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Sample records for drug induced parkinsonism

  1. Nicotine and Nicotinic Receptor Drugs: Potential for Parkinson's Disease and Drug-Induced Movement Disorders.

    PubMed

    Quik, Maryka; Bordia, Tanuja; Zhang, Danhui; Perez, Xiomara A

    2015-01-01

    Parkinson's disease is a progressive neurodegenerative disorder associated with tremor, rigidity, and bradykinesia, as well as nonmotor symptoms including autonomic impairments, olfactory dysfunction, sleep disturbances, depression, and dementia. Although the major neurological deficit is a loss of nigrostriatal dopaminergic neurons, multiple neurotransmitters systems are compromised in Parkinson's disease. Consistent with this observation, dopamine replacement therapy dramatically improves Parkinson's disease motor symptoms. Additionally, drugs targeting the serotonergic, glutamatergic, adenosine, and other neurotransmitter systems may be beneficial. Recent evidence also indicates that nicotinic cholinergic drugs may be useful for the management of Parkinson's disease. This possibility initially arose from the results of epidemiological studies, which showed that smoking was associated with a decreased incidence of Parkinson's disease, an effect mediated in part by the nicotine in smoke. Further evidence for this idea stemmed from preclinical studies which showed that nicotine administration reduced nigrostriatal damage in parkinsonian rodents and monkeys. In addition to a potential neuroprotective role, emerging work indicates that nicotinic receptor drugs improve the abnormal involuntary movements or dyskinesias that arise as a side effect of l-dopa treatment, the gold standard therapy for Parkinson's disease. Both nicotine and nicotinic receptor drugs reduced l-dopa-induced dyskinesias by over 50% in parkinsonian rodent and monkey models. Notably, nicotine also attenuated the abnormal involuntary movements or tardive dyskinesias that arise with antipsychotic treatment. These observations, coupled with reports that nicotinic receptor drugs have procognitive and antidepressant effects, suggest that central nervous system (CNS) nicotinic receptors may represent useful targets for the treatment of movement disorders. PMID:26472532

  2. Drug-induced parkinsonism following chronic methamphetamine use by a patient on haloperidol decanoate.

    PubMed

    Matthew, Binoj J; Gedzior, Joanna S

    2015-01-01

    This report attempts to highlight that use of an antipsychotic and concurrent chronic use of methamphetamine can cause drug-induced parkinsonism. Methamphetamine is usually not encountered in the list of agents that induce drug-induced parkinsonism and so its consideration particularly during chronic use by a patient who is also on an antipsychotic is worthwhile because of its popularity as an illegal narcotic. This case report describes just such a case of drug-induced parkinsonism which is a subacute syndrome that mimics Parkinson's disease. Although less alarming than dystonia, it is more common, more difficult to treat and can be the cause of significant disability during maintenance treatment especially in the elderly. In most cases, symptoms are reversible in days or weeks, but occasionally, especially in the elderly, or if long-acting injectable antipsychotics are used-as in this case-symptoms may last for weeks or months. The report also illustrates the neuronal workings due to chronic methamphetamine-use and the additive effects of dopamine blockade by antipsychotics such as haloperidol. PMID:26526398

  3. [Parkinson disease induced by flunarizine].

    PubMed

    de S√°, P N; Heinisch, L M

    1989-12-01

    The authors studied 19 patients with parkinsonism induced by flunarizine. All them improved when the drug therapy was discontinued for periods from 7 days to 10 months. Depression was observed in 68.5% of the patients. PMID:2634389

  4. Parkinson's Drug Shows Promise Against Macular Degeneration

    MedlinePLUS

    ... nih.gov/medlineplus/news/fullstory_155695.html Parkinson's Drug Shows Promise Against Macular Degeneration But more research ... no one is recommending that patients take the drug, levodopa (L-dopa), to thwart eye disease. But ...

  5. Drugs of abuse and Parkinson's disease.

    PubMed

    Mursaleen, Leah R; Stamford, Jonathan A

    2016-01-01

    The term "drug of abuse" is highly contextual. What constitutes a drug of abuse for one population of patients does not for another. It is therefore important to examine the needs of the patient population to properly assess the status of drugs of abuse. The focus of this article is on the bidirectional relationship between patients and drug abuse. In this paper we will introduce the dopaminergic systems of the brain in Parkinson's and the influence of antiparkinsonian drugs upon them before discussing this synergy of condition and medication as fertile ground for drug abuse. We will then examine the relationship between drugs of abuse and Parkinson's, both beneficial and deleterious. In summary we will draw the different strands together and speculate on the future merit of current drugs of abuse as treatments for Parkinson's disease. PMID:25816790

  6. New Clues to Easing Side Effects from Parkinson's Drug

    MedlinePLUS

    ... New Clues to Easing Side Effects From Parkinson's Drug Studies in mice, monkeys point to a compound ... 2015 WEDNESDAY, Nov. 18, 2015 (HealthDay News) -- The drug levodopa is a leading treatment for Parkinson's disease, ...

  7. Drug therapy in patients with Parkinsonís disease

    PubMed Central

    2012-01-01

    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

  8. Dementia Drug May Lower Risk of Falls Among Parkinson's Patients

    MedlinePLUS

    ... Dementia Drug May Lower Risk of Falls Among Parkinson's Patients Those who took rivastigmine in study were ... potential in reducing the risk of falls among Parkinson's patients, new research suggests. "With the degeneration of ...

  9. Effect of new dopamine-blocking agent (oxiperomide) on drug-induced dyskinesias in Parkinson's disease and spontaneous dyskinesias.

    PubMed Central

    Bťdard, P; Parkes, J D; Marsden, C D

    1978-01-01

    Oxiperomide, a new dopamine-receptor antagonist, was found to decrease dyskinesias in patients with Parkinson's disease receiving levodopa or other dopamine agonists without necessarily increasing Parkinsonian symptoms. Oxiperomide also decreased spontaneous dyskinesias in those with tics and chorea and to a less extent in those with torsion dystonia, without necessarily causing Parkinsonism. These results provide evidence that more than one population of dopamine receptors exist in the extra pyramidal system, and encourage the search for selective dopamine antagonists. PMID:638546

  10. Pharmacogenetics of Parkinsonís Disease Ė Through Mechanisms of Drug Actions

    PubMed Central

    Dro?dzik, Marek; Bia?ecka, Monika; Kurzawski, Mateusz

    2013-01-01

    In the last years due to development of molecular methods a substantial progress in understanding of genetic associations with drug effects in many clinical disciplines has been observed. The efforts to define the role of genetic polymorphisms in optimizing pharmacotherapy of Parkinsonís disease (PD) were also undertaken. So far, some promising genetic loci for PD treatment were determined. In the review pharmacogenetic aspects of levodopa, dopamine agonists and COMT inhibitors are discussed. PMID:24532988

  11. Drugs in development for Parkinson's disease.

    PubMed

    Johnston, Tom H; Brotchie, Jonathan M

    2004-07-01

    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

  12. Costs of drug treatment in Parkinson's disease.

    PubMed

    Dodel, R C; Eggert, K M; Singer, M S; Eichhorn, T E; Pogarell, O; Oertel, W H

    1998-03-01

    Parkinson's disease (PD) has a major socioeconomic impact on society. The chronic, progressive course of the disease, which often leads to severe disability, results in high expenses for the medical resources used for treatment, care, and rehabilitation of patients as well as reduced or lost productivity as a result of illness or premature death. In Great Britain, it has been estimated that the National Health Service spends up to 383 million pound sterling (1992) annually for the care of PD. This emphasizes the importance of assessing the costs related to this disease. A detailed knowledge of the cost allocation would provide a solid basis on which health care priorities can be rationally set. Next to hospitalization, drug treatment accounts for the highest expense for direct medical costs of PD. Therefore, this analysis focuses on the costs of drug treatment for PD. The cost analysis was based on a retrospective study of 409 patients with PD who were seen over a 1-year period in our movement disorders clinic. The cost of therapy varied considerably depending on the severity of the condition (assessed in the "off" phase), the incidence of motor fluctuations, and the type of PD. In the early stage of the disease (Hoehn and Yahr stage I [HY I]), mean daily costs for therapy were DM (German marks) 6.60, which increased in later stages of the disease (HY V) to DM 22.00. If rare cases requiring continuous subcutaneous apomorphine infusion were included, mean daily costs of patients in HY V rose to DM 32.50 (the mean daily costs of subcutaneous apomorphine-treated patients in HY V: DM 74.30). Patients with motor fluctuations accounted for higher costs (DM 16.50) compared with those without motor fluctuations (DM 7.80). With respect to the three subtypes of PD, the mean daily expenditure was DM 7.00 for the tremor-dominant type, DM 12.40 for the akinetic-rigid type, and DM 10.80 for the mixed type. In the group of 409 PD patients included in this analysis, the average daily expenditure for drug treatment totaled DM 10.70 per patient (including patients on subcutaneous apomorphine). PMID:9539337

  13. Drug discovery in Parkinsonís diseaseóUpdate and developments in the use of cellular models

    PubMed Central

    Skibinski, Gaia; Finkbeiner, Steven

    2013-01-01

    Parkinsonís 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

  14. Rasagiline induced hypersexuality in Parkinson's disease.

    PubMed

    Reyes, Dennys; Kurako, Kateryna; Galvez-Jimenez, Nestor

    2014-03-01

    Impulse control disorders (ICD) are increasingly recognized in patients with Parkinson's disease (PD), particularly when treated with commonly used dopamine agonists such as pramipexole and ropinirole. Less evident is the possible association between monoamine oxidase inhibitors type B (MAO-B) and the development of ICD. Rasagiline is a second generation MAO-B I inducing moderate symptomatic and possibly disease modifying benefits with apparently good tolerability and safety profile in PD patients. Rasagiline is effective and well tolerated in PD as a monotherapy or in combination with levodopa. Here, we report a patient with PD who developed ICD when treated de novo with MAO-B inhibitors. PMID:24055209

  15. Drug-induced hypertension

    MedlinePLUS

    Drug-induced hypertension is high blood pressure caused by using a chemical substance, drug, or medication. ... found. Secondary hypertension occurs because of another disorder. Drug-induced hypertension is a form of secondary hypertension ...

  16. Manganese-Induced Parkinsonism and Parkinson's Disease: Shared and Distinguishable Features.

    PubMed

    Kwakye, Gunnar F; Paoliello, Monica M B; Mukhopadhyay, Somshuvra; Bowman, Aaron B; Aschner, Michael

    2015-07-01

    Manganese (Mn) is an essential trace element necessary for physiological processes that support development, growth and neuronal function. Secondary to elevated exposure or decreased excretion, Mn accumulates in the basal ganglia region of the brain and may cause a parkinsonian-like syndrome, referred to as manganism. The present review discusses the advances made in understanding the essentiality and neurotoxicity of Mn. We review occupational Mn-induced parkinsonism and the dynamic modes of Mn transport in biological systems, as well as the detection and pharmacokinetic modeling of Mn trafficking. In addition, we review some of the shared similarities, pathologic and clinical distinctions between Mn-induced parkinsonism and Parkinson's disease. Where possible, we review the influence of Mn toxicity on dopamine, gamma aminobutyric acid (GABA), and glutamate neurotransmitter levels and function. We conclude with a survey of the preventive and treatment strategies for manganism and idiopathic Parkinson's disease (PD). PMID:26154659

  17. ABT-089 and ABT-894 Reduce L-Dopa-Induced Dyskinesias in a Monkey Model of Parkinsonís Disease

    PubMed Central

    Zhang, Danhui; Bordia, Tanuja; McGregor, Matthew; McIntosh, J. Michael; Decker, Michael W.; Quik, Maryka

    2014-01-01

    Background L-dopa-induced dyskinesias (LIDs) are a serious complication of L-dopa therapy for Parkinsonís disease for which there is little treatment. Accumulating evidence shows that nicotine and nicotinic acetylcholine receptor (nAChR) drugs decrease LIDs in parkinsonian animals. Here we examined the effect of two ?2 nAChR agonists, ABT-089 and ABT-894, previously approved for phase 2 clinical trials for other indications. Methods Two sets of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned monkeys were administered L-dopa/carbidopa (10/2.5 mg/kg) twice daily 5 days/week until stably dyskinetic. Each set had a vehicle-treated, a nAChR agonist-treated and a nicotine-treated group, as a positive control. Set A monkeys had previously received other nAChR drugs (nAChR drug-primed), while Set B monkeys were initially nAChR drug-naÔve. Results Both sets were administered the partial agonist ABT-089 (0.01-1.0 mg/kg) orally 5 d/week twice daily 30 min before L-dopa with each dose given for 1-5 weeks. ABT-089 decreased LIDs 30-50% compared to vehicle-treated monkeys. Nicotine reduced LIDs by 70% in a parallel group. After 4 weeks washout, the effect of the full agonist ABT-894 (0.0001-0.10 mg/kg) was assessed on LIDs in Set A and Set B. ABT-894 reduced LIDs 70%, similar to nicotine. Both drugs acted equally well at ?4?2* and ?6?2* nAChRs; however, ABT-089 was 30-60 times less potent than ABT-894. Tolerance did not develop for the time periods tested (3-4 months). NAChR drugs did not worsen parkinsonism or cognitive ability. Emesis, a common problem with nAChR drugs, was not observed. Conclusion ABT-894 and ABT-089 appear good candidate nAChR drugs for the management of LIDs in Parkinsonís disease. PMID:24515328

  18. [Drug-induced seizures].

    PubMed

    Block, F; Dafotakis, M

    2013-01-01

    Drug-induced seizures are in view of a constantly ageing population and increasingly frequent polypharmacotherapy an increasing problem in daily routine praxis. Identification of potentially seizure-inducing drugs may help generating risk profiles for individual patients. Drug-induced seizures have often been seen as a complication of psychopharmacological therapy, but its occurrence has also been described in response to a great diversity of compounds such as antibiotics, sympathomimetics and anaesthetics. The present article outlines a synopsis of the most prevalent seizure-inducing drugs as well as strategies how to deal with a patient suffering from a drug-induced seizure. PMID:23138222

  19. Tricyclic Antidepressants Amitriptyline and Desipramine Induced Neurotoxicity Associated with Parkinsonís Disease

    PubMed Central

    Lee, Min-yeong; Hong, Seokheon; Kim, Nahmhee; Shin, Ki Soon; Kang, Shin Jung

    2015-01-01

    Recent studies report that a history of antidepressant use is strongly correlated with the occurrence of Parkinsonís disease (PD). However, it remains unclear whether antidepressant use can be a causative factor for PD. In the present study, we examined whether tricyclic antidepressants amitriptyline and desipramine can induce dopaminergic cell damage, both in vitro and in vivo. We found that amitriptyline and desipramine induced mitochondria-mediated neurotoxicity and oxidative stress in SH-SY5Y cells. When injected into mice on a subchronic schedule, amitriptyline induced movement deficits in the pole test, which is known to detect nigrostriatal dysfunction. In addition, the number of tyrosine hydroxylase-positive neurons in the substantia nigra pars compacta was reduced in amitriptyline-injected mice. Our results suggest that amitriptyline and desipramine may induce PD-associated neurotoxicity. PMID:26242194

  20. A Case of SSRI Induced Irreversible Parkinsonism

    PubMed Central

    Khan, Shahbaj A; Azad, Sudip

    2015-01-01

    Serotonin specific reuptake inhibitors (SSRI) are widely used antidepressants for variety of clinical conditions and have found popularity. They are sometimes associated with extrapyramidal side effects including Parkinsonism. We report a case of generalized anxiety disorder on treatment with SSRI (fluoxetine / sertraline) who developed irreversible Parkinsonism. SSRI are known to cause reversible or irreversible motor disturbances through pathophysiological changes in basal ganglion motor system by altering the dopamine receptors postsynaptically. Clinician should keep risk benefit ratio in mind and change of antidepressant of different class may be considered. Case is reported to alert physicians to possibility of motor system damage while treating with SSRI. PMID:25859504

  1. Drug-induced valvular heart disease.

    PubMed

    Cosyns, Bernard; Droogmans, Steven; Rosenhek, Raphael; Lancellotti, Patrizio

    2013-01-01

    Drug-induced valvular heart disease (DIVHD) was first described in the 1960s. Initially, associations with ergot derivatives used for migraine prevention, or with anorectic drugs, were described. Drugs used for the treatment of Parkinson's disease and endocrine diseases, like hyperprolactinemia, may also induce VHD. More recently, the use of 3,4-methylendioxymetamphetamine (MDMA, 'Ecstasy') and benfluorexhave been found to be associated with DIVHD. Although some of these drugs were withdrawn from the market, several cases of patients requiring valve surgery even years after the cessation of therapy have been reported. DIVHD is not infrequent, may be severe, and has been described in association with several drugs. Even after drug cessation, long-term implications of this type of VHD may persist. The present review underlines the need for a careful evaluation of the associated clinical and echocardiographic risk factors to allow early recognition so as not to delay appropriate management. PMID:22875739

  2. Republished: drug-induced valvular heart disease.

    PubMed

    Cosyns, Bernard; Droogmans, Steven; Rosenhek, Raphael; Lancellotti, Patrizio

    2013-03-01

    Drug-induced valvular heart disease (DIVHD) was first described in the 1960s. Initially, associations with ergot derivatives used for migraine prevention, or with anorectic drugs, were described. Drugs used for the treatment of Parkinson's disease and endocrine diseases, like hyperprolactinemia, may also induce VHD. More recently, the use of 3,4-methylendioxymetamphetamine (MDMA, 'Ecstasy') and benfluorexhave been found to be associated with DIVHD. Although some of these drugs were withdrawn from the market, several cases of patients requiring valve surgery even years after the cessation of therapy have been reported. DIVHD is not infrequent, may be severe, and has been described in association with several drugs. Even after drug cessation, long-term implications of this type of VHD may persist. The present review underlines the need for a careful evaluation of the associated clinical and echocardiographic risk factors to allow early recognition so as not to delay appropriate management. PMID:23417686

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

    PubMed Central

    2013-01-01

    Background Dyskinesia, a major complication in the treatment of Parkinson's disease (PD), can require prolonged monitoring and complex medical management. Discussion The current paper proposes a new way to view the management of dyskinesia in an integrated fashion. We suggest that dyskinesia be considered as a factor in a signal-to-noise ratio (SNR) equation where the signal is the voluntary movement and the noise is PD symptomatology, including dyskinesia. The goal of clinicians should be to ensure a high SNR in order to maintain or enhance the motor repertoire of patients. To understand why such an approach would be beneficial, we first review mechanisms of dyskinesia, as well as their impact on the quality of life of patients and on the health-care system. Theoretical and practical bases for the SNR approach are then discussed. Summary Clinicians should not only consider the level of motor symptomatology when assessing the efficacy of their treatment strategy, but also breadth of the motor repertoire available to patients. PMID:23514355

  4. Exosomes as drug delivery vehicles for Parkinson's disease therapy.

    PubMed

    Haney, Matthew J; Klyachko, Natalia L; Zhao, Yuling; Gupta, Richa; Plotnikova, Evgeniya G; He, Zhijian; Patel, Tejash; Piroyan, Aleksandr; Sokolsky, Marina; Kabanov, Alexander V; Batrakova, Elena V

    2015-06-10

    Exosomes are naturally occurring nanosized vesicles that have attracted considerable attention as drug delivery vehicles in the past few years. Exosomes are comprised of natural lipid bilayers with the abundance of adhesive proteins that readily interact with cellular membranes. We posit that exosomes secreted by monocytes and macrophages can provide an unprecedented opportunity to avoid entrapment in mononuclear phagocytes (as a part of the host immune system), and at the same time enhance delivery of incorporated drugs to target cells ultimately increasing drug therapeutic efficacy. In light of this, we developed a new exosomal-based delivery system for a potent antioxidant, catalase, to treat Parkinson's disease (PD). Catalase was loaded into exosomes ex vivo using different methods: the incubation at room temperature, permeabilization with saponin, freeze-thaw cycles, sonication, or extrusion. The size of the obtained catalase-loaded exosomes (exoCAT) was in the range of 100-200nm. A reformation of exosomes upon sonication and extrusion, or permeabilization with saponin resulted in high loading efficiency, sustained release, and catalase preservation against proteases degradation. Exosomes were readily taken up by neuronal cells in vitro. A considerable amount of exosomes was detected in PD mouse brain following intranasal administration. ExoCAT provided significant neuroprotective effects in in vitro and in vivo models of PD. Overall, exosome-based catalase formulations have a potential to be a versatile strategy to treat inflammatory and neurodegenerative disorders. PMID:25836593

  5. [Parkinson disease induced by flunarizine: report of a case].

