McFarland, Krista; Mills, Roger G; Williams, Hilde

2014-10-01

48

Generalized mathematical-computational-electronic model of MPTP- induced Parkinsonism  

NASA Astrophysics Data System (ADS)

The substance 1-methyl-4-phenyl-1, 2, 3, 6 tetrahy dropyridine (MPTP) has been studied as a major cause of neurodegeneration dopaminica, which is specifically related to Parkinson's disease. The analysis is in terms of the diffusion of the substance to the mammalian brain, by evaluating the diffusion equation in a spherical coordinate system, being ? (collective diffusion term) spatially modulated. Although the progress of the disease with respect to time has not been established with certainty, an attempt to find a stable pattern of the concentration of MPTP and its effects has been made.

Jaramillo Raquejo, Daniela

2013-05-01

49

Drug-induced lupus erythematosus.  

PubMed

Drug-induced lupus erythematosus (DI-LE) is defined as an entity characterized by clinical manifestations and immunopathological serum findings similar to those of idiopathic lupus but which is temporally related to drug exposure and resolves after withdrawal of the implicated drug. Similarly to idiopathic lupus, DI-LE can be divided into systemic LE, subacute cutaneous LE (SCLE), chronic cutaneous LE (CCLE) and cutaneous LE tumidus. DI-SCLE is the most frequent variant of drug-induced cutaneous LE and presents mainly with annular-polycyclic lesions; the clinical picture is often widespread, with involvement of the lower legs that are usually spared in idiopathic SCLE. ANA and anti-Ro/SSA antibodies are typically present, whereas antihistone antibodies are uncommonly found. We have recently addressed the question whether DI-SCLE differs significantly from its idiopathic counterpart by virtue of clinical features and, based on our findings, we have suggested that the frequent occurrence of malar rash and bullous, erythema multiforme-like and vasculitic manifestations can be regarded as the hallmark of DI-SCLE. In contrast, the histology is not a useful diagnostic criterion for DI-SCLE, considering that the typical pattern of lichenoid interface dermatitis is seen only in the early stage of disease and tissue eosinophilia does not represent a differentiating histopathological feature. DI-CCLE and DI-LE tumidus, albeit possibly misdiagnosed, are rarely observed and are characterized by classic discoid lesions and erythematous-oedematous plaques on sun exposed areas, respectively. Management of DI-LE is based on the discontinuation of the offending drug; topical and/or systemic corticosteroids and other immunomodulating/immunosuppressive agents should be reserved for resistant cases. PMID:24819757

Marzano, A V; Tavecchio, S; Menicanti, C; Crosti, C

2014-06-01

50

Pharmacological strategies for the management of levodopa-induced dyskinesia in patients with Parkinson's disease.  

PubMed

L-Dopa-induced dyskinesias (LID) are the most common adverse effects of long-term dopaminergic therapy in Parkinson's disease (PD). However, the exact mechanisms underlying dyskinesia are still unclear. For a long time, nigrostriatal degeneration and pulsatile stimulation of striatal postsynaptic receptors have been highlighted as the key factors for the development of LID. In recent years, PD models have revealed a wide range of non-dopaminergic neurotransmitter systems involved in pre- and postsynaptic changes and thereby contributing to the pathophysiology of LID. In the current review, we focus on therapeutic LID targets, mainly based on agents acting on dopaminergic, glutamatergic, serotoninergic, adrenergic, and cholinergic systems. Despite a large number of clinical trials, currently only amantadine and, to a lesser extent, clozapine are being used as effective strategies in the treatment of LID in clinical settings. Thus, in the second part of the article, we review the placebo-controlled trials on LID treatment in order to disentangle the changing scenario of drug development. Promising results include the extension of L-dopa action without inducing LID of the novel monoamine oxidase B- and glutamate-release inhibitor safinamide; however, this had no obvious effect on existing LID. Others, like the metabotropic glutamate-receptor antagonist AFQ056, showed promising results in some of the studies; however, confirmation is still lacking. Thus, to date, strategies of continuous dopaminergic stimulation seem the most promising to prevent or ameliorate LID. The success of future therapeutic strategies once moderate to severe LID occur will depend on the translation from preclinical experimental models into clinical practice in a bidirectional process. PMID:25342080

Schaeffer, Eva; Pilotto, Andrea; Berg, Daniela

2014-12-01

51

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.

2010-02-15

52

Willingness to pay for a new drug delivery in Parkinson patients  

PubMed Central

Objective The Swedish reimbursement system operates a system where prices are set based on the expected value to the consumer. This value can be measured using willingness to pay (WTP). Aim To assess Parkinson’s disease (PD) patients’ WTP for newly developed microtablets of levodopa in combination with a drug-delivering electronic device (M/E) compared to standard treatment with levodopa in combination with the COMT (catechol-O-methyl transferase)-inhibitor entacapone (L/e). Method A total of 2,000 randomly included PD patients had a postal questionnaire covering demographics, disease-specific issues, views on medication and WTP in different hypothetical scenarios. The first scenario was M/E with no change in effects or side effects; the second scenario was M/E with same effect and less side effects; and the third scenario was M/E with improved effect and less side effects. These scenarios were coupled to different costs to choose from. Results A total of 999 patients (50%) responded, mean age of 71 years and a mean PD duration of 9 years. Of all respondents, 50% preferred M/E before L/e in scenario one with increasing preference to scenario three. The average monthly WTP among all respondents in scenario one was SEK 230 and SEK 226 in L/e, both with an almost longitudinal doubling up to scenario three. Duration of PD-related symptoms, high education, and high medication intake implied a higher WTP in all scenarios in contrast to age, sex, and extra doses of levodopa. Conclusion WTP for M/E increased gradually with high medication intake and education as well as with expected increased reduction of PD symptoms. PMID:25336962

Lokk, Johan; Olofsson, Sara; Persson, Ulf

2014-01-01

53

Clinical pharmacokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson's disease.  

PubMed

Current research in Parkinson's disease (PD) focuses on symptomatic therapy and neuroprotective interventions. Drugs that have been used for symptomatic therapy are levodopa, usually combined with a peripheral decarboxylase inhibitor, synthetic dopamine receptor agonists, centrally-acting antimuscarinic drugs, amantadine, monoamine oxidase-B (MAO-B) inhibitors and catechol-O-methyltransferase (COMT) inhibitors. Drugs for which there is at least some evidence for neuroprotective effect are certain dopamine agonists, amantadine and MAO-B inhibitors (selegiline). Levodopa remains the most effective drug for the treatment of PD. Several factors contribute to the complex clinical pharmacokinetics of levodopa: erratic absorption, short half-life, peripheral O-methylation and facilitated transport across the blood-brain barrier. In patients with response fluctuations to levodopa, the concentration-effect curve becomes steeper and shifts to the right compared with patients with stable response. Pharmacokinetic-pharmacodynamic modelling can affect decisions regarding therapeutic strategies. The dopamine agonists include ergot derivatives (bromocriptine, pergolide, lisuride and cabergoline), non-ergoline derivatives (pramipexole, ropinirole and piribedil) and apomorphine. Most dopamine agonists have their specific pharmacological profile. They are used in monotherapy and as an adjunct to levodopa in early and advanced PD. Few pharmacokinetic and pharmacodynamic data are available regarding centrally acting antimuscarinic drugs. They are characterised by rapid absorption after oral intake, large volume of distribution and low clearance relative to hepatic blood flow, with extensive metabolism. The mechanism of action of amantadine remains elusive. It is well absorbed and widely distributed. Since elimination is primarily by renal clearance, accumulation of the drug can occur in patients with renal dysfunction and dosage reduction must be envisaged. The COMT inhibitors entacapone and tolcapone dose-dependently inhibit the formation of the major metabolite of levodopa, 3-O-methyldopa, and improve the bioavailability and reduce the clearance of levodopa without significantly affecting its absorption. They are useful adjuncts to levodopa in patients with end-of-dose fluctuations. The MAO-B inhibitor selegiline may have a dual effect: reducing the catabolism of dopamine and limiting the formation of neurotoxic free radicals. The pharmacokinetics of selegiline are highly variable; it has low bioavailability and large volume of distribution. The oral clearance is many-fold higher than the hepatic blood flow and the drug is extensively metabolised into several metabolites, some of them being active. Despite the introduction of several new drugs to the antiparkinsonian armamentarium, no single best treatment exists for an individual patient with PD. Particularly in the advanced stage of the disease, treatment should be individually tailored. PMID:11978145

Deleu, Dirk; Northway, Margaret G; Hanssens, Yolande

2002-01-01

54

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

PubMed

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

2006-10-10

55

Differential Dopamine Receptor Occupancy Underlies L-DOPA-Induced Dyskinesia in a Rat Model of Parkinson's Disease  

PubMed Central

Dyskinesia is a major side effect of an otherwise effective L-DOPA treatment in Parkinson's patients. The prevailing view for the underlying presynaptic mechanism of L-DOPA-induced dyskinesia (LID) suggests that surges in dopamine (DA) via uncontrolled release from serotonergic terminals results in abnormally high level of extracellular striatal dopamine. Here we used high-sensitivity online microdialysis and PET imaging techniques to directly investigate DA release properties from serotonergic terminals both in the parkinsonian striatum and after neuronal transplantation in 6-OHDA lesioned rats. Although L-DOPA administration resulted in a drift in extracellular DA levels, we found no evidence for abnormally high striatal DA release from serotonin neurons. The extracellular concentration of DA remained at or below levels detected in the intact striatum. Instead, our results showed that an inefficient release pool of DA associated with low D2 receptor binding remained unchanged. Taken together, these findings suggest that differential DA receptor activation rather than excessive release could be the underlying mechanism explaining LID seen in this model. Our data have important implications for development of drugs targeting the serotonergic system to reduce DA release to manage dyskinesia in patients with Parkinson's disease. PMID:24614598

Sahin, Gurdal; Thompson, Lachlan H.; Lavisse, Sonia; Ozgur, Merve; Rbah-Vidal, Latifa; Dolle, Frederic

2014-01-01

56

Drug-induced peripheral neuropathy.  

PubMed

Peripheral neuropathy can be caused by medication, and various descriptions have been applied for this condition. In this MiniReview, the term 'drug-induced peripheral neuropathy' (DIPN) is used with the suggested definition: Damage to nerves of the peripheral nervous system caused by a chemical substance used in the treatment, cure, prevention or diagnosis of a disease. Optic neuropathy is included in this definition. A distinction between DIPN and other aetiologies of peripheral neuropathy is often quite difficult and thus, the aim of this MiniReview is to discuss the major agents associated with DIPN. PMID:24786912

Vilholm, Ole Jakob; Christensen, Alex Alban; Zedan, Ahmed Hussein; Itani, Mustapha

2014-08-01

57

Drugs developed for treatment of diabetes show protective effects in Alzheimer's and Parkinson's diseases.  

PubMed

Type 2 diabetes has been identified as a risk factor for Alzheimer's disease (AD) and Parkinson's disease (PD). In the brains of patients with AD and PD, insulin signaling is impaired. This finding has motivated new research that showed good effects using drugs that initially had been developed to treat diabetes. Preclinical studies showed good neuroprotective effects applying insulin or long lasting analogues of incretin peptides. In transgenic animal models of AD or PD, analogues of the incretin GLP-1 prevented neurodegenerative processes and improved neuronal and synaptic functionality and reduced the symptoms of the diseases. Amyloid plaque load and synaptic loss as well as cognitive impairment had been prevented in transgenic AD mouse models, and dopaminergic loss of transmission and motor function has been reversed in animal models of PD. On the basis of these promising findings, several clinical trials are being conducted with the first encouraging clinical results already published. In several pilot studies in AD patients, the nasal application of insulin showed encouraging effects on cognition and biomarkers. A pilot study in PD patients testing a GLP-1 receptor agonist that is currently on the market as a treatment for type 2 diabetes (exendin-4, Byetta) also showed encouraging effects. Several other clinical trials are currently ongoing in AD patients, testing another GLP-1 analogue that is on the market (liraglutide, Victoza). Recently, a third GLP-1 receptor agonist has been brought to the market in Europe (Lixisenatide, Lyxumia), which also shows very promising neuroprotective effects. This review will summarise the range of these protective effects that those drugs have demonstrated. GLP-1 analogues show promise in providing novel treatments that may be protective or even regenerative in AD and PD, something that no current drug does. PMID:25331995

Hölscher, Christian

2014-10-25

58

Nicotine reduces established L-dopa-induced dyskinesias in a monkey model of Parkinson's disease  

PubMed Central

Background Although 3,4-dihydroxyphenylalanine (L-dopa) is the gold-standard treatment for Parkinson’s disease, it can lead to disabling dyskinesias. Previous work showed that nicotine reduces L-dopa-induced dyskinesias (LIDs) in several parkinsonian animal models. The goal of this study was to determine if the time of nicotine administration affected its ability to reduce LIDs in L-dopa-primed and L-dopa naďve monkeys, and also to test if tolerance developed to nicotine’s beneficial effects. Methods Monkeys were injected with MPTP (1.9–2.0 mg/kg sc) over 3–5 months until parkinsonian. Nicotine (300 ?g/ml) was administered in drinking water (4–6 months) to L-dopa-primed or L-dopa-naďve monkeys, with L-dopa/carbidopa (10/2.5 mg/kg) gavaged twice daily. Results One set of MPTP-lesioned monkeys (n=23) was first gavaged with L-dopa and subsequently given nicotine 4 wk later when dyskinesias have plateaud or 8 wk later when dyskinesias are established. A 60–70% decrease in LIDs was observed after several weeks of nicotine treatment in both groups. A second set of monkeys (n=26) was given nicotine 8 or 2 weeks before L-dopa. In the 8 week nicotine pretreatment group, there was an immediate reduction in LIDs, which plateaud at 60–70%. In the 2 week nicotine pretreatment group, there were initial small decreases in LIDs, which plateaud at 60–70% several weeks later. Thus, nicotine pre- and post-treatment was similarly efficacious in reducing LIDs. The beneficial effect of nicotine persisted throughout the study (17–23 weeks). Nicotine did not worsen parkinsonism. Conclusion These data suggest that nicotine treatment has potential as a successful antidyskinetic therapy for Parkinson’s disease patients. PMID:23836409

Quik, Maryka; Mallela, Archana; Ly, Jason; Zhang, Danhui

2013-01-01

59

Dopamine-induced nonmotor symptoms of Parkinson's disease.  

PubMed

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. PMID:21603184

Park, Ariane; Stacy, Mark

2011-01-01

60

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. PMID:21603184

Park, Ariane; Stacy, Mark

2011-01-01

61

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

2011-01-01

62

A Model of Nitric Oxide Induced ?-Synuclein Misfolding in Parkinson's Disease  

PubMed Central

Inducible nitric oxide synthase (iNOS) upregulation and consequent NO formation are well-recognized neuroinflammatory responses associated with Parkinson’s disease (PD). These contribute to nitrosative protein modifications affecting neuronal injury and cell death. Indeed, a pathobiologic signature for PD is Lewy body formation containing misfolded and aggregated forms of alpha-synuclein (?-syn). Moreover, nitration of ?-syn promotes protein aggregation in disease. To model such pathological events, we constructed controllable iNOS and bicistronic ?-syn-IRES-tTA adeno-associated virus (AAV) expression vectors. Transduction of iNOS and ?-syn AAV constructs led to nitration of ?-syn in neurons and overexpression of iNOS promoted protein aggregation. We posit that this AAV system mimics critical protein misfolding events associated with the pathogenesis of PD. PMID:22776646

Stone, David K.; Kiyota, Tomomi; Mosley, R. Lee; Gendelman, Howard E.

2012-01-01

63

Manganese-Induced Parkinsonism due to Ephedrone Abuse  

PubMed Central

During recent years, a syndrome of hypokinesia, dysarthria, dystonia, and postural impairment, related to intravenous use of a “designer” psychostimulant derived from pseudoephedrine using potassium permanganate as the oxidant, has been observed in drug addicts in several countries in Eastern Europe with some cases also in Western countries. A levodopa unresponsive Parkinsonian syndrome occurs within a few months of abusing the homemade drug mixture containing ephedrone (methcathinone) and manganese. The development of this neurological syndrome has been attributed to toxic effects of manganese, but the role of the psychostimulant ephedrone is unclear. This paper describes the clinical syndrome, results of neuroimaging, and therapeutic attempts. PMID:21403909

Sikk, Katrin; Haldre, Sulev; Aquilonius, Sten-Magnus; Taba, Pille

2011-01-01

64

The Parkinson's disease death rate: carbidopa and vitamin B6  

PubMed Central

The only indication for carbidopa and benserazide is the management of L-3,4-dihydroxyphenylalanine (L-dopa)-induced nausea. Both drugs irreversibly bind to and permanently deactivate pyridoxal 5?-phosphate (PLP), the active form of vitamin B6, and PLP-dependent enzymes. PLP is required for the function of over 300 enzymes and proteins. Virtually every major system in the body is impacted directly or indirectly by PLP. The administration of carbidopa and benserazide potentially induces a nutritional catastrophe. During the first 15 years of prescribing L-dopa, a decreasing Parkinson’s disease death rate was observed. Then, in 1976, 1 year after US Food and Drug Administration approved the original L-dopa/carbidopa combination drug, the Parkinson’s disease death rate started increasing. This trend has continued to the present, for 38 years and counting. The previous literature documents this increasing death rate, but no hypothesis has been offered concerning this trend. Carbidopa is postulated to contribute to the increasing Parkinson’s disease death rate and to the classification of Parkinson’s as a progressive neurodegenerative disease. It may contribute to L-dopa tachyphylaxis. PMID:25364278

Hinz, Marty; Stein, Alvin; Cole, Ted

2014-01-01

65

Alterations in Polysomnographic (PSG) profile in drug-na?ve Parkinson's disease  

PubMed Central

Objective: We studied the changes in Polysomnographic (PSG) profile in drug-naďve patients of Parkinson's disease (PD) who underwent evaluation with sleep overnight PSG. Materials and Methods: This prospective study included 30 with newly diagnosed levodopa-naďve patients with PD, fulfilling the UK-PD society brain bank clinical diagnostic criteria (M:F = 25:5; age: 57.2 ± 10.7 years). The disease severity scales and sleep related questionnaires were administered, and then patients were subjected to overnight PSG. Results: The mean duration of illness was 9.7 ± 9.5 months. The mean Hoehn and Yahr stage was 1.8 ± 0.4. The mean Unified Parkinson's Disease Rating Scale (UPDRS) motor score improved from 27.7 ± 9.2 to 17.5 ± 8.9 with sustained usage of levodopa. Nocturnal sleep as assessed by Pittsburgh Sleep Quality Index (PSQI) was impaired in 10 (33.3%) patients (mean PSQI score: 5.1 ± 3.1). Excessive day time somnolence was recorded in three patients with Epworth Sleepiness Scale (ESS) score ? 10 (mean ESS score: 4.0 ± 3.4). PSG analysis revealed that poor sleep efficiency of <85% was present in 86.7% of patients (mean: 68.3 ± 21.3%). The latencies to sleep onset (mean: 49.8 ± 67.0 minutes) and stage 2 sleep (36.5 ± 13.1%) were prolonged while slow wave sleep was shortened. Respiration during sleep was significantly impaired in which 43.3% had impaired apnoea hyperpnoea index (AHI) ?5, mean AHI: 8.3 ± 12.1). Apnoeic episodes were predominantly obstructive (obstructive sleep apnea, OSA index = 2.2 ± 5.1). These patients had periodic leg movement (PLM) disorder (56.7% had PLM index of 5 or more, mean PLMI: 27.53 ± 4 9.05) that resulted in excessive daytime somnolence. Conclusions: To conclude, sleep macro-architecture is altered in frequently and variably in levodopa-naďve patients of PD and the alterations are possibly due to disease process per se.

Joy, Sanju P.; Sinha, Sanjib; Pal, Pramod Kumar; Panda, Samhita; Philip, Mariamma; Taly, Arun B.

2014-01-01

66

Secondary parkinsonism  

MedlinePLUS

Parkinsonism - secondary; Atypical Parkinson disease ... to be less responsive to medical therapy than Parkinson's disease. ... Unlike Parkinson disease, secondary parkinsonism may stabilize or even improve if the underlying cause is treated. Brain problems, such ...

67

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

PubMed

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

2013-09-01

68

Drug-induced Disorders of Teeth  

Microsoft Academic Search

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

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

2005-01-01

69

[Drug induced eosinophilic pleural effusion].  

PubMed

The hypersensitivity reactions induced by drugs, some widely used, like central nervous system medication, can have various presentations. The lung is a frequent target for such events. We present the case of 40-year-old male patient, non-smoker, with infant encephalopaty, seizures since age of 6 with polimorphic crisis (mainly absences), with anticonvulsivant treatment since 2011 (carbamazepine, sodium valproate, levetiracetam), with no respiratory medical history. Current symptoms started two weeks before, with chest pain, dry cough. He received no antibiotics. Chest X-ray and thoracic CT scan (27 June 2013) showed a left pleral effusion. Left exploratory thoracocentesis extracted 20 ml reddish pleural fluid: eosinophilic exsudate (60%) with normal adenosin deaminase. He also presents moderate blood eosinophilia (13.7%-1780/mm3). Pulmonary infarction with secondary pleurisy, thoracic trauma, acute pancreatitis with secondary pleurisy were excluded. No Loeffler transient infiltrates were documented, serology for Toxocara is IgG positive (historical) and not significant for current episode, no symptoms suggestive for toxocarosis (characteristic to young children, patient had no liver enlargement etc.), no hidatidosis or trichinelosis were found. As an exclusion diagnosis, a hypersensitivity reaction to anticonvulsivant medication was considered (mentioned in literature) carbamazepine and sodium valproate (even if medication was taken for a longer time), with blood and pleural eosinophilia. Together with the neurologist, the mentioned drugs were stopped and he was started on lamotrigine 2 tb/day and levetiracetam 1 tb/day, well tolerated, no absences were noticed. Total remission of blood eosinophilia and partial remission of pleural effusion were noticed. Subsequent follow-ups confirm favourable evolution, with healing of pleurisy and normal blood cell count, which are stable at 7 months after changing anticonvulsivant treatment. PMID:25241560

Vasilescu, Raluca

2014-01-01

70

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

2004-01-01

71

Psychotic symptoms in Parkinson’s disease  

Microsoft Academic Search

Psychotic symptoms are common in Parkinson’s disease (PD) and occur in at least 20% of medication-treated patients. Benign visual hallucinations usually appear earlier, while malignant hallucinations, confusional states, delusions, paranoid beliefs, agitation, and delirium become more frequent with disease progression. Virtually all antiparkinsonian drugs may produce psychotic symptoms. Cognitive impairment, increased age, disease duration and severity, depression, and sleep disorders

Spiridon Papapetropoulos; D. C. Mash

2005-01-01

72

Antipsychotic drugs which elicit little or no Parkinsonism bind more loosely than dopamine to brain D2 receptors, yet occupy high levels of these receptors  

Microsoft Academic Search

This review addresses two questions. First, why does clozapine apparently occupy low levels of dopamine D2 receptors in patients, in contrast to all other antipsychotic drugs which occupy 70–80% of brain dopamine D2 receptors? Second, what is the receptor basis of action of antipsychotic drugs which elicit low levels of Parkinsonism? Antipsychotic doses of clozapine occupy between 0% and 50%

P Seeman; T Tallerico

1998-01-01

73

Possible pharmacokinetic and pharmacodynamic factors affecting parkinsonism inducement by cinnarizine and flunarizine  

Microsoft Academic Search

Potentialities of cinnarizine [1-(diphenylmethyl)-4-(3-phenyl-2-propenyl)piperazine, CZ] and its fluorine derivative flunarizine [1-[bis(4-fluorophenyl)-methyl]-4-(3-phenyl-2-propenyl)piperazine, FZ] to induce parkinsonism as an adverse effect were evaluated pharmacokinetically and pharmacodynamically in rats. In multiple-dose experiments, CZ or FZ was given to rats at a daily dose of 20 ?mol\\/kg for 1, 5, 10, 15, and 30 days, and CZ, FZ, and the ring-hydroxylated metabolites of their

Satoru Kariya; Sadao Isozaki; Yasuhiro Masubuchi; Tokuji Suzuki; Shizuo Narimatsu

1995-01-01

74

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. PMID:24167412

Oh, Young J.

2013-01-01

75

MK-801 inhibits L-DOPA-induced abnormal involuntary movements only at doses that worsen parkinsonism  

PubMed Central

Amantadine and dextromethorphan suppress levodopa (L-DOPA)-induced dyskinesia in Parkinson's disease patients and abnormal involuntary movements (AIM) in the 6-hydroxydopamine (6-OHDA) rat model. These medications have been hypothesized to exert their therapeutic effects by a noncompetitive N-methyl-D-aspartate (NMDA) antagonist mechanism, but they also have known serotonin (5-HT) indirect agonist effects that could suppress AIM. This raised the possibility that NMDA antagonists lacking 5-HTergic effects would not have the antidyskinetic action predicted by previous investigators. To test this hypothesis, we investigated MK-801, the most widely-studied NMDA antagonist. We found that chronic low-dose MK-801 (0.1 mg/kg) had no effect on development of AIM or contraversive rotation. In addition, in L-DOPA primed rats, low-dose MK-801 (0.1 mg/kg) had no effect on expression of AIM, contraversive rotation, or sensorimotor function. Conversely, higher doses of MK-801 (0.2–0.3 mg/kg) suppressed expression of AIM. However, as we show for the first time, anti-dyskinetic doses of MK-801 also suppressed L-DOPA-induced contralateral rotation and impaired sensorimotor function, likely due to non-specific interference of MK-801 with L-DOPA-induced behavior. We conclude that noncompetitive NMDA antagonists are unlikely to suppress dyskinesia clinically without worsening parkinsonism. PMID:20079362

Paquette, Melanie A.; Anderson, Akari M.; Lewis, Jason R.; Meshul, Charles K.; Johnson, Steven W.; Berger, S. Paul

2010-01-01

76

Ameliorating Effects of Combined Curcumin and Desferrioxamine on 6-OHDA-Induced Rat Mode of Parkinson's Disease.  

PubMed

The catecholaminergic neurotoxin 6-hydroxydopamine has been widely used to mimic the lesions in dopaminergic neurons to develop Parkinson's disease. The present study was aimed to evaluate the combined treatment with Curcumin and desferrioxamine (DFO) on 6-OHDA- induced neurotoxicity in the striatum of rats. Rat models with 6-OHDA-induced Parkinson's disease were treated with curcumin, DFO, or both and the effect of different treatments on dopamine level was examined. Moreover, the effect of different treatments on the levels of PCC, SOD, and GSH was also assessed to elucidate the underlying mechanisms of the neuroprotective effects of combined treatment of curcumin and DFO. PMID:24989681

Lv, Hua; Liu, Jun; Wang, Li; Zhang, Hong; Yu, Shuqi; Li, Zhiwei; Jiang, Feng; Niu, Yu; Yuan, Jie; Cui, Xiaoli; Wang, Wenxiu

2014-11-01

77

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. PMID:21637303

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

2011-01-01

78

Computational approaches to predicting drug induced toxicity  

E-print Network

for prophylaxis, diagnosis, or therapy". The term “adverse drug event” may be considered to more broadly encompass any injury, including those resulting from overdose, induced upon administration of a drug.11 However, the term “adverse drug reaction” may... require data from certain preclinical in vitro (cell based) and in vivo (in animals) experimental toxicity assays, which must conform to Good Laboratory Practice (GLP), to be submitted for a clinical candidate.7,17 For example, the in vitro assays...

Marchese Robinson, Richard Liam

2013-01-08

79

Drug-induced disorders of teeth.  

PubMed

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

2005-07-01

80

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

1986-01-01

81

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

PubMed

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. 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

2014-02-01

82

Mechanisms of Drug-Induced Nephrotoxicity  

Microsoft Academic Search

Drug-induced nephrotoxicity is a common complication of several medications and diagnostic agents. It is seen in both inpatient\\u000a and outpatient settings with variable presentations ranging from mild, reversible injury to advanced kidney disease. Manifestations\\u000a of drug-induced nephrotoxicity include acid–base abnormalities, electrolyte imbalances, urine sediment abnormalities, proteinuria,\\u000a pyuria, hematuria, and, most commonly, a decline in the glomerular filtration rate. The mechanisms

Thomas D. Nolin; Jonathan Himmelfarb

83

[Drug-induced interstitial lung diseases].  

PubMed

Drug-induced infiltrative lung disease may manifest as variable clinical radiological patterns, including subacute or chronic interstitial pneumonia, pulmonary fibrosis, eosinophilic pneumonia, organising pneumonia, pulmonary edema, or sarcoidosis. A large amount of drugs have been incriminated, including those used in cardiovascular diseases (amiodarone, statins and angiotensin converting enzyme inhibitors), antibiotics (minocycline, nitrofurantoin), most of anticancer drugs (and especially chemotherapy and chest radiation), treatment of rheumatoid arthritis, as well as more recent drugs. A high index of suspicion is therefore required in any patient with infiltrative lung disease and the web-based tool www.pneumotox.com will help to list possible causative drugs. The following steps are necessary: history and timing of drug exposure, clinical and imaging pattern, exclusion of other causes of infiltrative lung disease, improvement following drug discontinuation. Rechallenge, dangerous, is not recommended. PMID:25362778

Bonniaud, Philippe; Georges, Marjolaine; Favrolt, Nicolas; Camus, Philippe

2014-09-01

84

PET Imaging a MPTP-Induced Mouse Model of Parkinson’s Disease Using the Fluoropropyl-Dihydrotetrabenazine Analog [18F]-DTBZ (AV-133)  

PubMed Central

Parkinson’s disease (PD) is characterized by the loss of dopamine-producing neurons in the nigrostriatal system. Numerous researchers in the past have attempted to track the progression of dopaminergic depletion in PD. We applied a quantitative non-invasive PET imaging technique to follow this degeneration process in an MPTP-induced mouse model of PD. The VMAT2 ligand 18F-DTBZ (AV-133) was used as a radioactive tracer in our imaging experiments to monitor the changes of the dopaminergic system. Intraperitoneal administrations of MPTP (a neurotoxin) were delivered to mice at regular intervals to induce lesions consistent with PD. Our results indicate a significant decline in the levels of striatal dopamine and its metabolites (DOPAC and HVA) following MPTP treatment as determined by HPLC method. Images obtained by positron emission tomography revealed uptake of 18F-DTBZ analog in the mouse striatum. However, reduction in radioligand binding was evident in the striatum of MPTP lesioned animals as compared with the control group. Immunohistochemical analysis further confirmed PET imaging results and indicated the progressive loss of dopaminergic neurons in treated animals compared with the control counterparts. In conclusion, our findings suggest that MPTP induced PD in mouse model is appropriate to follow the degeneration of dopaminergic system and that 18F-DTBZ analog is a potentially sensitive radiotracer that can used to diagnose changes associated with PD by PET imaging modality. PMID:22723923

Toomey, James S.; Bhatia, Shilpa; Moon, La'Wanda T.; Orchard, Elysse A.; Tainter, Kerrie H.; Lokitz, Stephen J.; Terry, Tracee; Mathis, J. Michael; Penman, Andrew D.

2012-01-01

85

Drug-induced impulse control disorders: a review.  

PubMed

The essential characteristic of impulse disorders is the failure to resist an impulse, drive or temptation to perform an act that is harmful to the person or to others. Clearly, impulse control disorders can occur without an induction of any drugs, and they may lead to very problematic situations that affect the adjustment of the patient and need to be treated immediately. However, the subject of the present review is impulsivity induced by a variety of drugs. In this context, the most frequently established agents are dopaminergic agonists that may affect the mesolimbic dopaminergic pathway, such as cocaine and methamphetamine. In Parkinson's disease, the triggering effect of levodopa on pounding has been known since the first description of the condition by Friedman. In this paper, we reviewed the role of a variety of psychopharmacological agents, including dopaminergic ones on the occurrence of impulse control disorders, by searching the PubMed database for relevant articles published in the period between 1980 and 2012 August in detail. PMID:24219002

Atmaca, Murad

2014-02-01

86

Olfaction in Three Genetic and Two MPTP-Induced Parkinson's Disease Mouse Models  

PubMed Central

Various genetic or toxin-induced mouse models are frequently used for investigation of early PD pathology. Although olfactory impairment is known to precede motor symptoms by years, it is not known whether it is caused by impairments in the brain, the olfactory epithelium, or both. In this study, we investigated the olfactory function in three genetic Parkinson’s disease (PD) mouse models and mice treated with MPTP intraperitoneally and intranasally. To investigate olfactory function, we performed electro-olfactogram recordings (EOGs) and an olfactory behavior test (cookie-finding test). We show that neither a parkin knockout mouse strain, nor intraperitoneal MPTP treated animals display any olfactory impairment in EOG recordings and the applied behavior test. We also found no difference in the responses of the olfactory epithelium to odorants in a mouse strain over-expressing doubly mutated ?-synuclein, while this mouse strain was not suitable to test olfaction in a cookie-finding test as it displays a mobility impairment. A transgenic mouse expressing mutated ?-synuclein in dopaminergic neurons performed equal to control animals in the cookie-finding test. Further we show that intranasal MPTP application can cause functional damage of the olfactory epithelium. PMID:24204848

Hatt, Hanns; Neuhaus, Eva M.; Lubbert, Hermann

2013-01-01

87

Drug-induced thrombosis: an update.  

PubMed

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

2013-08-01

88

Remission-inducing drugs in rheumatoid arthritis.  

PubMed Central

The administration of certain drugs to patients with established rheumatoid arthritis frequently results in improvement that is slow to appear but persists for long periods, even after the drug is discontinued. The three main drugs with this effect, whose efficacy and toxicity are reviewed in this paper, are gold salts, D-penicillamine and chloroquine. The cytotoxic agents used to treat rheumatoid arthritis, which likely have nonspecific anti-inflammatory actions and have serious long-term side effects, are also briefly reviewed. A new drug, levamisole, is currently being tested in patients with rheumatoid arthritis. It is suggested that the time for considering the introduction of a remission-inducing drug in patients with progressive rheumatoid arthritis is after an adequate trial of therapy with salicylates or other nonsteroidal anti-inflammatory agents, or both, and before the oral administration of steroids. It is difficult, however, on the basis of rigorous clinical comparisons, to recommend which of the three main remission-inducing drugs should be tried first, although gold salts have been used the most. Patients who have improved with 6 months of chrysotherapy may continue treatment for at least 3 years, during which time the frequency of mucocutaneous and renal toxic effects will steadily decrease. Some aspects of the medical economics of therapy with remission-inducing drugs for rheumatoid arthritis are discussed. PMID:6768438

Anastassiades, T. P.

1980-01-01

89

Tat-Fused Recombinant Human SAG Prevents Dopaminergic Neurodegeneration in a MPTP-Induced Parkinson’s Disease Model  

PubMed Central

Excessive reactive oxygen species (ROS) generated from abnormal cellular process lead to various human diseases such as inflammation, ischemia, and Parkinson’s disease (PD). Sensitive to apoptosis gene (SAG), a RING-FINGER protein, has anti-apoptotic activity and anti-oxidant activity. In this study, we investigate whether Tat-SAG, fused with a Tat domain, could protect SH-SY5Y neuroblastoma cells against 1-methyl-4-phenylpyridinium (MPP+) and dopaminergic (DA) neurons in the substantia nigra (SN) against 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine (MPTP) toxicity. Western blot and immunohistochemical analysis showed that, unlike SAG, Tat-SAG transduced efficiently into SH-SY5Y cells and into the brain, respectively. Tat-SAG remarkably suppressed ROS generation, DNA damage, and the progression of apoptosis, caused by MPP+ in SH-SY5Y cells. Also, immunohistochemical data using a tyrosine hydroxylase antibody and cresyl violet staining demonstrated that Tat-SAG obviously protected DA neurons in the SN against MPTP toxicity in a PD mouse model. Tat-SAG-treated mice showed significant enhanced motor activities, compared to SAG- or Tat-treated mice. Therefore, our results suggest that Tat-SAG has potential as a therapeutic agent against ROS-related diseases such as PD. PMID:24625574

Sohn, Eun Jeong; Shin, Min Jea; Kim, Dae Won; Ahn, Eun Hee; Jo, Hyo Sang; Kim, Duk-Soo; Cho, Sung-Woo; Han, Kyu Hyung; Park, Jinseu; Eum, Won Sik; Hwang, Hyun Sook; Choi, Soo Young

2014-01-01

90

Novel bifunctional drugs targeting monoamine oxidase inhibition and iron chelation as an approach to neuroprotection in Parkinson’s disease and other neurodegenerative diseases  

Microsoft Academic Search

Summary. Iron has been shown to accumulates at site where neurons degenerate in neurodegenerative diseases of Parkinson’s disease, Alzheimer’s disease, Huntington disease, amyotrophic lateral sclerosis and Friedreich ataxia. Iron is thought to participate or initiate oxidative stress via generation of reactive oxygen species (ROS), such as hydroxyl radical. Iron chelators are neuroprotective and prevent 6-hydroxydoapmine and MPTP dopaminergic neurotoxicity in

M. B. H. Youdim; M. Fridkin; H. Zheng

2004-01-01

91

PACAP27 prevents Parkinson-like neuronal loss and motor deficits but not microglia activation induced by prostaglandin J2.  

PubMed

Neuroinflammation is a major risk factor in Parkinson's disease (PD). Alternative approaches are needed to treat inflammation, as anti-inflammatory drugs such as NSAIDs that inhibit cyclooxygenase-2 (COX-2) can produce devastating side effects, including heart attack and stroke. New therapeutic strategies that target factors downstream of COX-2, such as prostaglandin J2 (PGJ2), hold tremendous promise because they will not alter the homeostatic balance offered by COX-2 derived prostanoids. In the current studies, we report that repeated microinfusion of PGJ2 into the substantia nigra of non-transgenic mice, induces three stages of pathology that mimic the slow-onset cellular and behavioral pathology of PD: mild (one injection) when only motor deficits are detectable, intermediate (two injections) when neuronal and motor deficits as well as microglia activation are detectable, and severe (four injections) when dopaminergic neuronal loss is massive accompanied by microglia activation and motor deficits. Microglia activation was evaluated in vivo by positron emission tomography (PET) with [(11)C](R)PK11195 to provide a regional estimation of brain inflammation. PACAP27 reduced dopaminergic neuronal loss and motor deficits induced by PGJ2, without preventing microglia activation. The latter could be problematic in that persistent microglia activation can exert long-term deleterious effects on neurons and behavior. In conclusion, this PGJ2-induced mouse model that mimics in part chronic inflammation, exhibits slow-onset PD-like pathology and is optimal for testing diagnostic tools such as PET, as well as therapies designed to target the integrated signaling across neurons and microglia, to fully benefit patients with PD. PMID:24970746

Shivers, Kai-Yvonne; Nikolopoulou, Anastasia; Machlovi, Saima Ishaq; Vallabhajosula, Shankar; Figueiredo-Pereira, Maria E

2014-09-01

92

Pathogenesis of Drug-Induced Exanthema  

Microsoft Academic Search

Background: In vitro data derived from drug-specific T cell clones have revealed that heterogeneous T cell subsets with distinct phenotypes (CD4+ > CD8+) and cell functions (strong IL-5 production, cytotoxic potential) are generated. The aim of this study was to elaborate the relevance of these findings in vivo. Methods: Skin biopsy specimens from drug-induced maculopapular exanthema and normal skin were

N. Yawalkar; W. J. Pichler

2001-01-01

93

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

2001-01-01

94

HIV transactivator of transcription enhances methamphetamine-induced Parkinson’s-like behavior in the rats  

PubMed Central

Abuse of methamphetamine (MA) increases the risk of infection of HIV-1, induces considerable neurotoxicity in several brain regions, and impairs the motor and cognitive function in individuals. HIV-1 transactivator of transcription (Tat) has also shown the potent capability to induce neuronal death and impaired brain function. The present study aims to study the synergistic effect of MA and Tat on cytokine synthesis in substantia nigra, striatal dopamine content, and behavioral performance in the rats. Although increased expression of cytokines (interleukin-1? and tumor necrosis factor-?) was observed in the substantia nigra in the rats receiving either MA or Tat alone, a combination of MA and Tat induced a larger and more sustained upregulation of cytokines. In the rats receiving either MA or Tat alone, significant loss in striatal dopamine content was found, which was further exacerbated in the rats receiving both MA and Tat. In the rats receiving either MA or Tat alone, significantly lower performance in the rotarod test and open-field test was observed, whereas the rats receiving both MA and Tat showed more sustained behavioral impairments. These results suggested that Tat protein synergized with MA to induce central neuroinflammation and impair the dopaminergic transmission, thus leading to sustained Parkinson’s-like behavior. PMID:24911386

Liu, Zengxun; Shi, Zhenchun; Liu, Jintong

2014-01-01

95

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. PMID:21079043

Kannankeril, Prince; Darbar, Dawood

2010-01-01

96

Drug-induced Sweet's syndrome by aceclofenac.  

PubMed

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

2011-12-01

97

Drug Induced Hypersensitivity and the HLA Complex  

PubMed Central

Drug-induced hypersensitivity reactions are of major concern and present a burden for national healthcare systems due to their often severe nature, high rate of hospital admissions and high mortality. They manifest with a wide range of symptoms and signs, and can be initiated by a wide range of structurally diverse chemical compounds. The pathophysiological mechanisms underlying hypersensitivity reactions are not well understood, but it is thought that they are immune mediated. MHC region on Chromosome 6 contains many genes with immune function. Classical MHC molecules are highly polymorphic cell surface glycoproteins whose function is to present peptide antigens to T cells. In addition to conferring protection from some diseases, HLA alleles are also associated with an increased risk of other diseases, including drug-induced hypersensitivity. Pharmacogenetic approach to predict the risk of drug-induced hypersensitivity has been established for several drugs. We will discuss the progress of hypersensitivity pharmacogenetics over the last few years and focus on current efforts of the international community to develop consortia which aim to standardize disease phenotypes and to identify affected individuals through international collaborations. In addition, we will discuss the clinical utility of HLA typing as predictive or diagnostic testing for drug-induced hypersensitivity.