    PubMed

    Galhardo, I; Coutinho, M O; De Albuquerque, E S; Medeiros, L de O

    1993-12-01

    The authors report the case of a female patient with parkinsonism induced by flunarizine, and refer the tremor to be of parkinsonian and also of wilsonian type. Cure was observed within three months, after withdrawal of flunarizine, and the use of L-dopa and biperiden. PMID:8147761

  6. Drug-induced tremor

    MedlinePLUS

    ... be a sign of another condition, such as Parkinson disease. The speed of the tremor can be an ... tremors may include: Alcohol withdrawal Cigarette smoking Hyperthyroidism Parkinson disease Pheochromocytoma Too much caffeine Wilson disease Blood tests ...

  7. őĪ6ő≤2* and őĪ4ő≤2* Nicotinic Acetylcholine Receptors As Drug Targets for Parkinson's Disease

    PubMed Central

    Wonnacott, Susan

    2011-01-01

    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 ‚Äúgold standard‚ÄĚ 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 őĪ6ő≤2* and őĪ4ő≤2* nAChR may prove useful in the management of Parkinson's disease. PMID:21969327

  8. Antipsychotic Drugs Tied to Risk of Early Death in Parkinson's Patients

    MedlinePLUS

    ... html Antipsychotic Drugs Tied to Risk of Early Death in Parkinson's Patients But it's unclear whether the ... seems to be an increased risk of early death. "This [study] does not necessarily answer whether the ...

  9. Blood Biomarkers Associated with Cognitive Decline in Early Stage and Drug-Naive Parkinsonís Disease Patients

    PubMed Central

    Santiago, Jose A.; Potashkin, Judith A.

    2015-01-01

    Early diagnosis of Parkinsonís disease (PD) continues to be a major challenge in the field. The lack of a robust biomarker to detect early stage PD patients has considerably slowed the progress toward the development of potential therapeutic agents. We have previously evaluated several RNA biomarkers in whole blood from participants enrolled in two independent clinical studies. In these studies, PD patients were medicated, thus, expression of these biomarkers in de novo patients remains unknown. To this end, we tested ten RNA biomarkers in blood samples from 99 untreated PD patients and 101 HC nested in the cross-sectional Parkinsonís Progression Markers Initiative by quantitative real-time PCR. One biomarker out of ten, COPZ1 trended toward significance (nominal p = 0.009) when adjusting for age, sex, and educational level. Further, COPZ1, EFTUD2 and PTBP1 mRNAs correlated with clinical features in PD patients including the Hoehn and Yahr scale, Movement Disorder Society revision of Unified Parkinsonís Disease Rating Scale (MDS-UPDRS) and Montreal Cognitive Assessment (MoCA) score. Levels of EFTUD2 and PTBP1 were significantly higher in cognitively normal PD patients (PD-CN) compared to cognitively impaired PD patients (PD-MCI). Interestingly, blood glucose levels were significantly higher in PD and PD-MCI patients (? 100 mg/dL, pre-diabetes) compared to HC. Collectively, we report the association of three RNA biomarkers, COPZ1, EFTUD2 and PTBP1 with clinical features including cognitive decline in early drug-naÔve PD patients. Further, our results show that drug-naÔve PD and PD-MCI patients have glucose levels characteristic of pre-diabetes patients, suggesting that impaired glucose metabolism is an early event in PD. Evaluation of these potential biomarkers in a larger longitudinal study is warranted. PMID:26566043

  10. Drug-induced hyperkalemia.

    PubMed

    Ben Salem, Chaker; Badreddine, Atef; Fathallah, Neila; Slim, Raoudha; Hmouda, Houssem

    2014-09-01

    Hyperkalemia is a common clinical condition that can be defined as a serum potassium concentration exceeding 5.0 mmol/L. Drug-induced hyperkalemia is the most important cause of increased potassium levels in everyday clinical practice. Drug-induced hyperkalemia may be asymptomatic. However, it may be dramatic and life threatening, posing diagnostic and management problems. A wide range of drugs can cause hyperkalemia by a variety of mechanisms. Drugs can interfere with potassium homoeostasis either by promoting transcellular potassium shift or by impairing renal potassium excretion. Drugs may also increase potassium supply. The reduction in renal potassium excretion due to inhibition of the renin-angiotensin-aldosterone system represents the most important mechanism by which drugs are known to cause hyperkalemia. Medications that alter transmembrane potassium movement include amino acids, beta-blockers, calcium channel blockers, suxamethonium, and mannitol. Drugs that impair renal potassium excretion are mainly represented by angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, direct renin inhibitors, nonsteroidal anti-inflammatory drugs, calcineurin inhibitors, heparin and derivatives, aldosterone antagonists, potassium-sparing diuretics, trimethoprim, and pentamidine. Potassium-containing agents represent another group of medications causing hyperkalemia. Increased awareness of drugs that can induce hyperkalemia, and monitoring and prevention are key elements for reducing the number of hospital admissions, morbidity, and mortality related to drug-induced hyperkalemia. PMID:25047526

  11. Drug-induced neuropathies.

    PubMed

    Manji, Hadi

    2013-01-01

    Although drug-induced neuropathies account for only 2-4% of referrals, their identification is important. Numerically, chemotherapy and antiretroviral drugs are the most important worldwide. Research is currently focused on elucidating pathogenic mechanisms and the earliest presymptomatic changes using neurophysiological and pharmacogenetic techniques in order to avoid the drug or make dosage changes before irreversible damage occurs. Chemoprotectants against chemotherapy-induced neuropathy are also an active area of research. This chapter focuses on the pathophysiology of drug-induced neuropathies in general, followed by detailed reviews of neuropathy due to; newer compounds such as TNF (tumor necrosis factor) ? antagonists and antibiotics such as linezolid; chemotherapeutic agents, old and new, where significant progress has been made; antiretroviral drugs; and amiodarone, which is unusual in that it causes a demyelinating neuropathy. The controversial issue of statin-induced neuropathy is also reviewed. PMID:23931812

  12. Does restraining nitric oxide biosynthesis rescue from toxins-induced parkinsonism and sporadic Parkinson's disease?

    PubMed

    Gupta, Satya Prakash; Yadav, Sharawan; Singhal, Naveen Kumar; Tiwari, Manindra Nath; Mishra, Sarad Kumar; Singh, Mahendra Pratap

    2014-02-01

    Nitric oxide (NO) is an important inorganic molecule of the biological system owing to diverse physiological implications. NO is synthesised from a semi-essential amino acid L-arginine. NO biosynthesis is catalysed by a family of enzymes referred to as nitric oxide synthases (NOSs). NO is accused in many acute and chronic illnesses, which include central nervous system disorders, inflammatory diseases, reproductive impairments, cancer and cardiovascular anomalies. Owing to very unstable nature, NO gets converted into nitrite, peroxynitrite and other reactive nitrogen species that could lead to nitrosative stress in the nigrostriatal system. Nitrosative stress is widely implicated in Parkinson's disease (PD), and its beneficial and harmful effects are demonstrated in in vitro, rodent and primate models of toxins-induced parkinsonism and in the blood, cerebrospinal fluid and nigrostriatal tissues of sporadic PD patients. The current article updates the roles of NO and NOSs in sporadic PD and toxins-induced parkinsonism in rodents along with the scrutiny of how inhibitors of NOSs could open a new line of approach to moderately rescue from PD pathogenesis based on the existing literature. The article also provides a perspective concerning the lack of ample admiration to such an approach and how to minimise the underlying lacunae. PMID:23900742

  13. Changes in the expression of genes encoding for mGlu4 and mGlu5 receptors and other regulators of the indirect pathway in acute mouse models of drug-induced parkinsonism.

    PubMed

    Cannella, Milena; Motolese, Marta; Bucci, Domenico; Molinaro, Gemma; Gradini, Roberto; Bruno, Valeria; Nicoletti, Ferdinando; Battaglia, Giuseppe

    2015-08-01

    Neuroadaptive changes involving the indirect pathway of the basal ganglia motor circuit occur in the early phases of parkinsonism. The precise identification of these changes may shed new light into the pathophysiology of parkinsonism and better define the time window of pharmacological intervention. We examined some of these changes in mice challenged with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), or with the dopamine receptor blocker, haloperidol. These two models clearly diverge from Parkinson's disease (PD); however, they allow an accurate time-dependent analysis of neuroadaptive changes occurring in the striatum. Acute haloperidol injection caused a significant increase in the transcripts of mGlu4 receptors, CB1 receptors and preproenkephalin-A at 2 and 24 h, and a reduction in the transcripts of mGlu5 and A2A receptors at 2 h. At least changes in the expression of mGlu4 receptors might be interpreted as compensatory because haloperidol-induced catalepsy was enhanced in mGlu4(-/-) mice. Mice injected with 30 mg/kg of MPTP also showed an increase in the transcripts of mGlu4 receptors, CB1 receptors, and preproenkephalin-A at 3 d, and a reduction of the transcript of A2A receptors at 1 d in the striatum. Genetic deletion of mGlu4 receptors altered the functional response to MPTP, assessed by counting c-Fos(+) neurons in the external globus pallidus and ventromedial thalamic nucleus. These findings offer the first evidence that changes in the expression of mGlu4 and mGlu5 receptors occur in acute models of parkinsonisms, and lay the groundwork for the study of these changes in models that better recapitulate the temporal profile of nigrostriatal dysfunction associated with PD. PMID:25747602

  14. 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 ...

  15. Drug-induced diarrhoea.

    PubMed

    Chassany, O; Michaux, A; Bergmann, J F

    2000-01-01

    Diarrhoea is a relatively frequent adverse event, accounting for about 7% of all drug adverse effects. More than 700 drugs have been implicated in causing diarrhoea; those most frequently involved are antimicrobials, laxatives, magnesium-containing antacids, lactose- or sorbitol-containing products, nonsteroidal anti-inflammatory drugs, prostaglandins, colchicine, antineoplastics, antiarrhythmic drugs and cholinergic agents. Certain new drugs are likely to induce diarrhoea because of their pharmacodynamic properties; examples include anthraquinone-related agents, alpha-glucosidase inhibitors, lipase inhibitors and cholinesterase inhibitors. Antimicrobials are responsible for 25% of drug-induced diarrhoea. The disease spectrum of antimicrobial-associated diarrhoea ranges from benign diarrhoea to pseudomembranous colitis. Several pathophysiological mechanisms are involved in drug-induced diarrhoea: osmotic diarrhoea, secretory diarrhoea, shortened transit time, exudative diarrhoea and protein-losing enteropathy, and malabsorption or maldigestion of fat and carbohydrates. Often 2 or more mechanisms are present simultaneously. In clinical practice, 2 major types of diarrhoea are seen: acute diarrhoea, which usually appears during the first few days of treatment, and chronic diarrhoea, lasting more than 3 or 4 weeks and which can appear a long time after the start of drug therapy. Both can be severe and poorly tolerated. In a patient presenting with diarrhoea, the medical history is very important, especially the drug history, as it can suggest a diagnosis of drug-induced diarrhoea and thereby avoid multiple diagnostic tests. The clinical examination should cover severity criteria such as fever, rectal emission of blood and mucus, dehydration and bodyweight loss. Establishing a relationship between drug consumption and diarrhoea or colitis can be difficult when the time elapsed between the start of the drug and the onset of symptoms is long, sometimes up to several months or years. PMID:10647976

  16. Drug-induced myopathies.

    PubMed

    Le Quintrec, J S; Le Quintrec, J L

    1991-04-01

    Myopathies are not an unusual complication of drug therapy. The major symptoms in drug-induced myopathies are proximal muscle weakness, increased muscle enzyme levels, electromyographic changes and histological lesions. Some drug-induced myopathies are associated with neuropathy. Drug-induced myopathies can be classified according to the presence or absence of muscular pain and associated neuropathy. Among painless myopathies, we can distinguish myopathies without neuropathy (corticosteroids), myopathies with neuropathy (colchicine, chloroquine and hydroxychloroquine) and myasthenic syndromes (D-penicillamine, antibiotics, beta-blockers). Among painful myopathies, the classification is similar: painful myopathies may or may not be associated with neuropathies. Painful myopathies include polymyositis (D-penicillamine, cimetidine, zidovudine) and other myopathies without polymyositis (clofibrate, statines, cyclosporin). Among the painful neuromyopathies, eosinophilia-myalgia syndrome is a recently described disorder associated with the use of L-tryptophan. Combinations of drugs (for example, a fibrate and a statine or cyclosporin and colchicine) can induce severe myopathies. If such drugs are used together a vigorous surveillance to detect any sign of myopathy is warranted. Instead of classifying drug-induced myopathies according to clinical features, a histological classification can be proposed. Many drugs can induce vacuolar myopathy (colchicine, chloroquine, amiodarone, cyclosporin, drugs causing hypokalaemia and lipid-lowering agents), some others cause a mitochondrial myopathy (zidovudine) or a necrotizing myopathy as seen with vincristine. Overall, several criteria for reporting drug-induced myopathy can be recommended: lack of pre-existent muscular symptoms, a free period between the beginning of the treatment and the appearance of symptoms, lack of another cause accounting for the myopathy, and complete or incomplete resolution after withdrawal of the treatment. Rechallenge of the treatment is not advisable because of the risk of a serious relapse. The exact mechanisms by which drugs cause myopathies are unknown. Some cases may be due to metabolic changes, whereas others may be immune mediated. Nevertheless, the aspect these conditions have in common is the regression of the myopathy with the discontinuation of the drug. PMID:2070426

  17. [Drug--induced splenomegaly].

    PubMed

    Petroianu, Andy

    2011-12-01

    The diagnosis of splenomegaly due to drugs is based on a recent history of exposure to a drug before the spleen enlargement. The purpose of this paper is to review studies of the literature on drugs that may induce to splenomegaly. Drugs may provoke the enlargement of spleen by direct effect in splenic cells or as a side effect of disturbances in other organs, mainly liver and haematoimmunologic system. Some drugs provoke severe haemolysis associated with splenomegaly. Another cause of spleen increasing in size is the venous congestion due to liver disturbance with portal vein occlusion. All these drug side effects are usually transitory and splenomegaly disappears when the medication is discontinued. This is a complex problem that must be better studied to be understood in order to prevent its occurrence and to find the best treatment. PMID:22863507

  18. [Drug-induced dyschromatopsias].

    PubMed

    Perdriel, G; Manent, P J

    1982-01-01

    Drug-induced dyschromatopsias are defined as functional or objective alterations of color sense following drug treatment. Drug induced chromatopsias are characterized by a perception of white surfaces as colored and occur following modifications of normally transparent structures or alterations of the chorioretina or higher centers. Digitalic intoxication is responsible for incorrect perception of yellow or blue; the retinal origin of the disorder is confirmed by electroretinograms and histologic modifications in the photoreceptor synapses. Santonin in doses exceeding 1 cg is associated with various color misperceptions due to injury to a peripheral neuron or problems of rhodopsin formation. Some sulfas and antibiotics may cause misperception of yellow, and the anticonvulsant drug Tridione may cause an almost complete disappearance of some colors. Chromotopsias of central origin due to direct action on cerebral neurons are rare but may follow use of phenacetine or atropine. Drug induced dyschromatopsias are more common and may be the initial symptoms of various kinds of drug intoxication. Various simple and reliable tests enable the practicing clinician to detect such disorders at an early stage. Synthetic antimalarial drugs derived from chloroquine and used in longterm treatment of rheumatism or during antimalarial prophylaxis, indomethacine, and the phenotiazins may cause dyschromatopsias due to retinal intoxication. Oral contraceptives diminish the chromatic perception in 20% of cases according to 1 author, and often cause deficits of blue-yellow perception. Disulfiram, certain antibiotics such as chloramphenicol, nystatin, isoniazide, and other drugs may cause dyschromatopsias due to alterations in the optical fibers. Ethambutol is the most harmful to color perception; its effects are usually but not always reversible on discontinuation of the drug. Systematic tests of color perception should be administered prior to and during treatment with any drug known to affect the color sense. PMID:6764596

  19. Prescribing Pattern of Anti-Parkinson Drugs in Japan: A Trend Analysis from 2005 to 2010

    PubMed Central

    Nakaoka, Sachiko; Ishizaki, Tatsuro; Urushihara, Hisashi; Satoh, Toshihiko; Ikeda, Shunya; Yamamoto, Mitsutoshi; Nakayama, Takeo

    2014-01-01

    Objective Therapeutic options for Parkinson's disease mainly consist of L-dopa and dopamine agonists. However, in Japan, the product labeling of the ergot dopamine agonists, cabergoline and pergolide, was revised in April 2007 due to the risk of developing cardiac valvulopathy. Here, we describe the prescribing trends of anti-Parkinson drugs from 2005 through 2010 in Japan, and examined whether these trends changed after the drug safety measures in 2007. Methods and Patients We used medical claim data from January 2005 to December 2010 for Parkinson's disease patients older than 30 years who were prescribed anti-Parkinson drugs. We calculated the proportion of patients prescribed each drug for each year, and compared the proportions of first-line drugs prescribed before and after April 2007. We also examined the prescription variations of cabergoline/pergolide users one year before or after April 2007. Results L-dopa was the most frequently prescribed drug for Parkinson's disease (2005, 58%; 2010, 51%). The proportion of patients prescribed ergot dopamine agonists markedly decreased and non-ergot dopamine agonists increased after 2007. Among first-line drugs, the proportion of non-ergot agents increased after April 2007. Among 54 cabergoline/pergolide users, 24 (44%) discontinued these drugs, nine of whom switched to non-ergot agents. Conclusion L-dopa was the mainstay of Parkinson's disease treatment between 2005 and 2010 in Japan. There was a decrease in ergot agents and an increase in non-ergot agents prescribed after the regulatory actions in 2007. PMID:24906013

  20. Drug-induced uveitis

    PubMed Central

    2013-01-01

    A number of medications have been associated with uveitis. This review highlights both well-established and recently reported systemic, topical, intraocular, and vaccine-associated causes of drug-induced uveitis, and assigns a quantitative score to each medication based upon criteria originally described by Naranjo and associates. PMID:23522744

  1. Drug-induced thrombocytopenic purpura

    PubMed Central

    Sathiasekar, Anisha Cynthia; Deepthi, D. Angeline; Sathia Sekar, G. Suresh

    2015-01-01

    Drug-induced thrombocytopenic purpura is a skin condition result from a low platelet count due to drug-induced anti-platelet antibodies caused by drugs. Drug-induced thrombocytopenic purpura should be suspected when a patient, child or adult, has sudden, severe thrombocytopenia. Drug-induced thrombocytopenic purpura is even more strongly suspected when a patient has repeated episodes of sudden, severe thrombocytopenia PMID:26538982

  2. Tea and Parkinson's disease: Constituents of tea synergize with antiparkinsonian drugs to provide better therapeutic benefits.

    PubMed

    Dutta, Debashis; Mohanakumar, Kochupurackal P

    2015-10-01

    The major neurodegenerative movement disorder Parkinson's disease (PD) is characterized by rest-tremor, akinesia, rigidity and inability to initiate movements. PD syndromes result from excessive loss of dopamine from the forebrain striatal region, due to dopaminergic neuronal death in the midbrain substantia nigra pars compacta. PD with multifactorial etiology is believed to ideally require a drug or different drugs that act(s) at multiple sites of action for symptomatic relief. Replenishing striatal dopamine by providing L-3,4-dihydroxyphenylalanine (l-DOPA) along with a peripheral aromatic amino acid decarboxylase inhibitor is the mainstay treatment for PD. Such prolonged therapy leads to debilitating effects, often worsening the affection. Interestingly some under-appreciated pharmaceutical compounds, including constituents of plants and nutraceuticals can synergize with l-DOPA to support mitochondrial function, suppress inflammation, ease oxidative stress, and in turn slow the progression of the disease. Tea and other dietary polyphenols are shown to provide relief to the disease syndromes and provide neuroprotection in cellular and animal models of PD. At par with these findings, random epidemiological studies in certain populations of the world support habitual tea drinking to reduce the risk of PD. The present review addresses how these tea constituents work at the cellular level to render effective control of the disease syndromes and suggests that tea synergizes with established drugs, such as l-DOPA to maximize their effects at certain levels in the disease phenotype-inducing canonical pathways of PD. PMID:26271432

  3. Sodium salicylate protects against rotenone-induced parkinsonism in rats.

    PubMed

    Madathil, Sindhu K; Karuppagounder, Saravanan S; Mohanakumar, Kochupurackal P

    2013-08-01

    Complex I deficiency culminating in oxidative stress is proposed as one of the upstream mechanisms of nigral neuronal death in Parkinson's disease. We investigated whether sodium salicylate, an active metabolite of aspirin, could afford protection against rotenone-induced oxidative stress, neuronal degeneration, and behavioral dysfunction in rats, because it has the potential to accept a molecule each of hydroxyl radical (ēOH) at the third or fifth position of its benzyl ring. Rotenone caused dose-dependent increase in ēOH in isolated mitochondria from the cerebral cortex and time- (24-48 h) and dose-dependent (0.1-100 ĶM) increase in the substantia nigra and the striatum, ipsilateral to the side of rotenone infusion. Administration of sodium salicylate at 12-h intervals for 4 days showed dose-dependent (50-100 mg/kg, i.p) reductions in the levels of ēOH in the nigra on the fifth day. These animals showed significant attenuation in rotenone-induced loss in striatal dopamine levels, number of nigral dopaminergic neurons, reduced and oxidized glutathione levels, and complex I activity loss, but superoxide dismutase activity was increased further. Amphetamine- or apomorphine-induced ipsilateral rotations in rotenone-treated rats were significantly reduced in rats treated with sodium salicylate. Our results indicate a direct role of ēOH in mediating nigral neuronal death by rotenone and confirm the neuroprotective potential of salicylate in a rodent model of parkinsonism. PMID:23447126

  4. Drug development in Parkinson's disease: from emerging molecules to innovative drug delivery systems.

    PubMed

    Garbayo, E; Ansorena, E; Blanco-Prieto, M J

    2013-11-01

    Current treatments for Parkinson's disease (PD) are aimed at addressing motor symptoms but there is no therapy focused on modifying the course of the disease. Successful treatment strategies have been so far limited and brain drug delivery remains a major challenge that restricts its treatment. This review provides an overview of the most promising emerging agents in the field of PD drug discovery, discussing improvements that have been made in brain drug delivery for PD. It will be shown that new approaches able to extend the length of the treatment, to release the drug in a continuous manner or to cross the blood-brain barrier and target a specific region are still needed. Overall, the results reviewed here show that there is an urgent need to develop both symptomatic and disease-modifying treatments, giving priority to neuroprotective treatments. Promising perspectives are being provided in this field by rasagiline and by neurotrophic factors like glial cell line-derived neurotrophic factor. The identification of disease-relevant genes has also encouraged the search for disease-modifying therapies that function by identifying molecularly targeted drugs. The advent of new molecular and cellular targets like őĪ-synuclein, leucine-rich repeat serine/threonine protein kinase 2 or parkin, among others, will require innovative delivery therapies. In this regard, drug delivery systems (DDS) have shown great potential for improving the efficacy of conventional and new PD therapy and reducing its side effects. The new DDS discussed here, which include microparticles, nanoparticles and hydrogels among others, will probably open up possibilities that extend beyond symptomatic relief. However, further work needs to be done before DDS become a therapeutic option for PD patients. PMID:23827471

  5. Protective effects of PEP-1-Catalase on stress-induced cellular toxicity and MPTP-induced Parkinsonís disease

    PubMed Central

    Eom, Seon Ae; Kim, Dae Won; Shin, Min Jea; Ahn, Eun Hee; Chung, Seok Young; Sohn, Eun Jeong; Jo, Hyo Sang; Jeon, Su-Jeong; Kim, Duk-Soo; Kwon, Hyeok Yil; Cho, Sung-Woo; Han, Kyu Hyung; Park, Jinseu; Eum, Won Sik; Choi, Soo Young

    2015-01-01

    Parkinsonís disease (PD) is a neurodegenerative disability caused by a decrease of dopaminergic neurons in the substantia nigra (SN). Although the etiology of PD is not clear, oxidative stress is believed to lead to PD. Catalase is antioxidant enzyme which plays an active role in cells as a reactive oxygen species (ROS) scavenger. Thus, we investigated whether PEP-1-Catalase protects against 1-methyl-4-phenylpyridinium (MPP+) induced SH-SY5Y neuronal cell death and in a 1-methyl-4-phenyl-1,2,3,6-trtrahydropyridine (MPTP) induced PD animal model. PEP-1-Catalase transduced into SH-SY5Y cells significantly protecting them against MPP+-induced death by decreasing ROS and regulating cellular survival signals including Akt, Bax, Bcl-2, and p38. Immunohistochemical analysis showed that transduced PEP-1-Catalase markedly protected against neuronal cell death in the SN in the PD animal model. Our results indicate that PEP-1-Catalase may have potential as a therapeutic agent for PD and other oxidative stress related diseases. [BMB Reports 2015; 48(7): 395-400] PMID:25322954

  6. Quantitative activation-induced manganese-enhanced MRI reveals severity of Parkinsonís disease in mice

    PubMed Central

    Kikuta, Satomi; Nakamura, Yukiyo; Yamamura, Yukio; Tamura, Atsushi; Homma, Noriyasu; Yanagawa, Yuchio; Tamura, Hajime; Kasahara, Jiro; Osanai, Makoto

    2015-01-01

    We demonstrate that activation-induced manganese-enhanced magnetic resonance imaging with quantitative determination of the longitudinal relaxation time (qAIM-MRI) reveals the severity of Parkinsonís disease (PD) in mice. We first show that manganese ion-accumulation depends on neuronal activity. A highly active region was then observed by qAIM-MRI in the caudate-putamen in PD-model mice that was significantly correlated to the severity of PD, suggesting its involvement in the expression of PD symptoms. PMID:26255701

  7. [Drug-induced dyspepsia].

    PubMed

    Gross, Manfred; Labenz, Joachim

    2015-05-01

    Gastrointestinal symptoms are among the most common side effects of drugs. There is a broad spectrum of symptoms. Patients often report upper abdominal pain, an early sense of satiety, epigastric discomfort or pain in the upper abdomen or behind the breastbone, flatulence, diarrhoea or constipation. Some of these symptoms are attributed to the stomach or upper abdomen by the patient and/or the physician. "Stomach pain", pain in the epigastric region, occurs in most cases in combination with other symptoms such as a feeling of pressure in the upper abdomen or bloating, early satiety, nausea or vomiting--a combination called dyspepsia. Given the high frequency of these symptoms in the general population and the large number of medications many patients are taking, it can be very difficult in a given patient to differentiate between drug-induced side effects and spontaneously occurring symptoms. PMID:25970411

  8. Nobiletin treatment improves motor and cognitive deficits seen in MPTP-induced Parkinson model mice.

    PubMed

    Yabuki, Y; Ohizumi, Y; Yokosuka, A; Mimaki, Y; Fukunaga, K

    2014-02-14

    Nobiletin, a polymethoxylated flavonoid found in citrus fruit peel, reportedly improves memory impairment in rodent models. Here we report its effect on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced motor and cognitive deficits. Nobiletin administration (50mg/kg i.p.) for 2 consecutive weeks improved motor deficits seen in MPTP-induced Parkinson model mice by 2weeks, an effect that continued until 2weeks after drug withdrawal. Drug treatment promoted similar rescue of MPTP-induced cognitive impairment at equivalent time points. Nonetheless, nobiletin treatment did not block loss of dopaminergic neurons seen in the MPTP-treated mouse midbrain, nor did it rescue decreased tyrosine hydroxylase (TH) protein levels seen in the striatum or hippocampal CA1 region of these mice. Interestingly, nobiletin administration (50mg/kg i.p.) rescued reduced levels of Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation and phosphorylation at Thr-34 of dopamine- and cAMP-regulated phosphoprotein-32 (DARPP-32) in striatum and hippocampal CA1 to levels seen in sham-operated mice. Likewise, CaMKII- and cAMP kinase-dependent TH phosphorylation was significantly restored by nobiletin treatment. MPTP-induced reduction of dopamine contents in the striatum and hippocampal CA1 region was improved by nobiletin administration (50mg/kg i.p.). Acute intraperitoneal administration of nobiletin also enhanced dopamine release in striatum and hippocampal CA1, an effect partially inhibited by treatment with nifedipine (a L-type Ca(2+) channel inhibitor) or NNC 55-0396 (a T-type Ca(2+) channel inhibitor) and completely abolished by combined treatment with both. Overall, our study describes a novel nobiletin activity in brain and suggests that nobiletin rescues motor and cognitive dysfunction in MPTP-induced Parkinson model mice, in part by enhancing dopamine release. PMID:24316474

  9. Drug-induced renal disorders

    PubMed Central

    Ghane Shahrbaf, Fatemeh; Assadi, Farahnak

    2015-01-01

    Drug-induced nephrotoxicity are more common among infants and young children and in certain clinical situations such as underlying renal dysfunction and cardiovascular disease. Drugs can cause acute renal injury, intrarenal obstruction, interstitial nephritis, nephrotic syndrome, and acid-base and fluid electrolytes disorders. Certain drugs can cause alteration in intraglomerular hemodynamics, inflammatory changes in renal tubular cells, leading to acute kidney injury (AKI), tubulointerstitial disease and renal scarring. Drug-induced nephrotoxicity tends to occur more frequently in patients with intravascular volume depletion, diabetes, congestive heart failure, chronic kidney disease, and sepsis. Therefore, early detection of drugs adverse effects is important to prevent progression to end-stage renal disease. Preventive measures requires knowledge of mechanisms of drug-induced nephrotoxicity, understanding patients and drug-related risk factors coupled with therapeutic intervention by correcting risk factors, assessing baseline renal function before initiation of therapy, adjusting the drug dosage and avoiding use of nephrotoxic drug combinations PMID:26468475

  10. Drug-induced renal disorders.

    PubMed

    Ghane Shahrbaf, Fatemeh; Assadi, Farahnak

    2015-01-01

    Drug-induced nephrotoxicity are more common among infants and young children and in certain clinical situations such as underlying renal dysfunction and cardiovascular disease. Drugs can cause acute renal injury, intrarenal obstruction, interstitial nephritis, nephrotic syndrome, and acid-base and fluid electrolytes disorders. Certain drugs can cause alteration in intraglomerular hemodynamics, inflammatory changes in renal tubular cells, leading to acute kidney injury (AKI), tubulointerstitial disease and renal scarring. Drug-induced nephrotoxicity tends to occur more frequently in patients with intravascular volume depletion, diabetes, congestive heart failure, chronic kidney disease, and sepsis. Therefore, early detection of drugs adverse effects is important to prevent progression to end-stage renal disease. Preventive measures requires knowledge of mechanisms of drug-induced nephrotoxicity, understanding patients and drug-related risk factors coupled with therapeutic intervention by correcting risk factors, assessing baseline renal function before initiation of therapy, adjusting the drug dosage and avoiding use of nephrotoxic drug combinations. PMID:26468475

  11. Rotigotine is safe and efficacious in Atypical Parkinsonism Syndromes induced by both ?-synucleinopathy and tauopathy

    PubMed Central

    Moretti, Davide Vito; Binetti, Giuliano; Zanetti, Orazio; Frisoni, Giovanni Battista

    2014-01-01

    Transdermal rotigotine (RTG) is a non-ergot dopamine agonist (D3>D2>D1), and is indicated for use in early and advanced Parkinsonís disease (PD). RTG patch has many potential advantages due to the immediacy of onset of the therapeutic effect. Of note, intestinal absorption is not necessary and drug delivery is constant, thereby avoiding drug peaks and helping patient compliance. In turn, transdermal RTG seems a suitable candidate in the treatment of atypical Parkinsonian disorders (APS). Fifty-one subjects with a diagnosis of APS were treated with transdermal RTG. The diagnoses were: Parkinsonís disease with dementia, multiple system atrophy Parkinsonian type, multiple system atrophy cerebellar type, progressive supranuclear palsy, corticobasal degeneration, Lewy body dementia, and frontotemporal dementia with Parkinsonism. Patients were evaluated by the Unified Parkinsonís Disease Rating Scale (UPDRS; part III), Neuropsychiatric Inventory (NPI), and miniĖmental state examination (MMSE) and all adverse events (AEs) were recorded. Patients treated with RTG showed an overall decrease of UPDRS III scores without increasing behavioral disturbances. Main AEs were hypotension, nausea, vomiting, drowsiness, tachycardia, and dystonia. On the whole, 15 patients were affected by AEs and seven patients suspended RTG treatment due to AEs. The results show that transdermal RTG is effective with a good tolerability profile. RTG patch could be a good therapeutic tool in patients with APS. PMID:24940065

  12. [Delirium induced by drug treatment].

    PubMed

    Back, Christine; Wittmann, Markus; Haen, Ekkehard

    2011-01-01

    Delirium may be induced by a variety of reasons, among them drugs and in particular the combination of drugs. In elderly people a delirium is often misinterpreted as dementia. Anticholinergic activity is the mode of action by which drugs cause delirium. Antipsychotic drugs, antidepressants, antihistamines, and of course anticholinergic drugs themselves are the major anticholinergic classes of drugs. In addition some opioids have anticholinergic effects. Other drugs may induce delirium by dehydration (loop diuretics like furosemide) or sedation (benzodiazapines like lorazepam). Elderly people are at especially high risk to develop delirium, because of the multitude of drugs often prescribed to them, because they tend to drink to little, and because their brain is more sensitive to psychoactive drugs. PMID:21184391

  13. Drug-Induced Metabolic Acidosis

    PubMed Central

    Pham, Amy Quynh Trang; Xu, Li Hao Richie; Moe, Orson W.