Alfirevic, Ana; Pirmohamed, Munir

2011-01-01

98

Drug-induced leukoencephalopathy presenting as catatonia.  

PubMed

We discuss the case of a 35-year-old woman who presented with thought impoverishment, disorganized behavior, and echolalia. The patient's condition progressed to treatment-refractory catatonia. She was started on oral Coenzyme Q10 after magnetic resonance imaging of the brain showed findings consistent with drug-induced leukoencephalopathy (DIL). Following improvement, she acknowledged cocaine use that suggested a diagnosis of cocaine-induced leukoencephalopathy (CIL). This case report seeks to elucidate radiological and clinical features of DIL. PMID:21353145

Anbarasan, Deepti; Campion, Paul; Howard, Jonathan

2011-01-01

99

Neuroprotective and neurotrophic effects of Apigenin and Luteolin in MPTP induced parkinsonism in mice.  

PubMed

In the present study, we aim to investigate the neuroprotective and neurotrophic effects of naturally occurring polyphenols like apigenin and luteolin and also to explore the underlying mechanisms with respect to Parkinson's disease (PD). MPTP (25 mg/kg) along with Probenecid (250 mg/kg) was administrated for five consecutive days to induce parkinsonism in mice. Apigenin (5, 10 and 20 mg/kg), luteolin (10 and 20 mg/kg) and Bromocriptine (10 mg/kg) were administrated orally for 26 days including 5 days of pretreatment. Behavioural analysis and biochemical estimation of oxidative stress biomarkers were conducted. Tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP) and brain derived neurotrophic factor (BDNF) were evaluated in substantia nigra (SN) region of the brain by immunostaining. TNF-? was estimated using ELISA technique. Our results demonstrate that apigenin and luteolin treatment improved the locomotor and muscular activities in MPTP treated mice. TH-positive cells decreased up to 7% in MPTP treated mice compared to normal mice (P < 0.001) and were found to be protected from degeneration in apigenin (69%) and luteolin (63%) treated mice (P < 0.001). Levels of GFAP were found to be decreased in the SN of the brain due to apigenin and luteolin treatment as compared to MPTP mice. BDNF levels were elevated significantly in apigenin and luteolin treatment groups when compared to MPTP treatment mice. In conclusion, apigenin and luteolin protected the dopaminergic neurons probably by reducing oxidative damage, neuroinflammation and microglial activation along with enhanced neurotrophic potential. The above results propose both these flavonoids as promising molecules in the therapeutics of PD. PMID:25087727

Patil, Sachin P; Jain, Pankaj D; Sancheti, Jayant S; Ghumatkar, Priya J; Tambe, Rufi; Sathaye, Sadhana

2014-11-01

100

Pharmacogenetics of antiepileptic drug-induced hypersensitivity.  

PubMed

Antiepileptic drugs can induce potentially life-threatening hypersensitivity reactions such as Stevens-Johnson syndrome at a frequency of one in 10,000 to one in 1000 treated patients. There is a considerable cross-reactivity among different antiepileptic drugs but the mechanisms are not known. In this review we have summarized current evidence on antiepileptic drug-induced hypersensitivity reactions and performed meta-analyses of published case-control studies that investigated associations between HLA alleles and several antiepileptic drugs in diverse populations. As the heterogeneity between studies was high, we conducted subsequent subgroup analyses and showed that HLA-B*15:02 was associated with carbamazepine, lamotrigine and phenytoin-induced Stevens-Johnson syndrome in Asian populations indicating that pretreatment testing may prevent cross-reactivity. Additionally, we explored the potential of new, high-throughput technologies that may help to understand the mechanisms and predict the risk of adverse drug reactions in the future. PMID:24897291

Bloch, Katarzyna M; Sills, Graeme J; Pirmohamed, Munir; Alfirevic, Ana

2014-04-01

101

Drug induced acute pancreatitis: incidence and severity.  

PubMed Central

To determine the incidence and severity of drug induced acute pancreatitis, data from 45 German centres of gastroenterology were evaluated. Among 1613 patients treated for acute pancreatitis in 1993, drug induced acute pancreatitis was diagnosed in 22 patients (incidence 1.4%). Drugs held responsible were azathioprine, mesalazine/sulfasalazine, 2',3'-dideoxyinosine (ddI), oestrogens, frusemide, hydrochlorothiazide, and rifampicin. Pancreatic necrosis not exceeding 33% of the organ was found on ultrasonography or computed tomography, or both, in three patients (14%). Pancreatic pseudocysts did not occur. A decrease of arterial PO2 reflecting respiratory insufficiency, and an increase of serum creatinine, reflecting renal insufficiency as complications of acute pancreatitis were seen in two (9%) and four (18%) patients, respectively. Artificial ventilation was not needed, and dialysis was necessary in only one (5%) case. Two patients (9%) died of AIDS and tuberculosis, respectively; pancreatitis did not seem to have contributed materially to their death. In conclusion, drugs rarely cause acute pancreatitis, and drug induced acute pancreatitis usually runs a benign course. PMID:7489946

Lankisch, P G; Droge, M; Gottesleben, F

1995-01-01

102

Mechanisms of Drug Induced Liver Injury  

PubMed Central

Synopsis 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 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). An biochemical stress is usually initiated by drugs and their reactive metabolites through covalent binding or direct damage to mitochondria, which leads to oxidative stress, activation of stress signaling pathways, impairment of mitochondrial function, endoplasmic reticulum stress, etc. The ultimate cell death pathways converges at mitochondria through acting on mitochondrial outer-membrane permeability (MOMP) or mitochondrial permeability transition (MPT). The striking HLA associations with idiosyncratic DILI highlight the critical role of the adaptive immune response in pathogenesis, which is now believed to be unmasked in genetically susceptible individuals by the biochemical stress in the liver triggered by drug and/or metabolites. The drug-induced biochemical stress may also contribute to the severity of injury by sensitizing hepatocytes to the lethal effects of the immune response. Adaptive mechanisms including antioxidant signaling (such as Nrf2 signaling) , mitophagy, autophagy, unfolded protein response, anti-inflammatory and immune tolerance dampen and ameliorate injury. All together, the development and severity of injury is determined on the battle between the hazardous stress and adaptive responses within the hepatocytes and the innate and adaptive immune systems. PMID:24099014

Yuan, Liyun; Kaplowitz, Neil

2013-01-01

103

Effective Treatment of Manganese-Induced Occupational Parkinsonism With p-Aminosalicylic Acid: A Case of 17-Year Follow-Up Study  

PubMed Central

Objective Chronic manganese (Mn) intoxication induces syndromes resembling Parkinson disease. The clinical intervention has largely been unsuccessful. We report a 17-year follow-up study of effective treatment of occupational Mn parkinsonism with sodium para-aminosalicylic acid (PAS). Methods The patient, female and aged 50 at the time of treatment, was exposed to airborne Mn for 21 years (1963–1984). The patient had palpitations, hand tremor, lower limb myalgia, hypermyotonia, and a distinct festinating gait. She received 6 g PAS per day through an intravenous drip infusion for 4 days and rested for 3 days as one therapeutic course. Fifteen such courses were carried out between March and June 1987. Results At the end of PAS treatment, her symptoms were significantly alleviated, and handwriting recovered to normal. Recent follow-up examination at age 67 years (in 2004) showed a general normal presentation in clinical, neurologic, brain magnetic resonance imaging, and handwriting examinations with a minor yet passable gait. Conclusions This case study suggests that PAS appears to be an effective drug for treatment of severe chronic Mn poisoning with a promising prognosis. PMID:16766929

Jiang, Yue-Ming; Mo, Xue-An; Du, Feng-Qi; Fu, Xue; Zhu, Xia-Yan; Gao, Hong-Yu; Xie, Jin-Lan; Liao, Feng-Ling; Pira, Enrico; Zheng, Wei

2014-01-01

104

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. PMID:22941107

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

2012-01-01

105

Nicotine and Parkinson's disease: implications for therapy.  

PubMed

Accumulating evidence suggests that nicotine, a drug that stimulates nicotinic acetylcholine receptors, may be of therapeutic value in Parkinson's disease. Beneficial effects may be several-fold. One of these is a protective action against nigrostriatal damage. This possibility stems from the results of epidemiological studies that consistently demonstrate an inverse correlation between tobacco use and Parkinson's disease. This reduced incidence of Parkinson's disease has been attributed to the nicotine in tobacco products, at least in part, based on experimental work showing a protective effect of nicotine against toxic insults. Second, several studies suggest a symptomatic effect of nicotine in Parkinson's disease, although effects are small and somewhat variable. Third, recent data in nonhuman primates show that nicotine attenuates levodopa-induced dyskinesias, a debilitating side effect that develops in the majority of patients on levodopa therapy. Collectively, these observations suggest that nicotine or CNS selective nicotinic receptor ligands hold promise for Parkinson's disease therapy to reduce disease progression, improve symptoms, and/or decrease levodopa-induced dyskinesias. PMID:18683238

Quik, Maryka; O'Leary, Kathryn; Tanner, Caroline M

2008-09-15

106

Drug-induced deaths - United States, 1999-2010.  

PubMed

Drug-induced deaths include all deaths for which drugs are the underlying cause, including those attributable to acute poisoning by drugs (drug overdoses) and deaths from medical conditions resulting from chronic drug use (e.g., drug-induced Cushing's syndrome). A drug includes illicit or street drugs (e.g., heroin and cocaine), as well as legal prescription and over-the-counter drugs; alcohol is not included. Deaths from drug overdose have increased sharply in the past decade. This increase has been associated with overdoses of prescription opioid pain relievers, which have more than tripled in the past 20 years, escalating to 16,651 deaths in the United States in 2010. Most drug-induced deaths are unintentional drug poisoning deaths, with suicidal drug poisoning and drug poisoning of undetermined intent comprising the majority of the remainder. PMID:24264508

Mack, Karin A

2013-11-22

107

Excessive daytime sleepiness in patients with Parkinson's disease.  

PubMed

Excessive daytime sleepiness (EDS) is described as inappropriate and undesirable sleepiness during waking hours and is a common non-motor symptom in Parkinson's disease, affecting up to 50% of patients. EDS has a large impact on the quality of life of Parkinson's disease patients as well as of their caregivers, in some cases even more than the motor symptoms of the disease. Drug-induced EDS is a particular problem as many dopamine agonists used for the treatment of Parkinson's disease have EDS as an adverse effect. Dopaminergic treatment may also render a subset of Parkinson's disease patients at risk for sudden-onset sleep attacks that occur without warning and can be particularly hazardous if the patient is driving. This demonstrates the need for early recognition and management not only to increase health-related quality of life but also to ensure patient safety. There are many assessment tools for EDS, including the Epworth Sleepiness Scale (ESS) and the Multiple Sleep Latency Test (MSLT), although only the Parkinson's Disease Sleep Scale (PDSS) and the SCales for Outcomes in PArkinson's Disease-Sleep (SCOPA-S) are specifically validated for Parkinson's disease. Polysomnography can be used when necessary. Management comprises non-pharmacological and pharmacological approaches. Non-pharmacological approaches can be the mainstay of treatment for mild to moderate EDS. Advice on good sleep hygiene is instrumental, as pharmacological approaches have yet to provide consistent and reliable results without significant adverse effects. The efficacy of pharmacological treatment of EDS in Parkinson's disease using wakefulness-promoting drugs such as modafinil remains controversial. Further areas of research are now also focusing on adenosine A(2A) receptor antagonists, sodium oxybate and caffeine to promote wakefulness. A definitive treatment for the highly prevalent drug-induced EDS has not yet been found. PMID:21323392

Knie, Bettina; Mitra, M Tanya; Logishetty, Kartik; Chaudhuri, K Ray

2011-03-01

108

Neuroprotective effects of swimming training in a mouse model of Parkinson's disease induced by 6-hydroxydopamine.  

PubMed

Parkinson's disease (PD) is characterized by progressive dopamine (DA) depletion in the striatum. Exercise has been shown to be a promising non-pharmacological approach to reduce the risk of neurodegeneration diseases. This study was designed to investigate the potential neuroprotective effect of swimming training (ST) in a mouse model of PD induced by 6-hydroxydopamine (6-OHDA) in mice. The present study demonstrated that a 4-week ST was effective in attenuating the following impairments resulting from 6-OHDA exposure: (i) depressive-like behavior in the tail suspension test; (ii) increase in the number of falls in the rotarod test; (iii) impairment on long-term memory in the object recognition test; (iv) increase of the reactive species and interleukin 1-beta (IL-1?) levels; (v) inhibition of the glutathione peroxidase (GPx) activity; (vi) rise of the glutathione reductase (GR) and glutathione S-transferase (GST) activities and vii) decrease of DA, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) levels. The mechanisms involved in this study are the modulation of GPx, GR and GST activities as well as IL-1? level in a PD model induced by 6-OHDA, protecting against the decrease of DA, DOPAC and HVA levels in the striatum of mice. These findings reinforce that one of the effects induced by exercise on neurodegenerative disease, such as PD, is due to antioxidant and anti-inflammatory properties. We suggest that exercise attenuates cognitive and motor declines, depression, oxidative stress, and neuroinflammation induced by 6-OHDA supporting the hypothesis that exercise can be used as a non-pharmacological tool to reduce the symptoms of PD. PMID:24090962

Goes, A T R; Souza, L C; Filho, C B; Del Fabbro, L; De Gomes, M G; Boeira, S P; Jesse, C R

2014-01-01

109

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

PubMed

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

2011-04-28

110

Drug-Provoked Psoriasis: Is It Drug Induced or Drug Aggravated?  

PubMed Central

Psoriasis is a commonly encountered dermatosis with a variety of internal and external paradoxical factors contributing to the clinical course of the disease. There are several drugs described in the literature that have been associated with the initiation, exacerbation, and aggravation of psoriasis. Understanding the pathophysiology can provide clues to treatment and management of drug-induced and drug-aggravated psoriasis, which may be indistinguishable from idiopathic psoriasis. The clinical manifestations of drug-associated psoriasis can range from plaque-type psoriasis to severe erythroderma, thus warranting astute and sustained clinical observation. PMID:20725536

Kim, Grace K.

2010-01-01

111

[Serotonin and anticancer drug-induced emesis].  

PubMed

Cytotoxic drug-induced nausea and vomiting are the side effects most feared by cancer patients. Emesis is an instinctive defense reaction caused by the somato-autonomic nerve reflex, which is integrated in the medulla oblongata. Emesis caused by anticancer drugs is associated with an increase in the concentration of serotonin (5-HT) (5-HT) in the intestinal mucosa and brainstem. 5-HT released from the enterochromaffin (EC) cells, which synthesize and secrete 5-HT, stimulates the 5-HT receptors on the adjacent vagal afferent nerves. The depolarization of the vagal afferent nerves stimulates the vomiting center in the brainstem and eventually induces a vomiting reflex. 5-HT released from EC cells appears to mediate the cisplatin-induced emesis sensitive to 5-HT(3) receptor antagonists. The precise role of 5-HT in the occurrence of vomiting has not been fully elucidated. The present review describes the role of 5-HT in anticancer drug-induced emesis from the viewpoint of 5-HT release and afferent vagal nerve activity. Various models and methods for predicting emesis are also evaluated. PMID:15297719

Minami, Masaru; Endo, Toru; Hamaue, Naoya; Hirafuji, Masahiko

2004-08-01

112

Gastrodin Protects Apoptotic Dopaminergic Neurons in a Toxin-Induced Parkinson's Disease Model  

PubMed Central

Gastrodia elata (GE) Blume is one of the most important traditional plants in Oriental countries and has been used for centuries to improve various conditions. The phenolic glucoside gastrodin is an active constituent of GE. The aim of this study was to investigate the neuroprotective role of gastrodin in 1-methyl-4-phenylpyridinium (MPP+)/1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine- (MPTP) induced human dopaminergic SH-SY5Y cells and mouse model of Parkinson's disease (PD), respectively. Gastrodin significantly and dose dependently protected dopaminergic neurons against neurotoxicity through regulating free radicals, Bax/Bcl-2 mRNA, caspase-3, and cleaved poly(ADP-ribose) polymerase (PARP) in SH-SY5Y cells stressed with MPP+. Gastrodin also showed neuroprotective effects in the subchronic MPTP mouse PD model by ameliorating bradykinesia and motor impairment in the pole and rotarod tests, respectively. Consistent with this finding, gastrodin prevented dopamine depletion and reduced reactive astrogliosis caused by MPTP as assessed by immunohistochemistry and immunoblotting in the substantiae nigrae and striatata of mice. Moreover, gastrodin was also effective in preventing neuronal apoptosis by attenuating antioxidant and antiapoptotic activities in these brain areas. These results strongly suggest that gastrodin has protective effects in experimental PD models and that it may be developed as a clinical candidate to ameliorate PD symptoms. PMID:23533492

Kumar, Hemant; Kim, In-Su; More, Sandeep Vasant; Kim, Byung-Wook; Bahk, Young-Yil; Choi, Dong-Kug

2013-01-01

113

Citalopram-induced hyponatraemia and parkinsonism: potentially fatal side-effects not to be missed.  

PubMed

The use of selective serotonin reuptake inhibitors (SSRIs), such as citalopram, is on the rise and, as such, clinicians must be vigilant of rare side-effects associated with this group of medications. We report the case of a 65-year-old man who presented to West Suffolk Hospital with a fall, confusion and movement abnormalities, and was found to have a serum sodium of 105 on admission. He was managed with hypertonic saline, dopamine agonists and intensive physiotherapy. Despite initially deteriorating neurologically, he made a remarkable recovery, and was discharged home at his pre-admission baseline. The learning points from this report are as follows: (1) regular monitoring of electrolytes on starting an SSRI (and similarly selective noradrenaline reuptake inhibitors-SNRIs) in SSRI/SNRIs naďve patients, (2) awareness of possible citalopram-induced parkinsonism and the potential benefits of dopamine agonists as one management strategy and (3) vigilant fluid/electrolyte monitoring in patients with profound hyponatraemia. PMID:25391825

Damali Amiri, Negin; Wijenaike, Nishan

2014-01-01

114

Olfaction in three genetic and two MPTP-induced Parkinson's disease mouse models.  

PubMed

Various genetic or toxin-induced mouse models are frequently used for investigation of early PD pathology. Although olfactory impairment is known to precede motor symptoms by years, it is not known whether it is caused by impairments in the brain, the olfactory epithelium, or both. In this study, we investigated the olfactory function in three genetic Parkinson's disease (PD) mouse models and mice treated with MPTP intraperitoneally and intranasally. To investigate olfactory function, we performed electro-olfactogram recordings (EOGs) and an olfactory behavior test (cookie-finding test). We show that neither a parkin knockout mouse strain, nor intraperitoneal MPTP treated animals display any olfactory impairment in EOG recordings and the applied behavior test. We also found no difference in the responses of the olfactory epithelium to odorants in a mouse strain over-expressing doubly mutated ?-synuclein, while this mouse strain was not suitable to test olfaction in a cookie-finding test as it displays a mobility impairment. A transgenic mouse expressing mutated ?-synuclein in dopaminergic neurons performed equal to control animals in the cookie-finding test. Further we show that intranasal MPTP application can cause functional damage of the olfactory epithelium. PMID:24204848

Kurtenbach, Stefan; Wewering, Sonja; Hatt, Hanns; Neuhaus, Eva M; Lübbert, Hermann

2013-01-01

115

Daytime Sleepiness in Parkinson's Disease: Perception, Influence of Drugs, and Mood Disorder  

PubMed Central

Parkinson's disease (PD) is associated with sleep complaints as excessive daytime sleepiness (EDS) and several factors have been implicated in the genesis of these complaints. Objective. To correlate the subjective perception of EDS with variables as the severity of the motor symptoms, medications, and the presence of depressive symptoms. Materials and Methods. A cross-sectional study, using specific scales as Epworth sleepiness scale (ESS), Beck depression inventory (iBeck) and Hoehn and Yahr (HY), in 42 patients with PD. Results. The patients had a mean age of 61.2 ± 11.3 years and mean disease duration of 4.96 ± 3.3 years. The mean ESS was 7.5 ± 4.7 and 28.6% of patients reached a score of abnormally high value (>10). There was no association with gender, disease duration, and dopamine agonists. Patients with EDS used larger amounts of levodopa (366.7 ± 228.0 versus 460.4 ± 332.25?mg, P = 0.038), but those who had an iBeck >20 reached lower values of ESS than the others (5.9 ± 4.1 versus 9.3 ± 4.8, P = 0.03). Conclusions. EDS was common in PD patients, being related to levodopa intake. Presence of depressed mood may influence the final results of self-assessment scales for sleep disorders. PMID:24587912

Ataide, M.; Franco, C. M. R.; Lins, O. G.

2014-01-01

116

Neuroprotective effect of Tinospora cordifolia ethanol extract on 6-hydroxy dopamine induced Parkinsonism  

PubMed Central

Objective: The present study investigates the neuroprotective activity of ethanol extract of Tinospora cordifolia aerial parts against 6-hydroxy dopamine (6-OHDA) lesion rat model of Parkinson's disease (PD). Materials and Methods: T. cordifolia ethanol extract (TCEE) was standardized with high performance thin layer chromatography using berberine. Experimental PD was induced by intracerebral injection of 6-OHDA (8 ?g). Animals were divided into five groups: sham operated, negative control, positive control (levodopa 6 mg/kg) and two experimental groups (n = 6/group). Experimental groups received 200 and 400 mg/kg of TCEE once daily for 30 days by oral gavage. Biochemical parameters including dopamine level, oxidative stress, complex I activity and brain iron asymmetry ratio and locomotor activity including skeletal muscle co-ordination and degree of catatonia were assessed. Results: TCEE exhibited significant neuroprotection by increasing the dopamine levels (1.96 ± 0.20 and 2.45 ± 0.40 ng/mg of protein) and complex I activity (77.14 ± 0.89 and 78.50 ± 0.96 nmol/min/mg of protein) at 200 and 400 mg/kg respectively when compared with negative control group. Iron asymmetry ratio was also significantly attenuated by TCEE at 200 (1.57 ± 0.18) and 400 mg/kg (1.11 ± 0.15) when compared with negative control group. Neuroprotection by TCEE was further supported by reduced oxidative stress and restored locomotor activity in treatment groups. Conclusion: Results show that TCEE possess significant neuroprotection in 6-OHDA induced PD by protecting dopaminergic neurons and reducing the iron accumulation. PMID:24741189

Kosaraju, Jayasankar; Chinni, Santhivardhan; Roy, Partha Deb; Kannan, Elango; Antony, A. Shanish; Kumar, M. N. Satish

2014-01-01

117

Tau deficiency induces parkinsonism with dementia by impairing APP-mediated iron export.  

PubMed

The microtubule-associated protein tau has risk alleles for both Alzheimer's disease and Parkinson's disease and mutations that cause brain degenerative diseases termed tauopathies. Aggregated tau forms neurofibrillary tangles in these pathologies, but little is certain about the function of tau or its mode of involvement in pathogenesis. Neuronal iron accumulation has been observed pathologically in the cortex in Alzheimer's disease, the substantia nigra (SN) in Parkinson's disease and various brain regions in the tauopathies. Here we report that tau-knockout mice develop age-dependent brain atrophy, iron accumulation and SN neuronal loss, with concomitant cognitive deficits and parkinsonism. These changes are prevented by oral treatment with a moderate iron chelator, clioquinol. Amyloid precursor protein (APP) ferroxidase activity couples with surface ferroportin to export iron, but its activity is inhibited in Alzheimer's disease, thereby causing neuronal iron accumulation. In primary neuronal culture, we found loss of tau also causes iron retention, by decreasing surface trafficking of APP. Soluble tau levels fall in affected brain regions in Alzheimer's disease and tauopathies, and we found a similar decrease of soluble tau in the SN in both Parkinson's disease and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model. These data suggest that the loss of soluble tau could contribute to toxic neuronal iron accumulation in Alzheimer's disease, Parkinson's disease and tauopathies, and that it can be rescued pharmacologically. PMID:22286308

Lei, Peng; Ayton, Scott; Finkelstein, David I; Spoerri, Loredana; Ciccotosto, Giuseppe D; Wright, David K; Wong, Bruce X W; Adlard, Paul A; Cherny, Robert A; Lam, Linh Q; Roberts, Blaine R; Volitakis, Irene; Egan, Gary F; McLean, Catriona A; Cappai, Roberto; Duce, James A; Bush, Ashley I

2012-02-01

118

Manganese induced parkinsonism: an outbreak due to an unrepaired ventilation control system in a ferromanganese smelter.  

PubMed

Several cases of parkinsonism were found in a ferromanganese smelter after the ventilation system had broken down and had not been repaired for eight months in 1985. To determine the aetiology and prevalence of parkinsonism, 132 workers were submitted to thorough medical examination and estimated air concentrations of carbon monoxide and manganese at different worksites. Only six of eight workers performing electrode fixation or welding during 1985 developed parkinsonism. They were exposed for 30 minutes each day, seven days a week, to high concentrations of air manganese (greater than 28.8 mg/m3). There was a consistent trend between the index of exposure to manganese and signs and symptoms exhibited by extrapyramidal systems. After repair of the ventilation system, the air concentration of manganese during electrode fixation and welding decreased to less than 4.4 mg/m3; furthermore, no new cases of parkinsonism have been observed. Workers with parkinsonism recovered partially after removal from original worksites and treatment with levodopa. It is concluded that the outbreak resulted from exposure to high concentrations of manganese fumes through the breakdown of the ventilation system. PMID:2611159

Wang, J D; Huang, C C; Hwang, Y H; Chiang, J R; Lin, J M; Chen, J S

1989-12-01

119

A Granulomatous Drug Eruption Induced by Entecavir  

PubMed Central

Entecavir (Baraclude®, Bristol-Myers Squibb) is a potent and selective antiviral agent that has demonstrated efficacy in patients with chronic hepatitis B. The most frequent adverse events attributed to entecavir include increased alanine aminotransferase, upper respiratory tract infection, headache, abdominal pain, cough, pyrexia, fatigue, and diarrhea. Although quite a few randomized double-blind studies including ones investigating adverse events along with these general symptoms have been reported, few cases of cutaneous adverse events have been described in detail. We demonstrate a case of granulomatous drug eruption as a cutaneous adverse event induced by entecavir. PMID:24371400

Yoon, Jimi; Park, Donghwa

2013-01-01

120

Drug-induced hyperthermia in Huntington's disease.  

PubMed

Until now, only three patients with Huntington's disease (HD) and a neuroleptic malignant syndrome (NMS) have been reported in the literature. We describe four cases with advanced stage Huntington's disease who within a period of one year developed drug-induced hyperthermia, either the neuroleptic malignant syndrome, or the serotonin syndrome. Possible contributing factors that may have been specific for HD patients could be identified and included advanced neurological disease with severe illness, occurrence in summer, with possible infectious disease, dehydration, and pre-existing extra-pyramidal signs that may mask incipient NMS/serotonin syndrome. Measures to avoid these potentially lifethreatening conditions are discussed. PMID:15083292

Gaasbeek, D; Naarding, P; Stor, T; Kremer, H P H

2004-04-01

121

Drug-induced acute liver failure and gastrointestinal complications.  

PubMed

The objective of this article is to describe adverse drug events related to the liver and gastrointestinal tract in critically ill patients. PubMed and other resources were used to identify information related to drug-induced acute liver failure, gastrointestinal hypomotility, constipation, diarrhea, gastrointestinal bleeding, and pancreatitis in critically ill patients. This information was reviewed, and data regarding pathophysiology, common drug causes, and guidelines for prevention and management were collected and summarized. In cases in which data in critically ill patients were unavailable, data were extrapolated from other patient populations. Drug-induced acute liver failure can be caused by many drugs routinely used in the intensive care unit and may be associated with significant morbidity and mortality. Drug-related hypomotility and constipation and drug-related diarrhea are reported with many drugs, and these are common adverse drug events in critically ill patients that can substantially complicate the care of these patients. Drug-induced gastrointestinal bleeding and drug-induced pancreatitis occur less frequently, can range in disease severity, and can be associated with morbidity and mortality. Many drugs used in critically ill patients are associated with adverse drug events related to the liver and gastrointestinal tract. Critical care clinicians should be aware of common drug causes of drug-induced acute liver failure, gastrointestinal hypomotility, constipation, diarrhea, gastrointestinal bleeding, and pancreatitis, and should be familiar with the prevention and management of these diverse conditions. PMID:20502172

Lat, Ishaq; Foster, David R; Erstad, Brian

2010-06-01

122

Adjunctive therapy in Parkinson's disease: the role of rasagiline  

PubMed Central

Parkinson’s disease is the second most common neurodegenerative disorder, currently affecting 1.5 million people in the US. In this review, we describe the diagnostic and pathological features of Parkinson’s disease, as well as its clinical course. We then review pharmacologic treatments for the disease, with a particular focus on therapies adjunctive to levodopa and specifically the role of rasagiline. We review the four pivotal rasagiline trials, and discuss rasagiline and its use as adjunctive therapy for Parkinson’s disease. Finally, we discuss potential side effects, drug interactions, and other practical aspects concerning the use of rasagiline in Parkinson’s disease. PMID:22802692

Gaines, Kathryn D; Hinson, Vanessa K

2012-01-01

123

Parkinson's Disease  

MedlinePLUS

... and some have been linked to specific gene mutations. Juvenile Parkinsonism In very rare cases, parkinsonian symptoms may appear in people before the age of 20. This condition is called juvenile parkinsonism. ...

124

Progressive loss of striatal dopamine terminals in MPTP-induced acute parkinsonism in cynomolgus monkeys using vesicular monoamine transporter type 2 PET imaging ([(18)F]AV-133).  

PubMed

The 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP)-induced parkinsonism model, particularly in non-human primates, remains the gold-standard for studying the pathogenesis and assessing novel therapies for Parkinson's disease. However, whether the loss of dopaminergic neurons in this model is progressive remains controversial, mostly due to the lack of objective in vivo assessment of changes in the integrity of these neurons. In the present study, parkinsonism was induced in cynomolgus monkeys by intravenous administration of MPTP (0.2 mg/kg) for 15 days; stable parkinsonism developed over 90 days, when the symptoms were stable. Noninvasive positron emission tomographic neuroimaging of vesicular monoamine transporter 2 with 9-[(18)F] fluoropropyl-(+)-dihydrotetrabenazine ([(18)F]AV-133) was used before, and 15 and 90 days after the beginning of acute MPTP treatment. The imaging showed evident progressive loss of striatal uptake of [(18)F]AV-133. The dopaminergic denervation severity had a significant linear correlation with the clinical rating scores and the bradykinesia subscores. These findings demonstrated that [(18)F]AV-133 PET imaging is a useful tool to noninvasively evaluate the evolution of monoaminergic terminal loss in a monkey model of MPTP-induced parkinsonism. PMID:24061965

Liu, Yajing; Yue, Feng; Tang, Rongping; Tao, Guoxian; Pan, Xiaomei; Zhu, Lin; Kung, Hank F; Chan, Piu

2014-06-01

125

Sodium Butyrate Improves Locomotor Impairment and Early Mortality in a Rotenone-Induced Drosophila Model of Parkinson's Disease  

PubMed Central

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 10 mM 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 (Sin3Alof) were resistant to rotenone-induced locomotor impairment and early mortality. Furthermore, SB-supplemented Sin3Alof 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, Robyn; O'Brien, Liam M.; Ahmad, S. Tariq

2013-01-01

126

Neuroprotective Effect of Pseudoginsenoside-F11 on a Rat Model of Parkinson's Disease Induced by 6-Hydroxydopamine  

PubMed Central

Pseudoginsenoside-F11 (PF11), a component of Panax quinquefolism (American ginseng), plays a lot of beneficial effects on disorders of central nervous system. In this paper, the neuroprotective effect of PF11 on Parkinson's disease (PD) and the possible mechanism were investigated in a rat PD model. PF11 was orally administered at 3, 6, and 12?mg/kg once daily for a period of 2 weeks before and 1 week after the unilateral lesion of left medial forebrain bundle (MFB) induced by 6-hydroxydopamine (6-OHDA). The results showed that PF11 markedly improved the locomotor, motor balance, coordination, and apomorphine-induced rotations in 6-OHDA-lesioned rats. The expression of tyrosine hydroxylase (TH) in substantia nigra (SN) and the content of extracellular dopamine (DA) in striatum were also significantly increased after PF11 treatment. Moreover, significant reduction in the levels of striatal extracellular hydroxyl radical (?OH), detected as 2,3- and 2,5-dihydroxy benzoic acid (2,3- and 2,5-DHBA), and increase in the level of striatal extracellular ascorbic acid (AA) were observed in the PF11-treated groups compared with 6-OHDA-lesioned rats. Taken together, we propose that PF11 has potent anti-Parkinson property possibly through inhibiting free radical formation and stimulating endogenous antioxidant release. PMID:24386001

Wang, Jian Yu; Yang, Jing Yu; Wang, Fang; Fu, Shi Yuan; Hou, Yue; Jiang, Bo; Ma, Jie; Song, Cui; Wu, Chun Fu

2013-01-01

127

Drug-induced immune hemolytic anemia  

MedlinePLUS

Immune hemolytic anemia secondary to drugs; Anemia - immune hemolytic - secondary to drugs ... Drugs that can cause this type of hemolytic anemia include: Cephalosporins (a class of antibiotics) -- most common ...

128

Hallucinations and sleep disturbances in Parkinson's disease.  

PubMed

Visual hallucinations (VHs) occur frequently in Parkinson's disease (PD). VHs occur more frequently in elderly patients with longer duration of illness, cognitive impairment, and sleep disturbances. The relationship between the use of antiparkinsonian drugs and VHs is complicated, but most drugs used to treat parkinsonian motor symptoms induce VHs and psychosis in some PD patients. The "continuum hypothesis" proposing that medication-induced psychiatric symptoms in PD begin with drug-induced sleep disturbances, followed by vivid dreams, with progression to hallucinatory and delusional experiences has been challenged. In some patients, VHs may represent intrusion of REM sleep-related imagery into wakefulness. Improving REM sleep abnormalities in PD (e.g., stimulants, anticholinesterase inhibitors) is one strategy now being tested to improve VHs in PD. PMID:15505140

Kulisevsky, Jaime; Roldan, Eliana

2004-10-26

129

Selective serotonin reuptake inhibition modulates response inhibition in Parkinson's disease  

PubMed Central

Impulsivity is common in Parkinson’s disease even in the absence of impulse control disorders. It is likely to be multifactorial, including a dopaminergic ‘overdose’ and structural changes in the frontostriatal circuits for motor control. In addition, we proposed that changes in serotonergic projections to the forebrain also contribute to response inhibition in Parkinson’s disease, based on preclinical animal and human studies. We therefore examined whether the selective serotonin reuptake inhibitor citalopram improves response inhibition, in terms of both behaviour and the efficiency of underlying neural mechanisms. This multimodal magnetic resonance imaging study used a double-blind randomized placebo-controlled crossover design with an integrated Stop-Signal and NoGo paradigm. Twenty-one patients with idiopathic Parkinson’s disease (46–76 years old, 11 male, Hoehn and Yahr stage 1.5–3) received 30 mg citalopram or placebo in addition to their usual dopaminergic medication in two separate sessions. Twenty matched healthy control subjects (54–74 years old, 12 male) were tested without medication. The effects of disease and drug on behavioural performance and regional brain activity were analysed using general linear models. In addition, anatomical connectivity was examined using diffusion tensor imaging and tract-based spatial statistics. We confirmed that Parkinson’s disease caused impairment in response inhibition, with longer Stop-Signal Reaction Time and more NoGo errors under placebo compared with controls, without affecting Go reaction times. This was associated with less stop-specific activation in the right inferior frontal cortex, but no significant difference in NoGo-related activation. Although there was no beneficial main effect of citalopram, it reduced Stop-Signal Reaction Time and NoGo errors, and enhanced inferior frontal activation, in patients with relatively more severe disease (higher Unified Parkinson’s Disease Rating Scale motor score). The behavioural effect correlated with the citalopram-induced enhancement of prefrontal activation and the strength of preserved structural connectivity between the frontal and striatal regions. In conclusion, the behavioural effect of citalopram on response inhibition depends on individual differences in prefrontal cortical activation and frontostriatal connectivity. The correlation between disease severity and the effect of citalopram on response inhibition may be due to the progressive loss of forebrain serotonergic projections. These results contribute to a broader understanding of the critical roles of serotonin in regulating cognitive and behavioural control, as well as new strategies for patient stratification in clinical trials of serotonergic treatments in Parkinson’s disease. PMID:24578545

Ye, Zheng; Altena, Ellemarije; Nombela, Cristina; Housden, Charlotte R.; Maxwell, Helen; Rittman, Timothy; Huddleston, Chelan; Rae, Charlotte L.; Regenthal, Ralf; Sahakian, Barbara J.; Barker, Roger A.; Robbins, Trevor W.

2014-01-01

130

Conditioning of drug-induced physiological responses  

Microsoft Academic Search

Presents an analysis of the conditioning of drug effects that permits the prediction of the nature and direction of conditioned responses and accounts for drug-conditioning results within stimulus-substitution theory. It is argued that failure to identify the UCS and UCR effects of a drug constitutes the source of the controversies about the relation of the CR to the observed drug

Roelof Eikelboom; Jane Stewart

1982-01-01

131

Does subthalamic stimulation induce personality modifications in Parkinson's disease? A Rorschach Test explorative study.  

PubMed

The aim of this study was to investigate personality, by means of the Rorschach Psychodiagnostic test, in a consecutive series of fourteen patients with Parkinson's disease (PD) submitted to bilateral deep brain stimulation of the subthalamic nucleus (DBS STN). Patients were evaluated pre-operatively and 1 year after surgery. Patients were also assessed for motor disability and cognitive status. All the patients obtained a significant amelioration of motor symptoms and could reduce the dopaminergic treatment after surgery. No cognitive decline was observed comparing the pre- to the post-operative neuropsychological assessment. The comparison between pre- and post-operative Rorschach indexes showed no major modifications of personality structure. The results of the present explorative study suggest that DBS of STN does not result in relevant personality modifications in patients with Parkinson's disease. PMID:18575180

Castelli, Lorys; Perozzo, Paola; Caglio, Marcella; Rizzi, Laura; Zibetti, Maurizio; Lanotte, Michele; Lopiano, Leonardo

2008-03-01

132

Intrastriatal GDNF gene transfer by inducible lentivirus vectors protects dopaminergic neurons in a rat model of parkinsonism.  

PubMed

Glial cell line-derived neurotrophic factor (GDNF) has neuroprotective effects on dopaminergic (DA) neurons both in vivo and in vitro. However, substantial evidence has shown that a long-term overexpression of GDNF gene is often associated with side effects. We previously improved tetracycline (Tet)-On lentivirus system carrying human GDNF (hGDNF) gene, and demonstrated that hGDNF gene expression was tightly regulated and functional in vitro. Here we further examined the efficiency and neuroprotection of Tet-On lentivirus-mediated hGDNF gene regulation in neural progenitor cells (NPCs) and a rat model of parkinsonism. The results showed that hGDNF gene expression was tightly regulated in transduced NPCs. Doxycycline (Dox)-induced hGDNF protected DA neurons from 6-hydroxydopamine (6-OHDA)-induced toxicity in vitro. Intrastriatal injections of Tet-On lentivirus vectors resulted in dramatically increased levels of hGDNF protein in the striatum of rats with Dox-drinking water, when compared to lentivirus-injected and saline-injected rats with normal drinking water, respectively. In addition, hGDNF protected nigral DA neurons and striatal DA fibers, and attenuated d-amphetamine-induced rotational asymmetry in the 6-OHDA lesioned rats. To the best of our knowledge, this is the first report that hGDNF gene transfer by Tet-On lentivirus vectors is tightly regulated in rat brain, and Dox-induced hGDNF is functional in neuroprotection of nigral DA neurons in a rat model of parkinsonism. PMID:24997241

Chen, Sha-Sha; Yang, Chun; Hao, Fei; Li, Chen; Lu, Tao; Zhao, Li-Ru; Duan, Wei-Ming

2014-11-01

133

Depression and Parkinson's Disease  

MedlinePLUS

... see the NIMH booklet on Depression . What is Parkinson's disease? Parkinson's disease is a chronic disorder that ... or prevent Parkinson's disease. How are depression and Parkinson's disease linked? For people with depression and Parkinson's ...

134

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

PubMed

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

2013-04-01

135

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. PMID:23573240

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

2013-01-01

136

The Parkinson's disease death rate: carbidopa and vitamin B6.  

PubMed

The only indication for carbidopa and benserazide is the management of L-3,4-dihydroxyphenylalanine (L-dopa)-induced nausea. Both drugs irreversibly bind to and permanently deactivate pyridoxal 5'-phosphate (PLP), the active form of vitamin B6, and PLP-dependent enzymes. PLP is required for the function of over 300 enzymes and proteins. Virtually every major system in the body is impacted directly or indirectly by PLP. The administration of carbidopa and benserazide potentially induces a nutritional catastrophe. During the first 15 years of prescribing L-dopa, a decreasing Parkinson's disease death rate was observed. Then, in 1976, 1 year after US Food and Drug Administration approved the original L-dopa/carbidopa combination drug, the Parkinson's disease death rate started increasing. This trend has continued to the present, for 38 years and counting. The previous literature documents this increasing death rate, but no hypothesis has been offered concerning this trend. Carbidopa is postulated to contribute to the increasing Parkinson's disease death rate and to the classification of Parkinson's as a progressive neurodegenerative disease. It may contribute to L-dopa tachyphylaxis. PMID:25364278

Hinz, Marty; Stein, Alvin; Cole, Ted

2014-01-01

137

The effect of piribedil on L-DOPA-induced dyskinesias in a rat model of Parkinson's disease: differential role of ?(2) adrenergic mechanisms.  