    2015-01-01

    Metabolic acidosis could emerge from diseases disrupting acid-base equilibrium or from drugs that induce similar derangements. Occurrences are usually accompanied by comorbid conditions of drug-induced metabolic acidosis, and clinical outcomes may range from mild to fatal. It is imperative that clinicians not only are fully aware of the list of drugs that may lead to metabolic acidosis but also understand the underlying pathogenic mechanisms. In this review, we categorized drug-induced metabolic acidosis in terms of pathophysiological mechanisms, as well as individual drugs’ characteristics. PMID:26918138

  14. Severe drug-induced dermatoses.

    PubMed

    Ahronowitz, Iris; Fox, Lindy

    2014-03-01

    A variety of common dermatoses are known to have drug-induced variants. This article discusses the clinical presentation, time frames, reported culprit medications, pathophysiology and management of drug-induced lupus, cutaneous vasculitis, pemphigus, pemphigoid, linear IgA bullous dermatosis, Sweet's syndrome, erythema nodosum, pyoderma gangrenosum, pseudolymphoma, lichen planus, and psoriasis. PMID:25037258

  15. The Endotoxin-Induced Neuroinflammation Model of Parkinson's Disease

    PubMed Central

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

    2011-01-01

    Parkinson's disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra. Although the exact cause of the dopaminergic neurodegeneration remains elusive, recent postmortem and experimental studies have revealed an essential role for neuroinflammation that is initiated and driven by activated microglial and infiltrated peripheral immune cells and their neurotoxic products (such as proinflammatory cytokines, reactive oxygen species, and nitric oxide) in the pathogenesis of PD. A bacterial endotoxin-based experimental model of PD has been established, representing a purely inflammation-driven animal model for the induction of nigrostriatal dopaminergic neurodegeneration. This model, by itself or together with genetic and toxin-based animal models, provides an important tool to delineate the precise mechanisms of neuroinflammation-mediated dopaminergic neuron loss. Here, we review the characteristics of this model and the contribution of neuroinflammatory processes, induced by the in vivo administration of bacterial endotoxin, to neurodegeneration. Furthermore, we summarize the recent experimental therapeutic strategies targeting endotoxin-induced neuroinflammation to elicit neuroprotection in the nigrostriatal dopaminergic system. The potential of the endotoxin-based PD model in the development of an early-stage specific diagnostic biomarker is also emphasized. PMID:21331154

  16. A novel compound PTIQ protects the nigral dopaminergic neurones in an animal model of Parkinson's disease induced by MPTP

    PubMed Central

    Son, Hyo Jin; Lee, Ji Ae; Shin, Nari; Choi, Ji Hyun; Seo, Jai Woong; Chi, Dae Yoon; Lee, Cheol Soon; Kim, Eun-Mee; Choe, Han; Hwang, Onyou

    2012-01-01

    BACKGROUND AND PURPOSE In Parkinson's disease, the dopaminergic neurones in the substantia nigra undergo degeneration. While the exact mechanism for the degeneration is not completely understood, neuronal apoptosis and neuroinflammation are thought to be key contributors. We have recently established that MMP-3 plays crucial roles in dopaminergic cell death and microglial activation. EXPERIMENTAL APPROACH We tested the effects of 7-hydroxy-6-methoxy-2-propionyl-1,2,3,4-tetrahydroisoquinoline (PTIQ) on expression of MMP-3 and inflammatory molecules and dopaminergic cell death in vitro and in an animal model of Parkinson's disease, and Parkinson's disease-related motor deficits. The pharmacokinetic profile of PTIQ was also evaluated. KEY RESULTS PTIQ effectively suppressed the production of MMP-3 induced in response to cellular stress in the dopaminergic CATH.a cell line and prevented the resulting cell death. In BV-2 microglial cells activated with lipopolysaccharide, PTIQ down-regulated expression of MMP-3 along with IL-1ő≤, TNF-őĪ and cyclooxygenase-2 and blocked nuclear translocation of NF-őļB. In the mouse model of Parkinson's disease, induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), PTIQ attenuated the associated motor deficits, prevented neurodegeneration and suppressed microglial activation in the substantia nigra. Pharmacokinetic analysis showed it was relatively stable against liver microsomal enzymes, did not inhibit the cytochrome p450 isozymes or the hERG ion channel, exhibited no cytotoxicity on liver cells or lethality when administered at 1000 mg kg‚ąí1 and entered the brain rather rapidly yielding a 28% brain:plasma ratio after i.p. injection. CONCLUSIONS AND IMPLICATIONS These results suggest PTIQ has potential as a candidate drug for disease-modifying therapy for Parkinson's disease. PMID:21951056

  17. [Treatment of Parkinson disease].

    PubMed

    Cardoso, F

    1995-03-01

    Parkinson's disease (PD) accounts for 58% of patients with Parkinsonism. The second most common cause is drug-induced Parkinsonism, diagnosed in 20% of patients. Levodopa remains as the mainstay of PD treatment. Although there is controversy regarding the timing for beginning levodopa, it should be used when the patient develops significant disability. Other drugs that may be used are anticholinergic agents, useful for tremor; amantadine, for rigidity and bradykinesia; dopamine agonists, for the management of levodopa complications; and selegiline which may be a neuroprotector agent. Problems in the management of PD include primary failure, secondary failure and levodopa complications. Antidopaminergic drugs, severe rest tremor and diagnosis error may lead to primary failure. Progression of PD is the most common explanation for secondary failure. The most important levodopa therapy complications are dyskinesias and fluctuations. Other common problems are dysautonomia, depression, psychosis and dementia. The author discusses the phenomenology and management of these complications. Future perspectives include brain repair surgeries. PMID:7575192

  18. PGE2 EP1 Receptor Deletion Attenuates 6-OHDA-Induced Parkinsonism in Mice: Old Switch, New Target

    PubMed Central

    Ahmad, Abdullah Shafique; Maruyama, Takayuki; Narumiya, Shuh; Dorť, Sylvain

    2015-01-01

    Recent experimental data on Parkinson's disease (PD) predicts the critical role of inflammation in the progression of neurodegeneration and the promising preventive effects of nonsteroidal anti-inflammatory drugs (NSAIDs). Previous studies suggest that NSAIDs minimize cyclooxygenase-2 (COX-2) activity and thereby attenuate free radical generation. Prostaglandin E2 (PGE2) is an important product of COX activity and plays an important role in various physiologic and pathophysiologic conditions through its EP receptors (EP1ĖEP4). Part of the toxic effect of PGE2 in the central nervous system has been reported to be through the EP1 receptor; however, the effect of the EP1 receptor in PD remains elusive. Therefore, in our pursuit to determine if deletion of the PGE2 EP1 receptor will attenuate 6-hydroxy dopamine (6-OHDA)-induced Parkinsonism, mice were given a unilateral 6-OHDA injection into the medial forebrain bundle. We found that apomorphine-induced contralateral rotations were significantly attenuated in the 6-OHDA-lesioned EP1?/? mice compared with the 6-OHDA-lesioned WT mice. Quantitative analysis showed significant protection of dopaminergic neurons in the substantia nigra pars compacta of the 6-OHDA-lesioned EP1?/? mice. To the best of our knowledge, this is the first in vivo study to implicate the PGE2 EP1 receptor in toxin-induced Parkinsonism. We propose the PGE2 EP1 receptor as a new target to better understand some of the mechanisms leading to PD. PMID:23385625

  19. Induced pluripotent stem cells and Parkinson's disease: modelling and treatment.

    PubMed

    Xu, Xiaoyun; Huang, Jinsha; Li, Jie; Liu, Ling; Han, Chao; Shen, Yan; Zhang, Guoxin; Jiang, Haiyang; Lin, Zhicheng; Xiong, Nian; Wang, Tao

    2016-02-01

    Many neurodegenerative disorders, such as Parkinson's disease (PD), are characterized by progressive neuronal loss in different regions of the central nervous system, contributing to brain dysfunction in the relevant patients. Stem cell therapy holds great promise for PD patients, including with foetal ventral mesencephalic cells, human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs). Moreover, stem cells can be used to model neurodegenerative diseases in order to screen potential medication and explore their mechanisms of disease. However, related ethical issues, immunological rejection and lack of canonical grafting protocols limit common clinical use of stem cells. iPSCs, derived from reprogrammed somatic cells, provide new hope for cell replacement therapy. In this review, recent development in stem cell treatment for PD, using hiPSCs, as well as the potential value of hiPSCs in modelling for PD, have been summarized for application of iPSCs technology to clinical translation for PD treatment. PMID:26748765

  20. Genetics, drugs and environmental factors in Parkinson's disease. A case-control study.

    PubMed

    Werneck, A L; Alvarenga, H

    1999-06-01

    A case-control study of Parkinson's disease (PD) was conducted in the city of Rio de Janeiro based on the assumption that neurotoxins with secondary parkinsonian action may be related to the development of Parkinson's disease. Ninety-two subjects with PD and 110 controls were queried through a questionnaire in order to investigate possible risk factors for the disease. The following factors were studied: herbicides/pesticides, exposure to chemicals, ingestion of drugs with secondary PD effects, rural life, water well source, family history, cranial trauma and cigarette smoking. Study of mentioned factors was achieved through univariate, stratified and multivariate analyses. Univariate and multivariate analyses demonstrated that PD was positively associated with family history (OR = 14.5; CI = 2.98-91.38), with the use of drugs with secondary PD action (OR = 11.01; CI = 3.41-39.41) and with exposure to chemical agents (OR = 5.87; CI = 1.48-27.23). PD was found to be inversely associated with cigarette smoking (OR = 0.39; IC = 0.16-0.95). Stratified analysis only confirmed family history and drug use, besides demonstrating that cigarette consumption could be a protection factor, when aforementioned factors were involved. This study might be a warning as to the cares that need to be taken regarding drug use and occupational exposure to chemical agents, as both types of substances present secondary PD action. PMID:10450337

  1. Drug-induced infertility.

    PubMed

    Buchanan, J F; Davis, L J

    1984-02-01

    Primary infertility may result from the use of various drugs. This phenomenon may be the result of an effect on the hypothalamic-pituitary-gonadal axis or a direct toxic effect on the gonads. Some of the drugs considered in this article demonstrate sex-related differences in their ability to cause infertility; there also may be age-related differences. The drugs described in this review, in regard to their association with the development of infertility, include various individual antineoplastic agents (cyclophosphamide, chlorambucil, busulphan, and methotrexate) and combinations of these chemotherapeutic drugs, glucocorticosteroids, hormonal steroids (diethylstilbestrol, medroxyprogesterone acetate, estrogen, and the constituents of oral contraceptives), antibiotics (sulfasalazine and co-trimoxazole), thyroid supplements, spironolactone, cimetidine, colchicine, marihuana, opiates, and neuroleptic agents. PMID:6141923

  2. [Drug-induced cholestasis].

    PubMed

    Pott, G

    1993-02-01

    Cholestasis is one kind of reaction of the liver to intolerable drugs. It is estimated that 2% of the patients who are treated for icterus in hospital suffer from drug intolerance. A differentiation is made between obligtory and optional liver-damaging substances. The latter are clinically important because they occur far more frequently. In principle nearly every drug may cause cholestasis, which must be taken into consideration especially with newly introduced drugs, e.g. in cholestasis caused by co-enzyme-A-reductase inhibitors in the treatment of hypercholesterinaemia. Cholestasis is most likely to occur after administration of the following group of substances: antiarrhythmics, antibiotics, tuberculostatics, salicylates, immunosuppressives, narcotics, tranquilizers, some antirheumatics, antidepressants, anticonvulsives, and sex hormones. This list does not claim to be complete or to be in any order of frequency. PMID:7483722

  3. Drug-induced diarrhea

    MedlinePLUS

    Diarrhea associated with medications ... Nearly all medicines may cause diarrhea as a side effect. The drugs listed below, however, are more likely to cause diarrhea. Laxatives are meant to cause diarrhea. ...

  4. Targeting ?-arrestin2 in the treatment of l-DOPAĖinduced dyskinesia in Parkinsonís disease

    PubMed Central

    Urs, Nikhil M.; Bido, Simone; Peterson, Sean M.; Daigle, Tanya L.; Bass, Caroline E.; Gainetdinov, Raul R.; Bezard, Erwan; Caron, Marc G.

    2015-01-01

    Parkinsonís disease (PD) is characterized by severe locomotor deficits and is commonly treated with the dopamine (DA) precursor l-3,4-dihydroxyphenylalanine (l-DOPA), but its prolonged use causes dyskinesias referred to as l-DOPAĖinduced dyskinesias (LIDs). Recent studies in animal models of PD have suggested that dyskinesias are associated with the overactivation of G protein-mediated signaling through DA receptors. ?-Arrestins desensitize G protein signaling at DA receptors (D1R and D2R) in addition to activating their own G protein-independent signaling events, which have been shown to mediate locomotion. Therefore, targeting ?-arrestins in PD l-DOPA therapy might prove to be a desirable approach. Here we show in a bilateral DA-depletion mouse model of Parkinsonís symptoms that genetic deletion of ?-arrestin2 significantly limits the beneficial locomotor effects while markedly enhancing the dyskinesia-like effects of acute or chronic l-DOPA treatment. Viral rescue or overexpression of ?-arrestin2 in knockout or control mice either reverses or protects against LIDs and its key biochemical markers. In other more conventional animal models of DA neuron loss and PD, such as 6-hydroxydopamineĖtreated mice or rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridineĖtreated nonhuman primates, ?-arrestin2 overexpression significantly reduced dyskinesias while maintaining the therapeutic effect of l-DOPA. Considerable efforts are being spent in the pharmaceutical industry to identify therapeutic approaches to block LIDs in patients with PD. Our results point to a potential therapeutic approach, whereby development of either a genetic or pharmacological intervention to enhance ?-arrestin2- or limit G protein-dependent D1/D2R signaling could represent a more mechanistically informed strategy. PMID:25918399

  5. Drug-induced lupus erythematosus

    MedlinePLUS

    Drug-induced lupus erythematosus is similar to systemic lupus erythematosus (SLE). It is an autoimmune disorder. This means your body attacks healthy tissue by mistake. It is caused by an overreaction ...

  6. Investigation into the dosage form attributes of currently UK licensed cardiovascular and Parkinson's disease drug products.

    PubMed

    Hanning, S M; Muhamed, J; Orlu-Gul, M

    2015-02-01

    Globally, there is a continuous rise in the older population (over 65 years), particularly in developed countries. As many diseases are age-related, older adults represent a highly heterogeneous cohort. This presents a major challenge for both the pharmaceutical industry and healthcare professionals. The purpose of this research was to attract attention towards the appropriateness of geriatric formulations by investigating the dosage form attributes of currently UK licensed cardiovascular and Parkinson's disease drug products. Medication available in the UK for cardiovascular disorders and Parkinson's disease were screened and the available formulations, packaging and patient information leaflets of these medicines were analysed, with the goal of raising awareness of the need to cater for elderly patients with increasing difficulty in managing their medication. It emerged that although cardiovascular disorders and Parkinson's disease are more prevalent in older people, many treatment options have not been optimised for this cohort. In particular, older patient centred dosage forms, specific dosing requirements, excipients, patient-friendly packaging and easy-to-follow patient information were highlighted as areas to be considered in order to optimise health outcomes in the ageing population. PMID:25556052

  7. Drug-induced gynecomastia.

    PubMed

    Thompson, D F; Carter, J R

    1993-01-01

    Gynecomastia is a relatively common physical finding in men. A wide variety of drugs have been implicated in its cause. Sufficient evidence in the literature suggests that calcium-channel blockers, cancer chemotherapeutic agents, and histamine2-receptor blockers may play a role in the disorder. Evidence for digitalis glycosides and neuroleptic agents is insufficient. Ketoconazole and spironolactone can also produce gynecomastia, and data for marijuana are contradictory. Large numbers of drugs have only case reports of temporal association with the disorder. PMID:8094898

  8. [Drug-induced cognitive impairment].

    PubMed

    Shinohara, Moeko; Yamada, Masahito

    2012-12-01

    Compared to young people, elderly people are more likely to develop cognitive impairments associated with medications. Dementia and delirium (acute confusional state) are known to be associated with drug toxicity. Anticholinergic medications are important causes of acute and chronic cognitive impairment. Psychoactive drugs, antidepressants, and anticonvulsants can cause delirium and dementia. In addition, non-psychoactive drugs such as histamine H2 receptor antagonists, cardiac medications, and antibiotics may cause acute and chronic cognitive impairments. Early diagnosis and withdrawal of the offending agent is essential for treating drug-induced dementia and delirium. PMID:23209067

  9. [Drug-induced heart failure].

    PubMed

    Negrusz-Kawecka, M

    2001-09-01

    Heart failure is a clinical syndrome caused mainly by cardiovascular diseases such as coronary heart disease, hypertension and valvular disease, but several categories of drugs may potentially induce heart failure in patients without previous heart disease or precipitate revealing of heart failure symptoms in patients with preexisting left ventricle impairment. Pathophysiologically drugs that increase preload, afterload or have negative inotropic properties may be able to cause this adverse reaction. In the article the potential role in the occurrence of heart failure of cytostatics, immunomodulating drugs, nonsteroidal anti-inflammatory drugs, calcium channel blockers, beta-adrenoceptor antagonists, antiarrhythmics, anesthetics and antidepressants is reviewed. PMID:11761828

  10. Drug-induced nail disorders.

    PubMed

    2014-07-01

    Nail disorders are defined according to their appearance and the part of the nail affected: the nail plate, the tissues that support or hold the nail plate in place, or the lunula. The consequences of most nail disorders are purely cosmetic. Other disorders, such as ingrown nails, inflammation, erythema, abscesses or tumours, cause functional impairment or pain. The appearance of the lesions is rarely indicative of their cause. Possible causes include physiological changes, local disorders or trauma, systemic conditions, toxic substances and drugs. Most drug-induced nail disorders resolve after discontinuation of the drug, although complete resolution sometimes takes several years. Drugs appear to induce nail disorders through a variety of mechanisms. Some drugs affect the nail matrix epithelium, the nail bed or the nail folds. Some alter nail colour. Other drugs induce photosensitivity. Yet others affect the blood supply to the nail unit. Nail abnormalities are common during treatment with certain cytotoxic drugs: taxanes, anthracyclines, fluorouracil, EGFR, tyrosine kinase inhibitors, etc. Some drugs are associated with a risk of serious and painful lesions, such as abscesses. When these disorders affect quality of life, the benefits of withdrawing the drug must be weighed against the severity of the condition being treated and the drug's efficacy, taking into account the harm-benefit balance of other options. Various anti-infective drugs, including tetracyclines, quinolones, clofazimine and zidovudine, cause the nail plate to detach from the nail bed after exposure to light, or cause nail discoloration. Psoralens and retinoids can also have the same effects. PMID:25162091

  11. Drug-induced hepatitis

    MedlinePLUS

    ... induced hepatitis. Painkillers and fever reducers that contain acetaminophen are a common cause of liver inflammation. These ... problem. However, if you took high doses of acetaminophen , treatment should be started as soon as possible ...

  12. The Progress of Induced Pluripotent Stem Cells as Models of Parkinson's Disease

    PubMed Central

    Kang, Ji-feng; Tang, Bei-sha; Guo, Ji-feng

    2016-01-01

    In recent years, induced pluripotent stem cells (iPSCs) were widely used for investigating the mechanisms of Parkinson's disease (PD). Somatic cells from patients with SNCA (őĪ-synuclein), LRRK2 (leucine-rich repeat kinase 2), PINK1 (PTEN induced putative kinase 1), Parkin mutations, and at-risk individuals carrying GBA (ő≤-glucocerebrosidase) mutations have been successfully induced to iPSCs and subsequently differentiated into dopaminergic (DA) neurons. Importantly, some PD-related cell phenotypes, including őĪ-synuclein aggregation, mitophagy, damaged mitochondrial DNA, and mitochondrial dysfunction, have been described in these iPSCs models, which further investigated the pathogenesis of PD. In 2007, Takahashi et al. and Vodyanik et al. generated iPSCs from human somatic cells for the first time. Since then, patients derived iPSCs were applied for disease modeling, drug discovery and screening, autologous cell replacement therapy, and other biological applications. iPSC research has now become a hot topic in a wide range of fields. This review summarizes the recent progress of PD patients derived iPSC models in pathogenic mechanism investigation and potential clinical applications, especially their promising strategy in pharmacological study and DA neurons transplantation therapy. However, the challenges of iPSC transplantation still exist, and it has a long way to go before it can be used in clinical application. PMID:26880962

  13. Drug-induced peripheral neuropathies.

    PubMed Central

    Argov, Z; Mastaglia, F L

    1979-01-01

    Review of the various drugs in current clinical use showed that over 50 of them may cause a purely sensory or mixed sensorimotor neuropathy. These include antimicrobials, such as isoniazid, ethambutol, ethionamide, nitrofurantoin, and metronidazole; antineoplastic agents, particularly vinca alkaloids; cardiovascular drugs, such as perhexiline and hydrallazine; hypnotics and psychotropics, notable methaqualone; antirheumatics, such as gold, indomethacin, and chloroquine; anticonvulsants, particularly phenytoin; and other drugs, including disulfiram, calcium carbimide, and dapsone. Patients receiving drug treatment who complain of paraesthesie, pain, muscle cramps, or other abnormal sensations and those without symptoms who are receiving drugs that are known or suspected to be neurotoxic should undergo neurological examination and studies of motor and sensory nerve conduction. This will allow the incidence of drug-induced peripheral neuropathy to be determined more precisely. PMID:219931

  14. Drug-induced interstitial pneumonia.

    PubMed

    2008-04-01

    (1) Interstitial pneumonia usually develops gradually. The signs and symptoms are non-specific, and generally include dyspnea, cough, fatigue, and weight loss. In other cases onset is acute, sometimes beginning with a flu-like syndrome. Interstitial pneumonia can lead to acute respiratory failure, sometimes gradual deterioration of respiratory function, and pulmonary fibrosis progressing to respiratory failure. The fibrosis does not regress when the causal factor is withdrawn. (2) There are numerous causes of interstitial pneumonia, including medicinal drugs. (3) Amiodarone generally induces slow and insidious lung disease. (4) Methotrexate induces lung disease. Most cytotoxic drugs cause chronic dose-dependent lung disease and fibrosis, in some cases long after treatment cessation. (5) The many other implicated drugs include nitrofurantoin, Nonsteroidal antiandrogens, drugs that induce connective tissue diseases, laxatives based on mineral oil, and many other drugs, some of which are known to cause hypersensitivity reactions. (6) In practice, a drug-related cause should be kept in mind in cases of interstitial pneumonia, as symptoms generally improve after drug withdrawal, unless fibrosis has already started to develop. PMID:18516814

  15. Yeast as a drug discovery platform in Huntington's and Parkinson's diseases.

    PubMed

    Outeiro, Tiago Fleming; Giorgini, Flaviano

    2006-03-01

    The high degree of conservation of cellular and molecular processes between the budding yeast Saccharomyces cerevisiae and higher eukaryotes have made it a valuable system for numerous studies of the basic mechanisms behind devastating illnesses such as cancer, infectious disease, and neurodegenerative disorders. Several studies in yeast have already contributed to our basic understanding of cellular dysfunction in both Huntington's and Parkinson's disease. Functional genomics approaches currently being undertaken in yeast may lead to novel insights into the genes and pathways that modulate neuronal cell dysfunction and death in these diseases. In addition, the budding yeast constitutes a valuable system for identification of new drug targets, both via target-based and non-target-based drug screening. Importantly, yeast can be used as a cellular platform to analyze the cellular effects of candidate compounds, which is critical for the development of effective therapeutics. While the molecular mechanisms that underlie neurodegeneration will ultimately have to be tested in neuronal and animal models, there are several distinct advantages to using simple model organisms to elucidate fundamental aspects of protein aggregation, amyloid toxicity, and cellular dysfunction. Here, we review recent studies that have shown that amyloid formation by disease-causing proteins and many of the resulting cellular deficits can be faithfully recapitulated in yeast. In addition, we discuss new yeast-based techniques for screening candidate therapeutic compounds for Huntington's and Parkinson's diseases. PMID:16897706

  16. Drug Induced Interstitial Lung Disease

    PubMed Central

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

    2012-01-01

    With an increasing number of therapeutic drugs, the list of drugs that is responsible for severe pulmonary disease also grows. Many drugs have been associated with pulmonary complications of various types, including interstitial inflammation and fibrosis, bronchospasm, pulmonary edema, and pleural effusions. Drug-induced interstitial lung disease (DILD) can be caused by chemotherapeutic agents, antibiotics, antiarrhythmic drugs, and immunosuppressive agents. There are no distinct physiologic, radiographic or pathologic patterns of DILD, and the diagnosis is usually made when a patient with interstitial lung disease (ILD) is exposed to a medication known to result in lung disease. Other causes of ILD must be excluded. Treatment is avoidance of further exposure and systemic corticosteroids in patients with progressive or disabling disease. PMID:22896776

  17. Ellagic acid improves hyperalgesia and cognitive deficiency in 6-hydroxidopamine induced rat model of Parkinsonís disease

    PubMed Central

    Dolatshahi, Mojtaba; Farbood, Yaghoob; Sarkaki, Alireza; Mansouri, Seyed Mohammad Taqhi; Khodadadi, Ali

    2015-01-01

    Objective(s): Parkinsonís disease (PD) is known for motor impairments. But often, there are non-motor symptoms such as cognitive deficiency and pain misperception, owing to possible role of nigrostriatal pathway. Antioxidants have protective effect on free radical-induced neuronal damage in PD. To further address, we examined the effects of ellagic acid (EA) in a rat model of PD induced by 6-hydroxidopamine (6-OHDA). Materials and Methods: Right medial forebrain bundle (MFB) was lesioned by injecting 6-OHDA (16 Ķg/2 Ķl), in PDĖanimals. Sham operated animals received vehicle instead of 6-OHDA. PD was approved by apomorphine-induced contralateral rotation. EA (50 mg/kg/2 ml, PO, for 10 days) was administered to PD-EA group. Some PD-animals received pramipexole (PPX; 2 mg/kg/2 ml, PO) as a positive control group. Analgesia was measured by tail-flick and hot-plate tests. Passive avoidance task was measured by shuttle box apparatus to record the initial and step-through latency. Spatial cognition task was evaluated by Morris water maze test, measuring the escape latency time, path length, swimming speed and time spent in target quadrant. Results: MFB-lesioned rats showed hyperalgesic responses to the stimulus in tail-flick and hot-plate tests. Also they showed memory and learning deficit in cognitive tests. These effects reversed by EA treatment. Conclusion: 6-OHDA can induce oxidative stress and can disrupt the neural mechanisms underlying proper integration of painful stimuli and cognitive processes in MFB-lesioned rats. Consequently, nigrostriatal pathway can play possible role in nociception and cognition. EA, a natural antioxidant, has neuroprotective effect on this pathway and can ameliorate this defect and be considered in PD management. PMID:25810874

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

    PubMed

    Gaki, Georgia S; Papavassiliou, Athanasios G

    2014-06-01

    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

  19. Cue-induced striatal dopamine release in Parkinson's disease-associated impulsive-compulsive behaviours.

    PubMed

    O'Sullivan, Sean S; Wu, Kit; Politis, Marios; Lawrence, Andrew D; Evans, Andrew H; Bose, Subrata K; Djamshidian, Atbin; Lees, Andrew J; Piccini, Paola

    2011-04-01

    Impulsive-compulsive behaviours are a significant source of morbidity for patients with Parkinson's disease receiving dopaminergic therapy. The development of these behaviours may reflect sensitization of the neural response to non-drug rewards, similar to that proposed for sensitization to drug rewards in addiction. Here, by using (11)C-raclopride positron emission tomography imaging, we investigated the effects of reward-related cues and L-dopa challenge in patients with Parkinson's disease with and without impulsive-compulsive behaviours on striatal levels of synaptic dopamine. Eighteen patients (11 with and seven without impulsive-compulsive behaviours) underwent three (11)C-raclopride positron emission tomography scans. The impulsive-compulsive behaviours included hypersexuality, binge eating, punding, compulsive use of dopamine replacement therapy, compulsive buying and pathological gambling, with eight patients exhibiting more than one impulsive-compulsive behaviour. There were no significant differences in baseline dopamine D2 receptor availability between the Parkinson's disease groups. No differences were found when comparing the percentage change of raclopride binding potential between the two Parkinson's disease groups following L-dopa challenge with neutral cues. The group with Parkinson's disease with impulsive-compulsive behaviours had a greater reduction of ventral striatum (11)C-raclopride binding potential following reward-related cue exposure, relative to neutral cue exposure, following L-dopa challenge (16.3% compared with 5.8% in Parkinson's disease controls, P?=?0.016). The heightened response of striatal reward circuitry to heterogeneous reward-related visual cues among a group of patients with different impulsive-compulsive behaviours is consistent with a global sensitization to appetitive behaviours with dopaminergic therapy in vulnerable individuals. Our findings are relevant for the broader debate on the relation between impulsive-compulsive behaviours and addictions and may have important implications with regards to advertisement legislation in an effort to prevent the onset of behavioural addictions. PMID:21349901

  20. Neurological morphofunctional differentiation induced by REAC technology in PC12. A neuro protective model for Parkinsonís disease

    PubMed Central

    Maioli, Margherita; Rinaldi, Salvatore; Migheli, Rossana; Pigliaru, Gianfranco; Rocchitta, Gaia; Santaniello, Sara; Basoli, Valentina; Castagna, Alessandro; Fontani, Vania; Ventura, Carlo; Serra, Pier Andrea

    2015-01-01

    Research for the use of physical means, in order to induce cell differentiation for new therapeutic strategies, is one of the most interesting challenges in the field of regenerative medicine, and then in the treatment of neurodegenerative diseases, Parkinsonís disease (PD) included. The aim of this work is to verify the effect of the radio electric asymmetric conveyer (REAC) technology on the PC12 rat adrenal pheochromocytoma cell line, as they display metabolic features of PD. PC12 cells were cultured with a REAC regenerative tissue optimization treatment (TO-RGN) for a period ranging between 24 and 192?hours. Gene expression analysis of specific neurogenic genes, as neurogenin-1, beta3-tubulin and Nerve growth factor, together with the immunostaining analysis of the specific neuronal protein beta3-tubulin and tyrosine hydroxylase, shows that the number of cells committed toward the neurogenic phenotype was significantly higher in REAC treated cultures, as compared to control untreated cells. Moreover, MTT and Trypan blue proliferation assays highlighted that cell proliferation was significantly reduced in REAC TO-RGN treated cells. These results open new perspectives in neurodegenerative diseases treatment, particularly in PD. Further studies will be needed to better address the therapeutic potential of the REAC technology. PMID:25976344

  1. Parkinson's disease.

    PubMed Central

    Playfer, J. R.

    1997-01-01

    Parkinson's disease is a common disabling disease of old age. The diagnosis of idiopathic Parkinson's disease is based on clinical signs and has poor sensitivity, with about 25% of patients confidently diagnosed as having the disease actually having other conditions such as multi-system atrophy and other parkinsonism-plus syndromes. Benign essential tremor and arteriosclerotic pseudo-parkinsonism can easily be confused with Parkinson's disease. The cause of Parkinson's disease remains unknown. Speculative research highlights the role of oxidative stress and free radical mediated damage to dopaminergic cells. Parkinson's disease is the one neurodegenerative disorder in which drugs have been demonstrated to be of value. There is now a wide variety of drugs and formulations available, including anticholinergics, amantidine, L-dopa, dopamine agonists including apomorphine, selegiline and soon to be available catechol-O-methyltransferase inhibitors. Disabling side-effects of treatment, fluctuations, dyskinesias and psychiatric problems require strategic use of the drugs available. There is an increasing potential for neurosurgical intervention. PMID:9196696

  2. Drug-induced ocular disorders.

    PubMed

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

    2008-01-01

    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

  3. Drug-induced visceral angioedema

    PubMed Central

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

    2014-01-01

    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

  4. [Significance of tachycardia induced by atrial stimulation in Wolff-Parkinson-White syndrome].

    PubMed

    Brembilla-Perrot, B

    1992-04-01

    Increased atrial vulnerability is one of the criteria of malignant Wolff-Parkinson-White syndrome. The aim of this study was to try to define the methods of induction of atrial tachycardias (tachycardia, flutter, fibrillation) by endocavitary and oesophageal stimulation characterising an increased vulnerability. The incidence of induced sustained tachycardia by fixed atrial stimulation at incremental rates until the Wenckebach point is attained and programmed atrial stimulation using 1 and 2 extrastimuli under basal conditions and then with isoproterenol was compared in subjects without cardiac disease, Wolff-Parkinson-White or spontaneous tachycardia (Group I) and patients with Wolff-Parkinson-White and spontaneous tachycardias (Group II). Atrial stimulation only induced tachycardia in 2.5% of normal subjects under basal conditions or with isoproterenol, by the endocavitary or oesophageal approaches. Programmed stimulation induced tachycardia in 15% of normal subjects under basal conditions or with isoproterenol by the endocavitary approach alone. In Group II, tachycardia was reproduced under basal conditions or with isoproterenol by atrial stimulation or programmed stimulation in all patients. In conclusion, the induction of a tachyarrhythmia by incremental atrial stimulation up to the Wenckebach point is always pathological even with isoproterenol. Programmed atrial stimulation is less specific except by the oesophageal approach. The use of bursts of very rapid stimuli in the Wolff-Parkinson-White syndrome is of no value as tachycardia can be induced by classical methods in all subjects at risk. PMID:1642499

  5. Drug-Path: a database for drug-induced pathways.

    PubMed

    Zeng, Hui; Qiu, Chengxiang; Cui, Qinghua

    2015-01-01

    Some databases for drug-associated pathways have been built and are publicly available. However, the pathways curated in most of these databases are drug-action or drug-metabolism pathways. In recent years, high-throughput technologies such as microarray and RNA-sequencing have produced lots of drug-induced gene expression profiles. Interestingly, drug-induced gene expression profile frequently show distinct patterns, indicating that drugs normally induce the activation or repression of distinct pathways. Therefore, these pathways contribute to study the mechanisms of drugs and drug-repurposing. Here, we present Drug-Path, a database of drug-induced pathways, which was generated by KEGG pathway enrichment analysis for drug-induced upregulated genes and downregulated genes based on drug-induced gene expression datasets in Connectivity Map. Drug-Path provides user-friendly interfaces to retrieve, visualize and download the drug-induced pathway data in the database. In addition, the genes deregulated by a given drug are highlighted in the pathways. All data were organized using SQLite. The web site was implemented using Django, a Python web framework. Finally, we believe that this database will be useful for related researches. PMID:26130661

  6. Treadmill exercise alleviates short-term memory impairment in 6-hydroxydopamine-induced Parkinsonís rats

    PubMed Central

    Cho, Han-Sam; Shin, Mal-Soon; Song, Wook; Jun, Tae-Won; Lim, Baek-Vin; Kim, Young-Pyo; Kim, Chang-Ju

    2013-01-01

    Progressive loss of dopaminergic neurons in substantia nigra is a key pathogenesis of Parkinsonís disease. In the present study, we investigated the effects of treadmill exercise on short-term memory, apoptotic dopaminergic neuronal cell death and fiber loss in the nigrostriatum, and cell proliferation in the hippocampal dentate gyrus of Parkinsonís rats. Parkinsonís rats were made by injection of 6-hydroxydopamine (6-OHDA) into the striatum using stereotaxic instrument. Four weeks after 6-OHDA injection, the rats in the 6-OHDA-injection group exhibited significant rotational asymmetry following apomorphine challenge. The rats in the exercise groups were put on the treadmill to run for 30 min once a day for 14 consecutive days starting 4 weeks after 6-OHDA injection. In the present results, extensive degeneration of the dopaminergic neurons in the substantia nigra with loss of dopaminergic fibers in the striatum were produced in the rats without treadmill running, which resulted in short-term memory impairment. However, the rats performing treadmill running for 2 weeks alleviated nigrostriatal dopaminergic cell loss and alleviated short-term memory impairment with increasing cell proliferation in the hippocampal dentate gyrus of Parkinsonís rats. The present results show that treadmill exercise may provide therapeutic value for the Parkinsonís disease. PMID:24278884

  7. Nanotechnology-mediated nose to brain drug delivery for Parkinson's disease: a mini review.

    PubMed

    Kulkarni, Abhijeet D; Vanjari, Yogesh H; Sancheti, Karan H; Belgamwar, Veena S; Surana, Sanjay J; Pardeshi, Chandrakantsing V

    2015-01-01

    Nose to brain delivery of neurotherapeutics have been tried by several researchers to explore the virtues of this route viz. circumvention of BBB, avoidance of hepatic metabolism, practicality, safety, ease of administration and non-invasiveness. Nanoparticle (NP) therapeutics is an emerging modality for the treatment of Parkinson's disease (PD) as it offers targeted delivery and enhances the therapeutic efficacy and/or bioavailability of neurotherapeutics. This review presents a concise incursion into the nanomedicines suitable for PD therapy delivered via naso-brain transport. Clinical signs of PD, its pathophysiology, specific genetic determinants, diagnosis and therapy involved have been hashed out. Properties of brain-targeting NPs, transport efficacy and various nanocarriers developed so far also been furnished. In our opinion, nanotechnology-enabled naso-brain drug delivery is an excellent means of delivering neurotherapeutics and is a promising avenue for researchers to develop new formulations for the effective management of PD. PMID:25758751

  8. The Lipopolysaccharide Parkinson's disease animal model: mechanistic studies and drug discovery

    PubMed Central

    Dutta, Garima; Zhang, Ping; Liu, Bin

    2008-01-01

    Research in the last two decades has unveiled an important role for neuroinflammation in the degeneration of the nigrostriatal dopaminergic pathway that constitutes the pathological basis of the prevailing movement disorder, Parkinson's disease (PD). Neuroinflammation is characterized by the activation of brain glial cells, primarily microglia and astrocytes that release various soluble factors that include free radicals (reactive oxygen and nitrogen species), cytokines, and lipid metabolites. The majority of these glia-derived factors are proinflammatory and neurotoxic and are particularly deleterious to oxidative damage-vulnerable nigral dopaminergic neurons. As a proof of concept, various immunologic stimuli have been employed to directly induce glial activation to model dopaminergic neurodegeneration in Parkinson's disease. The bacterial endotoxin, lipopolysaccharide (LPS), has been the most extensively utilized glial activator for the induction of inflammatory dopaminergic neurodegeneration. In this review, we will summarize the various in vitro and in vivo LPS PD models. Furthermore, we will highlight the contribution of the LPS PD models to the mechanistic studies of PD pathogenesis and the search for neuroprotective agents for the treatment of PD. PMID:18710400

  9. [Levodopa-induced dyskinesia in 176 patients with Parkinson's disease].