PubMed

Piribedil is a non-ergoline, dopamine D(2)/D(3) receptor agonist with ?(2) adrenoceptor antagonist properties that has been used in the treatment of Parkinson's disease (PD). Noradrenergic neurotransmission may be involved in the pathogenesis of dyskinesias induced by chronic treatment with L-DOPA (3,4-dihydroxyphenylalanine, levodopa), but its role in the in vivo action of piribedil or on different subclasses of abnormal involuntary movements (AIMs) remains unclear. The aims of this study were therefore (1) to investigate the anti-dyskinetic effects of piribedil on L-DOPA-induced contralateral turning behaviour, locomotive dyskinesias (LD), axial dystonia (AD), orolingual dyskinesia (OD) and forelimb dyskinesia (FD) and (2) to compare these effects to the ?(2) adrenoceptor antagonist, idazoxan, or the ?(2) adrenoceptor agonist, clonidine. Rats were unilaterally lesioned with 6-hydroxydopamine (6-OHDA) and injected intraperitoneally twice daily with L-DOPA methylester (12.5 mg/kg) and benserazide (3.25 mg/kg). After 3 weeks, the effects of piribedil (5, 15, 40 mg/kg), clonidine (0.15 mg/kg), idazoxan (10 mg/kg) and combinations of these drugs were scored during 2 h. Pre-treatment with 5 and 40 mg/kg, but not 15 mg/kg, of piribedil reduced turning behaviour and AD, OD and FD, but piribedil increased LD at the 40 mg/kg doses compared to the L-DOPA group. Idazoxan induced similar effects as piribedil (40 mg/kg), except that it had no effect on LD. Idazoxan blocked the effect of piribedil on AD and FD. Clonidine reduced all AIMs except OD, possibly because of its sedative effect. Clonidine blocked the effect of piribedil on AD, OD and FD. These data suggest a differential involvement of ?(2) adrenergic receptors in the action of piribedil on different subclasses of L-DOPA-induced dyskinesias. PMID:22592937

Gerlach, Manfred; Halley, Paul; Riederer, Peter; van den Buuse, Maarten

2013-01-01

138

Diabetes and the Risk of Developing Parkinson's Disease in Denmark  

PubMed Central

OBJECTIVE Insulin contributes to normal brain function. Previous studies have suggested associations between midlife diabetes and neurodegenerative diseases, including Parkinson’s disease. Using Danish population registers, we investigated whether a history of diabetes or the use of antidiabetes drugs was associated with Parkinson’s disease. RESEARCH DESIGN AND METHODS From the nationwide Danish Hospital Register hospital records, we identified 1,931 patients with a first-time diagnosis of Parkinson’s disease between 2001 and 2006. We randomly selected 9,651 population control subjects from the Central Population Registry and density matched them by birth year and sex. Pharmacy records comprising all antidiabetes and anti-Parkinson drug prescriptions in Denmark were available. Odds ratios (ORs) were estimated by logistic regression models. RESULTS Having diabetes, as defined by one or more hospitalizations and/or outpatient visits for the condition, was associated with a 36% increased risk of developing Parkinson’s disease (OR 1.36 [95% CI 1.08–1.71]). Similarly, diabetes defined by the use of any antidiabetes medications was associated with a 35% increased Parkinson’s disease risk (1.35 [1.10–1.65]). When diabetes was defined as the use of oral antidiabetes medications, effect estimates were stronger in women (2.92 [1.34–6.36]), whereas when diabetes was defined as any antidiabetes drug prescription, patients with early-onset Parkinson’s disease were at highest risk (i.e., Parkinson’s disease diagnosed before the age of 60 years; 3.07 [1.65–5.70]). CONCLUSIONS We found that a diagnosis of, or treatment received for, diabetes was significantly associated with an increased risk of developing Parkinson’s disease, especially younger-onset Parkinson’s disease. Our results suggest a common pathophysiologic pathway between the two diseases. Future studies should take age at Parkinson’s disease onset into account. PMID:21411503

Schernhammer, Eva; Hansen, Johnni; Rugbjerg, Kathrine; Wermuth, Lene; Ritz, Beate

2011-01-01

139

Functional characterization of drug-induced experimental papillary necrosis  

Microsoft Academic Search

Functional characterization of drug-induced experimental papillary necrosis. The functional expression of papillary necrosis was investigated with a model of drug-induced papillary necrosis. Bromoethylamine hydrobromide (BEA) administration to rats uniformly resulted in the development of papillary necrosis. All studies were performed 24 hours after BEA administration with the exception of the electrolyte balance studies, which were performed during the 72 hours

Jose A L Arruda; Sandra Sabatini; Pradeep K Mehta; Brijnandan Sodhi; Robert Baranowski

1979-01-01

140

Proposed Motor Scoring System in a Porcine Model of Parkinson's Disease induced by Chronic Subcutaneous Injection of MPTP  

PubMed Central

Destruction of dopaminergic neurons in the substantia nigra pars compacta (SNpc) is a common pathophysiology of Parkinson's disease (PD). Characteristics of PD patients include bradykinesia, muscle rigidity, tremor at rest and disturbances in balance. For about four decades, PD animal models have been produced by toxin-induced or gene-modified techniques. However, in mice, none of the gene-modified models showed all 4 major criteria of PD. Moreover, distinguishing between PD model pigs and normal pigs has not been well established. Therefore, we planned to produce a pig model for PD by chronic subcutaneous administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), neurotoxin. Changes in behavioral patterns of pigs were thoroughly evaluated and a new motor scoring system was established for this porcine model that was based on the Unified Parkinson's Disease Rating Scale (UPDRS) in human PD patients. In summary, this motor scoring system could be helpful to analyze the porcine PD model and to confirm the pathology prior to further examinations, such as positron emission tomography-computed tomography (PET-CT), which is expensive, and invasive immunohistochemistry (IHC) of the brain.

Moon, Joon Ho; Kim, Ji Ho; Im, Hyung-Jun; Lee, Dong Soo; Park, Eun Jung; Song, Kilyoung; Oh, Hyun Ju; Hyun, Su Bin; Kang, Sang Chul; Kim, Hyunil; Moon, Hyo Eun; Park, Hyung Woo; Lee, Hong Jae; Kim, Eun Ji; Kim, Seokjoong

2014-01-01

141

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

2009-01-01

142

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

2011-01-01

143

Ventricular Bigeminy after Subcutaneous Administration of Apomorphine in a Patient with Refractory Parkinson's Disease: A Case Report  

PubMed Central

Apomorphine is a well established treatment for the management of sudden, unexpected and refractory levodopa-induced “off” states in fluctuating Parkinson’s disease either as bolus injections or as continuous infusions. Incidents of atrial fibrillation associated with the administration of the drug have been reported in the past but no incidents of ventricular arrhythmias. We report a case of ventricular bigeminy recorded in a female patient after the administration of apomorphine. PMID:24868418

Kaminioti, Anastasia N.; Nikitas, Georgios T.; Terlis, Apostolos K.; Manolis, Athanasios G.; Thomaides, Thomas; Panousopoulou, Aggeliki N.

2013-01-01

144

PACAP Protects Against Salsolinol-Induced Toxicity in Dopaminergic SH-SY5Y Cells: Implication for Parkinson's Disease  

PubMed Central

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an endogenous 38 amino acid containing neuropeptide with various cytoprotective functions including neuroprotection. Administration of PACAP has been shown to reduce damage induced by ischemia, trauma or exogenous toxic substances. Moreover, mice deficient in PACAP are more vulnerable to damaging insults. In this study we sought to determine whether PACAP may also be protective against salsolinol-induced toxicity in SH-SY5Y cells and if so, elucidate its mechanism(s) of action. Salsolinol (SALS) is an endogenous dopamine metabolite with selective toxicity to nigral dopaminergic neurons, which are directly implicated in Parkinson’s disease (PD). SH-SY5Y cells, derived from human neuroblastoma cells express high levels of dopaminergic activity and are used extensively as a model to study these neurons. Exposure of SH-SY5Y cells to 400uM SALS for 24 h resulted in approximately 50% cell death that was mediated by apoptosis as determined by cell flow cyotmetry and increases in caspase 3 levels. Cellular toxicity was also associated with reductions in brain-derived neurotrophic factor (BDNF) and phosphorylated cyclic AMP response element-binding (p-CREB) protein. Pretreatment with PACAP dose-dependently attenuated SALS-induced toxicity and the associated apoptosis and the chemical changes. PACAP receptor antagonist PACAP 6-38 in turn, dose-dependently blocked the effects of PACAP. Neither PACAP nor PACAP antagonist had any effect of its own on cellular viability. These results suggest protective effects of PACAP in a cellular model of PD. Hence, PACAP or its agonists could be of therapeutic benefit in PD. PMID:23625270

Brown, Dwayne; Tamas, Andrea; Reglodi, Dora; Tizabi, Yousef

2013-01-01

145

Adverse drug reactions induced by valproic acid.  

PubMed

Valproic acid is a widely-used first-generation antiepileptic drug, prescribed predominantly in epilepsy and psychiatric disorders. VPA has good efficacy and pharmacoeconomic profiles, as well as a relatively favorable safety profile. However, adverse drug reactions have been reported in relation with valproic acid use, either as monotherapy or polytherapy with other antiepileptic drugs or antipsychotic drugs. This systematic review discusses valproic acid adverse drug reactions, in terms of hepatotoxicity, mitochondrial toxicity, hyperammonemic encephalopathy, hypersensitivity syndrome reactions, neurological toxicity, metabolic and endocrine adverse events, and teratogenicity. PMID:23792104

Nanau, Radu M; Neuman, Manuela G

2013-10-01

146

The predictive validity of the drug-naive bilaterally MPTP-treated monkey as a model of Parkinson's disease: effects of L-DOPA and the D1 agonist SKF 82958.  

PubMed

The aim of this study was twofold: (1) to study the predictive validity of the drug-naive, bilaterally MPTP-treated monkey as an animal model of Parkinson's disease (PD), and (2) to investigate the therapeutic and undesired effects of the D1 agonist SKF 82958 as compared to L-DOPA treatment, in drug-naive and L-DOPA pretreated monkeys. A detailed ethogram was used, allowing the separation of therapeutic and undesired effects. Eight weeks after bilateral intracarotid MPTP administration, SKF 82958 (1 mg/kg, n = 4, SKF 82958, naive group) or methyl-L-DOPA + carbi-dopa (10 + 2.5 mg/kg, n = 4, L-DOPA group) was administered intramuscularly for 22 days. After a drug-free period of eight weeks, the L-DOPA group was treated with SKF 82958 for 22 days (SKF 82959, 1 mg/kg, n=4, pretreated). All drug treatments increased the parameters used classically to evaluate dopaminergic drugs, namely body displacement, dyskinesia and dystonia. However, the new detailed analysis revealed that L-DOPA, but not SKF 82958, had therapeutic effects, reflected by an increase in goal-directed fore-limb use. SKF 82958, but not L-DOPA, induced additional undesired effects; including epileptoid behaviours in both drug-naive and drug-pretreated monkeys. In one L-DOPA-unresponsive monkey, SKF 82958 did induce minor therapeutic effects, as well as undesired effects. Although the effects of SKF 82958 on fore-limb movements, rotational behaviours and body displacement were comparable in the naive and pretreated group, SKF 82958 re-initiated undesired effects in the L-DOPA pretreated group from day one. It is concluded that the bilaterally MPTP-treated monkey is an animal model with predictive validity for PD: it adequately predicts the therapeutic effects and undesired effects of L-DOPA. Furthermore, it is concluded that SKF 82958 is less effective than L-DOPA in the treatment of PD, because it did not induce therapeutic effects, but instead elicited several undesired effects. PMID:10780830

Andringa, G; Lubbers, L; Drukarch, B; Stoof, J C; Cools, A R

1999-03-01

147

Identification of drugs inducing phospholipidosis by novel in vitro data.  

PubMed

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

2012-11-01

148

FDA-approved drug labeling for the study of drug-induced liver injury.  

PubMed

Drug-induced liver injury (DILI) is a leading cause of drugs failing during clinical trials and being withdrawn from the market. Comparative analysis of drugs based on their DILI potential is an effective approach to discover key DILI mechanisms and risk factors. However, assessing the DILI potential of a drug is a challenge with no existing consensus methods. We proposed a systematic classification scheme using FDA-approved drug labeling to assess the DILI potential of drugs, which yielded a benchmark dataset with 287 drugs representing a wide range of therapeutic categories and daily dosage amounts. The method is transparent and reproducible with a potential to serve as a common practice to study the DILI of marketed drugs for supporting drug discovery and biomarker development. PMID:21624500

Chen, Minjun; Vijay, Vikrant; Shi, Qiang; Liu, Zhichao; Fang, Hong; Tong, Weida

2011-08-01

149

Glutamate receptors as therapeutic targets for Parkinson’s disease  

PubMed Central

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor symptoms including tremor and bradykinesia. The primary pathophysiology underlying PD is the degeneration of dopaminergic neurons of the substantia nigra pars compacta. Loss of these neurons causes pathological changes in neurotransmission in the basal ganglia motor circuit. The ability of ionotropic and metabotropic glutamate receptors to modulate neurotransmission throughout the basal ganglia suggests that these receptors may be targets for reversing the effects of altered neurotransmission in PD. Studies in animal models suggest that modulating the activity of these receptors may alleviate the primary motor symptoms of PD as well as side effects induced by dopamine replacement therapy. Moreover, glutamate receptor ligands may slow disease progression by delaying progressive dopamine neuron degeneration. Antagonists of NMDA receptors have shown promise in reversing motor symptoms, levodopa-induced dyskinesias, and neurodegeneration in preclinical PD models. The effects of drugs targeting AMPA receptors are more complex; while antagonists of these receptors exhibit utility in the treatment of levodopa-induced dyskinesias, AMPA receptor potentiators show promise for neuroprotection. Pharmacological modulation of metabotropic glutamate receptors (mGluRs) may hold even more promise for PD treatment due to the ability of mGluRs to fine-tune neurotransmission. Antagonists of mGluR5, as well as activators of group II mGluRs and mGluR4, have shown promise in several animal models of PD. These drugs reverse motor deficits in addition to providing protection against neurodegeneration. Glutamate receptors therefore represent exciting targets for the development of novel pharmacological therapies for PD. PMID:19702565

Johnson, Kari A.; Conn, P. Jeffrey

2010-01-01

150

Antitubercular drug-induced violent suicide of a hospitalised patient.  

PubMed

We present a case where a young adult male, on treatment for multidrug-resistance tuberculosis (MDR-TB), developed drug-induced psychosis. The psychiatric symptoms were ascribed to the anti-TB drug and were duly withdrawn by the treating doctors and supplemented with other drugs. However, the victim continued to have psychiatric symptoms and committed suicide in the hospital. He ended his life in a violent manner by stabbing and cutting himself with a kitchen knife. The case is briefly reported in this paper with a discussion on anti-TB drug-induced psychiatric effects leading to suicide. PMID:24395874

Behera, C; Krishna, Karthik; Singh, H R

2014-01-01

151

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. PMID:23626796

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

2013-01-01

152

Dopamine Agonists and their risk to induce psychotic episodes in Parkinson's disease: a case-control study  

PubMed Central

Background Psychosis is rare in untreated patients with Parkinson's disease (PD) but the prevalence rises to 40% during dopaminergic treatment. So far, no systematic comparison of the psychogenic potential of different dopaminergic drugs had been performed. Methods Eighty PD patients with psychotic episodes were compared to an age-matched control group of PD patients without psychotic episodes (n = 120) in a cross-sectional retrospective study. Results We found a positive correlation between psychotic episodes and dementia, number of concomitant medication, and pergolide intake. Odds ratio calculation confirmed the association with dementia. With respect to dopaminergic treatment, pergolide showed the highest odds ratio, levodopa the lowest. An adjusted logistic regression model confirmed the strong association with psychotic episodes and pergolide and no association with levodopa (adjusted odds ratio 2.01 and 0.11, respectively). Conclusion The analysis indicates that dementia and concomitant medication are factors in PD associated with psychotic symptoms. Furthermore, different dopaminergic drugs showed markedly different associations with psychotic symptoms PMID:19515253

Ecker, Daniel; Unrath, Alexander; Kassubek, Jan; Sabolek, Michael

2009-01-01

153

Factors affecting drug-induced liver injury: antithyroid drugs as instances  

PubMed Central

Methimazole and propylthiouracil have been used in the management of hyperthyroidism for more than half a century. However, hepatotoxicity is one of the most deleterious side effects associated with these medications. The mechanism(s) of hepatic injury induced by antithyroid agents is not fully recognized yet. Furthermore, there are no specific tools for predicting the occurrence of hepatotoxicity induced by these drugs. The purpose of this article is to give an overview on possible susceptibility factors in liver injury induced by antithyroid agents. Age, gender, metabolism characteristics, alcohol consumption, underlying diseases, immunologic mechanisms, and drug interactions are involved in enhancing antithyroid drugs-induced hepatic damage. An outline on the clinically used treatments for antithyroid drugs-induced hepatotoxicity and the potential therapeutic strategies found to be effective against this complication are also discussed. PMID:25320726

Niknahad, Hossein; Jamshidzadeh, Akram; Abdoli, Narges

2014-01-01

154

Parkinson's Disease Dementia  

MedlinePLUS

Parkinson's Disease Dementia Tweet Parkinson's disease dementia is an impairment in thinking and reasoning that eventually affects ... disease. About Symptoms Diagnosis Causes & risks Treatments About Parkinson's disease dementia The brain changes caused by Parkinson's ...

155

Pain in Parkinson's Disease  

MedlinePLUS

... ways to manage it. Causes of Pain in Parkinson’s Researchers classify pain based on the separation of ... syndrome involving both nociceptive and neuropathic pain. Your Parkinson’s specialist, working with a pain specialist, may select ...

156

Neuroprotective effect of the chemical chaperone, trehalose in a chronic MPTP-induced Parkinson's disease mouse model.  

PubMed

Parkinson's disease (PD) is a progressive motor disease of unknown etiology in the majority of cases. The clinical features of PD emerge due to selective degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNc), which project to the caudate putamen (CPu) where they release DA. In the current in vivo mouse model study, we tested trehalose for its ability to protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced damage to DA neurons. Trehalose is a naturally occurring disaccharide present in plants and animals and appears capable of protecting cells against various environmental stresses. The effect of trehalose is likely due to its action as a pharmacological chaperone which promotes protein stability. In the present study, there were four treatment groups: saline only (control); probenecid only; MPTP+probenecid; and trehalose+MPTP+probenecid. MPTP-induced losses in tyrosine hydroxylase and DA transporter immunoreactivity in the ventral midbrain SNc and CPu were significantly reduced by trehalose. Decreases in CPu dopamine levels produced by MPTP were also blocked by trehalose. Microglial activation and astrocytic hypertrophy induced by MPTP were greatly reduced by trehalose, indicating protection against neuroinflammation. These effects are commensurate with the observed trehalose sparing of motor deficits produced by MPTP in this mouse model. Two tight junctional proteins, ZO-1 and occludin, are downregulated following MPTP treatment and trehalose blocks this effect. Likewise, the glucose transporter-1 that is expressed in brain endothelial cells is also protected by trehalose from MPTP-induced down-regulation. This study is the first to demonstrate using fluoro-turoquoise FT gel perfusion techniques, the protection afforded by trehalose from MPTP-induced damage to microvessels and endothelial and suggests that trehalose therapy may have the potential to slow or ameliorate PD pathology. PMID:25064079

Sarkar, Sumit; Chigurupati, Srinivasulu; Raymick, James; Mann, Dushyant; Bowyer, John F; Schmitt, Tom; Beger, Richard D; Hanig, Joseph P; Schmued, Larry C; Paule, Merle G

2014-09-01

157

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: akanthas@iastate.edu

2009-10-15

158

Epidemiology of cutaneous drug-induced reactions.  

PubMed

Cutaneous reactions represent in many surveillance systems, the most frequent adverse events attributable to drugs. The spectrum of clinical manifestations is wide and virtually encompasses any known dermatological disease. The introduction of biological agents and so-called targeted therapies has further enlarged the number of reaction patterns especially linked with cytokine release or in balance. The frequency and clinical patterns of cutaneous reactions are influenced by drug use, prevalence of specific conditions (e.g., HIV infection) and pharmacogenetic traits of a population, and they may vary greatly among the different populations around the world. Studies of reaction rates in cohorts of hospitalized patients revealed incidence rates ranging from, 1 out 1000 to 2 out 100 of all hospitalized patients. For drugs such as aminopenicillines and sulfamides the incidence of skin reactions is in the order of 3-5 cases out of 100 exposed people. Although the majority of cutaneous reactions are mild and self-limiting, there are reactions such as Stevens Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) which are associated with significant morbidity and mortality. Surveillance systems routed on sound epidemiologic methodology, are needed to raise signals and to assess risks associated with specific reactions and drug exposures. Identification of risk factors for adverse reactions and appropriate genetic screening of groups at higher risk may improve the outcomes of skin reactions. PMID:24819642

Naldi, L; Crotti, S

2014-04-01

159

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. PMID:23112538

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

2012-01-01

160

Modulatory effects of sodium salicylate on the factors affecting protein aggregation during rotenone induced Parkinson's disease pathology.  

PubMed

Sodium salicylate (SS) confers neuroprotection in various models of Parkinson's disease (PD) but the mechanisms behind its protective actions are not clear. PD pathology is multifactorial involving numerous processes such as protein aggregation, dysfunction of protein degradation machinery and apoptosis. Detailed evaluation of effects of SS on these processes can provide an insight into the mechanism of neuroprotection by SS in PD pathology. In a rotenone (2mg/kg b.w.) based rat model of PD, SS (100mg/kg b.w.) was administered in conjunction. Drug treatments continued for 5 weeks after which various analyses were conducted using mid-brain tissue. IHC analysis revealed a decline in the aggregation of ?-synuclein and ubiquitin with SS supplementation. These effects might be mediated by the elevation in HSF-1, HSP-40, and HSP-27 expression following SS co-treatment. This HSP upregulation helped in the improvement in proteasome activity as well as expression. Further, IHC analysis revealed that SS co-treatment prevented the activation of astrocytes caused by rotenone. Since astrocytes are involved in maintenance of glutathione (GSH) homeostasis, it resulted in a concomitant improvement in the GSH levels. As a result, decrease in apoptosis as indicated by caspase-9 and caspase-3 expression as well as TUNEL assay was also observed in the SS conjunction group. Our results indicate that besides being a known free radical scavenger and anti-inflammatory compound, SS can provide neuroprotection by differently upregulating the HSPs and reducing the protein aggregation burden. PMID:24852355

Thakur, Poonam; Nehru, Bimla

2014-09-01

161

Parkinson's Disease  

MedlinePLUS

... cells make and use a brain chemical called dopamine (say: DOH-puh-meen) to send messages to ... coordinate body movements. When someone has Parkinson's disease, dopamine levels are low. So, the body doesn't ...

162

Parkinson's disease  

MedlinePLUS

Nerve cells use a brain chemical called dopamine to help control muscle movement. With Parkinson's disease, the brains cells that make dopamine slowly die. Without dopamine, the cells that control movement ...

163

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

Microsoft Academic Search

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

Jin-zhong Huang; Ying-zhu Chen; Min Su; Hui-fen Zheng; Ya-ping Yang; Jing Chen; Chun-Feng Liu

2010-01-01

164

Contemporary review of drug-induced pancreatitis: A different perspective  

PubMed Central

Although gallstone and alcohol use have been considered the most common causes of acute pancreatitis, hundreds of frequently prescribed medications are associated with this disease state. The true incidence is unknown since there are few population based studies available. The knowledge of drug induced acute pancreatitis is limited by the availability and the quality of the evidence as the majority of data is extrapolated from case reports. Establishing a definitive causal relationship between a drug and acute pancreatitis poses a challenge to clinicians. Several causative agent classification systems are often used to identify the suspected agents. They require regular updates since new drug induced acute pancreatitis cases are reported continuously. In addition, infrequently prescribed medications and herbal medications are often omitted. Furthermore, identification of drug induced acute pancreatitis with new medications often requires accumulation of post market case reports. The unrealistic expectation for a comprehensive list of medications and the multifactorial nature of acute pancreatitis call for a different approach. In this article, we review the potential mechanisms of drug induced acute pancreatitis and provide the perspective of deductive reasoning in order to allow clinicians to identify potential drug induced acute pancreatitis with limited data.

Hung, Whitney Y; Abreu Lanfranco, Odaliz

2014-01-01

165

Contemporary review of drug-induced pancreatitis: A different perspective.  

PubMed

Although gallstone and alcohol use have been considered the most common causes of acute pancreatitis, hundreds of frequently prescribed medications are associated with this disease state. The true incidence is unknown since there are few population based studies available. The knowledge of drug induced acute pancreatitis is limited by the availability and the quality of the evidence as the majority of data is extrapolated from case reports. Establishing a definitive causal relationship between a drug and acute pancreatitis poses a challenge to clinicians. Several causative agent classification systems are often used to identify the suspected agents. They require regular updates since new drug induced acute pancreatitis cases are reported continuously. In addition, infrequently prescribed medications and herbal medications are often omitted. Furthermore, identification of drug induced acute pancreatitis with new medications often requires accumulation of post market case reports. The unrealistic expectation for a comprehensive list of medications and the multifactorial nature of acute pancreatitis call for a different approach. In this article, we review the potential mechanisms of drug induced acute pancreatitis and provide the perspective of deductive reasoning in order to allow clinicians to identify potential drug induced acute pancreatitis with limited data. PMID:25400984

Hung, Whitney Y; Abreu Lanfranco, Odaliz

2014-11-15

166

Living with Parkinson's  

MedlinePLUS

Living with Parkinson’sParkinson’s is a part of my life, but it is not life itself.” --David, 56, three years after diagnosis While your journey with Parkinson’s is different from anyone else's, from age of ...

167

Pulmonary and generalized lysosomal storage induced by amphiphilic drugs.  

PubMed Central

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. Images FIGURE 1. FIGURE 2. FIGURE 3. FIGURE 4. FIGURE 5. FIGURE 6. FIGURE 7. FIGURE 8. FIGURE 9. FIGURE 10. PMID:6376111

Hruban, Z

1984-01-01

168

The Brain Lesion Responsible for Parkinsonism After Carbon Monoxide Poisoning  

Microsoft Academic Search

Background: Parkinsonism is a common neurological sequela of carbon monoxide (CO) poisoning, but its pathophysiological mechanism has yet to be clarified. Objectives: To describe a married couple who were both affected by CO poisoning, but only 1 of whom devel- oped CO-induced parkinsonism, and to discuss the pos- sible underlying pathophysiological mechanism of CO- induced parkinsonism by comparing the neuroimaging

Young H. Sohn; Yong Jeong; Hyun S. Kim; Joo H. Im; Jin-Soo Kim

2000-01-01

169

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

2005-01-01

170

TOM40 mediates mitochondrial dysfunction induced by ?-synuclein accumulation in Parkinson's disease.  

PubMed

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. PMID:23626796

Bender, Andreas; Desplats, Paula; Spencer, Brian; Rockenstein, Edward; Adame, Anthony; Elstner, Matthias; Laub, Christoph; Mueller, Sarina; Koob, Andrew O; Mante, Michael; Pham, Emily; Klopstock, Thomas; Masliah, Eliezer

2013-01-01

171

Alterations in bioenergetic function induced by Parkinson's disease mimetic compounds: Lack of correlation with superoxide generation  

PubMed Central

In vitro and in vivo models of Parkinson's disease (PD) suggest that increased oxidant production leads to mitochondrial dysfunction in dopaminergic neurons and subsequent cell death. However, it remains unclear if cell death in these models is caused by inhibition of mitochondrial function or oxidant production. The objective of the present study was to determine the relationship between mitochondrial dysfunction and oxidant production in response to multiple PD neurotoxicant mimetics. MPP+ caused a dose-dependent decrease in the basal oxygen consumption rate (OCR) in dopaminergic N27 cells, indicating a loss of mitochondrial function. In parallel, we found that MPP+ only modestly increased oxidation of hydroethidine as a diagnostic marker of superoxide production in these cells. Similar results were found using rotenone as a mitochondrial inhibitor, or 6-hydroxydopamine as a mechanistically distinct PD neurotoxicant, but not with exposure to paraquat. Additionally, the Extracellular Acidification Rate, used as a marker of glycolysis, was stimulated to compensate for OCR inhibition after exposure to MPP+, rotenone, or 6-hydroxydopamine, but not paraquat. Together these data indicate that MPP+, rotenone and 6-hydroxydopamine dramatically shift bioenergetic function away from the mitochondria and towards glycolysis in N27 cells. PMID:22708893

Dranka, Brian P.; Zielonka, Jacek; Kanthasamy, Anumantha G.; Kalyanaraman, Balaraman

2012-01-01

172

Contrast between innovator drug- and generic drug-induced renal dysfunction on coronary angiography (CONTRAST study).  

PubMed

Contrast-induced nephropathy (CIN) has gained increasing attention in clinical practice, particularly during coronary angiography (CAG). However, some "bioequivalent" generic (GE) drugs are less effective than the innovator (IN) drug. Therefore, the aim of this study was to compare contrast media (IN drug)-induced renal dysfunction with contrast media (GE drug)-induced dysfunction. We enrolled 44 patients who underwent elective CAG or percutaneous coronary intervention (PCI) and randomly divided them into two groups that received contrast media (Iohexol, nonionic and low-osmolality contrast agent) containing either IN drug (Omnipaque) or GE drug (Iopaque). Blood and urine sampling were performed before and after (24 and 48 h) CAG or PCI. Biochemical parameters in blood (serum creatinine, cystatin C, high-sensitivity C-reactive protein, and pentraxin-3) and urine (urinary albumin/Cr and liver-type fatty acid binding protein/Cr) were measured. There were no significant differences in the biochemical parameters at baseline between the groups. In addition, there were no differences in changes in biochemical parameters in blood and urine before and after CAG or PCI between the groups, although one patient in the GE group had CIN. The degree of contrast in Iopaque-induced renal dysfunction was comparable with that in Omnipaque-induced dysfunction. PMID:24072136

Nakamura, Ayumi; Miura, Shin-Ichiro; Sugihara, Makoto; Miyase, Yuiko; Norimatsu, Kenji; Shiga, Yuhei; Nishikawa, Hiroaki; Saku, Keijiro

2014-09-01

173

Nicotine and Parkinson's disease: Implications for therapy  

Microsoft Academic Search

Accumulating evidence suggests that nicotine, a drug that stimulates nicotinic acetylcholine receptors, may be of therapeutic value in Parkinson's disease. Beneficial effects may be several-fold. One of these is a protective action against nigrostriatal damage. This possibility stems from the results of epidemiological studies that consistently demonstrate an inverse correlation between tobacco use and Parkinson's disease. This reduced incidence of

Maryka Quik; Kathryn O'Leary; Caroline M. Tanner

2008-01-01

174

Drug-induced renal Fanconi syndrome.  

PubMed

A number of therapeutic drugs are toxic to the kidney proximal tubule (PT) and can cause the renal Fanconi syndrome (FS). The most frequently implicated drugs are cisplatin, ifosfamide, tenofovir, sodium valproate and aminoglycoside antibiotics, and the new oral iron chelator deferasirox has also recently been associated with FS. The incidence of full or partial FS is almost certainly under-estimated due to a lack of appropriate systematic studies, variations in definitions of tubular dysfunction and under-reporting of adverse events. The clinical features of FS are amino aciduria, low molecular weight proteinuria, hypophosphataemia, metabolic acidosis and glycosuria. The most serious complications are bone demineralization from urinary phosphate wasting and progressive decline in kidney function. Commonly used tests for kidney function such as estimated glomerular filtration rate and urine albumin/creatinine ratio are not sensitive markers of PT toxicity; patients at risk should thus be monitored with more appropriate tests, and drugs should be stopped or reduced in dose if toxicity occurs. Substantial recovery of PT function can occur after withdrawal of therapy, but this can take months and chronic damage may persist in some cases. PMID:24368854

Hall, A M; Bass, P; Unwin, R J

2014-04-01

175

LC/MS characterization of rotenone induced cardiolipin oxidation in human lymphocytes: Implications for mitochondrial dysfunction associated with Parkinson's disease  

PubMed Central

Scope Rotenone is a toxicant believed to contribute to the development of Parkinson's disease. Methods and results Using human peripheral blood lymphocytes we demonstrated that exposure to rotenone resulted in disruption of electron transport accompanied by the production of reactive oxygen species, development of apoptosis and elevation of peroxidase activity of mitochondria. Employing LC/MS based lipidomics/oxidative lipidomics we characterized molecular species of cardiolipin (CL) and its oxidation/hydrolysis products formed early in apoptosis and associated with the rotenone-induced mitochondrial dysfunction. Conclusions The major oxidized CL species - tetra-linoleoyl-CL – underwent oxidation to yield epoxy-C18:2 and dihydroxy-C18:2 derivatives predominantly localized in sn-1 and sn-2 positions, respectively. In addition, accumulation of mono-lyso-CL species and oxygenated free C18:2 were detected in rotenone-treated lymphocytes. These oxidation/hydrolysis products may be useful for the development of new biomarkers of mitochondrial dysfunction. PMID:23650208

Tyurina, Yulia Y.; Winnica, Daniel E.; Kapralova, Valentina I.; Kapralov, Alexandr A.; Tyurin, Vladimir A.; Kagan, Valerian E.

2013-01-01

176

Drug-induced injury in the gastrointestinal tract.  

PubMed

Abnormalities of the gastrointestinal tract due to drug-induced injuries are common and often have important clinical consequences. Medications may cause damage by direct corrosive effects on mucosae or by alter processes, mucosal immunity, and local environmental conditions. The aim of this review is to guide practicing pathologists in the identification of drug-related injuries in gastrointestinal mucosal biopsies and resection specimens. Common causes of injury and their gross, endoscopic, and microscopic features are presented. PMID:24815941

Panarelli, Nicole C

2014-03-01

177

Addiction: A drug-induced disorder of memory reconsolidation  

PubMed Central

Persistent maladaptive memories that maintain drug seeking and are resistant to extinction are a hallmark of addiction. As such, disruption of memory reconsolidation after retrieval has received attention for its therapeutic potential. Unrestrained reconsolidation may have the opposite effect, leading to reiterative and cumulative strengthening of memory over long periods of time. Here we review the molecular mechanisms underlying reconsolidation of appetitive and drug-rewarded memories, and discuss how these findings contribute to our understanding of the nature of this process. Finally, we suggest that drug-induced alterations to signal transduction might lead to dysregulation of reconsolidation, causing enhancements of drug-related memory after retrieval, and significantly contribute to the compulsive drug seeking that is a core component of addiction. PMID:23415831

Tronson, Natalie C; Taylor, Jane R.

2013-01-01

178

In silico modeling to predict drug-induced phospholipidosis.  

PubMed

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

2013-06-01

179

Drug-induced methaemoglobinaemia. Treatment issues.  

PubMed

In normal erythrocytes, small quantities of methaemoglobin are formed constantly and are continuously reduced, almost entirely by the reduced nicotine adenine dinucleotide (NADH) diaphorase system, rather than the reduced nicotine adenine dinucleotide phosphate (NADPH) diaphorase system. Methaemoglobinaemias are usually the result of xenobiotics, either those that may directly oxidise haemoglobin or those that require metabolic activation to an oxidising species. The most clinically relevant direct methaemoglobin formers include local anaesthetics (such as benzocaine and, to a much lesser extent, prilocaine) as well as amyl nitrite and isobutyl nitrite, which have become drugs of abuse. Indirect, or metabolically activated, methaemoglobin formation by dapsone and primaquine may cause adverse reactions. The clinical consequences of methaemoglobinaemia are related to the blood level of methaemoglobin; dyspnoea, nausea and tachycardia occur at methaemoglobin levels of > or = 30%, while lethargy, stupor and deteriorating consciousness occur as methaemoglobin levels approach 55%. Higher levels may cause cardiac arrhythmias, circulatory failure and neurological depression, while levels of 70% are usually fatal. Cyanosis accompanied by a lack of responsiveness to 100% oxygen indicates a diagnosis of methaemoglobinaemia, which should be confirmed using a CO-oximeter. Pulse oximeters do not detect methaemoglobin and may give a misleading impression of patient oxygenation. Methaemoglobinaemia is treated with intravenous methylene blue (methyl-thioninium chloride; ;1 to 2 mg/kg of a 1% solution). If the patient does not respond, perhaps because of glucose-6-phosphate dehydrogenase (G6PD) deficiency or continued presence of toxin, admission to an intensive care unit and exchange transfusion may be required. Dapsone-mediated chronic methaemoglobin formation can be reduced by coadministration of cimetidine to aid patient tolerance. Increasing knowledge and awareness of drug-mediated acute methaemoglobinaemia among physicians should lead to prompt diagnosis and treatment of this potentially life-threatening condition. PMID:8828017

Coleman, M D; Coleman, N A

1996-06-01

180

Parkinson's UK Parkinson's UK Applicant Guide June 2012 Page 1  

E-print Network

Parkinson's UK Parkinson's UK Applicant Guide June 2012 Page 1 2012 INTERNAL USER GUIDE A Guide to the Parkinson's UK grant application system A Quick Guide for applicants applying for funding from Parkinson's UK Parkinson's UK web page: http://www.parkinsons.org.uk/ #12;Parkinson's UK Parkinson's UK Applicant

181

Drug-induced lysosomal storage of sulphated glycosaminoglycans  

Microsoft Academic Search

1.1. Certain compounds (e.g., the immunomodulator tilorone and congeners) are able to induce lysosomal storage of sulphated glycosaminoglycans (GAG), thus, producing cytological and biochemical alterations reminiscent of the inherited mucopolysaccharidoses. The drug-induced GAG storage has been studied in cultured fibroblasts of several species and in rats, and it is likely to occur also in humans.2.2. The cytological hallmarks of GAG

Jens Fischer; Heinz Lüllmann; Renate Lüllmann-Rauch

1996-01-01

182

Inflammatory Response in Parkinsonism  

Microsoft Academic Search

\\u000a Inflammatory responses have been proposed as important factors in dopaminergic neuro-degeneration in Parkinsonism. Increasing\\u000a evidence suggests that the alteration of the glial microenvironment induced by neuronal degeneration could be deleterious\\u000a to the remaining neurons. The activation of microglia\\/macrophages and reactive astrocytes may have a negative effect on the\\u000a surrounding parenchyma, perpetuating the neurodegenerative process. However, this alteration may also go

Carlos Barcia; Francisco Ros; María Angeles Carrillo; David Aguado-Llera; Carmen María Ros; Aurora Gómez; Cristina Nombela; Vicente Pablos; Emiliano Fernández-Villalba; Maria-Trinidad Herrero

183

National Parkinson Foundation, Inc.  

MedlinePLUS

Welcome to Parkinson.org Patients Do you have Parkinson’s Disease? Caregivers Are you a family member, friend or caregiver? Professionals Are ... or other health care professional? We Can Beat Parkinson’s! Stay Connected Signup to receive e-mail updates ...

184

In silico analyses of COMT, an important signaling cascade of dopaminergic neurotransmission pathway, for drug development of Parkinson's disease.  

PubMed

Catechol-O-methyltransferase (COMT) has a vital role for degradation of dopamine, a neurotransmitter, and this dopamine performs an important function in our mental and physical health. The scarcity of dopamine may lead to Parkinson's disease, and inhibition of COMT can stop dopamine metabolism. Here, we have carried out genomics and proteomics analyses of COMT in order to facilitate new inhibitors of COMT. For genomics analyses, we performed codon composition investigation of COMT gene which shows A+T content which is 53.3 %. For proteomics analyses, conservation patterns and residues (highly conserved amino acids GLU64, LEU65, GLY66, CYS69, GLY70, ALA77, GLU90, THR99, SER119, ASP136, LEU140, ASP141, THR164, ASN170, VAL171, and ILE172), binding grooves, binding pockets, binding and conformation with substrate, evaluation of amino acid composition (15 % leucine rich), high scoring hydrophobic segments, high scoring transmembrane segments, tandem and periodic repeats, and disulfide bonds (three numbers), sequence logos (maximum stack height of 3 b and minimum stack height of <0.5 b) have been investigated for COMT protein. Furthermore, using COMT sequences of different species (class Mammalia, class Amphibia, and class Pisces), a phylogenetic tree has been constructed to examine the evolutionary relationship among different species. PMID:22622642

Chakraborty, Chiranjib; Pal, Soumen; Doss, C George Priya; Wen, Zhi-Hong; Lin, Chan-Shing

2012-06-01

185

Drug-induced acne and rose pearl: similarities.  

PubMed

Drug-induced acne is a common skin condition whose classic symptoms can be similar to a rose pearl, as in the case of a male patient presenting with this condition after excessive use of a cream containing corticosteroids. PMID:24474128

Pontello, Rubens; Kondo, Rogerio Nabor

2013-01-01

186

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. PMID:19533803

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

2009-01-01

187

Combined treatment with acupuncture reduces effective dose and alleviates adverse effect of l-dopa by normalizing Parkinson's disease-induced neurochemical imbalance  

PubMed Central

This study first showed the behavioural benefits of novel combination therapy of l-dopa with acupuncture on Parkinson’s disease, and its underlying mechanisms within basal ganglia. The previous study reported that acupuncture may improve the motor function of a Parkinson’s disease (PD) mouse model by increasing the dopamine efflux and turnover ratio of dopamine. Hence, we hypothesised that combining l-dopa with acupuncture would have a behavioural benefit for those with PD. We performed unilateral injections of 6-OHDA into the striatum of C57Bl/6 mice to model hemi-Parkinsonian attributes. To test motor function and dyskinetic anomalies, we examined cylinder behaviour and abnormal involuntary movement (AIM), respectively. We found that (1) a 50% reduced dose of l-dopa (7.5 mg/kg) combined with acupuncture showed an improvement in motor function that was comparable to mice given the standard dose of l-dopa treatment (15 mg/kg) only, and that (2) the combination treatment (l-dopa +acupuncture) was significantly superior in reducing AIM scores when equivalent doses of l-dopa were used. The combination treatment also significantly reduces the abnormal increase of GABA contents in the substantia nigra compared to the standard l-dopa treatment. Furthermore, abnormal expression of FosB, the immediate early gene of l-dopa induced dyskinesia (LID), was mitigated in the striatum by the combination treatment. All of these results indicate that acupuncture enhances the benefits of l-dopa on motor function with reduced dose of l-dopa and alleviating LID by normalising neurochemical imbalance within the basal ganglia. PMID:24321617

Kim, Seung-Nam; Doo, Ah-Reum; Park, Ji-Yeun; Choo, Hyunwoo J.; Shim, Insop; Park, Jongbae J.; Chae, Younbyoung; Lee, Bena; Lee, Hyejung; Park, Hi-Joon

2014-01-01

188

Surgical Treatment of Dyskinesia in Parkinson's Disease  

PubMed Central

One of the main indications for stereotactic surgery in Parkinson’s disease (PD) is the control of levodopa-induced dyskinesia. This can be achieved by pallidotomy and globus pallidus internus (GPi) deep brain stimulation (DBS) or by subthalamotomy and subthalamic nucleus (STN) DBS, which usually allow for a cut down in the dosage of levodopa. DBS has assumed a pivotal role in stereotactic surgical treatment of PD and, in fact, ablative procedures are currently considered surrogates, particularly when bilateral procedures are required, as DBS does not produce a brain lesion and the stimulator can be programed to induce better therapeutic effects while minimizing adverse effects. Interventions in either the STN and the GPi seem to be similar in controlling most of the other motor aspects of PD, nonetheless, GPi surgery seems to induce a more particular and direct effect on dyskinesia, while the anti-dyskinetic effect of STN interventions is mostly dependent on a reduction of dopaminergic drug dosages. Hence, the si ne qua non-condition for a reduction of dyskinesia when STN interventions are intended is their ability to allow for a reduction of levodopa dosage. Pallidal surgery is indicated when dyskinesia is a dose-limiting factor for maintaining or introducing higher adequate levels of dopaminergic therapy. Also medications used for the treatment of PD may be useful for the improvement of several non-motor aspects of the disease, including sleep, psychiatric, and cognitive domains, therefore, dose reduction of medication withdrawal are not always a fruitful objective. PMID:24808889

Munhoz, Renato P.; Cerasa, Antonio; Okun, Michael S.