    PubMed

    Rocha, M S; Andrade, L A; Ferraz, H B; Borges, V

    1995-12-01

    Dyskinesias are frequently observed in parkinsonian patients during levodopa treatment. The occurrence of these movement disorders usually makes the therapeutic management of the patients very difficult. The clinical characteristics of 176 patients with dyskinesias were retrospectively studied. Dyskinesias occurred, on average, after 6.2 years of duration of Parkinson's disease and after 4.2 years on treatment with levodopa. Patients were more likely to have dyskinesias during more advanced stages (measured by Hoehn and Yahr scale). Peak of dose and square wave were the types of dyskinesia more frequently described and were associated with choreic movements in most cases. Dystonia occurred in 40% of the cases and was predominant in end of dose and diphasic dyskinesias. Thirty-five percent of dystonia cases presented as "early morning dystonia". Chorea was the most frequent involuntary movement and mostly generalized. Dystonia was most commonly described in lower limbs. Orofacial dyskinesia, when occurred alone, was more frequently seen in old rather than young patients. When dyskinesia was unilateral it was more likely to occur in the side where Parkinson's disease was more severe. PMID:8729765

  10. Identification of potential drugs for Parkinson's disease based on a sub-pathway method.

    PubMed

    Sun, Ai-Guo; Lin, Ai-Qi; Huang, Shao-Yue; Huo, Di; Cong, Chao-Hua

    2016-04-01

    Parkinson's disease (PD) is the second most prevalent neurodegenerative disease in ageing individuals. Current therapeutic regimen suffers from general side effects and a poor efficiency for PD symptoms. The need for development new therapeutic agents for PD is urgent. Here, we aimed to explore the metabolic mechanism of PD and identified potential novel agents for PD by a sub-pathway-based method. By using the GSE7621 microarray data from the GEO database, we first identified the 1226 differentially expressed genes (DEGs) between PD and normal samples. Then we identified 19 significant enriched metabolic sub-pathways, which may involve in development of PD. Finally, by an integrated analysis of PD-involved sub-pathways and drug-affected sub-pathways, we identified 49 novel small molecular drugs capable to target the PD-involved sub-pathways. Our method could not only identify existing drug (apomorphine) for PD, but also predict potentially novel agents (ketoconazole and astemizole), which might have therapeutic effects via targeting some key enzymes in arachidonic acid metabolism. These candidate agents identified by our approach may provide insights into a novel therapy approach for PD. PMID:25405535

  11. Brain aging and Parkinson's disease: New therapeutic approaches using drug delivery systems.

    PubMed

    RodrŪguez-Nogales, C; Garbayo, E; Carmona-AbellŠn, M M; Luquin, M R; Blanco-Prieto, M J

    2016-02-01

    The etiology and pathogenesis of Parkinson's disease (PD) is unknown, aging being the strongest risk factor for brain degeneration. Understanding PD pathogenesis and how aging increases the risk of disease would aid the development of therapies able to slow or prevent the progression of this neurodegenerative disorder. In this review we provide an overview of the most promising therapeutic targets and strategies to delay the loss of dopaminergic neurons observed both in PD and aging. Among them, handling alpha-synuclein toxicity, enhancing proteasome and lysosome clearance, ameliorating mitochondrial disruptions and modifying the glial environment are so far the most promising candidates. These new and conventional drugs may present problems related to their labile nature and to the difficulties in reaching the brain. Thus, we highlight the latest types of drug delivery system (DDS)-based strategies for PD treatment, including DDS for local and systemic drug delivery. Finally, the ongoing challenges for the discovery of new targets and the opportunities for DDS-based therapies to improve and efficacious PD therapy will be discussed. PMID:26653838

  12. Parkinson's disease.

    PubMed Central

    Wolters, E C; Calne, D B

    1989-01-01

    In Parkinson's disease there is degeneration of neurons in the substantia nigra, with consequent depletion of the neurotransmitter dopamine. The triad of tremor, rigidity and bradykinesia is the clinical hallmark. Drugs currently used for palliative therapy fall into three categories: anticholinergic agents, dopamine precursors (levodopa combined with extracerebral decarboxylase inhibitors) and artificial dopamine agonists. It has been argued, on theoretical grounds, that some drugs slow the progress of Parkinson's disease, although no firm evidence has supported this. Treatment must be individualized, and more than one type of drug can be given concurrently after a careful build-up in dosage. We review the adverse effects of various drugs and consider new developments such as slow-release preparations, selective D-1 and D-2 agonists and transplants of dopaminergic cells into the brain. The treatment of Parkinson's disease can be demanding, rewarding and sometimes frustrating, but it remains a most challenging exercise in pharmacotherapy. Images Fig. 1 Fig. 2 Fig. 3 PMID:2563667

  13. Sleep disturbances in drug naÔve Parkinson's disease (PD) patients and effect of levodopa on sleep

    PubMed Central

    Ferreira, Teresa; Prabhakar, Sudesh; Kharbanda, Parampreet S.

    2014-01-01

    Context: Parkinson's disease (PD) is associated with sleep disturbances, attributed to the neurodegenerative process and therapeutic drugs. Studies have found levodopa to increase wakefulness in some patients while increasing sleepiness in others. Aims: To confirm sleep disturbances in drug naÔve PD patients and understand the impact of levodopa on their sleep. Materials and Methods: Twenty-three drug naÔve PD patients and 31 age-gender matched controls were compared using the Parkinson's Disease Sleep Scale (PDSS) and Epworth Sleepiness Scale (ESS). A polysomnogram objectively compared sleep quality. Of the 23 patients, the 12 initiated on levodopa were reassessed subjectively and through polysomnography after 2 months of therapy. Statistical Analysis: Data was expressed as mean Ī standard deviation, median, and range. Continuous variables were analyzed by Student's T test for normally distributed data and MannĖWhitney U test for skewed data. Discrete variables were compared by Chi Square tests (Pearson Chi square Test or Fisher's Exact Test). Wilcoxon signed ranks test was applied in the analysis of paired data pre- and post-levodopa. A P value < 0.05 was considered as statistically significant. Statistical analysis of the data was done using the Statistical Package for the Social Sciences (SPSS) version 12. Results: Drug naÔve PD patients had lower PDSS scores than controls. The sleep architecture changes observed on polysomnogram were reduced NREM Stage III and REM sleep and increased sleep latency and wake after sleep onset time. Following levodopa, improved sleep efficiency with reduced sleep latency and wake after sleep onset time was noted, coupled with improved PDSS scores. However, NREM Stage III and REM sleep duration did not increase. Discussion: PD patients take longer to fall asleep and have difficulty in sleep maintenance. Sleep maintenance is affected by nocturia, REM behavioral disorder, nocturnal cramps, akinesia, and tremors, as observed in PDSS scores. Levodopa improves sleep efficiency by improving motor scores without altering sleep architecture. Conclusions: Poor sleep quality and sleep architecture changes occur secondary to the neurodegenerative process in PD patients. Though levodopa improves sleep quality by reducing rigidity and tremor, it does not reverse sleep architecture changes. PMID:25506163

  14. Willingness to pay for a new drug delivery in Parkinson patients

    PubMed Central

    LŲkk, Johan; Olofsson, Sara; Persson, Ulf

    2014-01-01

    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 Parkinsonís disease (PD) patientsí 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

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

    PubMed

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

    2013-11-01

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

  16. Stimulation, protection and regeneration of dopaminergic neurons by 9-methyl-?-carboline: a new anti-Parkinson drug?

    PubMed

    Polanski, Witold; Reichmann, Heinz; Gille, Gabriele

    2011-06-01

    ?-carbolines are potential endogenous and exogenous neurotoxins that may contribute to the pathogenesis of Parkinson's disease (PD). 9-methyl-?-carboline exhibits multimodal effects that could be beneficial in the treatment of PD. It shows stimulatory effects to dopaminergic neurons by increasing the expression of tyrosine hydroxylase and its transcription factors in pre-existing dopa decarboxylase immunoreactive neurons. Furthermore, 9-methyl-?-carboline has emerged as a substance with the rare property of a protective and regenerative/restorative potential for dopaminergic neurons by inducing gene expression of several neurotrophic factors and decreasing apoptotic cell signals. It reduces protein levels of ?-synuclein and inhibits monoamine oxidase A and B. Finally, 9-methyl-?-carboline acts on multiple targets in the inflammatory cascade by inhibiting the proliferation of microglia, by decreasing chemotactic cytokines and by creating an anti-inflammatory environment in the CNS. This article summarizes our current knowledge of 9-methyl-carboline and discusses its potential role as a new drug for the treatment of PD. PMID:21651332

  17. Drug-induced status epilepticus.

    PubMed

    Cock, Hannah R

    2015-08-01

    Drug-induced status epilepticus (SE) is a relatively uncommon phenomenon, probably accounting for less than 5% of all SE cases, although limitations in case ascertainment and establishing causation substantially weaken epidemiological estimates. Some antiepileptic drugs, particularly those with sodium channel or GABA(?-aminobutyric acid)-ergic properties, frequently exacerbate seizures and may lead to SE if used inadvertently in generalized epilepsies or less frequently in other epilepsies. Tiagabine seems to have a particular propensity for triggering nonconvulsive SE sometimes in patients with no prior history of seizures. In therapeutic practice, SE is most commonly seen in association with antibiotics (cephalosporins, quinolones, and some others) and immunotherapies/chemotherapies, the latter often in the context of a reversible encephalopathy syndrome. Status epilepticus following accidental or intentional overdoses, particularly of antidepressants or other psychotropic medications, has also featured prominently in the literature: whilst there are sometimes fatal consequences, this is more commonly because of cardiorespiratory or metabolic complications than as a result of seizure activity. A high index of suspicion is required in identifying those at risk and in recognizing potential clues from the presentation, but even with a careful analysis of patient and drug factors, establishing causation can be difficult. In addition to eliminating the potential trigger, management should be as for SE in any other circumstances, with the exception that phenobarbitone is recommended as a second-line treatment for suspected toxicity-related SE where the risk of cardiovascular complications is higher anyways and may be exacerbated by phenytoin. There are also specific recommendations/antidotes in some situations. The outcome of drug-induced status epilepticus is mostly good when promptly identified and treated, though less so in the context of overdoses. This article is part of a Special Issue entitled "Status Epilepticus". PMID:26210064

  18. Increased reflection impulsivity in patients with ephedrone induced Parkinsonism

    PubMed Central

    Djamshidian, Atbin; Sanotsky, Yanosh; Matviyenko, Yuriy; OíSullivan, Sean S.; Sharman, Stephen; Selikhova, Marianna; Fedoryshyn, Ludmyla; Filts, Yuriy; Bearn, Jenny; Lees, Andrew J.; Averbeck, Bruno B.

    2012-01-01

    Aims To examine a syndrome of chronic manganism that occurs in drug addicts in Eastern Europe who use intravenous methcathinone (ephedrone) contaminated with potassium permanganate. The basal ganglia, especially the globus pallidus and the putamen, are damaged irreversibly in many cases. Routine neuropsychological assessment has revealed no cognitive deficits despite widespread abnormalities on brain imaging studies and severe extrapyramidal motor handicap on clinical examination. Design Case control study. Setting Ephedrone patients and patients with opioid dependence were recruited from Lviv, Ukraine. Participants We tested 15 patients with ephedrone induced toxicity, 13 opiate dependent patients, who were receiving opioid replacement therapy and 18 matched healthy volunteers. Measurements The Ďbeads taskí, an information gathering task to assess reflection impulsivity was used and feedback learning, working memory and risk taking were also assessed. Findings Opiate dependent patients differed from controls on three out of four tasks, whereas ephedrone patients differed from controls on only one task. More specifically both patient groups were more impulsive and made more irrational choices on the beads task than controls (p<0.001). However, ephedrone patients had no deficits in working memory (p>0.1) or risk taking (p>0.1) compared with controls. Opioid dependent patients had significantly worse working memory (p<0.001) and were significantly more risk prone than controls (p=0.002). Conclusions Ephedrone patients may have similar deficits in information gathering and decision making to opiate dependent patients, with preservation of working memory and risk taking. This may reflect specific damage to anterior cingulate- basal ganglia loops. PMID:23228208

  19. Manganese-Induced Parkinsonism and Parkinson’s Disease: Shared and Distinguishable Features

    PubMed Central

    Kwakye, Gunnar F.; Paoliello, Monica M.B.; Mukhopadhyay, Somshuvra; Bowman, Aaron B.; Aschner, Michael

    2015-01-01

    Manganese (Mn) is an essential trace element necessary for physiological processes that support development, growth and neuronal function. Secondary to elevated exposure or decreased excretion, Mn accumulates in the basal ganglia region of the brain and may cause a parkinsonian-like syndrome, referred to as manganism. The present review discusses the advances made in understanding the essentiality and neurotoxicity of Mn. We review occupational Mn-induced parkinsonism and the dynamic modes of Mn transport in biological systems, as well as the detection and pharmacokinetic modeling of Mn trafficking. In addition, we review some of the shared similarities, pathologic and clinical distinctions between Mn-induced parkinsonism and Parkinson’s disease. Where possible, we review the influence of Mn toxicity on dopamine, gamma aminobutyric acid (GABA), and glutamate neurotransmitter levels and function. We conclude with a survey of the preventive and treatment strategies for manganism and idiopathic Parkinson’s disease (PD). PMID:26154659

  20. Human induced pluripotent stem cells in Parkinson's disease: A novel cell source of cell therapy and disease modeling.

    PubMed

    Li, Wen; Chen, Shengdi; Li, Jia-Yi

    2015-11-01

    Human induced pluripotent stem cells (hiPSCs) and human embryonic stem cells (hESCs) are two novel cell sources for studying neurodegenerative diseases. Dopaminergic neurons derived from hiPSCs/hESCs have been implicated to be very useful in Parkinson's disease (PD) research, including cell replacement therapy, disease modeling and drug screening. Recently, great efforts have been made to improve the application of hiPSCs/hESCs in PD research. Considerable advances have been made in recent years, including advanced reprogramming strategies without the use of viruses or using fewer transcriptional factors, optimized methods for generating highly homogeneous neural progenitors with a larger proportion of mature dopaminergic neurons and better survival and integration after transplantation. Here we outline the progress that has been made in these aspects in recent years, particularly during the last year, and also discuss existing issues that need to be addressed. PMID:26408505

  1. Dopamine-Induced Nonmotor Symptoms of Parkinson's Disease

    PubMed Central

    Park, Ariane; Stacy, Mark

    2011-01-01

    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

  2. Pathogenesis of Mortalin in Manganese-induced Parkinsonism

    NASA Astrophysics Data System (ADS)

    Cook, Travis J.

    Manganese (Mn) is an essential dietary micronutrient for which excessive exposure has long been known to be neurotoxic. Historically, short-term, high-intensity exposure in occupational settings was recognized to cause acute-onset parkinsonism (PS) termed manganism. Although modern day exposures are typically several orders of magnitude lower than those necessary to cause manganism, chronic, low-level exposures are not uncommon among a number of occupations and communities. Recent epidemiologic studies have demonstrated an association between Mn exposure and risk of PS, and in this regard Mn remains a public health concern. The work described here was designed to provide insight toward questions which remain with respect to Mn exposure and its toxic effect on the brain, and includes studies utilizing Mn exposed human populations and in vitro model systems to address these objectives. Blood plasma samples obtained from a cohort of welders, whose work is recognized as generating appreciable amounts of airborne Mn, and post-mortem brain tissue of Mn mine workers were both found to have discernable alterations related to the mitochondrial chaperone protein mortalin. Furthermore, in vitro studies demonstrated that reduced astroglial expression of mortalin confers neuronal susceptibility to toxicity elicited by low levels of Mn, possibly via mechanisms of endoplasmic reticulum and oxidative stress mediated by alpha-synuclein. Taken together, the results of these studies indicate that Mn exposures experienced by modern day populations are sufficient to cause biological alterations in humans that are potentially neurotoxic.