2014-01-01

189

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

Microsoft Academic Search

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 repre- sents a major limitation of the current technology since even low vector expression may alter the differ- entiation potential of the iPSCs or

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

2009-01-01

190

Understanding Suicide and Parkinson's Disease  

MedlinePLUS

... information. Learn More Press Releases Understanding Suicide and Parkinson’s Disease: PDF Response to Questions Regarding Suicide Risk and Medications for Parkinson's - Aug 20 2014 The Parkinson’s Disease Foundation (PDF), ...

191

[Drug-induced osteopathies. Drugs, pathogenesis, forms, diagnosis, prevention and therapy].  

PubMed

A number of drugs can have "side effects" on bone metabolism and formation, causing bone atrophy, impaired mineralisation, as well as osteonecrosis. In both clinical and general practitioner settings, these forms of bone damage have been hitherto considered as adverse drug side effects and have received insufficient attention; moreover, they have not been the subject of patient information. Preventive measures are not instigated prior to initiation of medication and even after onset of bone damage, therapeutic strategies are poorly implemented. Even fracture healing with its complex, staged course can be both positively and negatively influenced by a number of drugs and these effects require monitoring. Recommendations regarding practical screening and therapy of drug-induced osteopathies are presented. PMID:19888565

Bartl, R; Bartl, C; Gradinger, R

2009-12-01

192

[Drug-induced osteopathies. Drugs, pathogenesis, forms, diagnosis, prevention and therapy].  

PubMed

A number of drugs can have "side effects" on bone metabolism and formation, causing bone atrophy, impaired mineralisation, as well as osteonecrosis. In both clinical and general practitioner settings, these forms of bone damage have been hitherto considered as adverse drug side effects and have received insufficient attention; moreover, they have not been the subject of patient information. Preventive measures are not instigated prior to initiation of medication and even after onset of bone damage, therapeutic strategies are poorly implemented. Even fracture healing with its complex, staged course can be both positively and negatively influenced by a number of drugs and these effects require monitoring. Recommendations regarding practical screening and therapy of drug-induced osteopathies are presented. PMID:20146045

Bartl, R; Bartl, C; Gradinger, R

2010-03-01

193

Learning about Parkinson's Disease  

MedlinePLUS

... of Biological Chemistry , June 9, 2011 Learning About Parkinson's Disease What do we know about heredity and ... Disease What do we know about heredity and Parkinson's disease? Parkinson's disease (PD) is a neurological condition ...

194

Progression of Parkinson's Disease  

MedlinePLUS

Parkinson's HelpLine Learn More Educational Materials Do you want to know more about Parkinson's? PDF's materials provide ... out daily activities, and treatment complications. Severity of Parkinson's Below are some descriptions of mild, moderate and ...

195

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

2008-01-01

196

PNU-96391A (OSU6162) antagonizes the development of behavioral sensitization induced by dopamine agonists in a rat model for Parkinson’s Disease  

Microsoft Academic Search

PNU-96391A is a weak dopamine (DA) D2 receptor antagonist with behavioral stabilizing properties. Previous experiments revealed that PNU-96391A antagonizes the expression of L-DOPA induced behavioral sensitization (dyskinesias) in lesioned primates without inducing akinesia or reducing the anti-Parkinsonian efficacy of L-DOPA. This study evaluated the ability of PNU-96391A to block the development of DA agonist-induced behavioral sensitization in rats with unilateral

N. F Nichols; M. G Cimini; J. V Haas; B. A Staton; J Tedroff; K. A Svensson

2002-01-01

197

Asbestos, ergot drugs and the pleura  

Microsoft Academic Search

In this issue of the Journal, two groups of researchers with established experience in asbestos-induced respira- tory disease, independently report on patients with prior occupational exposure to asbestos, who developed exuda- tive pleural effusion and\\/or pleural thickening, while be- ing treated with bromocriptine for Parkinson's disease (1, 2). Ultimately, the pleural changes were largely rever- sible following drug withdrawal. Both

P. De Vuyst; P. Pfitzenmeyer; Ph. Camus

1997-01-01

198

In vitro validation of drug-induced phospholipidosis.  

PubMed

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

2012-01-01

199

PTTG1 Attenuates Drug-Induced Cellular Senescence  

PubMed Central

As PTTG1 (pituitary tumor transforming gene) abundance correlates with adverse outcomes in cancer treatment, we determined mechanisms underlying this observation by assessing the role of PTTG1 in regulating cell response to anti-neoplastic drugs. HCT116 cells devoid of PTTG1 (PTTG1?/?) exhibited enhanced drug sensitivity as assessed by measuring BrdU incorporation in vitro. Apoptosis, mitosis catastrophe or DNA damage were not detected, but features of senescence were observed using low doses of doxorubicin and TSA. The number of drug-induced PTTG1?/? senescent cells increased ?4 fold as compared to WT PTTG1-replete cells (p<0.001). p21, an important regulator of cell senescence, was induced ?3 fold in HCT116 PTTG1?/? cells upon doxorubicin or Trichostatin A treatment. Binding of Sp1, p53 and p300 to the p21 promoter was enhanced in PTTG1?/? cells after treatment, suggesting transcriptional regulation of p21. p21 knock down abrogated the observed senescent effects of these drugs, indicating that PTTG1 likely suppresses p21 to regulate drug-induced senescence. PTTG1 also regulated SW620 colon cancer cells response to doxorubicin and TSA mediated by p21. Subcutaneously xenografted PTTG1?/? HCT116 cells developed smaller tumors and exhibited enhanced responses to doxorubicin. PTTG1?/? tumor tissue derived from excised tumors exhibited increased doxorubicin-induced senescence. As senescence is a determinant of cell responses to anti-neoplastic treatments, these findings suggest PTTG1 as a tumor cell marker to predict anti-neoplastic treatment outcomes. PMID:21858218

Tong, Yunguang; Zhao, Weijiang; Zhou, Cuiqi; Wawrowsky, Kolja; Melmed, Shlomo

2011-01-01

200

Suspected drug-induced destructive cholangitis in a young dog.  

PubMed

A nine-month-old miniature doberman was referred for the evaluation of chronic icterus. History and clinical and histopathological findings were supportive of a diagnosis of drug-induced destructive cholangitis. The main histopathological findings were canalicular, centrilobular cholestasis and ductopenia with moderate inflammatory infiltrate. The dog had received three types of treatment for demodicosis before the onset of jaundice. Amoxicillin-clavulanate, amitraz, milbemycin oxime or an interaction between two of the three drugs may have been responsible for the destructive cholangitis. PMID:16761987

Gabriel, A; van den Ingh, T S G A M; Clercx, C; Peeters, D

2006-06-01

201

Methamphetamine and Parkinson's Disease  

PubMed Central

Parkinson's disease (PD) is a neurodegenerative disorder predominantly affecting the elderly. The aetiology of the disease is not known, but age and environmental factors play an important role. Although more than a dozen gene mutations associated with familial forms of Parkinson's disease have been described, fewer than 10% of all cases can be explained by genetic abnormalities. The molecular basis of Parkinson's disease is the loss of dopamine in the basal ganglia (caudate/putamen) due to the degeneration of dopaminergic neurons in the substantia nigra, which leads to the motor impairment characteristic of the disease. Methamphetamine is the second most widely used illicit drug in the world. In rodents, methamphetamine exposure damages dopaminergic neurons in the substantia nigra, resulting in a significant loss of dopamine in the striatum. Biochemical and neuroimaging studies in human methamphetamine users have shown decreased levels of dopamine and dopamine transporter as well as prominent microglial activation in the striatum and other areas of the brain, changes similar to those observed in PD patients. Consistent with these similarities, recent epidemiological studies have shown that methamphetamine users are almost twice as likely as non-users to develop PD, despite the fact that methamphetamine abuse and PD have distinct symptomatic profiles. PMID:23476887

Granado, Noelia; Ares-Santos, Sara; Moratalla, Rosario

2013-01-01

202

Diagnostic value of specific T cell reactivity to drugs in 95 cases of drug induced liver injury  

PubMed Central

Background—Diagnosis of drug induced liver injury is usually based on a temporal relation between drug intake and clinical picture as well as on the exclusion of alternative causes. More precise diagnosis has been attempted by using in vitro specific T cell reactivity to drugs but the test has never reached general acceptability because of frequent negative results which could be explained, in part, by prostaglandin producing suppressor cells (PPSC). ?Aim—To analyse the diagnostic value of a modified test where lymphocyte responses to drugs are detected in the presence of a prostaglandin inhibitor. ?Patients—Ninety five patients with a clinical diagnosis of drug induced liver injury, 106 healthy controls, 35 individuals with recent exposure to the same drugs without adverse effects, and 15 patients with liver disease unrelated to drugs. ?Methods—Peripheral blood mononuclear cells (PBMC) were cultured in the presence of drugs alone and in the presence of drugs and a prostaglandin inhibitor. Responses were assessed by 3H-thymidine incorporation in lymphocytes. Results were expressed as counts per minute and as stimulation indexes (SI). ?Results—When PBMC were stimulated with drugs alone, lymphocyte sensitisation to drugs (SI>2) was detected in 26% of the cases. This was noticeably increased (56%) when a prostaglandin inhibitor was added to the cultures. No reactivity was found in controls. In patients with possible sensitivity to several drugs, lymphocyte reactivity was detected to only one drug. The severity of the lesions, as assessed by aminotransferase concentrations and disease duration, was lower in patients with evidence of PPSC. ?Conclusions—This new approach is useful for the diagnosis of drug induced liver injury, particularly in patients exposed to more than one drug; furthermore, the presence of putative PPSC is associated with less severe forms of drug induced hepatitis. ?? Keywords: drug induced hepatitis; drug hypersensitivity; specific T cells; prostaglandin E2; suppressor cells; diagnostic tests PMID:9391255

Maria, V; Victorino, R

1997-01-01

203

A Comparison of the Effectiveness of Three Drug Regimens on Cognitive Performance of Patients with Parkinson's disease  

ERIC Educational Resources Information Center

In the present study, the effectiveness of 3 drug regimen on cognitive performance of PD patients was compared. 12 patients who had been using pramipexole, levodopa and amantadine for at least 1 month entered the study and compared with those 12 who had been using trihexiphenidyle, levodopa and amantadine. There was also a control group…

Emsaki, Golit; Asgari, Karim; Molavi, Hossein; Chitsaz, Ahmad

2013-01-01

204

Cancer Evolution under Drug-Induced Stress-Gradients  

NASA Astrophysics Data System (ADS)

The lack of long term success in eliminating cancer cells while avoiding the evolution of drug resistance indicates that our understanding of how cells evolve in response to stress is still incomplete. We interpret this not as a failure of the current approaches, but rather as an indication that new research venues should be undertaken, where conventional wisdom is challenged in order to drive forward our understanding of cancer. Of particular importance, we believe that the powerful role of evolution in the origin of drug resistance is ill-understood. We do not ask whether evolution occurs, but rather how. We do not describe molecular mechanisms underlying drug resistance at the single cell level, but rather ask how does resistance spread in cancerous tissues and metastatic lesions. We attempt to answer these questions by studying the population-wide dynamics of drug evolution and the collective stress response of cancer cells in a microfluidics device. We use microfluidics technologies to impose high levels of stress on cancer cell metapopulation by create smoothly varying gradients of either oxygen, chemotherapeutic drug, nutrient or pH. We present long-term studies of the adaptation of tumorigenic cancer cells to drug- induced stress gradients.

Lambert, Guillaume; Austin, Robert H.

2011-03-01

205

Neuroprotective effects of peroxisome proliferator-activated receptor alpha and gamma agonists in model of parkinsonism induced by intranigral 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine.  

PubMed

A large body of evidence suggests that peroxisome proliferator-activated receptor (PPAR) agonists may improve some of the pathological features of Parkinson's disease (PD). In the present study, we evaluated the effects of the PPAR-? agonist fenofibrate (100mg/kg) and PPAR-? agonist pioglitazone (30mg/kg) in a rat model of parkinsonism induced by intranigral 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine (MPTP). Male Wistar rats were pretreated with both drugs for 5 days and received an infusion of MPTP. The experiments were divided into two parts. First, 1, 7, 14, and 21 days after surgery, the animals were submitted to the open field test. On days 21 and 22, the rats were subjected to the forced swim test and two-way active avoidance task. In the second part of the study, 24h after neurotoxin administration, immunohistochemistry was performed to assess tyrosine hydroxylase activity. The levels of dopamine and its metabolites in the striatum were determined using high-performance liquid chromatography, and fluorescence detection was used to assess caspase-3 activation in the substantia nigra pars compacta (SNpc). Both fenofibrate as pioglitazone protected against hypolocomotion, depressive-like behavior, impairment of learning and memory, and dopaminergic neurodegeneration caused by MPTP, with dopaminergic neuron loss of approximately 33%. Fenofibrate and pioglitazone also protected against the increased activation of caspase-3, an effector enzyme of the apoptosis cascade that is considered one of the pathological features of PD. Thus, PPAR agonists may contribute to therapeutic strategies in PD. PMID:25127682

Barbiero, Janaína K; Santiago, Ronise M; Persike, Daniele Suzete; da Silva Fernandes, Maria José; Tonin, Fernanda S; da Cunha, Claudio; Lucio Boschen, Suelen; Lima, Marcelo M S; Vital, Maria A B F

2014-11-01

206

Parkinson's disease: recent advances.  

PubMed

While a curative treatment for Parkinson's disease remains elusive, our understanding of disease mechanisms as well as preclinical and pre-motor early manifestations has improved greatly over the past years. An agent with proven disease modifying properties has not yet been identified but symptomatic treatment options for affected patients have improved. For patients with motor complications, this includes invasive approaches such as deep brain stimulation and continuous device-aided drug delivery. The many facets of non-motor problems patients are faced with have finally been fully recognized and have become the target of treatment trials, as have been non-pharmacological approaches. PMID:24687891

Katzenschlager, Regina

2014-05-01

207

Dropped head associated with amantadine in Parkinson disease.  

PubMed

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

2011-01-01

208

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. PMID:19043519

Jankovic, Joseph; Aguilar, L Giselle

2008-01-01

209

A case of severe psychosis induced by novel recreational drugs  

PubMed Central

Introduction:  The use of novel recreational drugs is becoming of public interest, especially after recent international alerts about their cardiovascular and neurological toxicity. Additionally, little is known about the psychiatric consequences of the long-term use of these compounds. Case presentation: We describe a case of severe psychotic episode likely induced by chronic use of a combination of new recreational drugs (methylenedioxypyrovalerone, mephedrone, butylone and alpha-pyrrolidinopentiophenone). The patient had no psychiatric history and showed poor response to conventional antipsychotic treatment (haloperidol). Conclusions: This case illustrates the potential negative effects of recreational drugs that cannot be limited to an acute psychotic episode but might determine a condition of prolonged paranoid psychosis. Although the use of these compounds is currently increasing, such molecules might often pass undetected in patients accessing the emergency room, leading to misdiagnosis (e.g. schizophrenic episode) and lack of appropriate treatment. PMID:25352977

Dragogna, Filippo; Oldani, Lucio; Buoli, Massimiliano; Altamura, A. Carlo

2014-01-01

210

Lanosterol induces mitochondrial uncoupling and protects dopaminergic neurons from cell death in a model for Parkinson's disease  

Microsoft Academic Search

Parkinson's disease (PD) is a neurodegenerative disorder marked by the selective degeneration of dopaminergic neurons in the nigrostriatal pathway. Several lines of evidence indicate that mitochondrial dysfunction contributes to its etiology. Other studies have suggested that alterations in sterol homeostasis correlate with increased risk for PD. Whether these observations are functionally related is, however, unknown. In this study, we used

L Lim; V Jackson-Lewis; L C Wong; G H Shui; A X H Goh; S Kesavapany; A M Jenner; M Fivaz; S Przedborski; M R Wenk

2012-01-01

211

Characterizing the modulation of mGluR5 in a 6-OHDA-induced rat model of Parkinson's disease  

E-print Network

MicroPET imaging studies were conducted to investigate the role of metabotropic glutamate subtype-5 receptors (mGluR5) in Parkinson's disease (PD). Four analogical PET ligands were used to characterize modulation of mGluR5 ...

Lamb, Peter (Peter Alexander John)

2008-01-01

212

Levodopa-Induced Modifications of Prosody and Comprehensibility in Advanced Parkinson's Disease as Perceived by Professional Listeners  

ERIC Educational Resources Information Center

The prosodic aspects of hypokinetic dysarthria in Parkinson's disease (PD) have been the focus of numerous reports. Few data on the effects of levodopa on prosody, more specifically on the effects on the variability of prosodic characteristics such as pitch, loudness and speech rate, are available in advanced PD. The relation between these…

De Letter, Miet; Santens, Patrick; Estercam, Irina; Van Maele, Georges; De Bodt, Marc; Boon, Paul; Van Borsel, John

2007-01-01

213

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

PubMed

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

2011-05-01

214

The role of metabolic activation in drug-induced hepatotoxicity.  

PubMed

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

2005-01-01

215

Risk Factors for Idiosyncratic Drug-Induced Liver Injury  

PubMed Central

Idiosyncratic drug-induced liver injury (DILI) is a rare disorder that is not related directly to dosage and little is known about individuals who are at increased risk. There are no suitable preclinical models for the study of idiosyncratic DILI and its pathogenesis is poorly understood. It is likely to arise from complex interactions among genetic, nongenetic host susceptibility, and environmental factors. Nongenetic risk factors include age, sex, and other diseases (eg, chronic liver disease or human immunodeficiency virus infection). Compound-specific risk factors include daily dose, metabolism characteristics, and propensity for drug interactions. Alcohol consumption has been proposed as a risk factor for DILI from medications, but there is insufficient evidence to support this. Many studies have explored genetic defects that might be involved in pathogenesis and focused on genes involved in drug metabolism and the immune response. Multicenter databases of patients with DILI (the United States Drug Induced Liver Injury Network, DILIGEN, and the Spanish DILI registry) are important tools for clinical and genetic research. A genome-wide association study of flucloxacillin hepatotoxicity has yielded groundbreaking results and many similar studies are underway. Nonetheless, DILI is challenging to investigate because of its rarity, the lack of experimental models, the number of medications that might cause it, and challenges to diagnosis. PMID:20394749

CHALASANI, NAGA; BJORNSSON, EINAR

2011-01-01

216

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. PMID:23690667

Alitheen, Noorjahan Banu

2013-01-01

217

The combination of oral L-DOPA/rimonabant for effective dyskinesia treatment and cytological preservation in a rat model of Parkinson's disease and L-DOPA-induced dyskinesia.  

PubMed

Parkinson's disease is the second most prevalent neurodegenerative disease in the world. Its treatment is limited so far to the management of parkinsonian symptoms with L-DOPA (LD). The long-term use of LD is limited by the development of L-DOPA-induced dyskinesias and dystonia. However, recent studies have suggested that pharmacological targeting of the endocannabinoid system may potentially provide a valuable therapeutic tool to suppress these motor alterations. In the present study, we have explored the behavioral (L-DOPA-induced dyskinesias severity) and cytological (substantia nigra compacta neurons and striatum neuropil preservation) effects of the oral coadministration of LD and rimonabant, a selective antagonist of CB1 receptors, in the 6-hydroxydopamine rat model of Parkinson's disease. Oral coadministration of LD (30 mg/kg) and rimonabant (1 mg/kg) significantly decreased abnormal involuntary movements and dystonia, possibly through the conservation of some functional tyrosine hydroxylase-immunoreactive dopaminergic cells, which in turn translates into a well-preserved neuropil of a less denervated striatum. Our results provide anatomical evidence that long-term coadministration of LD with cannabinoid antagonist-based therapy may not only alleviate specific motor symptoms but also delay/arrest the degeneration of striatal and substantia nigra compacta cells. PMID:24196024

Gutiérrez-Valdez, Ana L; García-Ruiz, Ricardo; Anaya-Martínez, Verónica; Torres-Esquivel, Carmen; Espinosa-Villanueva, Jesús; Reynoso-Erazo, Leonardo; Tron-Alvarez, Rocio; Aley-Medina, Patricia; Sánchez-Betancourt, Javier; Montiel-Flores, Enrique; Avila-Costa, María R

2013-12-01

218

Environmental neurotoxin dieldrin induces apoptosis via caspase-3-dependent proteolytic activation of protein kinase C delta (PKCdelta): Implications for neurodegeneration in Parkinson's disease  

PubMed Central

Background In previous work, we investigated dieldrin cytotoxicity and signaling cell death mechanisms in dopaminergic PC12 cells. Dieldrin has been reported to be one of the environmental factors correlated with Parkinson's disease and may selectively destroy dopaminergic neurons. Methods Here we further investigated dieldrin toxicity in a dopaminergic neuronal cell model of Parkinson's disease, namely N27 cells, using biochemical, immunochemical, and flow cytometric analyses. Results In this study, dieldrin-treated N27 cells underwent a rapid and significant increase in reactive oxygen species followed by cytochrome c release into cytosol. The cytosolic cytochrome c activated caspase-dependent apoptotic pathway and the increased caspase-3 activity was observed following a 3 hr dieldrin exposure in a dose-dependent manner. Furthermore, dieldrin caused the caspase-dependent proteolytic cleavage of protein kinase C delta (PKC?) into 41 kDa catalytic and 38 kDa regulatory subunits in N27 cells as well as in brain slices. PKC? plays a critical role in executing the apoptotic process in dieldrin-treated dopaminergic neuronal cells because pretreatment with the PKC? inhibitor rottlerin, or transfection and over-expression of catalytically inactive PKC?K376R, significantly attenuates dieldrin-induced DNA fragmentation and chromatin condensation. Conclusion Together, we conclude that caspase-3-dependent proteolytic activation of PKC? is a critical event in dieldrin-induced apoptotic cell death in dopaminergic neuronal cells. PMID:18945348

Kanthasamy, Anumantha G; Kitazawa, Masashi; Yang, Yongjie; Anantharam, Vellareddy; Kanthasamy, Arthi

2008-01-01

219

Neuroprotective effects of the andrographolide analogue AL-1 in the MPP?/MPTP-induced Parkinson's disease model in vitro and in mice.  

PubMed

The andrographolide-lipoic acid conjugate AL-1 is a newly synthesized molecule by covalently linking andrographolide (Andro) with ?-lipoic acid (LA). In the present work, the neuroprotective effect of AL-1 was investigated in vitro and in a mouse model of the Parkinson's disease (PD). We found that AL-1 significantly prevented 1-methyl-4-phenylpyridinium (MPP(+))-induced neurotoxicity in SH-SY5Y cells and primary cerebellar granule neurons. In a mouse model of Parkinson's disease, AL-1 rescued 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP)-induced loss of tyrosine hydroxylase (TH)-positive neurons, improved the behavioral impairment, and elevated the striatal levels of dopamine and its metabolites 3,4-dihydroxyphenylacetic acid. Furthermore, AL-1 remarkably lowered the nitric oxide and malondialdehyde levels while increased the superoxide dismutase level in the substantial nigra of MPTP-treated mice. The immunoblotting data showed that AL-1 significantly ameliorated the decreased expression of TH protein in the substantial nigra and inhibited the up-regulation of phosphorylated NF-?B p65 in vitro and in vivo. Taken together, AL-1 exerted neuroprotective effect in vitro and in animal model of PD through anti-oxidation and inhibition of NF-?B activation. PMID:24726706

Zhang, Zaijun; Lai, Daoxu; Wang, Liang; Yu, Pei; Zhu, Longjun; Guo, Baojian; Xu, Lipeng; Zhou, Libing; Sun, Yewei; Lee, Simon Ming Yuen; Wang, Yuqiang

2014-07-01

220

Drug-induced cutaneous photosensitivity: incidence, mechanism, prevention and management.  

PubMed

The interaction of sunlight with drug medication leads to photosensitivity responses in susceptible patients, and has the potential to increase the incidence of skin cancer. Adverse photosensitivity responses to drugs occur predominantly as a phototoxic reaction which is more immediate than photoallergy, and can be reversed by withdrawal or substitution of the drug. The bias and inaccuracy of the reporting procedure for these adverse reactions is a consequence of the difficulty in distinguishing between sunburn and a mild drug photosensitivity reaction, together with the patient being able to control the incidence by taking protective action. The drug classes that currently are eliciting a high level of adverse photosensitivity are the diuretic, antibacterial and nonsteroidal anti-inflammatory drugs (NSAIDs). Photosensitising chemicals usually have a low molecular weight (200 to 500 Daltons) and are planar, tricyclic, or polycyclic configurations, often with heteroatoms in their structures enabling resonance stabilisation. All absorb ultraviolet (UV) and/or visible radiation, a characteristic that is essential for the chemical to be regarded as a photosensitiser. The photochemical and photobiological mechanisms underlying the adverse reactions caused by the more photoactive drugs are mainly free radical in nature, but reactive oxygen species are also involved. Drugs that contain chlorine substituents in their chemical structure, such as hydrochlorthiazide, furosemide and chlorpromazine, exhibit photochemical activity that is traced to the UV-induced dissociation of the chlorine substituent leading to free radical reactions with lipids, proteins and DNA. The photochemical mechanisms for the NSAIDs that contain the 2-aryl propionic acid group involve decarboxylation as the primary step, with subsequent free radical activity. In aerated systems, the reactive excited singlet form of oxygen is produced with high efficiency. This form of oxygen is highly reactive towards lipids and proteins. NSAIDs without the 2-arylpropionic acid group are also photoactive, but with differing mechanisms leading to a less severe biological outcome. In the antibacterial drug class, the tetracyclines, fluoroquinolones and sulfonamides are the most photoactive. Photocontact dermatitis due to topically applied agents interacting with sunlight has been reported for some sunscreen and cosmetic ingredients, as well as local anaesthetic and anti-acne agents. Prevention of photosensitivity involves adequate protection from the sun with clothing and sunscreens. In concert with the preponderance of free radical mechanisms involving the photosensitising drugs, some recent studies suggest that diet supplementation with antioxidants may be beneficial in increasing the minimum erythemal UV radiation dose. PMID:12020173

Moore, Douglas E

2002-01-01

221

Ovulation-inducing drugs: a drug utilization and risk study in the Dutch population.  

PubMed

This study describes the use of the ovulation stimulating drugs clomifene, human chorionic gonadotropin (hCG) and human menopausal gonadotropin (hMG) in a representative sample of a population of Dutch women in the child-bearing age group. Clomifene or hMG/hCG are seldom used alone. A considerable percentage of the women received at least four different ovulation-inducing and related drugs during the observation period of two years. Thirty percent of the women who used clomifene were treated for 6 or more cycles. These findings argue for a relative "overuse" and "misuse" of clomifene. Buserelin, a drug not registered for the indication ovulation induction in The Netherlands but used in in vitro fertilization (IVF) programs as inhibitors of pituitary gonadotropin production, was nevertheless prescribed to 38% of the hMG /hCG users and to 11 % of the clomifene users. Our study indicates that, though the potential risks of congenital malformations due to clomifene are difficult to assess, they may be considerable; this, and the fact that different ovulation-inducing drugs are used together with clomifene, emphasizes the need for post-marketing surveillance. PMID:23510871

de Jong-van den Berg, L T; Cornel, M C; van den Berg, P B; Bortolussi, A C; Twerda, H M; Lappöhn, R E; Wesseling, H

1992-01-01

222

Sleep attacks and Parkinson's disease treatment.  

PubMed

Three patients with Parkinson's disease had so-called sleep attacks at the wheel while taking bromocryptine, lisuride pergolide, or piribedil. We believe that all dopamine agonists can induce sleep attacks. PMID:10776750

Ferreira, J J; Galitzky, M; Montastruc, J L; Rascol, O

2000-04-15

223

Mechanisms of drug-induced diarrhoea in the elderly.  

PubMed

In the rapidly increasing elderly population, diarrhoea as a result of drug therapy is an important consideration. The elderly consume a disproportionately large number of drugs for multiple acute and chronic diseases. Drugs can compromise both immune and nonimmune responses. Aging decreases the quality and proportion of T cells which in turn reduces the production of secretory IgA, the primary immune response of the gut. Acid production in the stomach decreases with increasing age and this compromise its vital 'self-sterilising' function, thus increasing the risk of diarrhoea due to viral, bacterial and protozoal pathogens. Other nonimmune defence mechanisms include the motility of the small intestine and the host-protective commensal bacteria of the colon. Drug induced hypomotility may result in bacterial overgrowth, deconjugation of bile salts and diarrhoea. Less commonly, diarrhoea may occur due to hypermotility because of a cholinergic-like syndrome. In the colon the host-protective commensal bacteria provide a powerful defence against pathogens. Disruption of this commensal population by antibiotic therapy may result in Clostridium difficile supra-infection which causes diarrhoea through toxin production. This is especially important in the elderly patient on chemotherapy for malignancy and those with multiple diseases. The organism responds to vancomycin, metronidazole and bacitracin. Metronidazole is the suggested drug of choice, with vancomycin reserved for relapses. Drugs also cause diarrhoea by interfering with normal physiological processes. Drugs impair fluid absorption by activating adenylate cyclase within the small intestinal enterocyte which increases the level of cyclic AMP. This causes active secretion of Cl- and HCO3-, passive efflux of Na+, K+ and water and inhibition of Na+ and Cl- into the enterocyte. Examples of these drugs (secretagogues) are bisacodyl, misoprostol and chenodeoxycholic acid (used to dissolve cholesterol gallstones). Drugs may also affect a second mechanism that regulates water and electrolyte transport, the Na+, K+ exchange pump. The energy for this pump is provided by the ATPase mediated breakdown of ATP. ATPase may be inhibited by digoxin, auranofin, colchicine and olsalazine. A number of drugs cause osmotic diarrhoea including antacids containing magnesium trisilicate or hydroxide. Lactulose is being used increasingly in compensated liver disease to increase protein tolerance and prevent hepatic encephalopathy. Sorbitol, an osmotic laxative agent also used in some liquid pharmaceutical preparations, induces diarrhoea by virtue of its osmotic potential. Another mechanism by which drugs cause diarrhoea is by mucosal damage of the small and large bowel. In the small intestine mucosal damage causes diarrhoea and fat malabsorption, as may occur with neomycin and colchicine. In the colon, for example, gold salts and penicillamine cause colitis of varying severity. Though the causes of diarrhoea are diverse, a drug-associated aetiology should always be considered and actively sought and addressed to prevent the complications of dehydration, electrolyte imbalance and undernutrition. PMID:9789728

Ratnaike, R N; Jones, T E

1998-09-01

224

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

2007-01-01

225

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

2010-01-01

226

Stem cell therapy for Parkinson’s disease: where do we stand?  

Microsoft Academic Search

A major neuropathological feature of Parkinson’s disease (PD) is the loss of nigrostriatal dopaminergic neuron. Patients exhibit motor symptoms, including bradykinesia, rigidity, and tremor. Neural grafting has been reported to restore striatial dopaminergic neurotransmission and induce symptomatic relief. The major limitation of cell replacement therapy for PD is the shortage of suitable donor tissue. The present review describes the possible

Laurent Roybon; Nicolaj S. Christophersen; Patrik Brundin; Jia-Yi Li

2004-01-01

227

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

2001-01-01

228

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

PubMed Central

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

2013-01-01

229

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

2006-01-01

230

A case of acute onset parkinsonism.  

PubMed

Extra pontine myelinolysis (EPM) is a form of osmotic demyelination syndrome, characterized by the presence of signal alterations in varied sites in the brain other than the pons. When caudate and putamen are involved, it results in a constellation of extra pyramidal signs and symptoms resembling parkinsonism. Here we report a case of this unique syndrome presenting with features of parkinsonism which was successfully treated with dopaminergic drugs. PMID:25003061

John, Teny Mathew; Jacob, Ceena Neena; Xavier, Jerry; Kondanath, Saifudeen; Ittycheria, Cherian C; Jayaprakash, R

2013-01-01

231

Zebrafish as model organisms for studying drug induced liver injury  

PubMed Central

Drug induced liver injury (DILI) is a major challenge in clinical medicine and drug development. New models are needed for predicting which potential therapeutic compounds will cause DILI in humans, and new markers and mediators of DILI still need to be identified. This review will highlight the strengths and weaknesses of using zebrafish as a high throughput in vivo model for studying DILI. Although the zebrafish liver architecture is different to the mammalian liver, the main physiological processes remain similar. Zebrafish metabolize drugs using similar pathways as humans; they possess a wide range of cytochrome P450 enzymes enabling metabolic reactions including hydroxylation, conjugation, oxidation, demethylation and de-ethylation. Following exposure to a range of liver toxic drugs, the zebrafish liver develops histological patterns of injury comparable to mammals and liver injury biomarkers can be quantified in the zebrafish circulation. The zebrafish immune system is similar to mammals, but the zebrafish inflammatory response to DILI is not yet defined. To quantify DILI in zebrafish a wide variety of methods can be used including: visual assessment, quantification of serum enzymes and experimental serum biomarkers and scoring histopathology. With further development, the zebrafish may be a model that complements rodents and may have value for the discovery of new disease pathways and translational biomarkers. PMID:24773296

Vliegenthart, A D B; Tucker, C S; Del Pozo, J; Dear, J W

2014-01-01

232

Drug-induced liver injury in older adults  

PubMed Central

Drug-induced liver injury (DILI) is an important cause of hospitalisation and of medication deregistration. In old age, susceptibility to DILI is affected by changes in physiology and increased interindividual variability, compounded by an increased prevalence of disease and the frailty syndrome. While dose-related or predictable DILI reactions are often detected in preclinical trials, the occurrence of rare hypersensitivity or idiosyncratic reactions cannot be reliably predicted from preclinical studies or even by clinical trials. The limited participation of older adults in clinical trials means that the susceptibility of this population to DILI is largely unknown. Vigilance during clinical trials and postmarketing surveillance must be universally practised. A systematic approach should be taken to determine not only which medicines are hepatotoxic and should be removed from the market, but also the hepatotoxicity risks from marketed drugs to consumers with different characteristics, many of whom are older people. PMID:25083196

Mitchell, Sarah J.

2010-01-01

233

Invariant NKT cells increase drug-induced osteosarcoma cell death  

PubMed Central

BACKGROUND AND PURPOSE In osteosarcoma (OS) patients, only a limited number of drugs are active and the regimens currently in use include a combination of at least two of these drugs: doxorubicin, cisplatin, methotrexate and ifosfamide. Today, 30–40% of patients still die of OS highlighting the urgent need for new treatments. Invariant NKT (iNKT) cells are a lymphocyte lineage with features of both T and NK cells, playing important roles in tumour suppression. Our aim was to test whether the cytoxicity induced by cisplatin, doxorubicin and methotrexate against OS cells can be enhanced by iNKT cell treatment. EXPERIMENTAL APPROACH iNKT cells were purified from human peripheral blood mononuclear cells by cell sorting (V?24V?11+ cells) and used as effector cells against OS cells (U2-OS, HOS, MG-63). Cell death (calcein-AM method), perforin/granzyme B and Fas/FasL expressions were determined by flow cytometry. CD1d expression was analysed at both the gene and protein level. KEY RESULTS iNKT cells were cytotoxic against OS cells through a CD1d-dependent mechanism. This activity was specific for tumour cells, because human CD1d+ mesenchymal stem cells and CD1d- osteoblasts were not affected. iNKT cell treatment enhanced drug-induced OS cell death in a concentration-dependent manner and this effect was reduced in CD1d-silenced OS cells. CONCLUSION AND IMPLICATIONS iNKT cells kill malignant, but not non-malignant, cells. iNKT cell treatment enhances the cytotoxicity of anti-neoplastic drugs against OS cells in a CD1d-dependent manner. The present data encourage further studies on the use of iNKT cells in OS therapy. PMID:22817659

Fallarini, S; Paoletti, T; Orsi Battaglini, N; Lombardi, G

2012-01-01

234

Detection of preclinical Parkinson's disease with PET  

SciTech Connect

Putamen 18F-dopa uptake of patients with Parkinson's disease (PD) is reduced by at least 35% at onset of symptoms; therefore, positron-emission tomography (PET) can be used to detect preclinical disease in clinically unaffected twins and relatives of patients with PD. Three out of 6 monozygotic and 2 out of 3 dizygotic unaffected PD co-twins have shown reduced putamen 18F-dopa uptake to date. In addition, an intact sibling and a daughter of 1 of 4 siblings with PD both had low putamen 18F-dopa uptake. These preliminary findings suggest there may be a familial component to the etiology of PD. PET can also be used to detect underlying nigral pathology in patients with isolated tremor and patients who become rigid taking dopamine-receptor blocking agents (DRBAs). Patients with familial essential tremor have normal, and those with isolated rest tremor have consistently low, putamen 18F-dopa uptake. Drug-induced parkinsonism is infrequently associated with underlying nigral pathology.

Brooks, D.J. (MRC Cyclotron Unit, Hammersmith Hospital, London (England))

1991-08-01

235

Detection of preclinical Parkinson's disease with PET  

SciTech Connect

Putamen 18F-dopa uptake of patients with Parkinson's disease (PD) is reduced by at least 35% at onset of symptoms; therefore, positron-emission tomography (PET) can be used to detect preclinical disease in clinically unaffected twins and relatives of patients with PD. Three out of 6 monozygotic and 2 out of 3 dizygotic unaffected PD co-twins have shown reduced putamen 18F-dopa uptake to date. In addition, an intact sibling and a daughter of 1 of 4 siblings with PD both had low putamen 18F-dopa uptake. These preliminary findings suggest there may be a familial component to the etiology of PD. PET can also be used to detect underlying nigral pathology in patients with isolated tremor and patients who become rigid taking dopamine-receptor blocking agents (DRBAs). Patients with familial essential tremor have normal, and those with isolated rest tremor have consistently low, putamen 18F-dopa uptake. Drug-induced parkinsonism is infrequently associated with underlying nigral pathology.

Brooks, D.J. (MRC Cyclotron Unit, Hammersmith Hospital, London, (United Kingdom))

1991-05-01

236

Surgical treatments for Parkinson's disease.  

PubMed Central

OBJECTIVE: This article reviews surgical treatments for Parkinson's disease, emphasizing aspects pertinent to family physicians: rationale for and description of surgeries, patient selection issues, and outcome expectations. QUALITY OF EVIDENCE: No published series describes long-term follow up of a randomized controlled study of any surgery for Parkinson's disease. Some reports, however, describe thorough but brief follow up of functioning in small numbers of patients following surgery. MEDLINE articles were identified using Parkinson's disease, surgery, pallidotomy, thalamotomy, stimulation, grafting, and transplantation as search words. Articles chosen for this paper described patients with systematic follow up using accepted validated rating scales. MAIN MESSAGE: Reported series show impressive improvements to patients undergoing lesioning, stimulation, and grafting surgery for Parkinson's disease. These patients are typically severely disabled but highly selected, and follow up is brief. Stereotactic lesioning (pallidotomy and thalamotomy), deep brain stimulation (thalamic, and elsewhere) and grafting (striatal) can be performed safely, but results vary greatly among centres. CONCLUSIONS: Certain Parkinson's disease patients might benefit from surgery. Ideal candidates for pallidotomy experience motor fluctuations with disabling levodopa-induced dyskinesias. Tremors resistant to antiparkinsonian medications sometimes respond to thalamotomy or thalamic stimulation. Other parkinsonian syndromes, dementias, and difficulties with gait and balance respond poorly to unilateral pallidotomy. Bilateral deep brain stimulation procedures could benefit "midline" dysfunction. Images Figure 1 PMID:10690493

Uitti, R. J.

2000-01-01

237

Enhanced glutamate, IP3 and cAMP activity in the cerebral cortex of Unilateral 6-hydroxydopamine induced Parkinson's rats: Effect of 5-HT, GABA and bone marrow cell supplementation  

PubMed Central

Parkinson's disease is characterized by progressive cell death in the substantia nigra pars compacta, which leads to dopamine depletion in the striatum and indirectly to cortical dysfunction. Increased glutamatergic transmission in the basal ganglia is implicated in the pathophysiology of Parkinson's disease and glutamate receptor mediated excitotoxicity has been suggested to be one of the possible causes of the neuronal degeneration. In the present study, the effects of serotonin, gamma-aminobutyric acid and bone marrow cells infused intranigrally to substantia nigra individually and in combination on unilateral 6-hydroxydopamine induced Parkinson's rat model was analyzed. Scatchard analysis of total glutamate and NMDA receptor binding parameters showed a significant increase in Bmax (P < 0.001) in the cerebral cortex of 6-hydroxydopamine infused rat compared to control. Real Time PCR amplification of NMDA2B, mGluR5, bax, and ubiquitin carboxy-terminal hydrolase were up regulated in cerebral cortex of 6-hydroxydopamine infused rats compared to control. Gene expression studies of GLAST, ?-Synuclien and Cyclic AMP response element-binding protein showed a significant (P < 0.001) down regulation in 6-OHDA infused rats compared to control. Behavioural studies were carried out to confirm the biochemical and molecular studies. Serotonin and GABA along with bone marrow cells in combination showed reversal of glutamate receptors and behaviour abnormality shown in the Parkinson's rat model. The therapeutic significance in Parkinson's disease is of prominence. PMID:21235809

2011-01-01

238

Genetic basis of Parkinson's disease: inheritance, penetrance, and expression  

PubMed Central

Parkinson’s disease can be caused by rare familial genetic mutations, but in most cases it is likely to result from an interaction between multiple genetic and environmental risk factors. Over recent years, many variants in a growing number of genes involved in the pathogenesis of Parkinson’s disease have been identified. Mutations in several genes have been shown to cause familial parkinsonism. In this review, we discuss 12 of them (SNCA, LRRK2, Parkin, PINK1, DJ1, ATP13A2, PLA2G6, FBXO7, UCHL1, GIGYF2, HTRA2, and EIF4G1). Additionally, six genes have been shown conclusively to be risk factors for sporadic Parkinson’s disease, and are also discussed (GBA, MAPT, BST1, PARK16, GAK, and HLA). Many more genes and genetic loci have been suggested, but need confirmation. There is evidence that pathways involved in the rare familial forms also play a role in the sporadic form, and that the respective genes might also be risk factors for sporadic Parkinson’s disease. The identification of genes involved in the development of Parkinson’s disease will improve our understanding of the underlying molecular mechanisms, and will hopefully lead to new drug targets and treatment strategies. PMID:23776368

Schulte, Claudia; Gasser, Thomas

2011-01-01

239

On the modeling of drug induced respiratory depression in the non-steady-state  

Microsoft Academic Search

The ability of anesthetic agents to provide adequate analgesia and sedation is limited by the ventilatory depression associated with overdosing in spontaneously breathing patients. Therefore, quantitation of drug induced ventilatory depression is a pharmacokinetic-pharmacodynamic problem relevant to the practice of anesthesia. Although several studies describe the effect of respiratory depressant drugs on isolated endpoints, an integrated description of drug induced

Antonello L. G. Caruso; Thomas W. Bouillon; Peter M. Schumacher; Manfred Morari

2008-01-01

240

ERK2: a logical AND gate critical for drug-induced plasticity? Truncated title  

E-print Network

1 Title: ERK2: a logical AND gate critical for drug-induced plasticity? Truncated title: ERK2 and drug-induced plasticity Authors: Denis Hervé1 , Emmanuel Valjent1 , Jocelyne Caboche2 , Jean Drug addiction results in part from the distortion of dopamine-controlled plasticity. Extracellular

241

Drug delivery by polymeric nanoparticles induces autophagy in macrophages.  

PubMed

Drug delivery nanosystems are currently used in human therapy. In preliminary studies we have observed that Eudragit RS nanoparticles, prepared by nanoprecipitation or double emulsion techniques, are cytotoxic for NR8383 rat macrophages. In this study, we expand our previous analysis and suggest that unloaded Eudragit RS nanoparticles prepared by nanoprecipitation (NP/ERS) may induce important morphological and biochemical cellular modifications leading to cellular death. In NR8383 rat macrophages cell line exposed to doses varying from 15 to 100 ?g/mL, NP/ERS nanoparticles are internalized inside the cells, reach the mitochondria and alter the structure of these organelles. In addition, the exposure to nanoparticles induces cellular autophagy as demonstrated by electron microscopy analysis, microchip array, qRT-PCR and Western blot assays. Although toxicity of nanoparticles has already been evidenced, it is the first time that results show clearly that the toxicity of polymeric nanovectors may be related to an activation of autophagy. PMID:22119964

Eidi, H; Joubert, O; Némos, C; Grandemange, S; Mograbi, B; Foliguet, B; Tournebize, J; Maincent, P; Le Faou, A; Aboukhamis, I; Rihn, B H

2012-01-17

242

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

PubMed

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

2012-10-01

243

78 FR 5817 - Detecting and Evaluating Drug-Induced Liver Injury; What's Normal, What's Not, and What Should We...  

Federal Register 2010, 2011, 2012, 2013

...Detecting and Evaluating Drug-Induced Liver Injury; What's Normal, What's Not...Detecting and Evaluating Drug-Induced Liver Injury; What's Normal, What's Not...extent, and likelihood of drug causation of liver injury and dysfunction in people...

2013-01-28

244

Knockdown of Hsc70-5/mortalin Induces Loss of Synaptic Mitochondria in a Drosophila Parkinson's Disease Model  

PubMed Central

Mortalin is an essential component of the molecular machinery that imports nuclear-encoded proteins into mitochondria, assists in their folding, and protects against damage upon accumulation of dysfunctional, unfolded proteins in aging mitochondria. Mortalin dysfunction associated with Parkinson’s disease (PD) increases the vulnerability of cultured cells to proteolytic stress and leads to changes in mitochondrial function and morphology. To date, Drosophila melanogaster has been successfully used to investigate pathogenesis following the loss of several other PD-associated genes. We generated the first loss-of-Hsc70-5/mortalin-function Drosophila model. The reduction of Mortalin expression recapitulates some of the defects observed in the existing Drosophila PD-models, which include reduced ATP levels, abnormal wing posture, shortened life span, and reduced spontaneous locomotor and climbing ability. Dopaminergic neurons seem to be more sensitive to the loss of mortalin than other neuronal sub-types and non-neuronal tissues. The loss of synaptic mitochondria is an early pathological change that might cause later degenerative events. It precedes both behavioral abnormalities and structural changes at the neuromuscular junction (NMJ) of mortalin-knockdown larvae that exhibit increased mitochondrial fragmentation. Autophagy is concomitantly up-regulated, suggesting that mitochondria are degraded via mitophagy. Ex vivo data from human fibroblasts identifies increased mitophagy as an early pathological change that precedes apoptosis. Given the specificity of the observed defects, we are confident that the loss-of-mortalin model presented in this study will be useful for further dissection of the complex network of pathways that underlie the development of mitochondrial parkinsonism. PMID:24386261

Zhu, Jun-yi; Vereshchagina, Natalia; Sreekumar, Vrinda; Burbulla, Lena F.; Costa, Ana C.; Daub, Katharina J.; Woitalla, Dirk; Martins, L. Miguel; Kruger, Rejko; Rasse, Tobias M.

2013-01-01

245

[The treatment of Parkinson's disease].  

PubMed

Parkinson's disease belongs to the most prevalent neurodegenerative disorders and manifests both with motor and non-motor symptoms. Symptomatic treatment of this disorder became more multifaceted over the past years: besides classical dopaminergic drugs and physiotherapy, novel invasive escalation treatment strategies became gold standard in many countries. On the other hand, non-motor symptoms significantly impacts quality of life in many patients which necessitates initiation of adequate therapy. PMID:24326048

Baumann, Christian R; Waldvogel, Daniel

2013-12-11

246

Depression Impairs Learning Whereas Anticholinergics Impair Transfer Generalization in Parkinson Patients  

E-print Network

Depression Impairs Learning Whereas Anticholinergics Impair Transfer Generalization in Parkinson. Gluck, PhDw Abstract: In a study of acquired equivalence in Parkinson disease (PD), in which patients that anticholinergic drugs may particularly impair cognitive abilities that depend on the MT lobe. Key Words: Parkinson

Gluck, Mark

247

Risk factors for complications of drug-induced seizures.  

PubMed

The purpose of this study is to determine clinical factors associated with complications of drug-induced seizures. This prospective observational study was conducted at an American Association of Poison Control Centers-certified regional poison control center (PCC) over a 1-year period. All consecutive cases reported to a PCC involving seizures were forwarded to investigators, who obtained standardized information including the specific drug or medication exposure, dose, reason for exposure, vital signs, laboratory data, treatment, and outcome. Patients were monitored by daily telephone follow-up until death or discharge. Subjects were excluded if the seizure was deemed to be unrelated to exposure. Odds ratios were used to analyze variables for associations with admission to the hospital for >72 h, endotracheal intubation, status epilepticus, anoxic brain injury, or death. One hundred twenty-one cases met inclusion criteria. Sixty-three (52%) were male, and the mean age was 30 (SD14) years. Common exposures included: antidepressants (33%), stimulants (15%), and anticholinergics (10%). One hundred and three (85%) of the exposures were intentional, of which 74 were suicide attempts and 16 were drug abuse or misuse. Forty-nine (40%) patients required endotracheal intubation, 12(10%) had status epilepticus, 50(41%) were hospitalized for more than 72 h, and one patient died. Median hospital stay was 3 days. Variables significantly associated with complications included stimulant exposure (odds ratios, OR=11 [95% confidence intervals (CI) 1.9-52]), suicide attempt (OR=2.2 [95% CI 1.02-4.7]), initial hypotension (OR=11.2 [95% CI 1.4-89.3]), admission glucose >130 mg/dL (OR=5.4 [95% CI 1.6-18.1]), and admission HCO(3)?<20 mEq/L (OR=4.0 [95% CI 1.4-11.3]). Significant clinical factors associated with complications of drug-related seizures include stimulant exposure, suicide attempt, initial hypotension, and admission acidosis or hyperglycemia. PMID:20661684

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

2011-03-01

248

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

PubMed

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

2013-06-01

249

L-DOPA-induced dyregulation of extrastriatal dopamine and serotonin and affective symptoms in a bilateral rat model of Parkinson's disease  

PubMed Central

Convergent evidence indicates that raphestriatal serotonin (5-HT) neurons can convert and release dopamine (DA) derived from exogenous administration of the pharmacotherapeutic L-3,4-dihydroxyphenyl-L-alanine(L-DOPA) as a treatment for Parkinson’s disease (PD). While aspects of such neuroplasticity may be beneficial, chronic L-DOPA may also modify native 5-HT function, precipitating the appearance prevalent non-motor PD symptoms such as anxiety and depression. To examine this, male Sprague-Dawley rats were rendered parkinsonian with bilateral medial forebrain bundle 6-OHDA infusions and treated for at least 28 days with vehicle or L-DOPA. In the first experiment, striatal, hippocampal, amygdalar, and prefrontal cortex DA and 5-HT levels were examined at various post-treatment time-points. In experiment 2, L-DOPA’s effects on DA and 5-HT cell bodies in the substantia nigra pars compacta and dorsal raphe, respectively, were examined. Finally, the effects of L-DOPA on affective behaviors were assessed in locomotor chambers, social interaction, forced swim, and elevated plus maze behavioral tests. Bilateral 6-OHDA lesion induced approximately 80% DA and 30% 5-HT depletion in the striatum compared to sham-lesioned controls, while monoamine levels remained largely unchanged in extrastriatal regions. Tissue levels of DA were increased at the expense of 5-HT levels in parkinsonian rats subjected to chronic L-DOPA injections in all regions sampled, though DA or 5-HT cell bodies were unaffected. Behaviorally, rats could only be tested 24 hours after their last L-DOPA injection due to severe dyskinesia. Despite this, prior exposure to chronic L-DOPA treatment exerted a pronounced anxiogenic phenotype. Collectively, these results suggest that chronic L-DOPA treatment may interfere with the balance of DA and 5-HT function in affect-related brain regions and could induce and/or exacerbate non-motor symptoms in PD. PMID:22659568

Jaunarajs, Karen L. Eskow; George, Jessica A.; Bishop, Christopher

2012-01-01

250

"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

2010-01-01

251

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

2011-01-01

252

[Phencyclidine, a drug which induces psychosis: its neuropharmacological actions].  

PubMed

Phencyclidine (PCP) is a major drug of abuse as well as a 'drug of choice' among substance abusers in the U. S. A. Unfortunately, PCP use may result in the development of psychotic behavior. PCP-induced psychosis is characterized by confusion, excitation, aggression, paranoia, hallucinations and delusions of grandeur and may evoke violent or suicidal behavior. Therefore, many patients suffering from PCP-induced psychosis have been diagnosed initially as schizophrenic. However, PCP-related research has not kept pace with the rise in abuse and PCP-induced psychosis. The neurochemical effects of PCP are not well defined at present, but both behavioral and biochemical studies suggest that it may interact with dopaminergic, cholinergic, noradrenergic, serotonergic, GABAergic and enkephalinergic systems. In addition, the specific reversible, saturable, high affinity 3H-PCP binding site is discovered recently in rat brain. On the other hand, there is now a large body of evidence to suggest that opiate receptors may be subdivided into mu, sigma, kappa and delta receptors. On the basis of behavioral and binding studies, it is proposed that the sigma receptor and the PCP binding site are one and the same. This receptor interacts with PCP and psychotomimetic opioids to produce their psychotomimetic effects. In connection with this receptor, a trial to isolate an endogenous ligand produces psychotomimetic effects, "angeldustin" is progressing. This review has served to illustrate the paucity of information currently available on the central effects of PCP. However, our current notions of the mechanisms of action of PCP are very complicate. Such a review inevitably raises more question than it answers but it is hoped that these may stimulate further investigation in this field. PMID:6395556

Nabeshima, T; Furukawa, H; Kameyama, T

1984-09-01

253

Neuroprotective Effects of Jitai Tablet, a Traditional Chinese Medicine, on the MPTP-Induced Acute Model of Parkinson's Disease: Involvement of the Dopamine System  

PubMed Central

Jitai tablet (JTT) is a traditional Chinese medicine used to treat neuropsychiatric disorders. We previously demonstrated that JTT treatment led to increased level of dopamine transporter (DAT) in the striatum, thus indicating that JTT might have therapeutic potential for Parkinson's disease (PD), which is characterized by dysregulated dopamine (DA) transmission and decreased striatal DAT expression. The aim of this study was to investigate the neuroprotective effect of JTT on MPTP-induced PD mice. Using locomotor activity test and rotarod test, we evaluated the effects of JTT (0.50, 0.15, or 0.05?g/kg) on MPTP-induced behavioral impairments. Tyrosine hydroxylase TH-positive neurons in the substantia nigra and DAT and dopamine D2 receptor (D2R) levels in the striatum were detected by immunohistochemical staining and/or autoradiography. Levels of DA and its metabolites were determined by HPLC. In MPTP-treated mice, behavioral impairments were alleviated by JTT treatment. Moreover, JTT protected against impairment of TH-positive neurons and attenuated the MPTP-induced decreases in DAT and D2R. Finally, high dose of JTT (0.50?g/kg) inhibited the MPTP-induced increase in DA metabolism rate. Taken together, results from our present study provide evidence that JTT offers neuroprotective effects against the neurotoxicity of MPTP and thus might be a potential treatment for PD. PMID:24799940

Liu, Jia; Gao, Jinlong; Xu, Shasha; Liu, Ying; Shang, Weihu; Gu, Chenxin; Huang, Yiyun; Han, Mei

2014-01-01

254

Neuroprotective effects of puerarin on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine induced Parkinson's disease model in mice.  

PubMed

Puerarin, an active component of Pueraria montana var. lobata (Willd.) Sanjappa & Pradeep is well-known for its anti-oxidative and neuroprotective activities. Although anti-Parkinson's disease activity of puerarin was reported in both of in vivo and in vitro model, detailed mechanisms are not clarified. In this study, we addressed that puerarin attenuated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced behavioral deficits, dopaminergic neuronal degeneration and dopamine depletion. Puerarin administration enhanced glutathione (GSH) activity, glial cell line-derived neurotrophic factor (GDNF) expression and PI3K/Akt pathway activation, which might ameliorate MPTP injection-induced progressive elevation of reactive oxygen species (ROS) formation in mice. In addition to the effect on ROS, puerarin ameliorated MPTP-reduced lysosome-associated membrane protein type 2A (Lamp 2A) expression. Taken together, our data demonstrate that puerarin attenuates MPTP-induced dopaminergic neuronal degeneration via modulating GDNF expression, PI3K/Akt pathway and GSH activation, which subsequently ameliorate MPTP-induced ROS formation and decrease of Lamp 2A expression. PMID:23512787

Zhu, Guoqi; Wang, Xuncui; Wu, Shengbing; Li, Xiaoxiang; Li, Qinglin

2014-02-01

255

Parkinson's Disease Videos  

MedlinePLUS Videos and Cool Tools

... University of Pennsylvania What is the relationship between depression and Parkinson's disease? Michael J. Aminoff, MD University ... treatments exist for Parkinson's disease patients with a depression diagnosis? Michael J. Aminoff, MD University of California- ...

256

Unraveling Parkinson's: Three Clues  

MedlinePLUS

... Navigation Bar Home Current Issue Past Issues Unraveling Parkinson's: Three Clues Past Issues / Summer 2006 Table of ... or prevent disease progression. Studies have shown that Parkinson's patients have lost 60 to 80 percent of ...

257

Parkinson disease - discharge  

MedlinePLUS

Your doctor has told you that you have Parkinson disease . This disease affects the brain and leads ... have you take different medicines to treat your Parkinson disease and many of the problems that may ...

258

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

1985-01-01

259

Patients with quinine-induced immune thrombocytopenia have both "drug-dependent" and "drug-specific" antibodies  

PubMed Central

Immune thrombocytopenia induced by quinine and many other drugs is caused by antibodies that bind to platelet membrane glycoproteins (GPs) only when the sensitizing drug is present in soluble form. In this disorder, drug promotes antibody binding to its target without linking covalently to either of the reacting macro-molecules by a mechanism that has not yet been defined. How drug provides the stimulus for production of such antibodies is also unknown. We studied 7 patients who experienced severe thrombocytopenia after ingestion of quinine. As expected, drug-dependent, platelet-reactive antibodies specific for GPIIb/IIIa or GPIb/IX were identified in each case. Unexpectedly, each of 6 patients with GPIIb/IIIa-specific antibodies was found to have a second antibody specific for drug alone that was not platelet reactive. Despite recognizing different targets, the 2 types of antibody were identical in requiring quinine or desmethoxy-quinine (cinchonidine) for reactivity and in failing to react with other structural analogues of quinine. On the basis of these findings and previous observations, a model is proposed to explain drug-dependent binding of antibodies to cellular targets. In addition to having implications for pathogenesis, drug-specific antibodies may provide a surrogate measure of drug sensitivity in patients with drug-induced immune cytopenia. PMID:16861345

Bougie, Daniel W.; Wilker, Peter R.; Aster, Richard H.

2006-01-01

260

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

2000-01-01

261

Spectrum of addictions in Parkinson’s disease: from dopamine dysregulation syndrome to impulse control disorders  

Microsoft Academic Search

There is an increasing awareness that addictive disorders may occur in Parkinson’s disease (PD), either typical substance-related\\u000a addictions that are commonly known as dopamine dysregulation syndrome (DDS) or behavioral addictive syndromes, usually presenting\\u000a as impulse control disorders (ICDs) that include pathological gambling, hypersexuality, compulsive eating and buying. DDS\\u000a is characterized by the use of dopaminergic drugs in doses larger than

Roberto Ceravolo; Daniela Frosini; Carlo Rossi; Ubaldo Bonuccelli

2010-01-01

262

Neuropsychiatric Complications of Medical and Surgical Therapies for Parkinson’s Disease  

Microsoft Academic Search

This review deals with the range of neuropsychiatric problems that may arise from the use of medical and surgical therapies in the treatment of Parkinson’s disease. As new approaches emerge, these problems are diversifying. Well-recognized drug-related complications include hallucinations and psychosis and the so-called dopamine-dysregulation syndrome. The etiology of these problems has not been fully established and is not clearly

David J. Burn; Alexander I. Tröster

2004-01-01

263

Handwriting and speech changes across the levodopa cycle in Parkinson’s disease  

Microsoft Academic Search

Levodopa treatment is used to reduce rigidity and bradykinesia in Parkinson’s disease (PD). This study tracked the handwriting and speech performance of 10 PD patients at 30-minute intervals across one levodopa drug cycle to evaluate levodopa-related changes in temporal and spatial measures that are assumed to correspond to changes in rigidity and bradykinesia. The handwriting measures included l and e

Patricia C. Poluha; Hans-Leo Teulings; Robert H. Brookshire

1998-01-01

264

Antidiabetic Drug Metformin Suppresses Endotoxin-Induced Uveitis in Rats  

PubMed Central

Purpose. To investigate the therapeutic effects of metformin, a commonly used antidiabetic drug, in preventing endotoxin-induced uveitis (EIU) in rats. Methods. EIU in Lewis rats was developed by subcutaneous injection of lipopolysaccharide (LPS; 150 ?g). Metformin (300 mg/kg body weight, intraperitoneally) or its carrier was injected either 12 hours before or 2 hours after LPS induction. Three and 24 hours after EIU, eyes were enucleated and aqueous humor (AqH) was collected. The MILLIPLEX-MAG Rat cytokine-chemokine magnetic bead array was used to determine inflammatory cytokines. The expression of Cox-2, phosphorylation of AMPK, and NF-?B (p65) were determined immunohistochemically. Primary human nonpigmented ciliary epithelial cells (HNPECs) were used to determine the in vitro efficacy of metformin. Results. Compared with controls, the EIU rat AqH had significantly increased number of infiltrating cells and increased levels of various cytokines and chemokines (TNF-?, MCP-1, IL-1?, MIP-1?, IL-6, Leptin, and IL-18) and metformin significantly prevented the increase. Metformin also prevented the expression of Cox-2 and phosphorylation of p65, and increased the activation of AMPK in the ciliary bodies and retinal tissues. Moreover, metformin prevented the expression of Cox-2, iNOS, and activation of NF-kB in the HNPECs and decreased the levels of NO and PGE2 in cell culture media. Conclusions. Our results for the first time demonstrate a novel role of the antidiabetic drug, metformin, in suppressing uveitis in rats and suggest that this drug could be developed to prevent uveitis complications. PMID:22562515

Kalariya, Nilesh M.; Shoeb, Mohammad; Ansari, Naseem H.; Srivastava, Satish K.; Ramana, Kota V.

2012-01-01

265

Epidemiology of idiosyncratic drug-induced liver injury.  

PubMed

Idiosyncratic drug-induced liver injury (DILI) is a significant health problem because of its unpredictable nature, poorly understood pathogenesis, and potential to cause fatal outcomes. It is also a significant hurdle for drug development and marketing of safe prescription medications. Idiosyncratic DILI is generally rare, but its occurrence is likely underappreciated due to the lack of active reporting or surveillance systems and substantial challenges involved in its recognition and diagnosis. Nonetheless, DILI is a common cause of potentially serious and fatal acute liver failure in both children and adults. Population-based studies that accurately estimate the incidence and full spectrum of DILI are limited. However, using a prospective, population-based French study with an annual estimated incidence of 13.9 +/- 2.4 DILI cases per 100,000 inhabitants, it has been extrapolated that nearly 44,000 individuals in the United States will suffer from DILI each year. Although increasing numbers of patients are also being seen with DILI due to herbal and dietary supplements, the epidemiology of this entity requires further investigation. In this article, the epidemiology of DILI, both in the general population and in potentially high-risk subgroups, is reviewed. PMID:19826967

Bell, Lauren N; Chalasani, Naga

2009-11-01

266

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

2011-01-01

267

Glutathione, iron and Parkinson’s disease  

Microsoft Academic Search

Parkinson’s disease (PD) is a progressive neurodegenerative disease involving neurodegeneration of dopaminergic neurons of the substantia nigra (SN), a part of the midbrain. Oxidative stress has been implicated to play a major role in the neuronal cell death associated with PD. Importantly, there is a drastic depletion in cytoplasmic levels of the thiol tripeptide glutathione within the SN of PD

Srinivas Bharath; Michael Hsu; Deepinder Kaur; Subramanian Rajagopalan; Julie K Andersen

2002-01-01

268

PET imaging a MPTP-induced mouse model of Parkinson's disease using the fluoropropyl-dihydrotetrabenazine analog [18F]-DTBZ (AV-133).  

PubMed

Parkinson's disease (PD) is characterized by the loss of dopamine-producing neurons in the nigrostriatal system. Numerous researchers in the past have attempted to track the progression of dopaminergic depletion in PD. We applied a quantitative non-invasive PET imaging technique to follow this degeneration process in an MPTP-induced mouse model of PD. The VMAT2 ligand (18)F-DTBZ (AV-133) was used as a radioactive tracer in our imaging experiments to monitor the changes of the dopaminergic system. Intraperitoneal administrations of MPTP (a neurotoxin) were delivered to mice at regular intervals to induce lesions consistent with PD. Our results indicate a significant decline in the levels of striatal dopamine and its metabolites (DOPAC and HVA) following MPTP treatment as determined by HPLC method. Images obtained by positron emission tomography revealed uptake of (18)F-DTBZ analog in the mouse striatum. However, reduction in radioligand binding was evident in the striatum of MPTP lesioned animals as compared with the control group. Immunohistochemical analysis further confirmed PET imaging results and indicated the progressive loss of dopaminergic neurons in treated animals compared with the control counterparts. In conclusion, our findings suggest that MPTP induced PD in mouse model is appropriate to follow the degeneration of dopaminergic system and that (18)F-DTBZ analog is a potentially sensitive radiotracer that can used to diagnose changes associated with PD by PET imaging modality. PMID:22723923

Toomey, James S; Bhatia, Shilpa; Moon, La'Wanda T; Orchard, Elysse A; Tainter, Kerrie H; Lokitz, Stephen J; Terry, Tracee; Mathis, J Michael; Penman, Andrew D

2012-01-01

269

A novel therapeutic approach to 6-OHDA-induced Parkinson's disease in rats via supplementation of PTD-conjugated tyrosine hydroxylase  

SciTech Connect

The present study aimed to evaluate whether the protein transduction domain (PTD)-conjugated human tyrosine hydroxylase (TH) fusion protein was effective on the 6-hydroxydopamine (6-OHDA)-induced Parkinson's disease (PD) model rats. An expression vector pET-PTD-TH harbouring the PTD-TH gene was constructed and transformed to the Escherichia coli BL21 cells for expression. The expressed recombinant PTD-TH with a molecular weight of 61 kD was successfully transduced (1 {mu}M) into the dopaminergic SH-sy5y human neuroblastoma cells in vitro and visualized by immunohistochemical assay. An in vivo experiment in rats showed that the iv administered PTD-TH protein (8 mg/kg) permeated across the blood-brain barrier, penetrated into the striatum and midbrain, and peaked at 5-8 h after the injection. The behavioral effects of PTD-TH on the apomorphine-induced rotations in the PD model rats 8 weeks after the 6-OHDA lesion showed that a single bolus of PTD-TH (8 mg/kg) iv injection caused a decrement of 60% of the contralateral turns on day 1 and 40% on days 5-17. The results imply that iv delivery of PTD-TH is therapeutically effective on the 6-OHDA-induced PD in rats, the PTD-mediated human TH treatment opening a promising therapeutic direction in treatment of PD.

Wu Shaoping [Department of Biochemistry and Pharmacology, Beijing Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Tai Ping Road, 27, Beijing 100850 (China); Beijing Centers for Diseases Prevention and Control, Beijing 100013 (China); Fu Ailing [Department of Biochemistry and Pharmacology, Beijing Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Tai Ping Road, 27, Beijing 100850 (China); Wang Yuxia [Department of Biochemistry and Pharmacology, Beijing Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Tai Ping Road, 27, Beijing 100850 (China); Yu Leiping [Department of Pharmacology, State Key Laboratory of Drug Research, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 201203 (China); Jia Peiyuan [Department of Biochemistry and Pharmacology, Beijing Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Tai Ping Road, 27, Beijing 100850 (China); Li Qian [Department of Biochemistry and Pharmacology, Beijing Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Tai Ping Road, 27, Beijing 100850 (China); Jin Guozhang [Department of Pharmacology, State Key Laboratory of Drug Research, Shanghai Institutes of Biological Sciences, Chinese Academy of Sciences, Shanghai 201203 (China); Sun Manji [Department of Biochemistry and Pharmacology, Beijing Institute of Pharmacology and Toxicology, Academy of Military Medical Sciences, Tai Ping Road, 27, Beijing 100850 (China)]. E-mail: Sunmj@nic.bmi.ac.cn

2006-07-21

270

Parkinson's Disease  

MedlinePLUS

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

271

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. PMID:22319547

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

2012-01-01

272

Analysis of dopaminergic neuronal dysfunction in genetic and toxin-induced models of Parkinson's disease in Drosophila.  

PubMed

Drosophila melanogaster has contributed significantly to the understanding of disease mechanisms in Parkinson's disease (PD) as it is one of the very few PD model organisms that allow the study of age-dependent behavioral defects, physiology and histology, and genetic interactions among different PD-related genes. However, there have been contradictory results from a number of recent reports regarding the loss of dopaminergic neurons in different PD fly models. In an attempt to re-evaluate and clarify this issue, we have examined three different genetic (?-synuclein, Pink1, parkin) and two toxin-based (rotenone and paraquat) models of the disease for neuronal cell loss. Our results showed no dopaminergic neuronal loss in all models tested. Despite this surprising result, we found additional phenotypes showing the dysfunctional status of the dopaminergic neurons in most of the models analyzed. A common feature found in most models is a quantifiable decrease in the fluorescence of a green-fluorescent protein reporter gene in dopaminergic neurons that correlates well with other phenotypes found for these models and can be reliably used as a hallmark of the neurodegenerative process when modeling diseases affecting the dopaminergic system in Drosophila. Analyzing three genetic and two toxin-based Drosophila models of Parkinson's disease (PD) through green fluorescent protein reporter and ?-tyrosine hydroxylase staining, we have found the number of dopaminergic neurons to remain unchanged. Despite the lack of neuronal loss, we have detected a remarkable decrease in a reporter green-fluorescent protein (GFP) signal in dopaminergic neurons, suggesting an abnormal neuronal status that correlates with the phenotypes associated with those PD fly models. PMID:25040725

Navarro, Juan A; Heßner, Sabina; Yenisetti, Sarat C; Bayersdorfer, Florian; Zhang, Li; Voigt, Aaron; Schneuwly, Stephan; Botella, Jose A

2014-11-01

273

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. PMID:19132805

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

2013-01-01

274

Power Spectral Analysis of Recovery Sleep of Sleep Deprivation and Hypnotic Drug Induced Sleep  

Microsoft Academic Search

Hypnotic drugs induced sleep is usually different from physiological sleep in restoring body energy. The cause of the differences is not clear. To investigate the differences between these two types of sleep, in this study, hypnotic drug diazepam (DZP) induced sleep was compared with the recovery sleep following sleep deprivation. Power spectral analysis was used to reveal the different EEG

Zhouyan Feng; Fei Gu

2005-01-01

275

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. PMID:22821557

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.

2012-01-01

276

Covert drug dependence should be the null hypothesis for explaining drug-withdrawal-induced clinical deterioration: the necessity for placebo versus drug withdrawal trials on normal control subjects.  

PubMed

Just as a placebo can mimic an immediately effective drug so chronic drug dependence may mimic an effective long-term or preventive treatment. The discovery of the placebo had a profound result upon medical practice, since it became recognized that it was much harder to determine the therapeutic value of an intervention than was previously assumed. Placebo is now the null hypothesis for therapeutic improvement. As David Healy describes in the accompanying editorial on treatment induced stress syndromes [1], an analogous recognition of the effect of drug dependence is now overdue. Drug dependence and withdrawal effects should in future become the null hypothesis when there is clinical deterioration following cessation of treatment. The ideal methodology for detecting drug dependence and withdrawal is a double-blind placebo controlled and randomized trial using disease-free normal control subjects. Normal controls are necessary to ensure that the possibility of underlying chronic disease is eliminated: so long as subjects begin the trial as 'normal controls' it is reasonable to infer that any clinical or psychological problems (above placebo levels) which they experience following drug withdrawal can reasonably be attributed to the effects of the drug. This is important because the consequences of failing to detect the risk of covert drug dependence may be considerably worse than failing to detect a placebo effect. Drug dependent patients not only fail to receive benefit and suffer continued of inconvenience, expense and side effects; but the drug has actually created and sustained a covert chronic pathology. However, the current situation for drug evaluation is so irrational that it would allow chronic alcohol treatment to be regarded as a cure for alcoholism on the basis that delirium tremens follows alcohol withdrawal and alcohol can be used to treat delirium tremens! Therefore, just as placebo controlled trials of drugs are necessary to detect ineffective drugs, so drug withdrawal trials on normal control subjects should be regarded as necessary to detect dependence-producing drugs. PMID:20223602

Charlton, Bruce G

2010-05-01

277

Curcumin exposure induces expression of the Parkinson's disease-associated leucine-rich repeat kinase 2 (LRRK2) in rat mesencephalic cells.  

PubMed

Turmeric (curry powder), an essential ingredient of culinary preparations of Southeast Asia, contains a major polyphenolic compound known as curcumin or diferuloylmethane. Curcumin is a widely studied phytochemical with a variety of biological activities. In addition to its anti-inflammatory and antimicrobial/antiviral properties, curcumin is considered as a cancer chemopreventive agent as well as a modulator of gene expression and a potent antioxidant. Since oxidative stress has been implicated in the degeneration of dopaminergic neurons in the substantia nigra in Parkinson's disease (PD), curcumin has been proposed to have potential therapeutic value for the treatment of neurodegenerative diseases such as PD. Following age, a family history of PD is the most commonly reported risk factor, suggesting a genetic component of the disease in a subgroup of patients. The LRRK2 gene has emerged as the gene most commonly associated with both familial and sporadic PD. Here, we report that exposure of rat mesencephalic cells to curcumin induces the expression of LRRK2 mRNA and protein in a time-dependent manner. The expression of other PD-related genes, such alpha-synuclein and parkin, was not affected by exposure to curcumin, and PTEN-induced putative kinase 1 (PINK1) was not expressed in rat mesencephalic cells. As LRRK2 overexpression is strongly associated with the pathological inclusions found in several neurodegenerative disorders, further studies are needed to evaluate the effects of curcumin as a therapeutic agent for neurodegenerative diseases. PMID:19879924

Ortiz-Ortiz, Miguel A; Morán, José M; Ruiz-Mesa, Luz M; Niso-Santano, Mireia; Bravo-SanPedro, José M; Gómez-Sánchez, Rubén; González-Polo, Rosa A; Fuentes, José M

2010-01-01

278

Gene expression regulation of Bcl2, Bax and cytochrome-C by geraniol on chronic MPTP/probenecid induced C57BL/6 mice model of Parkinson's disease.  

PubMed

Parkinson's disease (PD) is a common disabling movement disorder owing to progressive depletion of dopamine in nigrostriatal region, and can be experimentally accelerated by the neurotoxin 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP). MPTP-treated mice are a representative animal model for searching for the therapeutic agents for PD without adverse effect. In this study we investigated the effect of geraniol (GE) on chronic MPTP/probenecid (MPTP/p) induced apoptotic changes in nigrostriatal region. We observed that chronic exposure to MPTP/p led to increased expression of apoptotic markers, results in neurodegeneration and motor behavioral impairments in mice. Pretreatment with GE to MPTP/p significantly improved motor functions and ameliorated striatal antioxidant balance. In addition, GE attenuated the expression of apoptotic markers evident by the normalized Bcl-2/Bax ratio and decreased expression of cytochrome-C and caspase-9 in the substantia nigra and striatum of MPTP/p induced mice model of PD. The findings of the present study suggested that GE, a new therapeutic potential avenue may have beneficial effects in slowing or preventing the progression of PD and other neurodegenerative disorders. PMID:24768735

Rekha, Karamkolly R; Selvakumar, Govindasamy P

2014-06-25

279

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. PMID:22928089

Agrawal, Shyam Sunder; Gullaiya, Sumeet; Dubey, Vishal; Singh, Varun; Kumar, Ashok; Nagar, Ashish; Tiwari, Poonam

2012-01-01

280

Poly (ADP-ribose) in the pathogenesis of Parkinson's disease  

PubMed Central

The defining feature of Parkinson’s disease is a progressive and selective demise of dopaminergic neurons. A recent report on Parkinson’s disease animal model demonstrates that poly (ADP-ribose) (PAR) dependent cell death, also named parthanatos, is accountable for selective dopaminergic neuronal loss. Parthanatos is a programmed necrotic cell death, characterized by PARP1 activation, apoptosis inducing factor (AIF) nuclear translocation, and large scale DNA fragmentation. Besides cell death regulation via interaction with AIF, PAR molecule mediates diverse cellular processes including genomic stability, cell division, transcription, epigenetic regulation, and stress granule formation. In this review, we will discuss the roles of PARP1 activation and PAR molecules in the pathological processes of Parkinson’s disease. Potential interaction between PAR molecule and Parkinson’s disease protein interactome are briefly introduced. Finally, we suggest promising points of therapeutic intervention in the pathological PAR signaling cascade to halt progression in Parkinson’s disease. [BMB Reports 2014; 47(8): 424-432] PMID:24874851

Lee, Yunjong; Kang, Ho Chul; Lee, Byoung Dae; Lee, Yun-Il; Kim, Young Pil; Shin, Joo-Ho

2014-01-01

281

Drug-Induced Gingival Overgrowth: The Genetic Dimension  

PubMed Central

Background: Currently, the etiology of drug-induced gingival overgrowth is not entirely understood but is clearly multifactorial. Phenytoin, one of the common drugs implicated in gingival enlargement, is metabolized mainly by cytochrome P450 (CYP)2C9 and partly by CYP2C19. The CYP2C9 and CYP2C19 genes are polymorphically expressed and most of the variants result in decreased metabolism of the respective substrates. Aims: The present study was undertaken to investigate the influence of the CYP2C9*2 and *3 variant genotypes on phenytoin hydroxylation in subjects diagnosed with epilepsy from South India, thus establishing the genetic polymorphisms leading to its defective hydroxylation process. Materials and Methods: Fifteen epileptic subjects, age 9 to 60 years were included in the study. Among the study subjects, 8 were males and 7 were females. Genomic DNA was extracted from patients’ blood using Phenol-chloroform method and genotyping was done for CYP2C9 using customized TaqMan genotyping assays on a real time thermocycler, by allelic discrimination method. The genetic polymorphisms *1, *2 and *3 on CYP2C9 were selected based on their function and respective allele frequencies in Asian subcontinent among the Asian populations. Results: CYP2C9*1*2 and CYP2C9*3/*3 were identified with equal frequency in the study population. There were seven subjects with CYP2C9*1/*2 genotype (heterozygous mutant), one subject with CYP2C9*1/*1 (wild type) and seven study subjects with CYP2C9*3/*3 (homozygous mutant). Conclusion: The results obtained in the present study will be helpful in the medical prescription purposes of phenytoin, and a more personalized patient approach with its administration can be advocated. PMID:25317394

Charles, Noronha Shyam Curtis; Chavan, Rahul; Moon, Ninad Joshirao; Nalla, Srinivas; Mali, Jaydeepchandra; Prajapati, Anchal

2014-01-01

282

Interactions of CaMKII with dopamine D2 receptors: roles in levodopa-induced dyskinesia in 6-hydroxydopamine lesioned Parkinson's rats  

PubMed Central

Ca2+/calmodulin-dependent protein kinase II is a synapse-enriched kinase in mammalian brains. This kinase interacts with various synaptic proteins to regulate expression and function of interacting proteins and thereby modulates synaptic transmission. CaMKII and its interacting partners are also believed to play a pivotal role in the pathogenesis of various neurological and neurodegenerative disorders, such as Parkinson's disease (PD). In this study, we found that CaMKII? binds to dopamine D2 receptors (D2R) in vitro. A distal region in the D2R third intracellular loop harbors CaMKII? binding. Endogenous CaMKII? was also found to interact with native D2Rs in rat striatal neurons in which D2Rs are expressed at a high level. In addition, in a rat 6-hydroxydopamine lesioned model of PD, chronic levodopa administration induced characteristic dyskinesia. In parallel, levodopa induced an increase in CaMKII?-D2R interactions in striatal neurons. Intrastriatal injection of a Tat-fusion and CaMKII?-D2R interaction-dead peptide (Tat-D2Ri) reversed this increase in the interaction between two proteins. Tat-D2Ri also alleviated dyskinetic behaviors induced by levodopa. These results reveal a new interaction between CaMKII? and D2Rs in striatal neurons which is sensitive to long-term administration of levodopa in PD rats. Prevention of the response of CaMKII?-D2R interactions to levodopa can alleviate levodopa-induced dyskinesia. PMID:25351365

Zhang, SuFang; Xie, ChengLong; Wang, Qiang; Liu, ZhenGuo

2014-01-01

283

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. PMID:23801948

Vaglini, Francesca; Viaggi, Cristina; Piro, Valentina; Pardini, Carla; Gerace, Claudio; Scarselli, Marco; Corsini, Giovanni Umberto

2013-01-01

284

Transmural dispersion of repolarization as a preclinical marker of drug-induced proarrhythmia.  