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

    PubMed Central

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

    2012-01-01

    Objectives: To evaluate the neuroprotective effect of Stereospermum suaveolens DC on 6-hydroxy dopamine induced Parkinson's disease model. Materials and Methods: The study was conducted on Sprague-Dawley rats where parkinson's disease was induced by producing the striatal 6-hydroxy dopamine lesions. The test animals received methanolic extract of Stereospermum suaveolens at dose of 125, 250 and 500 mg/kg for 42 days. Behavioral assessment, spontaneous locomotor activity and muscular coordination were studied. Antioxidant levels, striatal infraction area were assessed and histopathological studies were carried out. Results: The Stereospermum suaveolens DC methanolic extract showed significant dose dependent increase in behavioral activity, improved muscular coordination. Significant reduction of lipid peroxidation (LPO), increased antioxidant enzymes like superoxide dismutase (SOD), catalase (CAT) and non-enzymatic activity of glutathione (GSH) and total thiol levels in extract treated groups was observed in test groups as compared to control group. Striatal infarction area was significantly reduced in extract treated groups as compared to control group. Conclusion: The methanolic extract of Stereospermum suaveolens DC showed neuroprotective activity against 6-hydroxy dopamine induced Parkinson's disease in rats. PMID:23248404

  4. Serum uric acid is associated with apathy in early, drug-na√Įve Parkinson's disease.

    PubMed

    Picillo, Marina; Santangelo, Gabriella; Moccia, Marcello; Erro, Roberto; Amboni, Marianna; Prestipino, Elio; Longo, Katia; Vitale, Carmine; Spina, Emanuele; Orefice, Giuseppe; Barone, Paolo; Pellecchia, Maria Teresa

    2016-04-01

    Both low serum uric acid (UA) levels and apathy are considered biomarkers of cognitive decline and dementia in Parkinson's disease (PD). There is an urgent need to combine different biomarkers to predict disease course in PD. Data on the relationship between serum UA levels and apathy in PD are lacking. The aim of this study is to evaluate the relationship between serum UA levels and pure apathy in early, drug-na√Įve PD patients. Forty-nine early, drug-na√Įve PD patients were enrolled and stratified into two groups using the median serum UA levels at diagnosis (Group 1 serum UA¬†‚ȧ¬†4.8¬†mg/dl; Group 2 serum UA¬†>¬†4.8¬†mg/dl). The cohort was followed for the first 2¬†years of disease. Apathy was evaluated with the Apathy Evaluation Scale (AES). Patients with lower serum UA levels presented significant higher AES score compared to patients with higher serum UA levels. Regression analysis showed that baseline serum UA levels were significant determinants of AES scores at both baseline and 2-year follow up, irrespective of gender, age, attention/executive functions and dopamine replacement therapy when applicable. This is the first study showing a link between serum UA levels and apathy in non-demented, non-depressed, early, drug-na√Įve PD, being lower serum UA levels associated with greater apathy. Further follow up of our patients and replication of this observation in independent cohorts are needed to establish if this combination of biomarkers may help in characterizing a subgroup of PD patients at diagnosis. PMID:26739446

  5. Targeting the D1-N-methyl-d-aspartate receptor complex reduces l-dopa-induced dyskinesia in 6-hydroxydopamine-lesioned Parkinsonís rats

    PubMed Central

    Song, Lu; Zhang, Zhanzhao; Hu, Rongguo; Cheng, Jie; Li, Lin; Fan, Qinyi; Wu, Na; Gan, Jing; Zhou, Mingzhu; Liu, Zhenguo

    2016-01-01

    L-3,4-dihydroxyphenylalanine (l-dopa) remains the most effective therapy for Parkinsonís disease (PD), but its long-term administration is associated with the development of debilitating motor complications known as l-dopa-induced dyskinesia (LID). Enhanced function of dopamine D1 receptor (D1R) and N-methyl-d-aspartate receptor (NMDAR) is believed to participate in the pathogenesis of LID. Given the existence of physical and functional interactions between D1R and NMDAR, we explored the effects of uncoupling D1R and NMDA GluN1 (GluN1) interaction on LID by using the Tat-conjugated interfering peptide (Tat-D1-t2). In this study, we demonstrated in 6-hydroxydopamine (6-OHDA)-lesioned PD rat model that intrastriatal injection of Tat-D1-t2 alleviated dyskinetic behaviors and downregulated the phosphorylation of DARPP-32 at Thr34 induced by levodopa. Moreover, we also showed intrastriatal administration of Tat-D1-t2 elicited alterations in membranous GluN1 and D1R expression. These findings indicate that D1R/GluN1 complexes may be a molecular target with therapeutic potential for the treatment of dyskinesia in Parkinsonís patients. PMID:26893543

  6. Management of psychosis in Parkinson's disease.

    PubMed

    Wolters, E C; Berendse, H W

    2001-08-01

    Psychosis is quite common in Parkinson's disease (approximately 25% of patients) and therefore constitutes a serious public health problem. All patients suffering from idiopathic Parkinson's disease, and especially elderly and demented patients, are at risk of developing delusions or hallucinations. The most prominent psychotogenic factors are dopaminomimetic agents, which may induce dopamine hypersensitivity in the frontal and limbic dopamine projection regions, and consequently, either directly or indirectly, elicit psychotic signs and symptoms. A Parkinson's disease-related cholinergic deficit in combination with an age-related further loss of cholinergic integrity also plays a prominent role. Psychosis in Parkinson's disease patients appears to be a more important contributor to caregiver distress than motor parkinsonism. Psychosis therefore probably represents the single greatest risk factor for nursing home placement. Typical antipsychotic drugs, because of their selective dopamine receptor antagonistic effects, can reduce psychotic signs but at the cost of an increase in parkinsonism. As a consequence of a non-selective antagonism at both serotonergic and dopaminergic receptors, atypical antipsychotic drugs are associated with fewer extrapyramidal side-effects. On the other hand, hypersensitivity to these agents may induce delirium or a malignant neuroleptic syndrome. Atypical antipsychotic agents such as clozapine, quetiapine and olanzapine should therefore be started at very low doses that are increased gradually. Cholinomimetic therapy may prove to be helpful in the prevention and treatment of psychotic manifestations in Parkinson's disease patients, given the effects observed in patients suffering from dementia with Lewy bodies. PMID:11470967

  7. Loss of thalamic serotonin transporters in early drug-naÔve Parkinsonís disease patients is associated with tremor: an [123I]?-CIT SPECT study

    PubMed Central

    Stoffers, D.; Winogrodzka, A.; Isaias, I.-U.; Costantino, G.; Pezzoli, G.; Ferrarese, C.; Antonini, A.; Wolters, E.-Ch.; Booij, J.

    2008-01-01

    In vitro studies revealed serotonin transporter (5-HTT) decline in Parkinsonís disease (PD). Yet, few studies investigated thalamic 5-HTT in vivo and its effect on PD heterogeneity. We analyzed thalamic [123I]?-CIT binding (mainly reflecting 5-HTT binding) in 32 drug-naÔve PD patients and 13 controls with SPECT. Twenty-six patients were examined twice (17†months apart). Based on UPDRS scores, we identified subgroups of patients with moderate/severe tremor (PDT) and without tremor (PDWT) at the time of clinical diagnosis. Additionally, depressive symptoms were evaluated using the Beck Depression Inventory (BDI) at baseline. Mean thalamic specific to non-specific [123I]?-CIT binding ratio was lower in patients when compared to controls, and further decreased during follow-up. At baseline, average thalamic ratio was significantly lower in the PDT than in the PDWT subgroup. No correlation was found between BDI scores and thalamic binding ratios. Our findings show decline of [123I]?-CIT binding to thalamic 5-HTT in PD and its possible contribution to tremor onset. PMID:18335163

  8. Drug-induced movement disorders.

    PubMed

    Mehta, Shyamal H; Morgan, John C; Sethi, Kapil D

    2015-02-01

    Movement disorders are frequently a result of prescription drugs or of illicit drug use. This article focuses on prescribed drugs but briefly mentions drugs of abuse. The main emphasis is on movement disorders caused by dopamine receptor-blocking agents. However, movement disorders caused by other drugs are also briefly discussed. PMID:25432728

  9. Manganese-Induced Parkinsonism due to Ephedrone Abuse

    PubMed Central

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

    2011-01-01

    During recent years, a syndrome of hypokinesia, dysarthria, dystonia, and postural impairment, related to intravenous use of a ‚Äúdesigner‚ÄĚ 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

  10. Secondary parkinsonism

    MedlinePLUS

    Parkinsonism - secondary; Atypical Parkinson disease ... to be less responsive to medical therapy than Parkinson disease. ... Unlike Parkinson disease, some types of secondary parkinsonism may stabilize or even improve if the underlying cause is treated. ...

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

    PubMed Central

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

    2007-01-01

    Objective To investigate the associations between Parkinson's disease and other degenerative parkinsonian syndromes and environmental factors in five European countries. Methods A caseĖcontrol study of 959 prevalent cases of parkinsonism (767 with Parkinson's disease) and 1989 controls in Scotland, Italy, Sweden, Romania and Malta was carried out. Cases were defined using the United Kingdom Parkinson's Disease Society Brain Bank criteria, and those with drug?induced or vascular parkinsonism or dementia were excluded. Subjects completed an interviewer?administered questionnaire about lifetime occupational and hobby exposure to solvents, pesticides, iron, copper and manganese. Lifetime and average annual exposures were estimated blind to disease status using a job?exposure matrix modified by subjective exposure modelling. Results were analysed using multiple logistic regression, adjusting for age, sex, country, tobacco use, ever knocked unconscious and family history of Parkinson's disease. Results Adjusted logistic regression analyses showed significantly increased odds ratios for Parkinson's disease/parkinsonism with an exposureĖresponse relationship for pesticides (low vs no exposure, odds ratio (OR)?=?1.13, 95% CI 0.82 to 1.57, high vs no exposure, OR?=?1.41, 95% CI 1.06 to 1.88) and ever knocked unconscious (once vs never, OR?=?1.35, 95% CI 1.09 to 1.68, more than once vs never, OR?=?2.53, 95% CI 1.78 to 3.59). Hypnotic, anxiolytic or antidepressant drug use for more than 1 year and a family history of Parkinson's disease showed significantly increased odds ratios. Tobacco use was protective (OR?=?0.50, 95% CI 0.42 to 0.60). Analyses confined to subjects with Parkinson's disease gave similar results. Conclusions The association of pesticide exposure with Parkinson's disease suggests a causative role. Repeated traumatic loss of consciousness is associated with increased risk. PMID:17332139

  12. Nicotine reduces established levodopa-induced dyskinesias in a monkey model of Parkinson's disease.

    PubMed

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

    2013-09-01

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

  13. Attenuation by Nardostachys jatamansi of 6-hydroxydopamine-induced parkinsonism in rats: behavioral, neurochemical, and immunohistochemical studies.

    PubMed

    Ahmad, Muzamil; Yousuf, Seema; Khan, M Badruzzaman; Hoda, Md Nasrul; Ahmad, Abdullah Shafique; Ansari, Mubeen Ahmad; Ishrat, Tauheed; Agrawal, Ashok Kumar; Islam, Fakhrul

    2006-01-01

    Parkinson's disease (PD) is one of the commonest neurodegenerative diseases, and oxidative stress has been evidenced to play a vital role in its causation. In the present study, we evaluated whether ethanolic extract of Nardostachys jatamansi roots (ENj), an antioxidant and enhancer of biogenic amines, can slow the neuronal injury in a 6-OHDA-rat model of Parkinson's. Rats were treated with 200, 400, and 600 mg/kg body weight of ENj for 3 weeks. On day 21, 2 microl of 6-OHDA (12 microg in 0.01% in ascorbic acid-saline) was infused into the right striatum, while the sham-operated group received 2 microl of vehicle. Three weeks after the 6-OHDA injection, the rats were tested for neurobehavioural activity and were sacrificed after 6 weeks for the estimation of lipid peroxidation, reduced glutathione content, the activities of glutathione-S-transferase, glutathione reductase, glutathione peroxidase, superoxide dismutase and catalase, quantification of catecholamines, dopaminergic D2 receptor binding and tyrosine hydroxylase expression. The increase in drug-induced rotations and deficits in locomotor activity and muscular coordination due to 6-OHDA injections were significantly and dose-dependently restored by ENj. Lesioning was followed by an increased lipid peroxidation and significant depletion of reduced glutathione content in the substantia nigra, which was prevented with ENj pretreatment. The activities of glutathione-dependent enzymes, catalase and superoxide dismutase in striatum, which were reduced significantly by lesioning, were dose-dependently restored by ENj. A significant decrease in the level of dopamine and its metabolites and an increase in the number of dopaminergic D2 receptors in striatum were observed after 6-OHDA injection, and both were significantly recovered following ENj treatment. All of these results were exhibited by an increased density of tyrosine hydroxylase immunoreactive (TH-IR) fibers in the ipsilateral striatum of the lesioned rats following treatment with ENj; 6-OHDA injection had induced almost a complete loss of TH-IR fibers. This study indicates that the extract of Jatamansi might be helpful in attenuating Parkinsonism. PMID:16500697

  14. Treatment of Parkinsonís disease: nanostructured solĖgel silicaĖdopamine reservoirs for controlled drug release in the central nervous system

    PubMed Central

    Lůpez, Tessy; Bata-GarcŪa, Josť L; Esquivel, Dulce; Ortiz-Islas, Emma; Gonzalez, Richard; Ascencio, Jorge; Quintana, Patricia; Oskam, Gerko; Ńlvarez-Cervera, Fernando J; Heredia-Lůpez, Francisco J; Gůngora-Alfaro, Josť L

    2011-01-01

    Introduction We have evaluated the use of silicaĖdopamine reservoirs synthesized by the solĖgel approach with the aim of using them in the treatment of Parkinsonís disease, specifically as a device for the controlled release of dopamine in the striatum. Theoretical calculations illustrate that dopamine is expected to assume a planar structure and exhibit weak interactions with the silica surface. Methods Several samples were prepared by varying the wt% of dopamine added during the hydrolysis of tetraethyl orthosilicate. The silicaĖdopamine reservoirs were characterized by N2 adsorption, scanning and transmission electron microscopy, and Fourier transform infrared spectroscopy. The in vitro release profiles were determined using ultraviolet visible absorbance spectroscopy. The textural analyses showed a maximum value for the surface area of 620 m2/g nanostructured silica materials. The stability of dopamine in the silica network was confirmed by infrared and 13C-nuclear magnetic resonance spectroscopy. The reservoirs were evaluated by means of apomorphine-induced rotation behavior in hemiparkisonian rats. Results The in vitro dopamine delivery profiles indicate two regimes of release, a fast and sustained dopamine delivery was observed up to 24 hours, and after this time the rate of delivery became constant. Histologic analysis of formalin-fixed brains performed 24Ė32 weeks after reservoir implantation revealed that silicaĖdopamine implants had a reddish-brown color, suggesting the presence of oxidized dopamine, likely caused by the fixation procedure, while implants without dopamine were always translucent. Conclusion The major finding of the study was that intrastriatal silicaĖdopamine implants reversed the rotational asymmetry induced by apomorphine, a dopamine agonist, in hemiparkinsonian rats. No dyskinesias or other motor abnormalities were observed in animals implanted with silica or silicaĖdopamine. PMID:21289978

  15. Cerebellar and Motor Cortical Transcranial Stimulation Decrease Levodopa-Induced Dyskinesias in Parkinson's Disease.

    PubMed

    Ferrucci, Roberta; Cortese, Francesca; Bianchi, Marta; Pittera, Dario; Turrone, Rosanna; Bocci, Tommaso; Borroni, Barbara; Vergari, Maurizio; Cogiamanian, Filippo; Ardolino, Gianluca; Di Fonzo, Alessio; Padovani, Alessandro; Priori, Alberto

    2016-02-01

    Transcranial direct current stimulation (tDCS) is a non-invasive technique for inducing prolonged functional changes in the human cerebral cortex. This simple and safe neurostimulation technique for modulating motor functions in Parkinson's disease could extend treatment option for patients with movement disorders. We assessed whether tDCS applied daily over the cerebellum (cerebellar tDCS) and motor cortex (M1-tDCS) improves motor and cognitive symptoms and levodopa-induced dyskinesias in patients with Parkinson's disease (PD). Nine patients (aged 60-85†years; four women; Hoehn & Yahr scale score 2-3) diagnosed as having idiopathic PD were recruited. To evaluate how tDCS (cerebellar tDCS or M1-tDCS) affects motor and cognitive function in PD, we delivered bilateral anodal (2†mA, 20†min, five consecutive days) and sham tDCS, in random order, in three separate experimental sessions held at least 1†month apart. In each session, as outcome variables, patients underwent the Unified Parkinson's Disease Rating Scale (UPDRS III and IV) and cognitive testing before treatment (baseline), when treatment ended on day 5 (T1), 1†week later (T2), and then 4†weeks later (T3), at the same time each day. After patients received anodal cerebellar tDCS and M1-tDCS for five days, the UPDRS IV (dyskinesias section) improved (p??0.05). Despite the small sample size, our preliminary results show that anodal tDCS applied for five consecutive days over the motor cortical areas and cerebellum improves parkinsonian patients' levodopa-induced dyskinesias. PMID:26542731

  16. Drug-Induced Acute Pancreatitis: A Review

    PubMed Central

    Jones, Mark R.; Hall, Oliver Morgan; Kaye, Adam M.; Kaye, Alan David

    2015-01-01

    Background The majority of drug-induced pancreatitis cases are mild to moderate in severity, but severe and even fatal cases can occur. Management of drug-induced pancreatitis requires withdrawal of the offending agent and supportive care. Methods This review focuses on differential diagnosis, clinical presentation, drug-mediated effects, treatments, and mechanisms of pancreatitis, with an emphasis on drug-induced pancreatitis. Results Although only a minority of cases associated with acute pancreatitis are linked to drugs, clinical presentation and mechanisms of injury to the pancreas are not well understood by clinicians in terms of individual drug effects in the mediation or modulation of injury to the pancreas. In recent years, a large number of commonly prescribed medications has been linked to drug-induced pancreatitis pathogenesis. Although mechanisms are proposed, the exact cause of injury is either not well understood or controversial. Conclusion Future investigation into the mechanisms of pancreatitis and an appreciation by clinicians of the drugs commonly linked to the condition will help establish earlier diagnosis and quicker cessation of offending drugs in the treatment of drug-induced acute pancreatitis. PMID:25829880

  17. Role of 5-Hydroxytryptamine 1A Receptors in 6-Hydroxydopmaine-induced Catalepsy-like Immobilization in Rats: a Therapeutic Approach for Treating Catalepsy of Parkinsonís Disease

    PubMed Central

    eyhani-rad, Siamak; Mohajjel Nayebi, Alireza; Mahmoudi, Javad; Samini, Morteza; Babapour, Vahab

    2012-01-01

    We have shown that buspirone, a partial agonist of 5-hydroxytryptamine 1A (5-HT1A) receptors, improves motor dysfunctions induced by 6-hydroxydopamine (6-OHDA) and haloperidol in rats. The present work extends these findings by investigating the role of 5-HT1A receptors on catalepsy-like immobilization in rats, a model of Parkinsonís disease. Catalepsy was induced by unilateral infusion of 6-OH-dopamine (8 ?g/2?L/rat) into the central region of the substantia nigra, compact part (SNc) and assayed by bar-test method 5, 60, 120 and 180 min after the drugs administration. The involvement of 5-HT1A receptors in 6-OHDA-induced catalepsy was studied through intraperitoneal (0.25, 0.5 and 1mg/Kg IP) and intrasubstantia nigra, compact part (10 ?g/rat, intra-SNc) injection of 8-hydroxy-2-[di-n-propylamino] tetralin (8-OHDPAT) as well as administration of 1-(2-methoxyphenyl)-4-[4-(2-pthalimmido) butyl] piperazine hydrobromide (0.1, 0.5 and 1 mg/Kg, NAN-190, IP). NAN-190 (1 mg/Kg, IP) and 8-OHDPAT (1 mg/Kg, IP and 10 ?g/rat, intra-SNc) increased and decreased 6-OHDA-induced catalepsy respectively. In normal (non 6-OHDA-lesioned) rats, NAN-190 (1 mg/Kg, IP) increased the elapsed time in bar-test while 8-OHDPAT did not produce any significant effect. The anticataleptic effect of 8-OHDPAT (1 mg/Kg, IP) was reversed markedly by co-injection with NAN-190 (1 mg/Kg, IP). These findings suggest that 5-HT1A receptors are involved in 6-OHDA-induced catalepsy-like immobilization. PMID:24250551

  18. Prevalence of parkinsonism estimated using the drug prescription archive: a possible method to estimate the prevalence of a chronic neurological disease?