PubMed

Torsade de Pointes (TdP) proarrhythmia is a major complication of therapeutic drugs that block the delayed rectifier current. QT interval prolongation, the principal marker used to screen drugs for proarrhythmia, is both insensitive and nonspecific. Consequently, better screening methods are needed. Drug-induced transmural dispersion of repolarization (TDR) is mechanistically linked to TdP. Therefore, we hypothesized that drug-induced enhancement of TDR is more predictive of proarrhythmia than QT interval. High-resolution transmural optical action potential mapping was performed in canine wedge preparations (n = 19) at baseline and after perfusion with 4 different QT prolonging drugs at clinically relevant concentrations. Two proarrhythmic drugs in patients (bepridil and E4031) were compared with 2 nonproarrhythmic drugs (risperidone and verapamil). Both groups prolonged the QT (all P < 0.02), least with the proarrhythmic drug bepridil, reaffirming that QT is a poor predictor of TdP. In contrast, TDR was enhanced only by proarrhythmic drugs (P < 0.03). Increased TDR was due to a preferential prolongation of midmyocardial cell, relative to epicardial cell, APD, whereas nonproarrhythmic drugs similarly prolonged both cell types. In contrast to QT prolongation, augmentation of TDR was induced by proarrhythmic but not nonproarrhythmic drugs, suggesting TDR is a superior preclinical marker of proarrhythmic risk during drug development. PMID:22561361

Said, Tamer H; Wilson, Lance D; Jeyaraj, Darwin; Fossa, Anthony A; Rosenbaum, David S

2012-08-01

285

Personality, Addiction, Dopamine: Insights from Parkinson's Disease  

Microsoft Academic Search

In rare instances, patients with Parkinson's disease (PD) may become addicted to their own medication or develop behavioral addictions such as pathological gambling. This is surprising because PD patients typi- cally have a very low incidence of drug abuse and display a personality type that is the polar opposite of the addictive personality. These rare addictive syndromes, which appear to

Alain Dagher; Trevor W. Robbins

2009-01-01

286

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

SciTech Connect

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 and animal models of PD. Treatment of mesencephalic dopaminergic neuronal N27 cells with 6-OHDA (100 {mu}M) for 24 h significantly reduced mitochondrial activity and increased cytosolic cytochrome c, followed by sequential activation of caspase-9 and caspase-3. Co-treatment with the free radical scavenger MnTBAP (10 {mu}M) significantly attenuated 6-OHDA-induced caspase activities. Interestingly, 6-OHDA induced proteolytic cleavage and activation of protein kinase C delta (PKC{delta}) was completely suppressed by treatment with a caspase-3-specific inhibitor, Z-DEVD-FMK (50 {mu}M). Furthermore, expression of caspase-3 cleavage site-resistant mutant PKC{delta}{sup D327A} and kinase dead PKC{delta}{sup K376R} or siRNA-mediated knockdown of PKC{delta} protected against 6-OHDA-induced neuronal cell death, suggesting that caspase-3-dependent PKC{delta} promotes oxidative stress-induced dopaminergic degeneration. Suppression of PKC{delta} expression by siRNA also effectively protected N27 cells from 6-OHDA-induced apoptotic cell death. PKC{delta} cleavage was also observed in the substantia nigra of 6-OHDA-injected C57 black mice but not in control animals. Viral-mediated delivery of PKC{delta}{sup D327A} protein protected against 6-OHDA-induced PKC{delta} activation in mouse substantia nigra. Collectively, these results strongly suggest that proteolytic activation of PKC{delta} is a key downstream event in dopaminergic degeneration, and these results may have important translational value for development of novel treatment strategies for PD.

Latchoumycandane, Calivarathan; Anantharam, Vellareddy; Jin, Huajun; Kanthasamy, Anumantha; Kanthasamy, Arthi, E-mail: arthik@iastate.edu

2011-11-15

287

Drug-induced torsades de pointes: the evolving role of pharmacogenetics.  

PubMed

Drug-induced torsades de pointes (TdP) is a rare, but potentially lethal, unwanted effect of drugs, including many commonly prescribed noncardiac drugs. Despite its low frequency, drug-induced TdP has generated a great deal of angst among physicians and pharmaceutical companies as well as tragedy, albeit rare, among patients. Although in retrospect many patients who died suddenly as a result of drug-induced TdP had identifiable risk factors, prediction in individual cases remains problematic. Over the past decade, tremendous progress has been made with respect to elucidating the fundamental pathogenic mechanisms that underlie drug-induced TdP. The vast majority of drugs associated with "QT liability" and the potential for drug-induced TdP, including all of the drugs removed from the market because of this side effect, are "HERG (human ether-á-go-go-related gene) blockers." These drugs inhibit the KCNH2-encoded HERG potassium channel, which is one of the critical repolarizing forces involved in the exquisite orchestration of the heart's action potential. Consequently, myocyte repolarization is potentially delayed as evidenced by prolongation of the QT interval, thus providing the substrate for drug-induced TdP. Rare mutations in KCNH2 provide the pathogenic substrate for type 2 congenital long QT syndrome (LQTS), thus placing this cardiac potassium channel squarely in the intersection between congenital LQTS (the "Rosetta stone" of the heritable channelopathies) and acquired LQTS (drug-induced TdP). In addition, common polymorphisms residing in the LQTS-causing channel genes may confer heightened arrhythmogenic susceptibility and contribute to the makings of a vulnerable host. This review focuses on the present strategy of identifying "at-risk compounds" and the potential future strategy involving pharmacogenetics to pinpoint "at-risk hosts" in an effort to curb this rare, unintended, but potentially life-threatening side effect. PMID:16253929

Fitzgerald, Patrick T; Ackerman, Michael J

2005-11-01

288

Higher iron in the red nucleus marks Parkinson's dyskinesia.  

PubMed

Dopamine cell loss and increased iron in the substantia nigra (SN) characterize Parkinson's disease (PD), with cerebellar involvement increasingly recognized, particularly in motor compensation and levodopa-induced dyskinesia (LID) development. Because the red nucleus (RN) mediates cerebellar circuitry, we hypothesized that RN iron changes might reflect cerebellum-related compensation, and/or the intrinsic capacity for LID development. We acquired high resolution magnetic resonance images from 23 control and 38 PD subjects (12 with PD and history of LID [PD+DYS]) and 26 with PD and no history of LID (PD-DYS). Iron content was estimated from bilateral RN and SN transverse relaxation rates (R2*). PD subjects overall displayed higher R2* values in both the SN and RN. RN R2* values correlated with off-drug Unified Parkinson's Disease Rating Scale-motor scores, but not disease duration or drug dosage. RN R2* values were significantly higher in PD+DYS compared with control and PD-DYS subjects; control and PD-DYS subjects did not differ. The association of higher RN iron content with PD-related dyskinesia suggests increased iron content is involved in, or reflects, greater cerebellar compensatory capacity and thus increased likelihood of LID development. PMID:23177595

Lewis, Mechelle M; Du, Guangwei; Kidacki, Michal; Patel, Nisargkumar; Shaffer, Michele L; Mailman, Richard B; Huang, Xuemei

2013-05-01

289

Toxic Epidermal Necrolysis induced by rarely implicated drugs.  

PubMed

Toxic Epidermal Necrolysis (TEN) and Steven-Johnson Syndrome (SJS) are serious disorders commonly caused as idiosyncratic reactions to drugs, the most common ones being oxicams, anticonvulsants, allopurinol, and sulfonamides. We present a case of TEN in a patient who developed the lesions after ingesting multiple drugs including paracetamol, metoclopramide, antihistamines, and multivitamins. These drugs have rarely been implicated in this disorder. The suspected drugs in this case were paracetamol and metoclopramide. However, the role of other drugs could not be ruled out definitely. The patient was managed with antibiotics, corticosteroids, and parenteral fluids and recovered well. PMID:22529493

Rajagopalan, Sujit; Kaur, Sharonjeet; Dogra, Sunil; Shafiq, Nusrat; Bhalla, Ashish; Pandhi, Promila; Malhotra, Samir

2012-03-01

290

Toxic Epidermal Necrolysis induced by rarely implicated drugs  

PubMed Central

Toxic Epidermal Necrolysis (TEN) and Steven-Johnson Syndrome (SJS) are serious disorders commonly caused as idiosyncratic reactions to drugs, the most common ones being oxicams, anticonvulsants, allopurinol, and sulfonamides. We present a case of TEN in a patient who developed the lesions after ingesting multiple drugs including paracetamol, metoclopramide, antihistamines, and multivitamins. These drugs have rarely been implicated in this disorder. The suspected drugs in this case were paracetamol and metoclopramide. However, the role of other drugs could not be ruled out definitely. The patient was managed with antibiotics, corticosteroids, and parenteral fluids and recovered well. PMID:22529493

Rajagopalan, Sujit; Kaur, Sharonjeet; Dogra, Sunil; Shafiq, Nusrat; Bhalla, Ashish; Pandhi, Promila; Malhotra, Samir

2012-01-01

291

A fixed-dose randomized controlled trial of olanzapine for psychosis in Parkinson disease  

PubMed Central

Background: Psychosis is a common and debilitating side effect of long-term dopaminergic treatment of Parkinson disease (PD). While clozapine is an effective treatment, the need for blood monitoring has limited its first-line use.  Objective: Since olanzapine shows similar receptor affinity to clozapine, we hypothesized that it might be an effective alternative to clozapine for treatment of drug-induced psychosis (DIP) in PD, and that lower doses than usual might make it tolerable. Methods: In 1998-2003 we conducted a four-week, double-blind, placebo-controlled, parallel group, fixed-dose trial of olanzapine (0, 2.5mg, or 5mg) in 23 PD patients with DIP while allowing for clinically realistic dose adjustments of dopaminomimetic mid-study. The primary outcome measures were Brief Psychiatric Rating Scale (BPRS) ratings scored from videotaped interviews after study termination by an observer blinded to dose assignment and to interview timing, and CGI (Clinical Global Impression). The Unified Parkinson’s Disease Rating Scale motor subscale (UPDRS) was the primary measure of tolerability. Results: Intention-to-treat analysis found no significant differences among treatment groups in study completion or serious adverse events. However, a disproportionate number of olanzapine vs. placebo subjects reported mild side effects (p<0.04), many citing motor worsening. Fourteen patients completed the study (seven on placebo, two on 2.5mg olanzapine, five on 5mg olanzapine). In study completers, analysis by repeated measures ANOVA revealed no significant difference between olanzapine and placebo groups in BPRS psychosis reduction (p=0.536), parkinsonism (p=0.608), or any other measured parameters (CGI, MMSE, Beck Depression Inventory, Hamilton Depression score, PDQ?39, Schwab-England ADL assessment, and sleep scores). Conclusion: This study adds to other evidence that olanzapine is ineffective in treating medication-induced psychosis in Parkinson disease. PMID:24627787

Black, Kevin J

2013-01-01

292

Dementia in Parkinson’s disease  

Microsoft Academic Search

Opinion statement  One of the more recently recognized problems in treatment of patients with Parkinson’s disease (PD) is development of cognitive\\u000a dysfunction and, in many cases, frank dementia. As patients with PD live longer, because of improved care and treatment of\\u000a motor symptoms, dementia in PD is becoming a major contributor to morbidity in the illness. Prevalence studies suggest that\\u000a up

Karen E. Anderson

2004-01-01

293

The genetics of Parkinson’s disease  

Microsoft Academic Search

The recent identification of several genes and gene loci linked to familial forms of Parkinson’s disease (PD) has contributed\\u000a significantly to our understanding of the genetic contribution in PD. Although the etiology of sporadic PD remains unknown,\\u000a it is currently assumed that genetic susceptibilities may be involved. The advent of genome-wide scanning techniques has now\\u000a made it possible to conduct

Kah Leong Lim; Valina L. Dawson; Ted M. Dawson

2002-01-01

294

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

1999-01-01

295

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

2009-01-01

296

Quantitative structure-activity relationship models for predicting drug-induced liver injury based on FDA-approved drug labeling annotation and using a large collection of drugs.  

PubMed

Drug-induced liver injury (DILI) is one of the leading causes of the termination of drug development programs. Consequently, identifying the risk of DILI in humans for drug candidates during the early stages of the development process would greatly reduce the drug attrition rate in the pharmaceutical industry but would require the implementation of new research and development strategies. In this regard, several in silico models have been proposed as alternative means in prioritizing drug candidates. Because the accuracy and utility of a predictive model rests largely on how to annotate the potential of a drug to cause DILI in a reliable and consistent way, the Food and Drug Administration-approved drug labeling was given prominence. Out of 387 drugs annotated, 197 drugs were used to develop a quantitative structure-activity relationship (QSAR) model and the model was subsequently challenged by the left of drugs serving as an external validation set with an overall prediction accuracy of 68.9%. The performance of the model was further assessed by the use of 2 additional independent validation sets, and the 3 validation data sets have a total of 483 unique drugs. We observed that the QSAR model's performance varied for drugs with different therapeutic uses; however, it achieved a better estimated accuracy (73.6%) as well as negative predictive value (77.0%) when focusing only on these therapeutic categories with high prediction confidence. Thus, the model's applicability domain was defined. Taken collectively, the developed QSAR model has the potential utility to prioritize compound's risk for DILI in humans, particularly for the high-confidence therapeutic subgroups like analgesics, antibacterial agents, and antihistamines. PMID:23997115

Chen, Minjun; Hong, Huixiao; Fang, Hong; Kelly, Reagan; Zhou, Guangxu; Borlak, Jürgen; Tong, Weida

2013-11-01

297

Imaging of the dopamine transporter predicts pattern of disease progression and response to levodopa in patients with schizophrenia and parkinsonism: a 2-year follow-up multicenter study.  

PubMed

Similarly to subjects with degenerative parkinsonism, (123)I-FP-CIT SPECT has been reported either normal or abnormal in patients with drug-induced parkinsonism (DIP), challenging the notion that parkinsonism might be entirely due to post-synaptic D2-receptors blockade by antipsychotic drugs. In a previous multicenter cross-sectional study conducted on a large sample of patients with schizophrenia, we identified 97 patients who developed parkinsonism with a similar bi-modal distribution of DAT-SPECT. In this longitudinal study, we reported clinical and imaging features associated with progression of motor disability over 2-year follow-up in 60 out of those 97 patients with schizophrenia and parkinsonism who underwent (123)I-FP-CIT SPECT at baseline evaluation (normal SPECT=33; abnormal SPECT=27). As second end-point, chronic response to levodopa over a 3-month period was tested in a subgroup of subjects. Motor Unified Parkinson's Disease Rating Scale (UPDRS) at follow-up significantly increased in patients with abnormal SPECT. Specifically, a 6-point worsening was demonstrated in 18.5% of the subjects with abnormal SPECT and in none of the subjects with normal SPECT. Levodopa treatment improved motor UPDRS only in the group with abnormal SPECT. After adjustment for possible confounders, linear regression analysis demonstrated that abnormal SPECT findings at baseline were the only predictor of motor disability progression and of better outcome of levodopa treatment. Our results support the notion that a degenerative disease might underlie parkinsonism in a minority of schizophrenic patients chronically exposed to antipsychotics. Functional imaging of the dopamine transporter can be helpful to select this patient sub-group that might benefit from levodopa therapy. PMID:24369987

Tinazzi, Michele; Morgante, Francesca; Matinella, Angela; Bovi, Tommaso; Cannas, Antonino; Solla, Paolo; Marrosu, Francesco; Nicoletti, Alessandra; Zappia, Mario; Luca, Antonina; Di Stefano, Angela; Morgante, Letterio; Pacchetti, Claudio; Minafra, Brigida; Sciarretta, Massimo; Dallocchio, Carlo; Rossi, Simone; Ulivelli, Monica; Ceravolo, Roberto; Frosini, Daniela; Cipriani, Andrea; Barbui, Corrado

2014-02-01

298

Prediction of clinical drug efficacy by classification of drug-induced genomic expression profiles in vitro  

Microsoft Academic Search

Assays of drug action typically evaluate biochemical activity. However, accurately matching therapeutic efficacy with biochemical activity is a challenge. High-content cellular assays seek to bridge this gap by capturing broad information about the cellular physiology of drug action. Here, we present a method of predicting the general therapeutic classes into which various psychoactive drugs fall, based on high-content statistical categorization

Erik C. Gunther; David J. Stone; Robert W. Gerwien; Patricia Bento; Melvyn P. Heyes

2003-01-01

299

Mangiferin attenuates MPTP induced dopaminergic neurodegeneration and improves motor impairment, redox balance and Bcl-2/Bax expression in experimental Parkinson's disease mice.  

PubMed

Mangiferin, a polyphenol compound of C-glucoside, is well-known for its anti-inflammatory, antioxidant, anticancer, antidiabetic and cognitive enhancement properties. In this study, we investigated the neuroprotective effect of mangiferin against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), which is most popular and widely used to evaluate therapeutic implications of new protective agents. Male C57BL/6 mice were orally treated with mangiferin (10, 20 and 40 mg/kg body wt.) for 14 days and from 10th day onwards MPTP (30 mg/kg, i.p.) was injected for last 5 days. MPTP treatment leads to enhanced oxidative stress, induction of apoptosis (upregulates the expression of Bax, proapoptotic protein and downregulates the expression of anti-apoptotic marker Bcl-2), and loss of dopominergic neurons which results in motor impairments. Results of our study confirmed that mangiferin prevented MPTP-induced behavioral deficits, oxidative stress, apoptosis, dopaminergic neuronal degeneration and dopamine depletion. Taken together, we conclude that mangiferin attenuates the dopaminergic neurodegeneration mainly through its potent antioxidant and antiapoptotic properties. PMID:24095822

Kavitha, Mani; Nataraj, Jagatheesan; Essa, Musthafa Mohammed; Memon, Mushtaq A; Manivasagam, Thamilarasan

2013-11-25

300

Drug Rash With Eosinophilia and Systemic Symptoms Syndrome Induced by Chloral Hydrate in Early Childhood  

PubMed Central

Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome, also known as drug-induced hypersensitivity syndrome (DIHS), is a rare, acute and severe life-threatening systemic disease. DRESS syndrome is characterized by fever, lymphadenopathy, rash, hypereosinophilia and involvement of systemic organs. The most commonly implicated drugs are anticonvulsants, sulfonamides and allopurinol. Chloral hydrate is a sedative and hypnotic drug frequently used in pediatric patients. We first report a case of DRESS syndrome induced by chloral hydrate in a 14-month-old female. PMID:24843805

Yoo, Suk Dong; Kim, Su Gon; Kim, Seong Heon

2014-01-01

301

Drug-induced acute pancreatitis: A rare manifestation of an incomplete "dapsone syndrome"  

PubMed Central

Drug-induced acute pancreatitis (AP) is under-reported, and a large number of drugs are listed as offenders, but are often overlooked. Knowledge about the possible association of medications in causing AP is important, and needs a high index of suspicion, especially with drugs that have been reported to be the etiology only rarely. Dapsone, a commonly used drug, can cause various hypersensitivity reactions including AP collectively called “dapsone syndrome.” Here, we report dapsone-induced AP in a young man. Our case shows certain dissimilarities like associated acute renal failure and acute hemolysis not previously described. PMID:25097293

Das, Anup K.; Jawed, Qaiser

2014-01-01

302

[Impulse control disorders in Parkinson's disease].  

PubMed

Of the patients having Parkinson's disease, up to third encounters some degree of impulse control problems and one out of seven suffers from true impulse control disorders such as pathological gambling, hypersexuality, compulsive shopping and binge eating. Dopaminergic drugs used in anti-Parkinson therapy, especially dopamine agonists, increase the risk of these disorders. Impulse control disorders are associated with a relatively more active dopamine-mediated neurotransmission of the mesolimbic and mesocortical system. Discontinuation of dopamine agonist medication can thus be considered as the first line treatment of these disorders. PMID:24397147

Joutsa, Juho; Kaasinen, Valtteri

2013-01-01

303

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 other self-administered drugs could readily be substituted with little modification to the procedures. PMID:23093352

Beardsley, Patrick M.; Shelton, Keith L.

2012-01-01

304

Drug-induced autoimmunity: experience of the French Pharmacovigilance system  

Microsoft Academic Search

Spontaneous reporting of suspected adverse drug reactions to a pharmacovigilance structure is a reasonable tool to detect new associations between drugs and a given toxic effect. An analysis of the French national database of pharmacovigilance was undertaken to evaluate how such a system is relevant to survey and\\/or detect drug-associated autoimmune disorders. Only 0.2% of reports were coded with terms

Thierry Vial; Brigitte Nicolas; Jacques Descotes

1997-01-01

305

Steroidal and nonsteroidal drugs in endotoxin-induced uveitis.  

PubMed

Various classes of anti-inflammatory compounds like steroids (dexamethasone), cyclooxygenase inhibitors (indomethacin and flurbiprofen), 5-lipoxygenase inhibitors (BWA 218C and BWA 4C), immunosuppressive drugs (cyclosporin and rapamycin) and cod liver oil were tested for their antiinflammatory activities in endotoxin-induced uveitis model in rabbits. Intraocular inflammation was assessed in terms of two inflammatory responses i.e. breakdown of blood-aqueous barrier (BAB) and leukocyte infiltration into aqueous humor and iris ciliary body (ICB). Prostaglandin (PG) E2 and leukotriene (LT) B4 release into aqueous humor was also measured. Indomethacin significantly inhibited PGE2 release without affecting leukocyte or BAB response. Flurbiprofen prevented leukocyte, PGE2 and LTB4 release into aqueous humor but not ICB chemotaxis. BWA 218C and BWA 4C also significantly inhibited leukocyte and LTB4 release but not BAB responses. Dexamethasone (2mg/kg, i.m.) and cyclosporin A (25 mg/kg i.m.) significantly inhibited leukocyte infiltration into aqueous humor and ICB, and PGE2 release but they failed to inhibit breakdown of BAB and LTB4 release. On the other hand, rapamycin (10mg/kg i.m.) and cod liver oil (1 ml daily i.m. up to 15 days) significantly prevented leukocyte and BAB response. Cod liver oil also significantly inhibited PGE2 and LTB4 release but rapamycin affected only PGE2 release into aqueous humor. It is concluded that arachidonic acid metabolites may not play a vital role in this uveitis model and additional proinflammatory mediators like cytokines may be involved. PMID:8207337

Kulkarni, P S

1994-01-01

306

Drug-induced respiratory depression: an integrated model of drug effects on the hypercapnic and hypoxic drive  

Microsoft Academic Search

Drug-induced respiratory depression is a common side effect of the agents used in anesthesia practice to provide analgesia and sedation. Depression of the ventilatory drive in the spontaneously breathing patient can lead to severe cardiorespiratory events and it is considered a primary cause of morbidity. Reliable predictions of respiratory inhibition in the clinical setting would therefore provide a valuable means

Antonello L. G. Caruso; Thomas W. Bouillon; Peter M. Schumacher; M. Luginbuhl; M. Morari

2007-01-01

307

Role of CRF and other neuropeptides in stress-induced reinstatement of drug seeking  

PubMed Central

A central problem in the treatment of drug addiction is high rates of relapse to drug use after periods of forced or self-imposed abstinence. This relapse is often provoked by exposure to stress. Stress-induced relapse to drug seeking can be modeled in laboratory animals using a reinstatement procedure. In this procedure, drug-taking behaviors are extinguished and then reinstated by acute exposure to stressors like intermittent unpredictable footshock, restraint, food deprivation, and systemic injections of yohimbine, an alpha-2 adrenoceptor antagonist that induces stress-like responses in humans and nonhumans. For this special issue entitled “The role of neuropeptides in stress and addiction”, we review results from studies on the role of corticotropin-releasing factor (CRF) and several other peptides in stress-induced reinstatement of drug seeking in laboratory animals. The results of the studies reviewed indicate that extrahypothalamic CRF plays a critical role in stress-induced reinstatement of drug seeking; this role is largely independent of drug class, experimental procedure, and type of stressor. There is also limited evidence for the role of dynorphins, hypocretins (orexins), nociceptin (orphanin FQ), and leptin in stress-induced reinstatement of drug seeking. PMID:19631614

Shalev, Uri; Erb, Suzanne; Shaham, Yavin

2009-01-01

308

Initiation of autoimmunity by a reactive metabolite of a lupus-inducing drug in the thymus.  

PubMed Central

Drug-induced lupus is a side effect of deliberate ingestion of various medications, but its etiology, underlying mechanisms, and pathogenesis are puzzling. In vivo metabolic transformation of lupus-inducing drugs to reactive products explains how a heterogeneous set of drugs can mediate the same disease syndrome. Evidence has accumulated that drugs are transformed by extracellular oxidation from reactive oxygen species and myeloperoxidase produced when neutrophils are activated, maximizing the in situ accumulation of reactive drug metabolites within lymphoid compartments. The metabolite of procainamide, procainamide hydroxylamine, displays diverse biologic properties, but no apparent autoimmune effect has been observed. However, when procainamide hydroxylamine was introduced into the thymus of young adult normal mice, a delayed but robust autoimmune response developed. Disruption of central T-cell tolerance by intrathymic procainamide hydroxylamine resulted in the production of chromatin-reactive T cells that apparently drove the autoantibody response in the periphery. Drug-induced autoantibodies in this mouse model were remarkably similar to those in patients with procainamide-induced lupus. Therefore, this system has considerable promise to provide insight into the initiating events in drug-induced lupus and may provide a paradigm for how other xenobiotics might induce systemic autoimmunity. PMID:10502546

Rubin, R L; Kretz-Rommel, A

1999-01-01

309

[Assessment of hyper- and hypodopaminergic behaviors in Parkinson's disease].  

PubMed

The common perception that Parkinson's disease patients tend to be depressed, anxious, apathetic and harm-avoiding has currently been challenged by the recognition that they can also exhibit a hedonistic, novelty-seeking personality. Thus, Parkinson's disease patients may indulge in their passions in an irresponsible and disinhibited manner, and engage in repetitive, compulsive behaviors that may be harmful and destructive to their social or professional lives. The dopamine dysregulation syndrome includes hypersexuality, pathological gambling, and compulsive shopping; it is associated with addiction to dopaminergic medication. However, not all behavioral changes are necessarily accompanied by a dopaminergic addiction. After antiparkinson treatment is initiated, patients enter a 'honeymoon period' during which changes in mood and behavior reflect a return to the patients' premorbid personality. The increased motivation and higher level of activity in professional as well as leisure activities are considered positive changes by both the patients and their relatives. With prolonged and increased dopaminergic treatment, these positive behavioral changes can become excessive and evolve into nocturnal hyperactivity and stereotyped, repetitive and time consuming behaviors which ultimately disorganize the patient's everyday routine and herald behavioral addictions. These drug-induced behavioral changes are under-appreciated by neurologists and under-reported by the patients who neither complain about the behaviors nor understand the relationship between motivated behavior and dopaminergic medication. For these reasons, we propose a new scale for the assessment of behavior and mood to quantify and track changes related to Parkinson's disease, to dopaminergic medication, and to non-motor fluctuations. This scale is based on the concept of hypo- and hyperdopaminergic mood and behavior. The scale consists of 18 items addressing non-motor symptoms, grouped in four parts: general psychological evaluation, apathy, non-motor fluctuations and hyperdopaminergic behaviors. The rating in five points (0-4 from absent to severe) is carried out during a semi-structured interview. Open-ended questions introduce each item, allowing patients to express themselves as freely as possible. Close-ended questions permit the rating of severity and intensity. This new instrument can be used by psychologists, psychiatrists or neurologists familiar with Parkinson's disease. Designed to detect changes in mood and behavior of Parkinson's disease patients resulting either from the disease or its treatment, this tool can be used in conjunction with the neurocognitive evaluation, to help tailor the treatment of motor and non-motor symptoms to each individual's needs. PMID:19683776

Ardouin, C; Chéreau, I; Llorca, P-M; Lhommée, E; Durif, F; Pollak, P; Krack, P

2009-11-01

310

Noradrenaline neuron degeneration contributes to motor impairments and development of L-DOPA-induced dyskinesia in a rat model of Parkinson's disease.  

PubMed

Parkinson's disease (PD) is characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra. However, studies of post-mortem PD brains have shown that not only DA neurons but also the noradrenergic (NA) neurons in the locus coeruleus degenerate, and that the NA neurodegeneration may be as profound, and also precede degeneration of the midbrain DA neurons. Previous studies in animal models of PD have suggested that loss of forebrain NA will add to the development of motor symptoms in animals with lesions of the nigrostriatal DA neurons, but the results obtained in rodents have been inconclusive due to the shortcomings of the toxin, DSP-4, used to lesion the NA projections. Here, we have developed an alternative double-lesion paradigm using injections of 6-OHDA into striatum in combination with intraventricular injections of a powerful NA immunotoxin, anti-DBH-Saporin, to eliminate the NA neurons in the locus coeruleus, and associated pontine nuclei. Animals with combined DA and NA lesions were more prone to develop L-DOPA-induced dyskinesia, even at low L-DOPA doses, and they performed significantly worse in tests of reflexive and skilled paw use, the stepping and staircase tests, compared to DA-only lesioned rats. Post-mortem analysis revealed that NA depletion did not affect the degree of DA depletion, or the loss of tyrosine hydroxylase-positive innervation in the striatum. Cell loss in the substantia nigra was similar in both single and double lesioned animals, showing that the worsening effect was not due to increased loss of nigral DA neurons. The results show that damage to brainstem NA neurons, contributes to the development of motor impairments and the appearance of L-DOPA-induced dyskinesia in 6-OHDA lesioned rats, and provide support for the view that the development of motor symptoms and dyskinetic side effects in PD patients reflects the combined loss of midbrain DA neurons and NA neurons. PMID:24747357

Shin, Eunju; Rogers, James T; Devoto, Paola; Björklund, Anders; Carta, Manolo

2014-07-01

311

Nonsteroidal antiinflammatory drug-induced intestinal inflammation in humans  

SciTech Connect

This study examines the effects of nonsteroidal antiinflammatory drugs on the small intestine in humans. Using an /sup 111/In-leukocyte technique in patients with rheumatoid arthritis (n = 90) and osteoarthritis (n = 7), it appears that nonsteroidal antiinflammatory drugs cause small intestinal inflammation in two-thirds of patients on long-term treatment and on discontinuation, the inflammation may persist for up to 16 mo. The prevalence and magnitude of the intestinal inflammation was unrelated to the type and dose of nonsteroidal drugs and previous or concomitant second-line drug treatment. There was a significant inverse correlation (r = -0.29, p less than 0.05) between fecal /sup 111/In excretion and hemoglobin levels in patients treated with nonsteroidal antiinflammatory drugs. The kinetics of fecal indium 111 excretion in patients treated with nonsteroidal antiinflammatory drugs was almost identical to that of patients with small bowel Crohn's disease. Eighteen patients on nonsteroidal antiinflammatory drugs underwent a radiologic examination of the small bowel and 3 were found to have asymptomatic ileal disease with ulceration and strictures. Nineteen patients on nonsteroidal antiinflammatory drugs, 20 healthy controls, and 13 patients with Crohn's ileitis underwent a dual radioisotopic ileal function test with tauro 23 (/sup 75/Se) selena-25-homocholic acid and cobalt 58-labeled cyanocobalamine. On day 4, more than half of the patients with rheumatoid arthritis had evidence of bile acid malabsorption, but the ileal dysfunction was much milder than seen in patients with Crohn's ileitis.

Bjarnason, I.; Zanelli, G.; Smith, T.; Prouse, P.; Williams, P.; Smethurst, P.; Delacey, G.; Gumpel, M.J.; Levi, A.J.

1987-09-01

312

Mortalin inhibition in experimental Parkinson's disease.  

PubMed

Among heat shock proteins, mortalin has been linked to the pathogenesis of Parkinson's disease. In the present work a rat model of Parkinson's disease was used to analyze the expression of striatal proteins and, more specifically, mortalin expression. The possible involvement of mortalin in Parkinson's disease pathogenesis was further investigated by utilizing an electrophysiological approach and pharmacological inhibition of mortalin in both the physiological and the parkinsonian states. Proteomic analysis was used to investigate changes in striatal protein expression in the 6-hydroxydopamine rat model of Parkinson's disease. The electrophysiological effects of MKT-077, a rhodamine-123 analogue acting as an inhibitor of mortalin, were measured by field potential recordings from corticostriatal brain slices obtained from control, sham-operated, and 6-hydroxydopamine-denervated animals. Slices in the presence of rotenone, an inhibitor of mitochondrial complex I, were also analyzed. Proteomic analysis revealed downregulation of mortalin in the striata of 6-hydroxydopamine-treated rats in comparison with sham-operated animals. MKT-077 reduced corticostriatal field potential amplitude in physiological conditions, inducing membrane depolarization and inward current in striatal medium spiny neurons. In addition, we observed that concentrations of MKT-077 not inducing any electrophysiological effect in physiological conditions caused significant changes in striatal slices from parkinsonian animals as well as in slices treated with a submaximal concentration of rotenone. These findings suggest a critical link between mortalin function and mitochondrial activity in both physiological and pathological conditions mimicking Parkinson's disease. PMID:21542017

Chiasserini, Davide; Tozzi, Alessandro; de Iure, Antonio; Tantucci, Michela; Susta, Federica; Orvietani, Pier Luigi; Koya, Keizo; Binaglia, Luciano; Calabresi, Paolo

2011-08-01

313

Smoking and Parkinson's disease  

Microsoft Academic Search

In a case control study of the relationship between smoking habits and Parkinson's disease a negative association was demonstrated with a relative risk of 0 x 52. A history of smoking up to 20 years earlier was associated with a risk of developing Parkinson's disease equal to about half that in non-smokers. The type of disease, age of onset and

R B Godwin-Austen; P N Lee; M G Marmot; G M Stern

1982-01-01

314

Postural Abnormality as a Risk Marker for Leg Deep Venous Thrombosis in Parkinson's Disease  

PubMed Central

Background Pulmonary thromboembolism is a common cause of death in patients with autopsy-confirmed Parkinsonism. This study investigated the incidence of leg deep vein thrombosis in Parkinson’s disease and relationships between deep vein thrombosis and clinical/laboratory findings, including postural abnormalities as assessed by photographic measurements. Methods This cross-sectional study assessed the presence of deep vein thrombosis using bilateral leg Doppler ultrasonography in 114 asymptomatic outpatients with Parkinson’s disease. Results Deep vein thrombosis was detected in 23 patients (20%) with Parkinson’s disease. Deep vein thrombosis was located in the distal portion in 18 patients and in the proximal portion in 5 patients. No significant differences in age, sex, body mass index, disease duration, Hoehn-Yahr stage, anti-Parkinson’s drugs, or daily levodopa-equivalent dose were seen between deep vein thrombosis-positive and -negative groups. Univariate analysis for developing deep vein thrombosis in patients with Parkinson’s disease identified the following markers: long-term wheelchair use, bent knee, bent spine, and D-dimer elevation. Bending angles were significantly greater in the deep vein thrombosis-positive group at the knee and spine than in the deep vein thrombosis-negative group. Half of Parkinson’s disease patients with camptocormia had deep vein thrombosis. Among diabetes mellitus cases, long-term wheelchair use, bent knee over 15°, camptocormia, D-dimer elevation, the more risk markers were associated with a higher incidence of DVT. The presence of risk markers contributed to the development of deep vein thrombosis. On multivariate logistic regression analysis, a bent knee posture was strongly associated with an increased risk of deep vein thrombosis. Conclusion Presence of leg deep vein thrombosis correlated with postural abnormalities in Parkinson’s disease. We recommend non-invasive ultrasonographic screening for leg deep vein thrombosis in these high-risk patients with Parkinson’s disease. PMID:23843975

Yamane, Kazushi; Kimura, Fumiharu; Unoda, Kiichi; Hosokawa, Takafumi; Hirose, Takahiko; Tani, Hiroki; Doi, Yoshimitsu; Ishida, Simon; Nakajima, Hideto; Hanafusa, Toshiaki

2013-01-01

315

hERG trafficking inhibition in drug-induced lethal cardiac arrhythmia.  

PubMed

Acquired long QT syndrome induced by non-cardiovascular drugs can cause lethal cardiac arrhythmia called torsades de points and is a significant problem in drug development. The prolongation of QT interval and cardiac action potential duration are mainly due to reduced physiological function of the rapidly activating voltage-dependent potassium channels encoded by human ether-a-go-go-related gene (hERG). Structurally diverse groups of drugs are known to directly inhibit hERG channel conductance. Therefore, the ability of acute hERG inhibition is routinely assessed at the preclinical stages in pharmaceutical testing. Recent findings indicated that chronic treatment with various drugs not only inhibits hERG channels but also decreases hERG channel expression in the plasma membrane of cardiomyocytes, which has become another concern in safety pharmacology. The mechanisms involve the disruption of hERG trafficking to the surface membrane or the acceleration of hERG protein degradation. From this perspective, we present a brief overview of mechanisms of drug-induced trafficking inhibition and pathological regulation. Understanding of drug-induced hERG trafficking inhibition may provide new strategies for predicting drug-induced QT prolongation and lethal cardiac arrhythmia in pharmaceutical drug development. PMID:24998878

Nogawa, Hisashi; Kawai, Tomoyuki

2014-10-15

316

Investigational targeted drug induces responses in aggressive lymphomas  

Cancer.gov

Preliminary results from clinical trials in a subtype of lymphoma show that for a number of patients whose disease was not cured by other treatments, the drug ibrutinib can provide significant anti-cancer responses with modest side effects.

317

Role of Reactive Metabolites in Drug-Induced Hepatotoxicity  

Microsoft Academic Search

Drugs are generally converted to biologically inactive forms and eliminated from the body, principally by hepatic metabolism.\\u000a However, certain drugs undergo biotransformation to metabolites that can interfere with cellular functions through their intrinsic\\u000a chemical reactivity towards glutathione, leading to thiol depletion, and functionally critical macromolecules, resulting in\\u000a reversible modification, irreversible adduct formation, and irreversible loss of activity. There is now

A. Srivastava; J. L. Maggs; D. J. Antoine; D. P. Williams; D. A. Smith; B. K. Park

318

Hypoxia-Induced Cytotoxic Drug Resistance in Osteosarcoma Is Independent of HIF-1Alpha  

PubMed Central

Survival rates from childhood cancer have improved dramatically in the last 40 years, such that over 80% of children are now cured. However in certain subgroups, including metastatic osteosarcoma, survival has remained stubbornly poor, despite dose intensive multi-agent chemotherapy regimens, and new therapeutic approaches are needed. Hypoxia is common in adult solid tumours and is associated with treatment resistance and poorer outcome. Hypoxia induces chemotherapy resistance in paediatric tumours including neuroblastoma, rhabdomyosarcoma and Ewing’s sarcoma, in vitro, and this drug resistance is dependent on the oxygen-regulated transcription factor hypoxia inducible factor-1 (HIF-1). In this study the effects of hypoxia on the response of the osteosarcoma cell lines 791T, HOS and U2OS to the clinically relevant cytotoxics cisplatin, doxorubicin and etoposide were evaluated. Significant hypoxia-induced resistance to all three agents was seen in all three cell lines and hypoxia significantly reduced drug-induced apoptosis. Hypoxia also attenuated drug-induced activation of p53 in the p53 wild-type U2OS osteosarcoma cells. Drug resistance was not induced by HIF-1? stabilisation in normoxia by cobalt chloride nor reversed by the suppression of HIF-1? in hypoxia by shRNAi, siRNA, dominant negative HIF or inhibition with the small molecule NSC-134754, strongly suggesting that hypoxia-induced drug resistance in osteosarcoma cells is independent of HIF-1?. Inhibition of the phosphoinositide 3-kinase (PI3K) pathway using the inhibitor PI-103 did not reverse hypoxia-induced drug resistance, suggesting the hypoxic activation of Akt in osteosarcoma cells does not play a significant role in hypoxia-induced drug resistance. Targeting hypoxia is an exciting prospect to improve current anti-cancer therapy and combat drug resistance. Significant hypoxia-induced drug resistance in osteosarcoma cells highlights the potential importance of hypoxia as a target to reverse drug resistance in paediatric osteosarcoma. The novel finding of HIF-1? independent drug resistance suggests however other hypoxia related targets may be more relevant in paediatric osteosarcoma. PMID:23785417

Adamski, Jennifer; Price, Andrew; Dive, Caroline; Makin, Guy

2013-01-01

319

Updates in the medical management of Parkinson disease.  

PubMed

Most, if not all, currently available drugs for Parkinson disease address dopaminergic loss and relieve symptoms. However, their adverse effects can be limiting and they do not address disease progression. Moreover, nonmotor features of Parkinson disease such as depression, dementia, and psychosis are now recognized as important and disabling. A cure remains elusive. However, promising interventions and agents are emerging. As an example, people who exercise regularly are less likely to develop Parkinson disease, and if they develop it, they tend to have slower progression. PMID:22219231

Fernandez, Hubert H

2012-01-01

320

Granulomatous interstitial nephritis associated with atypical drug-induced hypersensitivity syndrome induced by carbamazepine.  

PubMed

We report the case of a 70-year-old female patient with granulomatous interstitial nephritis (GIN) induced by carbamazepine (CBZ). The patient had a 22-year history of bipolar disorder. Approximately 50 days before admission to our hospital, she was switched from valproic acid to 200 mg/day CBZ for mood swings. Forty days later, she presented with mild transient platelet depletion and liver dysfunction along with a C-reactive protein (CRP) level of 2.65 mg/dL. At that time, she discontinued CBZ without consulting the doctor. She subsequently developed high fever and a pruritic maculopapular rash. Laboratory tests revealed an elevated CRP level (11.98 mg/dL) and serum creatinine (sCr) of 1.6 mg/dL. Hence, she was admitted to our hospital, where she showed eosinophilia and immunoglobulin suppression. She was diagnosed with atypical drug-induced hypersensitivity syndrome (DIHS). All drugs prescribed by the previous doctor were discontinued. A lymphocyte transformation test showed CBZ positivity; a renal biopsy revealed many granulomatous lesions connected to arterioles, without angionecrotic findings. The patient had no history of allergic disorders or tuberculosis. Because of psychological instability, we treated her conservatively without steroid administration. She had a good recovery except for mild residual renal insufficiency (sCr, 1.0 mg/dL). Although granuloma formation has been observed in kidney biopsy specimens of rare cases with DIHS, no previous studies have reported on the relationship between arterioles and granuloma formation. PMID:21947692

Eguchi, Eriko; Shimazu, Keiji; Nishiguchi, Kensuke; Yorifuji, Soushi; Tanaka, Atsuo; Kuwahara, Takashi

2012-02-01

321

Slow (1Hz) Repetitive Transcranial Magnetic Stimulation (rTMS) Induces Sustained Change in Cortical Excitability in Patients with Parkinson's Disease  

PubMed Central

Objective Low frequency (? 1 Hz) rTMS (LF-rTMS) can reduce excitability in the underlying cortex and/or promote inhibition. In patients with Parkinson’s disease (PD) several TMS elicited features of motor corticospinal physiology suggest presence of impaired inhibitory mechanisms. These include shortened silent period (SP) and steeper input-output (I-O) curve of motor evoked potential (MEP) size than in normal controls. However, studies of LF-rTMS effects on inhibitory mechanisms in PD are scarce. In this companion paper to the clinical paper describing effects of 4 consecutive days of LF-rTMS on dyskinesia in PD (Filipovi? et al., 2009), we evaluate the delayed (24h) effects of the LF-rTMS treatment on the physiological measures of excitability of the motor cortex in the patients. There are very few studies of physiological follow up of daily rTMS treatments. Methods Nine patients with PD in Hoehn & Yahr stages 2 or 3 and prominent medication induced dyskinesia were studies. This was a placebo-controlled, crossover study, with two treatment arms, “real” rTMS and “sham” rTMS (placebo). In each of the treatment arms, the rTMS (1800 pulses; 1Hz rate; intensity of the real stimuli just-below the active motor threshold) was delivered over the motor cortex for four consecutive days. Motor cortex excitability was evaluated at the beginning of the study and the next day following each of the four-day rTMS series (real and sham) with patients first in the practically defined “off” state, following 12h withdrawal of medication, and subsequently in a typical “on” state following usual morning medication dose. Results The SP was significantly longer following real rTMS in comparison to both baseline and sham rTMS. The effect was independent from the effects of dopaminergic treatment. There was no difference in MEP size, rest and active motor threshold. The I-O curve, recorded from the relaxed muscle, showed a trend towards diminished slope in comparison to baseline, but the difference was not significant. There was no consistent correlation between prolongation of SP and concomitant reduction in dyskinesia following real rTMS. Conclusions Low-frequency rTMS delivered over several consecutive days is able to induce changes in excitability of motor cortex and promote apparent increase in inhibitory activity that can persist for at least a day after. Significance The results confirm the existence of a residual after-effect of consecutive daily applications of rTMS that might be relevant to the clinical effect that was observed in this group of patients and could be further exploited for potential therapeutic uses. PMID:20350836

Filipovic, Sasa R.; Rothwell, John C.; Bhatia, Kailash

2010-01-01

322

Deletion of adenosine A? or A(?A) receptors reduces L-3,4-dihydroxyphenylalanine-induced dyskinesia in a model of Parkinson's disease.  

PubMed

Adenosine A(?A) receptor antagonism provides a promising approach to developing nondopaminergic therapy for Parkinson's disease (PD). Clinical trials of A(?A) antagonists have targeted PD patients with L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) in an effort to improve parkinsonian symptoms. The role of adenosine in the development of LID is little known, especially regarding its actions via A? receptors. We aimed to examine the effects of genetic deletion and pharmacological blockade of A? and/or A(?A) receptors on the development of LID, on the induction of molecular markers of LID including striatal preprodynorphin and preproenkephalin (PPE), and on the integrity of dopaminergic nigrostriatal neurons in hemiparkinsonian mice. Following a unilateral 6-hydroxydopamine lesion A?, A(?A) and double A?-A(?A) knockout (KO) and wild-type littermate mice, and mice pretreated with caffeine (an antagonist of both A? and A(?A) receptors) or saline were treated daily for 18-21 days with a low dose of L-DOPA. Total abnormal involuntary movements (AIMs, a measure of LID) were significantly attenuated (p<0.05) in A? and A(?A) KOs, but not in A?-A(?A) KOs and caffeine-pretreated mice. An elevation of PPE mRNA ipsilateral to the lesion in WT mice was reduced in all KO mice. In addition, neuronal integrity assessed by striatal dopamine content was similar in all KOs and caffeine-pretreated mice following 6-hydroxydopamine lesioning. Our findings raise the possibility that A? or A(?A) receptors blockade might also confer a disease-modifying benefit of reduced risk of disabling LID, whereas the effect of their combined inactivation is less clear. PMID:20828543

Xiao, Danqing; Cassin, Jared J; Healy, Brian; Burdett, Thomas C; Chen, Jiang-Fan; Fredholm, Bertil B; Schwarzschild, Michael A

2011-01-01

323

L-DOPA-induced dyskinesia in a rat model of Parkinson's disease is associated with the fluctuational release of norepinephrine in the sensorimotor striatum.  

PubMed

L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID) is the most common complication of standard L-DOPA therapy for Parkinson's disease experienced by most parkinsonian patients. LID is associated with disruption of dopaminergic homeostasis in basal ganglia following L-DOPA administration. Norepinephrine (NE) is another important catecholaminergic neurotransmitter that is also believed to be involved in the pathogenesis of LID. This study compared NE release in the ipsilateral sensorimotor striatum of dyskinetic and nondyskinetic 6-hydroxydopamine-lesioned hemiparkinsonian rats treated chronically with L-DOPA. After L-DOPA injection, the time-course curves of NE levels in the sensorimotor striatum were significantly different between dyskinetic and nondyskinetic rats. Several metabolic kinetic parameters of NE levels were also differentially expressed between the two groups. In comparison with nondyskinetic rats, the ?Cmax of NE was significantly higher in dyskinetic rats, whereas Tmax and t1/2 of NE were significantly shorter. Intrastriatal perfusion of NE into the lesioned sensorimotor striatum revealed a moderate dyskinesia in dyskinetic rats, which was similar to the dyskinetic behavior after L-DOPA administration. The L-DOPA-related dyskinetic behavior was inhibited significantly by a further pretreatment of noradrenergic neurotoxin N-?(2-?chloroethyl)?-?N-?ethyl-?2-?bromobenzylamine or intrastriatal administration of the ?2 -adrenoceptor antagonist idazoxan, accompanied by significant changes in metabolic kinetic parameters of NE in the sensorimotor striatum. The results provide evidence to support the correlation between abnormal NE neurotransmission and the induction of LID and suggest that the aberrant change of the quantitative and temporal releasing of NE in the sensorimotor striatum might play an important role in the pathogenesis of LID. © 2014 Wiley Periodicals, Inc. PMID:24975553

Wang, Yong; Wang, Hui Sheng; Wang, Tao; Huang, Chen; Liu, Jian

2014-12-01

324

Effect of nicotine on L-dopa-induced dyskinesia in animal models of Parkinson's disease: a systematic review and meta-analysis.  

PubMed

L-dopa-induced dyskinesias (LIDs) are abnormal involuntary movements (AIM) that develop with long-term L-dopa therapy for Parkinson's disease (PD). In this study, we used these tools to describe the efficacy of nicotine reduced LID in animal models of PD. Studies were identified by electronic searching of six online databases up to September of 2013 to identify preclinical trials involving nicotine for LID in animal model. Data were extracted for AIM compared with LID animals. Pre-specified subgroup analysis was carried out according to method of model, gender, anesthetic used, and species. Combined standardized mean difference (SMD) estimates and 95 % confidence intervals (CIs) were calculated using a random-effects model. Eleven studies involving 181 animals which described the effect of nicotine on LID were included in the meta-analysis. Nicotine was efficacious in reducing total AIM compared with control group (SMD -3.77, 95 % CI -5.30 to -2.23, P < 0.00001). Meanwhile, four studies showed certain effects of nicotine for improving the axial AIM (SMD -2.21, 95 % CI -4.17 to -0.24, P = 0.03); oral AIM and forelimb AIM were obvious improved in six studies in the nicotine group (SMD -3.00, 95 % CI -4.55 to -1.44, P = 0.0002; SMD -2.52, 95 % CI -3.52 to -1.53, P < 0.00001, respectively). We conclude that nicotine appears to have efficacy in animal models of LID. Large randomized clinical trials testing the effect of nicotine in PD patients with LID are warranted. PMID:24510151

Xie, Cheng-Long; Pan, Jia-Lin; Zhang, Su-Fang; Gan, Jing; Liu, Zhen-Guo

2014-05-01

325

Drug-induced parkinsonism: cinnarizine and flunarizine are potent uncouplers of the vacuolar H +ATPase in catecholamine storage vesicles  

Microsoft Academic Search

Cinnarizine (1-diphenylmethyl-4-(3-phenyl-2-propenyl)piperazine) and its di-fluorinated derivative flunarizine inhibit the MgATP-dependent generation of a transmembrane proton electrochemical gradient in chromaffine granule ghosts. The concentrations giving 50% inhibition (IC50) of the MgATP-dependent generation of the pH-gradient were 5.9±0.6 ?M (n=6) and 3.0±0.3 ?M (n=5) for cinnarizine and flunarizine, respectively. The IC50 values for inhibiting the generation of the membrane potential were even

Ole Terland; Torgeir Flatmark

1999-01-01

326

Impact of theophylline use in Wolff-Parkinson-White syndrome.  

PubMed Central

Methylxanthine use in the treatment of apnea of prematurity is well documented. This drug is avoided in patients with aberrant pathways of conduction such as Wolff-Parkinson-White syndrome. In theory, methylxanthines enhance precipitation and exacerbation of tachyarrhythmias to which these patients are predisposed. This article reports a case of Wolff-Parkinson-White syndrome in a preterm neonate with severe apneic episodes in which methylxanthines were used. However, no adverse effects on cardiac rate or rhythm were encountered. PMID:8764528

Agwunobi, J.; Abedin, M.; Young, M.; Beeram, M.; Sinkford, S.

1996-01-01

327

Effects of Donepezil on Central Processing Speed and Attentional Measures in Parkinson’s Disease with Dementia and Dementia with Lewy Bodies  

Microsoft Academic Search

Background: We examined attention-enhancing effects of the cholinesterase inhibitor donepezil in Dementia with Lewy bodies (DLB) and Parkinson’s disease with dementia (PDD) by means of open label study. Methods: 22 DLBs and 23 PDDs were assessed over 20 weeks using the Cognitive Drug Research Computerized Attentional Tasks. We examined how much closer our patients moved towards being normal for their

Elise Rowan; Ian G. McKeith; Brian K. Saxby; John T. O’Brien; David Burn; Urs Mosimann; Jane Newby; Sarah Daniel; Jonathan Sanders; Keith Wesnes

2007-01-01

328

Pathophysiology of Parkinsonism  

PubMed Central

The motor signs of Parkinson’s disease are thought to result in large part from reduction of dopamine in the basal ganglia. Over the last few years, many of the functional and anatomical consequences of dopamine loss in these structures have been identified, both in the basal ganglia and in related areas in thalamus and cortex. This knowledge has contributed significantly to our understanding of the link between degeneration of dopamine neurons in the midbrain, and the development of parkinsonism. This review discusses the evidence that implicates electrophysiologic changes (including altered discharge rates, increased incidence of burst firing, interneuronal synchrony, oscillatory activity, and altered sensorimotor processing) in basal ganglia, thalamus, and cortex, in parkinsonism. From these studies, parkinsonism emerges as a complex network disorder, in which abnormal activity in groups of neurons in the basal ganglia strongly affect the excitability, oscillatory activity, synchrony and sensory responses of areas of the cerebral cortex that are involved in the planning and execution of movement, as well as in executive, limbic or sensory functions. Detailed knowledge of these changes will help us to develop more effective and specific symptomatic treatments for patients with Parkinson’s disease. PMID:18467168

Galvan, Adriana; Wichmann, Thomas

2008-01-01

329

Gap junction inhibition prevents drug-induced liver toxicity and fulminant hepatic failure.  

PubMed

Drug-induced liver injury (DILI) limits the development and application of many therapeutic compounds and presents major challenges to the pharmaceutical industry and clinical medicine. Acetaminophen-containing compounds are among the most frequently prescribed drugs and are also the most common cause of DILI. Here we describe a pharmacological strategy that targets gap junction communication to prevent amplification of fulminant hepatic failure and acetaminophen-induced hepatotoxicity. We demonstrate that connexin 32 (Cx32), a key hepatic gap junction protein, is an essential mediator of DILI by showing that mice deficient in Cx32 are protected against liver damage, acute inflammation and death caused by liver-toxic drugs. We identify a small-molecule inhibitor of Cx32 that protects against liver failure and death in wild-type mice when co-administered with known hepatotoxic drugs. These findings indicate that gap junction inhibition could provide a pharmaceutical strategy to limit DILI and improve drug safety. PMID:22252509

Patel, Suraj J; Milwid, Jack M; King, Kevin R; Bohr, Stefan; Iracheta-Velle, Arvin; Li, Matthew; Vitalo, Antonia; Parekkadan, Biju; Jindal, Rohit; Yarmush, Martin L

2012-02-01

330

Inhibitors of Leucine Rich Repeat Kinase 2 (LRRK2) Protect Against LRRK2-Models of Parkinson’s Disease  

PubMed Central

Leucine rich repeat kinase 2 (LRRK2) mutations are a common cause of Parkinson’s disease (PD). Here, we identify inhibitors of LRRK2 kinase, which are protective in in vitro and in vivo models of LRRK2-induced neurodegeneration. These results establish that LRRK2-induced degeneration of neurons in vivo is kinase dependent and that LRRK2 kinase inhibition provides a potential new neuroprotective paradigm for the treatment of PD. PMID:20729864

Lee, Byoung Dae; Shin, Joo-Ho; VanKampen, Jackalina; Petrucelli, Leonard; West, Andrew B.; Ko, Han Seok; Lee, Yun; Maguire-Zeiss, Kathleen A.; Bowers, William J.; Federoff, Howard J.; Dawson, Valina L.; Dawson, Ted M.

2010-01-01

331

A possible case of drug-induced familial pemphigus.  

PubMed

Two sisters developed pemphigus vulgaris and pemphigus erythematosus within 3 years. The diagnosis was confirmed by clinical, histologic and immunofluorescent antibody studies. One of the sisters experienced a common cold before the pemphigus developed and displayed a positive macrophage migration inhibition (MIF) test to a combination drug compounded of paracetamol, caffeine, chlorpheniramine maleate and phenylephrine HCl, which she had received 2 weeks prior to the appearance of the cutaneous lesions. It is suggested that her pemphigus was triggered by the drug. Although the patient had a strong genetic and familial predisposition to pemphigus, her clinical symptoms did not become evident until they were activated through an exogenous factor, namely, the causative drug. This case offers an example of a possible interaction between endogenous, genetic factors, and exogenous, triggering factors in the development of full-blown disease. PMID:1977268

Brenner, S; Hodak, E; Dascalu, D; Lurie, R; Wolf, R

1990-01-01

332

Role of reactive metabolites in drug-induced hepatotoxicity.  

PubMed

Drugs are generally converted to biologically inactive forms and eliminated from the body, principally by hepatic metabolism. However, certain drugs undergo biotransformation to metabolites that can interfere with cellular functions through their intrinsic chemical reactivity towards glutathione, leading to thiol depletion, and functionally critical macromolecules, resulting in reversible modification, irreversible adduct formation, and irreversible loss of activity. There is now a great deal of evidence which shows that reactive metabolites are formed from drugs known to cause hepatotoxicity, such as acetaminophen, tamoxifen, isoniazid, and amodiaquine. The main theme of this article is to review the evidence for chemically reactive metabolites being initiating factors for the multiple downstream biological events culminating in toxicity. The major objectives are to understand those idiosyncratic hepatotoxicities thought to be caused by chemically reactive metabolites and to define the role of toxic metabolites. PMID:20020263

Srivastava, A; Maggs, J L; Antoine, D J; Williams, D P; Smith, D A; Park, B K

2010-01-01

333

Fixed drug eruption induced by topical olopatadine ophthalmic solution.  

PubMed

Fixed drug eruption (FDE) usually develops after oral administration and is described as a cutaneous reaction recurring at the same location each time the drug is taken. Olopatadine is both a H1 histamine receptor antagonist and a mast cell stabilizer, indicated for the treatment of allergic conjunctivitis. Here, we report a 14-year-old male patient who developed FDE localised on the lateral side of periorbital rim bilaterally, whilst applying olopatadine 0.1% ophthalmic solution for the treatment of allergic conjunctivitis. As far as we know, FDE due to olopatadine has not been previously reported in the literature. We deem it appropriate to report this case because FDE that results from the application of topical drugs is a rare event in the literature. PMID:22531967

Bilgili, S G; Karadag, A S; Karadag, R; Bulut, G; Calka, O

2012-12-01

334

Complications of Therapy in Parkinson's Disease  

PubMed Central

Despite several more effective combinations, the incidence of disability and intractable complications from levodopa therapy for Parkinson's disease is unchanged. Many of these appear to be related to the development of denervation hypersensitivity as well as to drug tolerance and loss of effect. They include dyskinesia, `wearing off' phenomenon, `on-off' phenomenon, and various psychic changes. More current forms of therapy with bromocriptine and drug holidays are described, emphasizing methods of preventing and controlling the incapacitating complications associated with long term drug therapy. Some future therapeutic considerations are also described. PMID:21286582

Kofman, Oscar S.

1983-01-01

335

A simple transcriptomic signature able to predict drug-induced hepatic steatosis.  

PubMed

It is estimated that only a few marketed drugs are able to directly induce liver steatosis. However, many other drugs may exacerbate or precipitate fatty liver in the presence of other risk factors or in patients prone to non-alcoholic fatty liver disease. On the other hand, current in vitro tests for drug-induced steatosis in preclinical research are scarce and not very sensitive or reproducible. In the present study, we have investigated the effect of well-characterized steatotic drugs on the expression profile of 47 transcription factors (TFs) in human hepatoma HepG2 cells and found that these drugs are able to up- and down-regulate a substantial number of these factors. Multivariate data analysis revealed a common TF signature for steatotic drugs, which consistently and significantly repressed FOXA1, HEX and SREBP1C in cultured cells. This signature was also observed in the livers of rats and in cultured human hepatocytes. Therefore, we selected these three TFs as predictive biomarkers for iatrogenic steatosis. With these biomarkers, a logistic regression analysis yielded a predictive model, which was able to correctly classify 92 % of drugs. The developed algorithm also predicted that ibuprofen, nifedipine and irinotecan are potential steatotic drugs, whereas troglitazone is not. In summary, this is a sensitive, specific and simple RT-PCR test that can be easily implemented in preclinical drug development to predict drug-induced steatosis. Our results also indicate that steatotic drugs affect expression of both common and specific subsets of TF and lipid metabolism genes, thus generating complex transcriptomic responses that cause or contribute to steatosis in hepatocytes. PMID:24469900

Benet, Marta; Moya, Marta; Donato, M Teresa; Lahoz, Agustín; Hervás, David; Guzmán, Carla; Gómez-Lechón, M José; Castell, José Vicente; Jover, Ramiro

2014-04-01

336

Impulse control disorders in Parkinson's disease.  

PubMed

Impulse control disorders (ICDs), a group of complex behavioral disorders, occur more commonly in Parkinson's disease (PD) patients than in the general population, with a reported prevalence up to 13.6% in some studies. The most common ICDs reported are pathological gambling (PG), hypersexuality (HS), compulsive shopping and compulsive eating. More than a quarter of the patients with ICDs have 2 or more behavioral addictions. These abnormal behaviors impair activities of daily living and have a negative impact on quality of life of patients and their families. As with many other non motor symptoms in PD, ICDs are frequently under-reported by patients and caregivers and may be under-recognized by the treating physicians. Treatment with dopamine agonists (DA) is the main risk factor for developing ICDs, and stimulation of mesolimbic D3 receptors by DA is thought to underlie their development. The DA effect seems to be a class effect and not specific for any DA. Levodopa can also induce ICDs but much less so than the DAs. The management of ICDs in PD is complex. Modifications in dopaminergic drug treatment are frequently necessary. In some cases alternative therapies such as atypical antipsychotics, antidepressants or deep brain stimulation if motor symptoms become incapacitating after adjustment of dopamine replacement therapy should be considered. PMID:22166463

Vilas, Dolores; Pont-Sunyer, Claustre; Tolosa, Eduardo

2012-01-01

337

Pathological behaviors provoked by dopamine agonist therapy of Parkinson's disease  

Microsoft Academic Search

The dopamine agonist medications, pramipexole and ropinirole, are commonly used to treat Parkinson's disease. These two drugs have a highly specific affinity for cerebral D3 receptors, known to be localized to the mesolimbic system. Herein is described a common side effect of these drugs, encountered in our routine clinical practice: pathological behaviors. This includes excessive gambling, hypersexuality, shopping, hyperphagia or

J. Eric Ahlskog

2011-01-01

338

Acute Hepatitis E Infection Accounts for Some Cases of Suspected Drug-Induced Liver Injury  

PubMed Central

Background & Aims The diagnosis of drug-induced liver injury relies upon exclusion of other causes, including viral hepatitis A, B, and C. Hepatitis E virus (HEV) infection has been proposed as another cause of suspected drug-induced liver disease. We assessed the frequency of HEV infection among patients with drug-induced liver injury in the United States. Methods The drug-induced liver injury network (DILIN) is a prospective study of patients with suspected drug-induced liver injury; clinical information and biological samples are collected to investigate pathogenesis and disease progression. We analyzed serum samples, collected from patients enrolled in DILIN, for immunoglobulin (Ig)G and IgM against HEV; selected samples were tested for HEV RNA. Results Among 318 patients with suspected drug-induced liver injury, 50 (16%) tested positive for anti-HEV IgG and 9 (3%) for anti-HEV IgM. The samples that contained anti-HEV IgM (collected 2 to 24 weeks after onset of symptoms) included 4 that tested positive for HEV RNA, genotype 3. Samples from the 6-month follow-up visit were available from 4 patients; they were negative for anti-HEV IgM, but levels of anti-HEV IgG increased with time. Patients that had anti-HEV IgM were mostly from older men (89%; mean age, 67 years) and 2 were HIV positive. Clinical reassessment of the 9 patients with anti-HEV IgM indicated that acute hepatitis E was the most likely diagnosis for 7 and might be the primary diagnosis for 2. Conclusion HEV infection contributes to a small but important proportion of cases of acute liver injury that are suspected of being drug induced. Serologic testing for HEV infection should be performed—particularly if clinical features are compatible with acute viral hepatitis. PMID:21855518

Davern, Timothy J.; Chalasani, Naga; Fontana, Robert J.; Hayashi, Paul H.; Protiva, Petr; Kleiner, David E.; Engle, Ronald E.; Nguyen, Hanh; Emerson, Suzanne U.; Purcell, Robert H.; Tillmann, Hans L.; Gu, Jiezhun; Serrano, Jose; Hoofnagle, Jay H.

2013-01-01

339

Drug-Induced Gambling: Valid Excuse of True Addiction?  

Microsoft Academic Search

It sounds crazy that a drug can cause a person to voluntarily risk a sum of money based on the outcome of a game or event. This 'behavior' is known as gambling: a game in which a person chooses to wager money in hopes of winning more money. This allegation has become quite popular lately, with the buzz surrounding a

Lareina Maskell

340

Targeting impulsivity in Parkinson's disease using atomoxetine  

PubMed Central

Noradrenergic dysfunction may play a significant role in cognition in Parkinson’s disease due to the early degeneration of the locus coeruleus. Converging evidence from patient and animal studies points to the role of noradrenaline in dopaminergically insensitive aspects of the parkinsonian dysexecutive syndrome, yet the direct effects of noradrenergic enhancement have not to date been addressed. Our aim was to directly investigate these, focusing on impulsivity during response inhibition and decision making. To this end, we administered 40 mg atomoxetine, a selective noradrenaline re-uptake inhibitor to 25 patients with Parkinson’s disease (12 female /13 male; 64.4 ± 6.9 years old) in a double blind, randomized, placebo controlled design. Patients completed an extensive battery of neuropsychological tests addressing response inhibition, decision-making, attention, planning and verbal short term memory. Atomoxetine improved stopping accuracy on the Stop Signal Task [F(1,19) = 4.51, P = 0.047] and reduced reflection impulsivity [F(1,9) = 7.86, P = 0.02] and risk taking [F(1,9) = 9.2, P = 0.01] in the context of gambling. The drug also conferred effects on performance as a function of its measured blood plasma concentration: it reduced reflection impulsivity during information sampling [adjusted R2 = 0.23, F(1,16) = 5.83, P = 0.03] and improved problem solving on the One Touch Stockings of Cambridge [adjusted R2 = 0.29, F(1,17) = 8.34, P = 0.01]. It also enhanced target sensitivity during sustained attention [F(1,9) = 5.33, P = 0.046]. The results of this exploratory study represent the basis of specific predictions in future investigations on the effects of atomoxetine in Parkinson’s disease and support the hypothesis that targeting noradrenergic dysfunction may represent a new parallel avenue of therapy in some of the cognitive and behavioural deficits seen in the disorder. PMID:24893708

Housden, Charlotte R.; Regenthal, Ralf; Barker, Roger A.; Muller, Ulrich; Rowe, James; Sahakian, Barbara J.; Robbins, Trevor W.

2014-01-01

341

Drug-Induced Reactivation of Apoptosis Abrogates HIV-1 Infection  

PubMed Central

HIV-1 blocks apoptosis, programmed cell death, an innate defense of cells against viral invasion. However, apoptosis can be selectively reactivated in HIV-infected cells by chemical agents that interfere with HIV-1 gene expression. We studied two globally used medicines, the topical antifungal ciclopirox and the iron chelator deferiprone, for their effect on apoptosis in HIV-infected H9 cells and in peripheral blood mononuclear cells infected with clinical HIV-1 isolates. Both medicines activated apoptosis preferentially in HIV-infected cells, suggesting that the drugs mediate escape from the viral suppression of defensive apoptosis. In infected H9 cells, ciclopirox and deferiprone enhanced mitochondrial membrane depolarization, initiating the intrinsic pathway of apoptosis to execution, as evidenced by caspase-3 activation, poly(ADP-ribose) polymerase proteolysis, DNA degradation, and apoptotic cell morphology. In isolate-infected peripheral blood mononuclear cells, ciclopirox collapsed HIV-1 production to the limit of viral protein and RNA detection. Despite prolonged monotherapy, ciclopirox did not elicit breakthrough. No viral re-emergence was observed even 12 weeks after drug cessation, suggesting elimination of the proviral reservoir. Tests in mice predictive for cytotoxicity to human epithelia did not detect tissue damage or activation of apoptosis at a ciclopirox concentration that exceeded by orders of magnitude the concentration causing death of infected cells. We infer that ciclopirox and deferiprone act via therapeutic reclamation of apoptotic proficiency (TRAP) in HIV-infected cells and trigger their preferential elimination. Perturbations in viral protein expression suggest that the antiretroviral activity of both drugs stems from their ability to inhibit hydroxylation of cellular proteins essential for apoptosis and for viral infection, exemplified by eIF5A. Our findings identify ciclopirox and deferiprone as prototypes of selectively cytocidal antivirals that eliminate viral infection by destroying infected cells. A drug-based drug discovery program, based on these compounds, is warranted to determine the potential of such agents in clinical trials of HIV-infected patients. PMID:24086341

Hanauske-Abel, Hartmut M.; Saxena, Deepti; Palumbo, Paul E.; Hanauske, Axel-Rainer; Luchessi, Augusto D.; Cambiaghi, Tavane D.; Hoque, Mainul; Spino, Michael; Gandolfi, Darlene D'Alliessi; Heller, Debra S.; Singh, Sukhwinder; Park, Myung Hee; Cracchiolo, Bernadette M.; Tricta, Fernando; Connelly, John; Popowicz, Anthony M.; Cone, Richard A.; Holland, Bart; Pe'ery, Tsafi; Mathews, Michael B.

2013-01-01

342

A novel immunosuppressive drug, FTY720, prevents the cancer progression induced by cyclosporine  

Microsoft Academic Search

Cyclosporine A (CsA), the most frequently used immunosuppressive drug, has been reported to induce cancer by a cell-autonomous mechanism. Herein, we report that FTY720, a novel immunosuppressant, prevents CsA-induced alterations in both morphology and cell motility at a low concentration (0.1?M) and induces the CsA-treated cancer cells to undergo apoptosis at a higher concentration (more than 5?M). The inhibitory activity

Toshiyuki Tanaka; Shiro Takahara; Motoaki Hatori; Kazuhiro Suzuki; Jing-Ding Wang; Naotsugu Ichimaru; Seiichi Suzuki; Kunio Morozumi; Akihiko Okuyama; Hidetoshi Yamanaka

2002-01-01

343

Parkinson's Disease Foundation  

MedlinePLUS

... View All News PDF Champions: Atlantic City Half Marathon Sunday, October 19 (Atlantic City, NJ) Katherine Lewis will run the Atlantic City Half Marathon to benefit the Parkinson's Disease Foundation. Learn More ...

344

Managing Advanced Parkinson Disease  

MedlinePLUS

... Voices from the Parkinson community “Slowly I am learning that smaller, more frequent meals work well for ... time and choices, but it is an important aspect of maintaining dignity and self-esteem. What to ...

345

Post-dengue parkinsonism  

PubMed Central

Background Dengue is a common illness in the tropics. Equally common are neurological complications that stem from dengue infection. However, to date, parkinsonism following dengue has not been reported in medical literature. Case presentation A previously well 18-year old man developed parkinsonism, in addition to other neurological symptoms following serologically confirmed dengue fever. Alternative etiologies were excluded by way of imaging and blood investigations. Conclusions The authors detail the first reported case of parkinsonism complicating dengue fever. Keeping rare presentations of common illnesses in mind, it behoves clinicians to consider parkinsonism as a complication following dengue infection. This would prevent injudicious treatment with L-dopa and dopamine agonists. Immunosuppression with steroids has been shown to be helpful in certain cases. PMID:23594500

2013-01-01

346

Antipsychotic drugs rapidly induce dopamine neuron depolarization block in a developmental rat model of schizophrenia  

PubMed Central

Repeated administration of antipsychotic drugs to normal rats has been shown to induce a state of dopamine neuron inactivation known as depolarization block, which correlates with the ability of the drugs to exhibit antipsychotic efficacy and extrapyramidal side-effects in schizophrenia patients. Nonetheless, in normal rats depolarization block requires weeks of antipsychotic drug administration, whereas schizophrenia patients exhibit initial effects soon after initiating antipsychotic drug treatment. We now report that, in a developmental disruption rat model of schizophrenia (methyl-azoxymethanol acetate (20 mg/kg i.p.) injected into G17 pregnant female rats, with offspring tested as adults), the extant hyperdopaminergic state combines with the excitatory actions of a first (haloperidol; 0.6 mg/kg, i.p.)- and second (sertindole; 2.5 mg/kg, i.p.)-generation antipsychotic drug to rapidly induce depolarization block in ventral tegmental area dopamine neurons. Acute injection of either antipsychotic drug induced an immediate reduction in the number of spontaneously active dopamine neurons (cells per electrode track; termed population activity). Repeated administration of either antipsychotic drug for 1 day, 3 days, 7 days, 15 days, and 21 days continued to reduce dopamine neuron population activity. Both acute and repeated effects on population activity were reversed by acute apomorphine injections, which is consistent with the reversal of dopamine neuron depolarization block. Although this action may account for the effects of D2 antagonist drugs on alleviating psychosis and the lack of development of tolerance in humans, the drugs appear to do so by inducing an offsetting deficit rather than attacking the primary pathology present in schizophrenia. PMID:21865475

Valenti, Ornella; Cifelli, Pierangelo; Gill, Kathryn M.; Grace, Anthony A.

2011-01-01

347

Antipsychotic drugs rapidly induce dopamine neuron depolarization block in a developmental rat model of schizophrenia.  

PubMed

Repeated administration of antipsychotic drugs to normal rats has been shown to induce a state of dopamine neuron inactivation known as depolarization block, which correlates with the ability of the drugs to exhibit antipsychotic efficacy and extrapyramidal side effects in schizophrenia patients. Nonetheless, in normal rats depolarization block requires weeks of antipsychotic drug administration, whereas schizophrenia patients exhibit initial effects soon after initiating antipsychotic drug treatment. We now report that, in a developmental disruption rat model of schizophrenia [methyl-azoxymethanol acetate (20 mg/kg, i.p.) injected into G17 pregnant female rats, with offspring tested as adults], the extant hyperdopaminergic state combines with the excitatory actions of a first- (haloperidol; 0.6 mg/kg, i.p.) and a second- (sertindole; 2.5 mg/kg, i.p.) generation antipsychotic drug to rapidly induce depolarization block in ventral tegmental area dopamine neurons. Acute injection of either antipsychotic drug induced an immediate reduction in the number of spontaneously active dopamine neurons (cells per electrode track; termed population activity). Repeated administration of either antipsychotic drug for 1, 3, 7, 15, and 21 d continued to reduce dopamine neuron population activity. Both acute and repeated effects on population activity were reversed by acute apomorphine injections, which is consistent with the reversal of dopamine neuron depolarization block. Although this action may account for the effects of D2 antagonist drugs on alleviating psychosis and the lack of development of tolerance in humans, the drugs appear to do so by inducing an offsetting deficit rather than attacking the primary pathology present in schizophrenia. PMID:21865475

Valenti, Ornella; Cifelli, Pierangelo; Gill, Kathryn M; Grace, Anthony A

2011-08-24

348

Selective loss of bi-directional synaptic plasticity in the direct and indirect striatal output pathways accompanies generation of parkinsonism and l-DOPA induced dyskinesia in mouse models.  

PubMed

Parkinsonian symptoms arise due to over-activity of the indirect striatal output pathway, and under-activity of the direct striatal output pathway. l-DOPA-induced dyskinesia (LID) is caused when the opposite circuitry problems are established, with the indirect pathway becoming underactive, and the direct pathway becoming over-active. Here, we define synaptic plasticity abnormalities in these pathways associated with parkinsonism, symptomatic benefits of l-DOPA, and LID. We applied spike-timing dependent plasticity protocols to cortico-striatal synapses in slices from 6-OHDA-lesioned mouse models of parkinsonism and LID, generated in BAC transgenic mice with eGFP targeting the direct or indirect output pathways, with and without l-DOPA present. In naďve mice, bidirectional synaptic plasticity, i.e. LTP and LTD, was induced, resulting in an EPSP amplitude change of approximately 50% in each direction in both striatal output pathways, as shown previously. In parkinsonism and dyskinesia, both pathways exhibited unidirectional plasticity, irrespective of stimulation paradigm. In parkinsonian animals, the indirect pathway only exhibited LTP (LTP protocol: 143.5±14.6%; LTD protocol 177.7±22.3% of baseline), whereas the direct pathway only showed LTD (LTP protocol: 74.3±4.0% and LTD protocol: 63.3±8.7%). A symptomatic dose of l-DOPA restored bidirectional plasticity on both pathways to levels comparable to naďve animals (Indirect pathway: LTP protocol: 124.4±22.0% and LTD protocol: 52.1±18.5% of baseline. Direct pathway: LTP protocol: 140.7±7.3% and LTD protocol: 58.4±6.0% of baseline). In dyskinesia, in the presence of l-DOPA, the indirect pathway exhibited only LTD (LTP protocol: 68.9±21.3% and LTD protocol 52.0±14.2% of baseline), whereas in the direct pathway, only LTP could be induced (LTP protocol: 156.6±13.2% and LTD protocol 166.7±15.8% of baseline). We conclude that normal motor control requires bidirectional plasticity of both striatal outputs, which underlies the symptomatic benefits of l-DOPA. Switching from bidirectional to unidirectional plasticity drives global changes in striatal pathway excitability, and underpins parkinsonism and dyskinesia. PMID:25171793

Thiele, Sherri L; Chen, Betty; Lo, Charlotte; Gertler, Tracey S; Warre, Ruth; Surmeier, James D; Brotchie, Jonathan M; Nash, Joanne E

2014-11-01

349

A case of levocetirizine-induced fixed drug eruption and cross-reaction with piperazine derivatives  

PubMed Central

Fixed drug eruption is an uncommon adverse drug reaction caused by delayed cell-mediated hypersensitivity. Levocetirizine is an active (R)-enatiomer of cetirizine and there have been a few reports of fixed drug eruption related to these antihistamines. We experienced a case of levocetirizine-induced fixed drug eruption and cross-reaction with other piperazine derivatives confirmed by patch test. A 73-year-old female patient presented with recurrent generalized itching, cutaneous bullae formation, rash and multiple pigmentation at fixed sites after taking drugs for common cold. She took bepotastine besilate (Talion®) and levocetirizine (Xyzal®) as antihistamine. She took acetaminophen, pseudoephedrine 60 mg / triprolidine 2.5 mg (Actifed®), dihydrocodeinebitartrate 5 mg / di-methylephedrine hydrochloride 17.5 mg / chlorpheniramine maleate 1.5 mg / guaifenesin 50 mg (Codening®) and aluminium hydroxide 200 mg / magnesium carbonate 120 mg (Antad®) at the same time. Patch test was done with suspected drugs and the result was positive with levocetirizine. We additionally performed patch test for other antihistamines such as cetirizine, hydroxyzine, fexofenadine and loratadine. Piperazine derivatives (cetirizine and hydroxyzine) were positive, but piperidine derivatives (fexofenadine and loratadine) were negative to patch test. There was no adverse drug reaction when she was challenged with fexofenadine. We report a case of levocetirizine-induced fixed drug eruption confirmed by patch test. Cross-reactions were only observed in the piperazine derivatives and piperidine antihistamine was tolerant to the patient. PMID:24260733

Kim, Mi-Yeong; Jo, Eun-Jung; Chang, Yoon-Seok; Cho, Sang-Heon; Min, Kyung-Up

2013-01-01

350

A case of levocetirizine-induced fixed drug eruption and cross-reaction with piperazine derivatives.  

PubMed

Fixed drug eruption is an uncommon adverse drug reaction caused by delayed cell-mediated hypersensitivity. Levocetirizine is an active (R)-enatiomer of cetirizine and there have been a few reports of fixed drug eruption related to these antihistamines. We experienced a case of levocetirizine-induced fixed drug eruption and cross-reaction with other piperazine derivatives confirmed by patch test. A 73-year-old female patient presented with recurrent generalized itching, cutaneous bullae formation, rash and multiple pigmentation at fixed sites after taking drugs for common cold. She took bepotastine besilate (Talion®) and levocetirizine (Xyzal®) as antihistamine. She took acetaminophen, pseudoephedrine 60 mg / triprolidine 2.5 mg (Actifed®), dihydrocodeinebitartrate 5 mg / di-methylephedrine hydrochloride 17.5 mg / chlorpheniramine maleate 1.5 mg / guaifenesin 50 mg (Codening®) and aluminium hydroxide 200 mg / magnesium carbonate 120 mg (Antad®) at the same time. Patch test was done with suspected drugs and the result was positive with levocetirizine. We additionally performed patch test for other antihistamines such as cetirizine, hydroxyzine, fexofenadine and loratadine. Piperazine derivatives (cetirizine and hydroxyzine) were positive, but piperidine derivatives (fexofenadine and loratadine) were negative to patch test. There was no adverse drug reaction when she was challenged with fexofenadine. We report a case of levocetirizine-induced fixed drug eruption confirmed by patch test. Cross-reactions were only observed in the piperazine derivatives and piperidine antihistamine was tolerant to the patient. PMID:24260733

Kim, Mi-Yeong; Jo, Eun-Jung; Chang, Yoon-Seok; Cho, Sang-Heon; Min, Kyung-Up; Kim, Sae-Hoon

2013-10-01

351

Detection and reporting of drug-induced proarrhythmias: room for improvement.  

PubMed

Recently adopted guidelines mandate the inclusion of detailed non-clinical and clinical QT data in future drug labels. As a result of increasing recognition of drug-induced proarrhythmias, and the bias introduced by the prescribing physician's awareness of these events, it is likely that the number of adverse drug reaction (ADR) reports of life-threatening ventricular arrhythmias and sudden death, allegedly caused by the drug, will increase. To illustrate how different approaches have been used to assess proarrhythmic liability and validate ADR reports on serious ventricular arrhythmias, this overview assesses pharmacoepidemiology studies on terfenadine and cisapride, the quality of ADR reports and the effect of label changes on prescribing patterns and other information to prescribing physicians. Clinical and pharmacoepidemiology studies, which in most cases did not demonstrate an increased risk for proarrhythmias with these two drugs, are discussed with emphasis on limitations, studied endpoints, and populations. Recommendations are made on how to improve the effectiveness of labelled precautions and contraindications, which may include the implementation of more effective alert systems. Given the low incidence of drug-induced proarrhythmias, 'signal' generation through ADR reports will continue to have a key role for early identification of proarrhythmic liability of newly marketed drugs. The quality of these reports varies widely, and can be improved through implementation of procedures by which complementary information is captured and events are adjudicated and classified into confidence categories using a consistent scheme across different classes of drugs. PMID:17766321

Darpö, Börje

2007-09-01

352

The Movement Disorder Society--14th International Congress of Parkinson's Disease and Movement Disorders.  

PubMed

The 14th International Congress of Parkinson's Disease and Movement Disorders, held in Buenos Aires, included topics covering new therapeutic developments in the field of Parkinson's disease and other movement disorders. This conference report highlights selected presentations on drug treatments for movement disorders, including safinamide (Merck Serono SA), PYM-50028 (Phytopharm plc), droxidopa, pardoprunox (Abbott Laboratories); treatment considerations for dystonia; exploiting existing drugs for new indications; and using genetics to assess drug therapy responses. PMID:20721824

Grosset, Donald; Grosset, Andrew

2010-08-01

353

S100B is increased in Parkinson's disease and ablation protects against MPTP-induced toxicity through the RAGE and TNF-? pathway.  

PubMed

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. PMID:23169921

Sathe, Kinnari; 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; Teismann, Peter

2012-11-01

354

Possible mechanisms of drug-induced aspirin and clopidogrel resistance  

Microsoft Academic Search

Aspirin (ASA) and clopidogrel have been identified as standard of care in the prevention of major cardiovascular events. Aspirin\\u000a irreversibly inhibits the cyclooxygenase-1 (COX-1) enzyme, whereas non-steroidal anti-inflammatory drugs (NSAIDs) reversibly\\u000a inhibit the COX-1 enzyme. An analysis of the literature revealed a statistically significant decrease in clinical benefit\\u000a of ASA with concomitant administration of ibuprofen. Another NSAID, diclofenac, showed minimal

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

2006-01-01

355

Drug-induced esophagitis detected by double-contrast radiography  

SciTech Connect

Patients with esophageal symptoms following drug ingestion underwent double-contrast upper gastrointestinal studies, and radiographic findings are described. Superficial esophageal ulceration and subtle mucosal abnormalities, which have not been seen on single-contrast radiographs, were confirmed on double-contrast radiographs. Erosions or ulcers usually occur in the region of the aortic arch and occasionally lower in the esophagus. Repeat esophagrams after withdrawal of the medication indicate resolution of the symptoms.

Creteur, V. (Hospital of the Univ. of Pennsylvania, Philadelphia); Laufer, I.; Kressel, H.Y.; Caroline, D.F.; Goren, R.A.; Evers, K.A.; Glick, S.N.; Gatenby, R.A.

1983-05-01

356

Seizure-Inducing Drugs Used for the Critically Ill  

Microsoft Academic Search

Critically ill patients are subjected to numerous medication effects during their stay in the intensive care unit (ICU). Some\\u000a of them have epileptogenic potentials. The most common pathophysiologic mechanism is through blockade of the ?-aminobutyric\\u000a acid (GABA) receptor, and the most commonly used family of ICU drugs, reducing the seizure threshold, is the antibiotics.\\u000a The exact role of these medications

Rebecca E. Schuman; Panayiotis N. Varelas

357

OATP1B1-related drug-drug and drug-gene interactions as potential risk factors for cerivastatin-induced rhabdomyolysis  

PubMed Central

Objective Genetic variation in drug metabolizing enzymes and membrane transporters as well as concomitant drug therapy can modulate the beneficial and the deleterious effects of drugs. We investigated whether patients exhibiting rhabdomyolysis who were taking cerivastatin possess functional genetic variants in SLCO1B1 and whether they were on concomitant medications that inhibit OATP1B1, resulting in accumulation of cerivastatin. Methods This study had three components: (a) resequencing the SLCO1B1 gene in 122 patients who developed rhabdomyolysis while on cerivastatin; (b) functional evaluation of the identified SLCO1B1 nonsynonymous variants and haplotypes in in-vitro HEK293/FRT cells stably transfected with pcDNA5/FRT empty vector, SLCO1B1 reference, variants, and haplotypes; and (c) in-vitro screening of 15 drugs commonly used among the rhabdomyolysis cases for inhibition of OATP1B1-mediated uptake of cerivastatin in HEK293/FRT cells stably transfected with reference SLCO1B1. Results The resequencing of the SLCO1B1 gene identified 54 variants. In-vitro functional analysis of SLCO1B1 nonsynonymous variants and haplotypes showed that the V174A, R57Q, and P155T variants, a novel frameshift insertion, OATP1B1*14 and OATP1B1*15 haplotype were associated with a significant reduction (P<0.001) in cerivastatin uptake (32, 18, 72, 3.4, 2.1 and 5.7% of reference, respectively). Furthermore, clopidogrel and seven other drugs were shown to inhibit OATP1B1-mediated uptake of cerivastatin. Conclusion Reduced function of OATP1B1 related to genetic variation and drug–drug interactions likely contributed to cerivastatin-induced rhabdomyolysis. Although cerivastatin is no longer in clinical use, these findings may translate to related statins and other substrates of OATP1B1. PMID:23652407

Tamraz, Bani; Fukushima, Hisayo; Wolfe, Alan R.; Kaspera, Rudiger; Totah, Rheem A.; Floyd, James S.; Ma, Benjamin; Chu, Catherine; Marciante, Kristin D.; Heckbert, Susan R.; Psaty, Bruce M.; Kroetz, Deanna L.; Kwok, Pui-Yan

2014-01-01

358

Cell based therapy in Parkinsonism  

PubMed Central

Parkinson’s disease (PD) is a synucleinopathy-induced chronic progressive neurodegenerative disorder, worldwide affecting about 5 million humans. As of yet, actual therapies are symptomatic, and neuroprotective strategies are an unmet need. Due to their capability to transdifferentiate, to immune modulate and to increase neuroplasticity by producing neurotrophic factors, adult stem cells (ASC) might fill this gap. Preclinical research in 6-hydroxydopamine (6-OHDA) and/or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) lesioned animals established persistent improvements of motor behavior after ASC-treatment. Histological/histochemical measurements in these animals evidenced an intracerebral applied ASC-induced increase of Tyrosine Hydroxylase-positive (TH+) cells with increased striatal dopamine levels, suggesting cell rescue. Likewise, clinical experience with subventricular applied ASCs in PD patients, although limited, is encouraging, evidencing neurorescue especially during the early phase of the disease. In multiple system atrophy (MSA) or progressive supranuclear palsy (PSP) patients, though, only marginal reduced progression of natural progression could be established after subventricular or intravasal ASC implantations. PMID:23734727

2013-01-01

359

Reinstatement of cocaine seeking induced by drugs, cues, and stress in adolescent and adult rats  

Microsoft Academic Search

Rationale  In human and animal studies, adolescence marks a period of increased vulnerability to the initiation and subsequent abuse\\u000a of drugs. Adolescents may be especially vulnerable to relapse, and a critical aspect of drug abuse is that it is a chronically\\u000a relapsing disorder. However, little is known of how vulnerability factors such as adolescence are related to conditions that\\u000a induce relapse,

Justin J. Anker; Marilyn E. Carroll

2010-01-01

360

Determination of threshold energy dose for ultrasound-induced transdermal drug transport  

Microsoft Academic Search

Low-frequency (20 kHz) ultrasound has been shown to enhance transdermal transport of drugs, a phenomenon referred to as sonophoresis. In this paper, we report the threshold energy dose for ultrasound-induced transdermal drug transport. The threshold was determined by in vitro measurements of the dependence of sonophoretic enhancement on ultrasound parameters, including intensity, duty cycle, and exposure time. While the enhancement

Samir Mitragotri; Joanne Farrell; Hua Tang; Takaaki Terahara; Joseph Kost; Robert Langer

2000-01-01

361

Dopaminergic drugs may counteract behavioral and biochemical changes induced by models of brain injury  

Microsoft Academic Search

The dopaminergic drugs, bromocriptine, cabergoline, dihydroergocryptine, pergolide and ropinirole were injected subcutaneously (s.c.) at the dose of 0.1, 0.5 and 1 mg\\/kg\\/day for 7 days into male rats of the Sprague–Dawley strain. The drug pre-treatment reverted amnesia induced in rats by hypobaric hypopxia and tested in active and passive avoidance tasks. A restoration of memory retention, as assessed in a

V. Micale; T. Incognito; A. Ignoto; L. Rampello; M. Spartŕ; F. Drago

2006-01-01

362

Drug-induced sexual dysfunction and mental health patients' attitude to psychotropic medications  

Microsoft Academic Search

The objective of the study was to explore sexual dysfunction in adults with enduring mental health problem treated with psychotropic medications, focusing on associations between drug-induced sexual dysfunction and attitude to prescribed medications. Participants were invited to complete an anonymous self-administered survey questionnaire, which comprised of the 10-Item Drug Attitude Inventory and the Arizona Sexual Experience Scale (ASEX). In addition,

Tunde Apantaku-Olajide; Pat Gibbons; Agnes Higgins

2011-01-01

363

Treatment of depression in Parkinson’s disease  

Microsoft Academic Search

Depression is one of the most common nonmotor features observed in Parkinson’s disease (PD), affecting approximately 40% of\\u000a patients. Depression in Parkinson’s disease (dPD) significantly affects quality of life of both patients and their families\\u000a and has been shown to be more predictive of distress than motor disability. Depression frequently goes unrecognized in this\\u000a population, however, in part because the

Matthew Menza; Roseanne DeFronzo Dobkin; Humberto Marin

2006-01-01

364

Upregulation of a small vault RNA (svtRNA2-1a) is an early event in Parkinson disease and induces neuronal dysfunction  

PubMed Central

MicroRNAs (miRNAs) and other small non-coding RNAs (sncRNAs) are post-transcriptional regulators of gene expression, playing key roles in neuronal development, plasticity, and disease. Transcriptome deregulation caused by miRNA dysfunction has been associated to neurodegenerative diseases. Parkinson disease (PD) is the second most common neurodegenerative disease showing deregulation of the coding and small non-coding transcriptome. On profiling sncRNA in PD brain areas differently affected, we found that upregulation of a small vault RNA (svtRNA2-1a) is widespread in PD brains, occurring early in the course of the disease (at pre-motor stages). SvtRNA2-1a biogenesis was dependent on Dicer activity on its precursor (vtRNA2-1) but independent of Drosha endonuclease, unlike the canonical miRNAs. Although endogenous svtRNA2-1a was enriched in Ago-2 immunoprecipitates in differentiated SH-SY5Y neuronal cells, overexpression of svtRNA2-1a induced subtle transcriptomic changes, suggesting that gene expression regulation may involve other mechanisms than mRNA decay only. Function enrichment analysis of the genes deregulated by svtRNA2-1a overexpression or svtRNA2-1a predicted targets identified pathways related to nervous system development and cell type specification. The expression pattern of svtRNA2-1a during development and aging of the human brain and the detrimental consequences of a svtRNA2-1a mimic overexpression in neuronal cells further indicate that low svtRNA2-1a levels may be important for the maintenance of neurons. Our results suggest that early svtRNA2-1a upregulation in PD may contribute to perturbations of gene expression networks, underlying metabolic impairment and cell dysfunction. A better understanding of the pathways regulated by svtRNA2-a, and also the mechanisms regulating its expression should facilitate the identification of new targets for therapeutic approaches in PD. PMID:23673382

Minones-Moyano, Elena; Friedlander, Marc R.; Pallares, Joan; Kagerbauer, Birgit; Porta, Silvia; Escaramis, Georgia; Ferrer, Isidre; Estivill, Xavier; Marti, Eulalia

2013-01-01

365

Immunosuppressant Drug Prevents Tobacco-induced Lung Cancer in Mice  

Cancer.gov

Rapamycin, an FDA-approved drug normally used to help prevent the body from rejecting organ and bone marrow transplants and also used to coat cardiac stents, was highly effective in preventing the development of tobacco-related lung tumors in mice. Researhers found that mice that were administered rapamycin one week after exposure to a very common tobacco-specific carcinogen showed a 90 percent decrease in the number of tumors, a 74 percent decrease in tumor size, and fewer abnormalities within their cancer cells.

366

Lichen planus pemphigoides induced by a weight reduction drug.  

PubMed

Lichen planus pemphigoides is a rare autoimmune dermatosis characterized by bullous lesions arising on lichen planus (LP) papules and on clinically uninvolved skin, coexistence of histological features of LP and bullous pemphigoid and linear deposits of IgG and/or C3 along the basal membrane zone on direct immunofluorescence of peribullous skin. LPP has been reported to be associated with several medications such as ramipril, cinnarizine, simvastatin, captopril, psoralen ultraviolet A therapy and antituberculous medications. We report a case of a 41-year-old woman with LPP associated with a weight reduction drug. PMID:21428725

Rosmaninho, Aristoteles; Sanches, Madalena; Oliveira, Ana; Alves, Rosario; Selores, Manuela

2011-12-01

367

Drug Tolerance in Replicating Mycobacteria Mediated by a Macrophage-Induced Efflux Mechanism  

PubMed Central

SUMMARY Treatment of tuberculosis, a complex granulomatous disease, requires long-term multidrug therapy to overcome tolerance, an epigenetic drug resistance that is widely attributed to nonreplicating bacterial subpopulations. Here, we deploy Mycobacterium marinum-infected zebrafish larvae for in vivo characterization of antitubercular drug activity and tolerance. We describe the existence of multi-drug tolerant organisms that arise within days of infection, are enriched in the replicating intracellular population, and are amplified and disseminated by the tuberculous granuloma. Bacterial efflux pumps that are required for intracellular growth mediate this macrophage-induced tolerance. This newly discovered tolerant population also develops when Mycobacterium tuberculosis infects cultured macrophages, suggesting that it contributes to the burden of drug tolerance in human tuberculosis. Efflux pump inhibitors like verapamil reduce this tolerance. Thus, the addition of this currently approved drug, or more specific inhibitors, to standard antitubercular therapy may shorten the duration of curative treatment. PMID:21376383

Adams, Kristin N.; Takaki, Kevin; Connolly, Lynn E.; Wiedenhoft, Heather; Winglee, Kathryn; Humbert, Olivier; Edelstein, Paul H.; Cosma, Christine L.; Ramakrishnan, Lalita

2011-01-01

368

What can we learn about schizophrenia from studying the human model, drug-induced psychosis?  

PubMed

When drug-induced psychoses were first identified in the mid-20th century, schizophrenia was considered a discrete disease with a likely genetic cause. Consequently, drug-induced psychoses were not considered central to understanding schizophrenia as they were thought to be phenocopies rather than examples of the illness secondary to a particular known cause. However, now that we know that schizophrenia is a clinical syndrome with multiple component causes, then it is clear that the drug-induced psychoses have much to teach us. This article shows how the major neuropharmacological theories of schizophrenia have their origins in studies of the effects of drugs of abuse. Research into the effects of LSD initiated the serotonergic model; amphetamines the dopamine hypothesis, PCP and ketamine the glutamatergic hypothesis, while most recently the effects of cannabis have provoked interest in the role of endocannabinoids in schizophrenia. None of these models account for the complete picture of schizophrenia; rather the various drug models mimic different aspects of the illness. Determining the different molecular effects of those drugs whose pharmacological effects do and do not mimic the various aspects of schizophrenia has much to teach us concerning the pathogenesis of the illness. PMID:24132898

Murray, Robin M; Paparelli, Alessandra; Morrison, Paul D; Marconi, Arianna; Di Forti, Marta

2013-10-01

369

Neuroimaging in Parkinson’s Disease  

Microsoft Academic Search

Summary  Parkinson’s disease (PD) is a common disorder in which the primary features can be related to dopamine deficiency. Changes\\u000a on structural imaging are limited, but a wealth of abnormalities can be detected using positron emission tomography, single\\u000a photon emission computed tomography, or functional magnetic resonance imaging to detect changes in neurochemical pathology\\u000a or functional connectivity. The changes detected on these

A. Jon Stoessl; Pacific Parkinson

2011-01-01

370

Adenosine A2A Receptor Antagonists and Parkinson's Disease  

PubMed Central

This Review summarizes and updates the work on adenosine A2A receptor antagonists for Parkinson’s disease from 2006 to the present. There have been numerous publications, patent applications, and press releases within this time frame that highlight new medicinal chemistry approaches to this attractive and promising target to treat Parkinson’s disease. The Review is broken down by scaffold type and will discuss the efforts to optimize particular scaffolds for activity, pharmacokinetics, and other drug discovery parameters. The majority of approaches focus on preparing selective A2A antagonists, but a few approaches to dual A2A/A1 antagonists will also be highlighted. The in vivo profiles of compounds will be highlighted and discussed to compare activities across different chemical series. A clinical report and update will be given on compounds that have entered clinical trials. PMID:22860156

2011-01-01

371

Nonconvulsive status epilepticus due to drug induced neurotoxicity in chronically ill children.  

PubMed

Nonconvulsive status epilepticus (NCSE) is a specific form of status epilepticus and is defined as epileptic activity on an EEG without seizures and as an alteration in mental status lasting more than 30 min. NCSE may be caused by drugs, cerebrovascular events, metabolic disorders or toxins. Herein, we present four cases of patients with drug-induced NCSE who were chronically ill due to renal failure or childhood leukemia. NCSE should be suspected in patients with an altered mental status without clinical seizures who are being treated with multiple drugs. PMID:22445289

Ekici, Arzu; Yakut, Ayten; Kural, Nurdan; Bör, Özcan; Yimenicio?lu, Sevgi; Çarman, Kür?at Bora

2012-11-01

372

Study on slow release anti-cancer drugs prepared by radiation induced polymerization  

NASA Astrophysics Data System (ADS)

This paper reports the research results which the anticancer drugs Ara-C with controlled slow release were made by radiation induced polymerization of monomers such as methacrylates at room temperature. Our studies showed that not only hydrophilic synthetic polymers but also hydrophobic polymers such as hydrophobic methacrylates (including MMA, EMA, and BMA) could be used to the immobilization. In vitro the rate of drugs release was controlled by the many factors such as the content of drugs, the monomer material, the crosslinking agent, the irradiation dose and the water content, etc.

Huaijiang, Xie; Juzhong, Song; Tao, Peng

1993-10-01

373

Artesunate overcomes drug resistance in multiple myeloma by inducing mitochondrial stress and non-caspase apoptosis  

PubMed Central

Although novel drugs have contributed immensely to improving outcomes of patients with multiple myeloma (MM), many patients develop drug resistance and ultimately succumb to MM. Here, we show that artesunate, an anti-malarial drug, reliably induces cell death in vitro in naďve as well as drug-resistant MM cells at concentrations shown to be safe in humans. Artesunate induced apoptosis predominantly through the non-caspase mediated pathway by primarily targeting mitochondria and causing outer mitochondrial membrane permeabilization that led to cytosolic and subsequent nuclear translocation of mitochondrial proteins apoptosis inducing factor (AIF) and endonuclease G (EndoG). Nuclear translocation of AIF and EndoG was accompanied by low levels of reactive oxygen species (ROS) and increased mitochondrial production of superoxide. These effects were present before apoptosis was evident and were related to intracellular levels of bivalent iron (Fe+2). Artesunate's unique mechanism probably was at least partially responsible for, its ability to act synergistically with multiple anti-myeloma agents. Our findings suggest that artesunate acts through iron to affect the mitochondria and induce low ROS and non-caspase–mediated apoptosis. Its potency, toxicity profile, and synergism with other drugs make it an intriguing new candidate for MM treatment. PMID:24948357

Papanikolaou, Xenofon; Johnson, Sarah; Garg, Tarun; Tian, Erming; Tytarenko, Ruslana; Zhang, Qing; Stein, Caleb; Barlogie, Bart; Epstein, Joshua; Heuck, Christoph

2014-01-01

374

Cisplatin as an Anti-Tumor Drug: Cellular Mechanisms of Activity, Drug Resistance and Induced Side Effects  

PubMed Central

Platinum complexes are clinically used as adjuvant therapy of cancers aiming to induce tumor cell death. Depending on cell type and concentration, cisplatin induces cytotoxicity, e.g., by interference with transcription and/or DNA replication mechanisms. Additionally, cisplatin damages tumors via induction of apoptosis, mediated by the activation of various signal transduction pathways, including calcium signaling, death receptor signaling, and the activation of mitochondrial pathways. Unfortunately, neither cytotoxicity nor apoptosis are exclusively induced in cancer cells, thus, cisplatin might also lead to diverse side-effects such as neuro- and/or renal-toxicity or bone marrow-suppression. Moreover, the binding of cisplatin to proteins and enzymes may modulate its biochemical mechanism of action. While a combination-chemotherapy with cisplatin is a cornerstone for the treatment of multiple cancers, the challenge is that cancer cells could become cisplatin-resistant. Numerous mechanisms of cisplatin resistance were described including changes in cellular uptake, drug efflux, increased detoxification, inhibition of apoptosis and increased DNA repair. To minimize cisplatin resistance, combinatorial therapies were developed and have proven more effective to defeat cancers. Thus, understanding of the biochemical mechanisms triggered by cisplatin in tumor cells may lead to the design of more efficient platinum derivates (or other drugs) and might provide new therapeutic strategies and reduce side effects. PMID:24212665

Florea, Ana-Maria; Büsselberg, Dietrich

2011-01-01

375

Wolff-Parkinson-White syndrome  

MedlinePLUS

Wolff-Parkinson-White syndrome is a heart condition in which there is an abnormal extra electrical pathway of the ... to episodes of rapid heart rate ( tachycardia ). Wolff-Parkinson-White syndrome is one of the most common ...

376

Parkinson's Disease: The Newest Advances  

MedlinePLUS

Skip Navigation Bar Home Current Issue Past Issues Parkinson's Disease: The Newest Advances Past Issues / Summer 2006 ... Landis What are the risk factors for developing Parkinson's? The clearest risk factor is age. In addition, ...

377

Cognitive Impairment in Parkinson's Disease  

Microsoft Academic Search

Abstract Background:Cognitive impairment,plays a role in Parkinson’s disease (PD) and has important consequences for patient management. However, many aspects of cognitive impairment,in PD remain,unclear because,of the use of different and often invalid measurement instruments. In this study, a reliable and valid instrument, the SCales for Outcomes in PArkinson’s disease-COGnition (SCOPA-COG), was used. Aim:To evaluate cognitive functioning,in a large cohort of

Vânia Lúcia Soares; Cândida Dias Soares; S M van Rooden; A M Stiggelbout; H A M Middelkoop; J J van Hilten

2010-01-01

378

Asymmetrical Ventricular Enlargement in Parkinson's  

E-print Network

Asymmetrical Ventricular Enlargement in Parkinson's Disease Xuemei Huang, MD, PhD,1 * Yueh Z. Lee, Chapel Hill, North Carolina, USA; 3 Department of Medicine (Neurology), Pacific Parkinson's Research, Bethesda, Maryland, USA Abstract: Parkinson's disease (PD) typically manifests with asymmetric motor

Utah, University of

379

Drug-induced autoimmune liver disease: A diagnostic dilemma of an increasingly reported disease  

PubMed Central

The aetiology of autoimmune hepatitis (AIH) is uncertain but the disease can be triggered in susceptible patients by external factors such as viruses or drugs. AIH usually develops in individuals with a genetic background mainly consisting of some risk alleles of the major histocompatibility complex (HLA). Many drugs have been linked to AIH phenotypes, which sometimes persist after drug discontinuation, suggesting that they awaken latent autoimmunity. At least three clinical scenarios have been proposed that refers to drug- induced autoimmune liver disease (DIAILD): AIH with drug-induced liver injury (DILI); drug induced-AIH (DI-AIH); and immune mediated DILI (IM-DILI). In addition, there are instances showing mixed features of DI-AIH and IM-DILI, as well as DILI cases with positive autoantibodies. Histologically distinguishing DILI from AIH remains a challenge. Even more challenging is the differentiation of AIH from DI-AIH mainly relying in histological features; however, a detailed standardised histologic evaluation of large cohorts of AIH and DI-AIH patients would probably render more subtle features that could be of help in the differential diagnosis between both entities. Growing information on the relationship of drugs and AIH is being available, being drugs like statins and biologic agents more frequently involved in cases of DIAILD. In addition, there is some evidence on the fact that patients diagnosed with DIAILD may have had a previous episode of hepatotoxicity. Further collaborative studies in DIAILD will strengthen the knowledge and understanding of this intriguing and complex disorder which might represent different phenotypes across the spectrum of disease PMID:24799984

Castiella, Agustin; Zapata, Eva; Lucena, M Isabel; Andrade, Raul J

2014-01-01

380

Integrated Systems Pharmacology Analysis of Clinical Drug-Induced Peripheral Neuropathy  

PubMed Central

A systems pharmacology approach was undertaken to define and identify the proteins/genes significantly associated with clinical incidence and severity of drug-induced peripheral neuropathy (DIPN). Pharmacological networks of 234 DIPN drugs, their known targets (both intended and unintended), and the intermediator proteins/genes interacting with these drugs via their known targets were examined. A permutation test identified 230 DIPN-associated intermediators that were enriched with apoptosis and stress response genes. Neuropathy incidence and severity were curated from drug labels and literature and were used to build a predictive model of DIPN using a regression tree algorithm, based on the drug targets and their intermediators. DIPN drugs whose targets interacted with both v-myc avian myelocytomatosis viral oncogene homolog (MYC) and proliferating cell nuclear antigen-associated factor (PAF15) were associated with a neuropathy incidence of 38.1%, whereas drugs interacting only with MYC had an incidence of 2.9%. These results warrant further investigation in order to develop a predictive tool for the DIPN potential of a new drug. PMID:24827872

Hur, J; Guo, A Y; Loh, W Y; Feldman, E L; Bai, J P F

2014-01-01

381

New treatments for the motor symptoms of Parkinson's disease.  

PubMed

Levodopa remains the most potent drug to treat motor symptoms in Parkinson's disease (PD); however, motor fluctuations and levodopa-induced dyskinesia that occur with long-term use restrict some of its therapeutic value. Despite these limitations, the medical treatment of PD strives for continuous relief of symptoms using different strategies throughout the course of the illness: increasing the half-life of levodopa, using 'levodopa-sparing agents' and adding non-dopaminergic drugs. New options to 'improve' delivery of levodopa are under investigation, including long-acting levodopa, nasal inhalation and continuous subcutaneous or intrajejunal administration of levodopa. Long-acting dopamine agonists were recently developed and are undergoing further comparative studies to investigate potential superiority over the immediate-release formulations. Non-dopaminergic drugs acting on adenosine receptors, cholinergic, adrenergic, serotoninergic and glutamatergic pathways are newly developed and many are being evaluated in Phase II and Phase III trials. This article focuses on promising novel therapeutic approaches for the management of PD motor symptoms and motor complications. We will provide an update since 2011 on new formulations of current drugs, new drugs with promising results in Phase II and Phase III clinical trials, old drugs with new possibilities and some new potential strategies that are currently in Phase I and II of development (study start date may precede 2011 but are included as study is still ongoing or full data have not yet been published). Negative Phase II and Phase III clinical trials published since 2011 will also be briefly mentioned. PMID:25318835

Vijverman, Anne-Catherine; Fox, Susan H

2014-11-01

382

Carvedilol, an Antihypertensive Drug with Antioxidant Properties, Protects against Glycerol-Induced Acute Renal Failure  

Microsoft Academic Search

Background\\/Aims: The pathogenesis of glycerol-induced myoglobinuric acute renal failure involves, among other causes, ischaemia, vascular congestion and reactive oxygen metabolites. The aim of this study was to investigate the role of carvedilol, an antihypertensive drug with antioxidative potential, in glycerol-induced acute renal failure in rats. Methods: Three groups of rats were employed in this study. Group 1 served as control,

Devinder Singh; Vikas Chander; Kanwaljit Chopra

2003-01-01

383

Diagnosis of drug-induced renal tubular toxicity using global gene expression profiles  

PubMed Central

Toxicogenomics can measure the expression of thousands of genes to identify changes associated with drug induced toxicities. It is expected that toxicogenomics can be an alternative or complementary approach in preclinical drug safety evaluation to identify or predict drug induced toxicities. One of the major concerns in applying toxicogenomics to diagnose or predict drug induced organ toxicity, is how generalizable the statistical classification model is when derived from small datasets? Here we presented that a diagnosis of kidney proximal tubule toxicity, measured by pathology, can successfully be achieved even with a study design of limited number of training studies or samples. We selected a total of ten kidney toxicants, designed the in life study with multiple dose and multiple time points to cover samples at doses and time points with or without concurrent toxicity. We employed SVM (Support Vector Machine) as the classification algorithm for the toxicogenomic diagnosis of kidney proximal tubule toxicity. Instead of applying cross validation methods, we used an independent testing set by dividing the studies or samples into independent training and testing sets to evaluate the diagnostic performance. We achieved a Sn (sensitivity) = 88% and a Sp (specificity) = 91%. The diagnosis performance underscores the potential application of toxicogenomics in a preclinical lead optimization process of drugs entering into development. PMID:17908307

Jiang, Ying; Gerhold, David L; Holder, Daniel J; Figueroa, David J; Bailey, Wendy J; Guan, Ping; Skopek, Thomas R; Sistare, Frank D; Sina, Joseph F

2007-01-01

384

In vivo imaging of drug-induced mitochondrial outer membrane permeabilization at single-cell resolution.  

PubMed

Observing drug responses in the tumor microenvironment in vivo can be technically challenging. As a result, cellular responses to molecularly targeted cancer drugs are often studied in cell culture, which does not accurately represent the behavior of cancer cells growing in vivo. Using high-resolution microscopy and fluorescently labeled genetic reporters for apoptosis, we developed an approach to visualize drug-induced cell death at single-cell resolution in vivo. Stable expression of the mitochondrial intermembrane protein IMS-RP was established in human breast and pancreatic cancer cells. Image analysis was then used to quantify release of IMS-RP into the cytoplasm upon apoptosis and irreversible mitochondrial permeabilization. Both breast and pancreatic cancer cells showed higher basal apoptotic rates in vivo than in culture. To study drug-induced apoptosis, we exposed tumor cells to navitoclax (ABT-263), an inhibitor of Bcl-2, Bcl-xL, and Bcl-w, both in vitro and in vivo. Although the tumors responded to Bcl-2 inhibition in vivo, inducing apoptosis in around 20% of cancer cells, the observed response was much higher in cell culture. Together, our findings show an imaging technique that can be used to directly visualize cell death within the tumor microenvironment in response to drug treatment. PMID:22505651

Earley, Sarah; Vinegoni, Claudio; Dunham, Joshua; Gorbatov, Rostic; Feruglio, Paolo Fumene; Weissleder, Ralph

2012-06-15

385

Maladaptive Reward-Learning and Impulse Control Disorders in Patients with Parkinson’s Disease: A Clinical Overview and Pathophysiology Update  

PubMed Central

Impulse control disorders (ICD) in Parkinson’s disease (PD) are a disabling non-motor symptom with frequencies of 13–35% among patients receiving dopamine replacement therapy. ICD in PD is strongly associated with dopaminergic drug use, especially non-ergot dopamine agonists (DA). However, individual susceptibility and disease-related neural changes are also important contributors to the development of ICD. Discrepancies between nigrostriatal and mesolimbic dopaminergic degeneration and non-physiological administration of dopaminergic drugs may induce abnormal ’hyperstimulation’ of the mesolimbic system, which alters reward-learning behaviors in PD patients. In addition, DA can make patients more impulsive during decision-making and seek risk-taking behaviors. DA intake is also related to the biased representation of rewards. Ultimately, loss of negative feedback control due to dysfunctional frontostriatal connections is necessary for the establishment of ICD in PD. The subsequent behavioral and neural changes are affected by PD treatment and disease progression; thus, proper treatment guidelines for physicians are needed to prevent the development of ICD. Future studies aimed at producing novel therapeutics to control the risk factors for ICD or treat ICD behaviors in PD are warranted. This review summarizes recent advances from epidemiological and pathophysiological studies on ICD in PD. Management principles and limitations of current therapeutics are briefly discussed. PMID:25360230

Lee, Jee-Young; Jeon, Beom Seok

2014-01-01

386

Pharmacogenomics of severe cutaneous adverse reactions and drug-induced liver injury.  

PubMed

Rare but severe adverse drug reactions (ADRs) are an important issue in drug development and in the proper usage of drugs during the post-approval phase. The ability to predict patient susceptibility to severe ADRs would prevent drug administration to high-risk patients. This would save lives and ensure the quality of life for these patients, but occurrence of idiosyncratic severe ADRs had been very difficult to predict for a long time. However, in this decade, genetic markers have been found for several ADRs, especially for severe cutaneous adverse reactions (SCARs) and drug-induced liver injury (DILI). In this review, we summarize recent progress in identifying genetic markers for SCARS and DILI, and discuss issues that remain unresolved. As for SCARs, associations of HLA-B*15:02 or HLA-A*31:01 and HLA-B*58:01 have been revealed for carbamazepine- and allopurinol-related Stevens-Johnson syndrome and toxic epidermal neclolysis, respectively. HLA-B*57:01 is strongly associated with abacavir-induced hypersensitivity syndrome. Several HLA alleles also demonstrate drug-specific associations with DILI, such as HLA-A*33:03 for ticlopidine, HLA-B*57:01 for flucloxacillin and HLA-DQA1*02:01 for lapatinib. Efforts should be continued to find other genetic markers to achieve high predictability for ADRs, with the goal being development of genetic tests for use in clinical settings. PMID:23635947

Kaniwa, Nahoko; Saito, Yoshiro

2013-06-01

387

Segmenting the substantia nigra in ultrasound images for early diagnosis of Parkinson`s disease  

E-print Network

Segmenting the substantia nigra in ultrasound images for early diagnosis of Parkinson`s disease C diagnosis of Parkinson's disease (PD) is of immense importance, since clinical symptoms do not occur until; Investigator Independence; Parkinson's Disease; Substantia Nigra; Segmentation; Transcranial

Lübeck, Universität zu

388

Use of semiconducting laser in drug-induced chronic bilateral inflammation of parotid glands  

NASA Astrophysics Data System (ADS)

A case of chronic bilateral inflammation of parotid glands in a patient as a results of complication induced by the drug Ospolot in the treatment of epilepsy was presented. Apart from conventional methods a semiconducting laser was used. The laser beam had beneficial effect on elimination of pain and increase in the parotid gland secretion activity.

Grzesiak-Janas, Grazyna

1997-10-01

389

Mechanisms of drug-induced liver injury: from bedside to bench  

Microsoft Academic Search

The low incidence of idiosyncratic drug-induced liver injury (DILI), together with the lack of a reliable diagnostic biomarker and robust preclinical and in vitro toxicology test systems for the condition have limited our ability to define the mechanisms of DILI. A notable exception is acetaminophen hepatotoxicity, which is associated with the formation of a well-characterized and highly reactive intermediate metabolite,

Shannan Tujios; Robert J. Fontana

2011-01-01

390

Simultaneous quantitative monitoring of drug-induced caspase cascade pathways in carcinoma cells  

E-print Network

]chromen-7-ol} (a newly synthesized candidate), camptothecin or naringenin (agents known to induce apoptosis an intrinsic apoptotic pathway, whereas camptothecin treatment triggered both intrinsic and extrinsic caspase utilizes two commercially available drugs, camptothecin (CAM) and naringenin (NAR), and a newly synthesized

Suh, Young-Ger

391

Evaluation of mast cell activation (tryptase) in two patients suffering from drug-induced hypotensoid reactions  

Microsoft Academic Search

Tryptase is predominantly found in mast cells, where it resides in secretory granules, and is released with other mediators during mast cell degranulation. By using a newly developed commercial assay for measurements of tryptase levels we have investigated two cases of suspected drug-induced anaphylaxis. Each patient had a similar clinical presentation, consisting of hypotension and cyanosis after administration of thiopentone

P. Matsson; I. Enander; A.-S. Andersson; J. Nystrand; L. Schwartz; J. Watkins

1991-01-01

392

Reduced Palatability in Drug-Induced Taste Aversion: II. Aversive and Rewarding Unconditioned Stimuli  

PubMed Central

Drugs of abuse are known to reduce intake of a taste conditioned stimulus (CS), a behavioral response sometimes seen as paradoxical because the same drugs also serve as rewards in other behavioral procedures. In the present study we compared patterns of intake and palatability (assessed using microstructural analysis of licking) for a standard saccharin CS paired with: lithium chloride, morphine, amphetamine, or sucrose. We found that morphine and amphetamine, like lithium-induced illness, each suppressed CS intake and caused a reduction in saccharin palatability. Sucrose, a rewarding stimulus, did not reduce the palatability of the saccharin CS. We interpret these finds as evidence that drugs of abuse induce conditioned taste aversions. PMID:22409482

Arthurs, Joe; Lin, Jian-You; Amodeo, Leslie Renee; Reilly, Steve

2012-01-01

393

Sequence-Specific Biosensors Report Drug-Induced Changes in Epigenetic Silencing in Living Cells  

PubMed Central

Treatment with demethylating drugs can induce demethylation and reactivation of abnormally silenced tumor suppressor genes in cancer cells, but it can also induce potentially deleterious loss of methylation of repetitive elements. To enable the observation of unwanted drug effects related to loss of methylation of repetitive DNA, we have developed a novel biosensor capable of reporting changes in DNA accessibility via luminescence, in living cells. The biosensor design comprises two independent modules, each with a polydactyl zinc finger domain fused to a half intein and to a split-luciferase domain that can be joined by conditional protein splicing after binding to adjacent DNA targets. We show that an artificial zinc finger design specifically targeting DNA sequences near the promoter region of the L1PA2 subfamily of Line-1 retroelements is able to generate luminescent signals, reporting loss of epigenetic silencing and increased DNA accessibility of retroelements in human cells treated with the demethylating drugs decitabine or 5-azacytidine. PMID:22313050

Huang, Xudong; Narayanaswamy, Rammohan; Fenn, Kathleen; Szpakowski, Sebastian; Sasaki, Clarence; Costa, Jose; Blancafort, Pilar

2012-01-01

394

Application of urine proteomics for biomarker discovery in drug-induced liver injury.  

PubMed

Abstract The leading cause of hepatic damage is drug-induced liver injury (DILI), for which currently no adequate predictive biomarkers are available. Moreover, for most drugs related to DILI, the mechanisms underlying the adverse reaction have not yet been elucidated. Urinary protein biomarker candidates for DILI have emerged in the past few years and correlate well with clinical studies for serum DILI biomarkers. The goal of this review was to investigate the use of urine as a source of protein biomarkers for drug-induced liver injury. Finally, we discuss some of the current strategies required to advance the field of biomarker discovery for DILI with respect to appropriate clinical biobanking and adequate translational research. PMID:25264586

van Swelm, Rachel P L; Kramers, Cornelis; Masereeuw, Rosalinde; Russel, Frans G M

2014-11-01

395

IntroductionIntroduction Mercury: Monitoring Patients with ParkinsonMercury: Monitoring Patients with Parkinson''s Diseases Disease  

E-print Network

IntroductionIntroduction Mercury: Monitoring Patients with ParkinsonMercury: Monitoring Patients with Parkinson''s Diseases Disease using Wearable Wireless Sensorsusing Wearable Wireless Sensors Konrad Lorincz1 Patel3, Paolo Bonato3,4, and Matt Welsh1 Application: Parkinson's DiseaseApplication: Parkinson

Chen, Yiling

396

Drug-induced glucose-6-phosphate dehydrogenase deficiency-related hemolysis risk assessment.  

PubMed

Glucose-6-phosphate dehydrogenase (G6PD) is an essential enzyme that protects human red blood cells from premature destruction caused by oxidative damage. People suffering from G6PD deficiency would be vulnerable to various oxidative substances, such as fava beans and oxidant drugs. Until now, many institutes, organizations or domain experts have compiled low-risk or high-risk drugs collection for patients with G6PD deficiency, mainly from the case report or clinical trails. Recently, we have explored a classification system to predict drug-induced hemolytic potential. In this paper, we screen the normally used over-the-counter (OTC) drugs for "high-risk" and "low-risk" ones to G6PD deficient patients by this system. PMID:21704265

Yang, Yang; Li, Zuofeng; Nan, Peng; Zhang, Xiaoyan

2011-06-01

397

Glucosylceramide and lysophosphatidylcholines as potential blood biomarkers for drug-induced hepatic phospholipidosis.  

PubMed

Drug-induced phospholipidosis is one of the major concerns in drug development and clinical treatment. The present study involved the use of a nontargeting lipidomic analysis with liquid chromatography-mass spectrometry to explore noninvasive blood biomarkers for hepatic phospholipidosis from rat plasma. We used three tricyclic antidepressants (clomipramine [CPM], imipramine [IMI], and amitriptyline [AMT]) for the model of phospholipidosis in hepatocytes and ketoconazole (KC) for the model of phospholipidosis in cholangiocytes and administered treatment for 3 and 28 days each. Total plasma lipids were extracted and measured. Lipid molecules contributing to the separation of control and drug-treated rat plasma in a multivariate orthogonal partial least squares discriminant analysis were identified. Four lysophosphatidylcholines (LPCs) (16:1, 18:1, 18:2, and 20:4) and 42:1 hexosylceramide (HexCer) were identified as molecules separating control and drug-treated rats in all models of phospholipidosis in hepatocytes. In addition, 16:1, 18:2, and 20:4 LPCs and 42:1 HexCer were identified in a model of hepatic phospholipidosis in cholangiocytes, although LPCs were identified only in the case of 3-day treatment with KC. The levels of LPCs were decreased by drug-induced phospholipidosis, whereas those of 42:1 HexCer were increased. The increase in 42:1 HexCer was much higher in the case of IMI and AMT than in the case of CPM; moreover, the increase induced by IMI was dose-dependent. Structural characterization determining long-chain base and hexose delineated that 42:1 HexCer was d18:1/24:0 glucosylceramide (GluCer). In summary, our study demonstrated that d18:1/24:0 GluCer and LPCs are potential novel biomarkers for drug-induced hepatic phospholipidosis. PMID:24980264

Saito, Kosuke; Maekawa, Keiko; Ishikawa, Masaki; Senoo, Yuya; Urata, Masayo; Murayama, Mayumi; Nakatsu, Noriyuki; Yamada, Hiroshi; Saito, Yoshiro

2014-10-01

398

Drug-induced myocardial infarction secondary to coronary artery spasm in teenagers and young adults.  

PubMed

There is no published registry for drug-induced acute myocardial infarction (AMI) with subsequent patent coronary angiogram in teenagers. To highlight the mechanism and impact of drug-induced MI with patent coronary arteries among teenagers who have relatively few coronary risk factors in comparison with older patients, we conducted a review of the literature. In this review most of the pertinent published (English and non-English) articles through the Medline, Scopus, Cochrane Database of Systematic Reviews and EBSCO Host research databases from 1970 to 2005 have been revised. Teenagers and young adults with AMI and subsequent patent coronary angiogram were included. In those cases drug-induced coronary spasm was highlighted. Among 220 articles (>12000 cases) related with AMI with normal coronary angiogram, 50 articles (approximately 100 cases) reported the role of drug in AMI secondary to coronary artery spasm (CAS). There is no well-conducted trial for AMI secondary to CAS in young adults but only a series of case reports and the diagnosis in most of cases was based on the clinical and laboratory findings without provocation. CAS was associated with 12 illicit substances in teenagers (i.e, cocaine, marijuana, alcohol, butane and amphetamine). Smoking is not only the initiative but also might harbor other illicit substances that increase the risk for CAS. Cocaine-associated AMI is the most frequent in various research papers. CAS was reported with 19 types of medications (i.e, over-the-counter, chemotherapy, antimigraine and antibiotics) without strong relation to age. Despite drug-induced AMI being not a common event, attention to smoking and drugs in teenagers and young adults will have major therapeutic and prognostic implications. PMID:16534169

El Menyar, Ayman A

2006-01-01

399

76 FR 4918 - Drug-Induced Liver Injury: Are We Ready to Look?; Public Conference; Request for Comments  

Federal Register 2010, 2011, 2012, 2013

...FDA-2008-D-0128)] Drug-Induced Liver Injury: Are We Ready to Look?; Public...conference entitled ``Drug-Induced Liver Injury: Are We Ready to Look?'' The...the American Association for the Study of Liver Diseases (AASLD) and the...

2011-01-27

400

Parkinson's Disease: Diagnosis and Treatment | NIH MedlinePlus the Magazine  

MedlinePLUS

... Parkinson's medications. The first includes drugs that increase dopamine in the brain. The most common is levodopa (L-dopa, for short). Others mimic dopamine or prevent or slow its breakdown. The second ...

401

Drugs.  

ERIC Educational Resources Information Center

This document contains the third volume of "Today's Delinquent," an annual publication of the National Center for Juvenile Justice. This volume deals with the issue of drugs and includes articles by leading authorities in delinquency and substance abuse who share their views on causes and cures for the drug problem among youth in this country.…

Hurst, Hunter, Ed.; And Others

1984-01-01