    PubMed

    Di Napoli, Anteo; Scalmana, Silvia; Franco, Francesco; Di Lallo, Domenico; Lacorte, Eleonora; Vanacore, Nicola

    2016-04-01

    Many surveys estimated prevalence of parkinsonism, with results varying largely. We used prescription records of medications for parkinsonism to estimate the prevalence of this condition. Retrospective survey based on Lazio (Italy) regional drugs' prescriptions registry. Cases of parkinsonism were defined as those who received a medication for parkinsonism (Dopa and dopa derivatives or Monoamine oxidase B-inhibitors) for at least 6 months in a 5-year period (2005-2009). Crude and standardized prevalence rates at June 2009 were calculated. Crude and standardized prevalence rates of parkinsonism in Lazio were, respectively, 283 per 100,000 (95 % CI 278-287), and 294 per 100,000 (95 % CI 289-298), higher in men than in women (292 per 100,000 vs. 274 per 100,000). The highest overall prevalence rate was observed among people aged 85-89 years (246 per 100,000), while the lowest in subjects aged <65 (38 per 100,000). Prevalence rates in people older than 65 and older 75 were, respectively, 1275 per 100,000 and 1912 per 100,000. Using a regional drug registry, based on currently available health information systems, may be a suitable method to estimate prevalence of parkinsonism, which is essential for public health programming, the more in presence of a demographic shift as the current one. PMID:26687506

  19. The high-affinity D2/D3 agonist D512 protects PC12 cells from 6-OHDA-induced apoptotic cell death and rescues dopaminergic neurons in the MPTP mouse model of Parkinsonís disease

    PubMed Central

    Shah, Mrudang; Rajagopalan, Subramanian; Xu, Liping; Voshavar, Chandrashekhar; Shurubor, Yevgeniya; Beal, Flint; Andersen, Julie K; Dutta, Aloke K

    2014-01-01

    In this study, in vitro and in vivo experiments were carried out with the high-affinity multifunctional D2/D3 agonist D-512 in order to explore its potential neuroprotective effects in models of Parkinsonís disease (PD) and the potential mechanism(s) underlying such properties. Pretreatment with D-512 in vitro was found to rescue rat adrenal phaeochromocytoma PC12 cells from toxicity induced by 6-hydroxydopamine (6-OHDA) administration in a dose-dependent manner. Neuroprotection was found to coincide with reductions in intracellular reactive oxygen species, lipid peroxidation, and DNA damage. In vivo, pretreatment with 0.5 mg/kg D-512 was protective against neurodegenerative phenotypes associated with systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), including losses in striatal dopamine (DA), reductions in numbers of DAergic neurons in the substantia nigra (SN), and locomotor dysfunction. These observations strongly suggest that the multifunctional drug D-512 may constitute a novel viable therapy for PD. PMID:24848702

  20. Treatment of drug-induced seizures.

    PubMed

    Chen, Hsien-Yi; Albertson, Timothy E; Olson, Kent R

    2016-03-01

    Seizures are a common complication of drug intoxication, and up to 9% of status epilepticus cases are caused by a drug or poison. While the specific drugs associated with drug-induced seizures may vary by geography and change over time, common reported causes include antidepressants, stimulants and antihistamines. Seizures occur generally as a result of inadequate inhibitory influences (e.g., gamma aminobutyric acid, GABA) or excessive excitatory stimulation (e.g. glutamate) although many other neurotransmitters play a role. Most drug-induced seizures are self-limited. However, status epilepticus occurs in up to 10% of cases. Prolonged or recurrent seizures can lead to serious complications and require vigorous supportive care and anticonvulsant drugs. Benzodiazepines are generally accepted as the first line anticonvulsant therapy for drug-induced seizures. If benzodiazepines fail to halt seizures promptly, second line drugs include barbiturates and propofol. If isoniazid poisoning is a possibility, pyridoxine is given. Continuous infusion of one or more anticonvulsants may be required in refractory status epilepticus. There is no role for phenytoin in the treatment of drug-induced seizures. The potential role of ketamine and levetiracetam is promising but not established. PMID:26174744

  1. [Drug-induced acute kidney injury].

    PubMed

    Derungs, Adrian

    2015-12-01

    Due to their physiological function, the kidneys are exposed to high concentrations of numerous drugs and their metabolites, making them vulnerable to drug-related injuries. This article provides an overview of the pathophysiological mechanisms involved in nephrotoxicity, the most common nephrotoxic drugs, and the risk factors for the occurrence of drug-induced acute kidney injuries. NSAIDs, diuretics, ACE inhibitors, and angiotensin II receptor blockers (ARBs} are the most frequent prerenal causes of an acute elevation in creatinine levels. Primary vascular damage arises from thrombotic microangiopathy (e. g. due to cic/osporin, tacrolimus, muromonab-CD3, mitomycin C, quinine, ticlopidine, clopidogrel}. Anticoagulants and thrombolytic medications lead to secondary blood vessel damage by cholesterol emboli, embolism of thrombus material into the periphery or bleeding. Tubulopathies can be observed on treatment with ifosfamide and cisplatin (rarely with cyclophosphamide or carboplatin), aminoglycosides, vancomycin, and radiocontrast agents. Immunological mechanisms underlie interstitial nephritides, which are induced by drugs in about 85% of cases. In drug-induced glomerulopathies;- renal biopsy allows closer identification of the triggering medication. Drug-induced systemic lupus erythematosus (SLE} represents a special form of immune complex glomerulonephritis and can be triggered by procainamide, hydralazine, isoniazid, methyldopa, quinidine, chlorpromazine, and propylthiouracil. Crystal-induced kidney injury is caused by precipitation of drugs (e. g. aciclovir, sulfonamide antibiotics, methotrexate, indinavir) in the renal tubules and the urine-conducting organs with consecutive obstruction thereof. PMID:26654816

  2. Non-steroidal drug-induced glaucoma.

    PubMed

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

    2011-08-01

    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

  3. Drug-induced pulmonary disease

    MedlinePLUS

    ... mediastinitis ) Abnormal buildup of fluid in the lungs ( pulmonary edema ) Buildup of fluid between the layers of tissue that line the lungs and chest cavity ( pleural effusion ) Many ... as bleomycin, cyclophosphamide, and methotrexate Illegal drugs

  4. [Drug-induced sexual dysfunction].

    PubMed

    Taegtmeyer, Anne B; Kr√§henb√ľhl, Stephan

    2015-12-01

    Drugs can affect sexual function through their effects on the central nervous system, the peripheral (autonomic) nervous system or through hormonal effects. As most patients do not spontaneously talk about their sex life, it is important to assess patients with critical medication for possible sexual dysfunction. Critical medication in relation to sexual function include sedative drugs, drugs that affect the central serotonin, dopamine and/ or prolactin signaling pathways as well as certain antihypertensives. It is important to note, however, that the indications for these therapies, such as schizophrenia, depression and the metabolic syndrome are themselves associated with sexual dysfunction. if a disturbing sexual dysfunction arises, treatment with the suspected drug should be discontinued and possibly changed to one with fewer adverse effects. The use of phosphodiesterase 5 inhibitors, which are largely efficacious and safe for both patients with psychiatric conditions and patients with hypertension, can be considered PMID:26654815

  5. Azithromycin induced bullous fixed drug eruption

    PubMed Central

    Das, Anupam; Sancheti, Karan; Podder, Indrashis; Das, Nilay Kanti

    2016-01-01

    Fixed drug eruption (FDE) is a common type of drug eruption seen in skin clinics. It is characterized by solitary or multiple, round to oval erythematous patches with dusky red centers, some of which may progress to bulla formation. Bullous FDE may be caused by a number of drugs. We hereby describe a case of azithromycin-induced bullous FDE; to the best of our knowledge, this is the first such case being reported.

  6. Phenotype Standardization for Drug Induced Kidney Disease

    PubMed Central

    Mehta, Ravindra L; Awdishu, Linda; Davenport, Andrew; Murray, Patrick; Macedo, Etienne; Cerda, Jorge; Chakaravarthi, Raj; Holden, Arthur; Goldstein, Stuart L.

    2015-01-01

    Drug induced kidney disease is a frequent cause of renal dysfunction; however, there are no standards to identify and characterize the spectrum of these disorders. We convened a panel of international, adult and pediatric, nephrologists and pharmacists to develop standardized phenotypes for drug induced kidney disease as part of the phenotype standardization project initiated by the International Serious Adverse Events Consortium. We propose four phenotypes of drug induced kidney disease based on clinical presentation: acute kidney injury, glomerular, tubular and nephrolithiasis, along with primary and secondary clinical criteria to support the phenotype definition, and a time course based on the KDIGO/AKIN definitions of acute kidney injury, acute kidney disease and chronic kidney disease. Establishing causality in drug induced kidney disease is challenging and requires knowledge of the biological plausibility for the specific drug, mechanism of injury, time course and assessment of competing risk factors. These phenotypes provide a consistent framework for clinicians, investigators, industry and regulatory agencies to evaluate drug nephrotoxicity across various settings. We believe that this is first step to recognizing drug induced kidney disease and developing strategies to prevent and manage this condition. PMID:25853333

  7. Parkinson Disease Protein DJ-1 Binds Metals and Protects against Metal-induced Cytotoxicity*

    PubMed Central

    BjŲrkblom, Benny; Adilbayeva, Altynai; Maple-GrÝdem, Jodi; Piston, Dominik; ÷kvist, Mats; Xu, Xiang Ming; Brede, Cato; Larsen, Jan Petter; MÝller, Simon Geir

    2013-01-01

    The progressive loss of motor control due to reduction of dopamine-producing neurons in the substantia nigra pars compacta and decreased striatal dopamine levels are the classically described features of Parkinson disease (PD). Neuronal damage also progresses to other regions of the brain, and additional non-motor dysfunctions are common. Accumulation of environmental toxins, such as pesticides and metals, are suggested risk factors for the development of typical late onset PD, although genetic factors seem to be substantial in early onset cases. Mutations of DJ-1 are known to cause a form of recessive early onset Parkinson disease, highlighting an important functional role for DJ-1 in early disease prevention. This study identifies human DJ-1 as a metal-binding protein able to evidently bind copper as well as toxic mercury ions in vitro. The study further characterizes the cytoprotective function of DJ-1 and PD-mutated variants of DJ-1 with respect to induced metal cytotoxicity. The results show that expression of DJ-1 enhances the cells' protective mechanisms against induced metal toxicity and that this protection is lost for DJ-1 PD mutations A104T and D149A. The study also shows that oxidation site-mutated DJ-1 C106A retains its ability to protect cells. We also show that concomitant addition of dopamine exposure sensitizes cells to metal-induced cytotoxicity. We also confirm that redox-active dopamine adducts enhance metal-catalyzed oxidation of intracellular proteins in vivo by use of live cell imaging of redox-sensitive S3roGFP. The study indicates that even a small genetic alteration can sensitize cells to metal-induced cell death, a finding that may revive the interest in exogenous factors in the etiology of PD. PMID:23792957

  8. Tranexamic Acid-Induced Fixed Drug Eruption

    PubMed Central

    Matsumura, Natsuko; Hanami, Yuka; Yamamoto, Toshiyuki

    2015-01-01

    A 33-year-old male showed multiple pigmented patches on his trunk and extremities after he took tranexamic acid for common cold. He stated that similar eruptions appeared when he was treated with tranexamic acid for influenza 10 months before. Patch test showed positive results at 48 h and 72 h by 1% and 10% tranexamic acid at the lesional skin only. To our knowledge, nine cases of fixed drug eruption induced by tranexamic acid have been reported in Japan. Tranexamic acid is a safe drug and frequently used because of its anti-fibrinolytic and anti-inflammatory effects, but caution of inducing fixed drug eruption should be necessary. PMID:26288438

  9. Viral Parkinsonism

    PubMed Central

    Jang, Haeman; Boltz, David A.; Webster, Robert G.; Smeyne, Richard Jay

    2015-01-01

    Parkinson's disease is a debilitating neurological disorder characterized that affects 1-2% of the adult population over 55 years of age. For the vast majority of cases, the etiology of this disorder is unknown, although it is generally accepted that there is a genetic susceptibility to any number of environmental agents. One such agent may be viruses. It has been shown that numerous viruses can enter the nervous system, i.e. they are neurotropic, and induce a number of encephalopathies. One of the secondary consequences of these encephalopathies can be parkinsonism, that is both transient as well as permanent. One of the most highlighted and controversial cases of viral parkinsonism is that which followed the 1918 influenza outbreak and the subsequent induction of von Economo's encephalopathy. In this review, we discuss the neurological sequelae of infection by influenza virus as well as that of other viruses known to induce parkinsonism including Coxsackie, Japanese encephalitis B, St. Louis, West Nile and HIV viruses. PMID:18760350

  10. Dopamine improves exploration after expectancy violations and induces psychotic-like experiences in patients with Parkinson's disease.

    PubMed

    Polner, Bertalan; Moustafa, Ahmed A; Nagy, Helga; Tak√°ts, Annam√°ria; GyŇĎrfi, Orsolya; K√©ri, Szabolcs

    2016-03-11

    Dopamine neurons are sensitive to novel and rewarding events, and dopamine signals can modulate learning in higher-level brain networks. Additionally, dopamine abnormalities appear to be central to the pathophysiology of schizophrenia spectrum disorders. In this study, we investigate the dopaminergic modulation of schizotypal traits and exploration after expectancy violations in Parkinson's disease (PD) patients on dopamine replacement therapy. Exploration after expectancy violations was measured with a latent inhibition and an anomaly categorisation task. Patients with PD had significantly elevated levels of schizotypy and reduced latent inhibition, relative to the controls. Anomaly categorisation was enhanced at trend level among the patients. Dopaminergic antiparkinsonian drugs showed dose-dependent effects: they induced psychotic-like experiences, and at the same time, they disrupted latent inhibition and made categorisation of anomaly more efficient. Most of these findings were replicated in an independent sample of patients with PD. An up-regulated dopamine system in medicated PD patients might tune higher-level brain networks to engage in learning when faced with unexpected information, and therefore hasten the updating of internal models. PMID:26820375

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

    PubMed Central

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

    2010-01-01

    Synopsis Drug-induced movement disorders have dramatically declined with the widespread use of second generation antipsychotics but remain important in clinical practice and for understanding antipsychotic pharmacology. The diagnosis and management of dystonia, parkinsonism, akathisia, catatonia, neuroleptic malignant syndrome and tardive dyskinesia are reviewed in relation to the decreased liability of the second generation antipsychotics contrasted with evidence from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) Schizophrenia Trial. Data from the CATIE trial imply that advantages of second generation antipsychotics in significantly reducing extrapyramidal side effects compared with haloperidol may be diminished when compared with modest doses of lower-potency first generation drugs, that the dichotomy between first and second generation drugs may be oversimplified, and that antipsychotics could be conceptualized as a single drug class with a spectrum of risk for movement disorders depending upon receptor binding affinities and individual patient susceptibility. PMID:21172575

  12. Drug-induced rash: nuisance or threat?

    PubMed

    Wick, Jeannette Y

    2013-03-01

    Drug-induced rash is the most commonly reported drug reaction and occurs in a dizzying array of presentations. Changes in lean and fat body tissue, gastrointestinal acid and mucosal permeability, cardiac output, and renal and hepatic metabolism can affect drug absorption, distribution, metabolism, and elimination. Elders may develop cutaneous eruptions from drugs or biologics and be more sensitive to topical medications. Almost all medications have been associated with rash to some degree. Consultant pharmacists should be able to distinguish between the rashes that are uncomfortable from those that are potentially life-threatening. Some drug therapies tend to induce or aggravate "companion" rashes. With select medications, rash is a clinical indicator that the medication is working. Extensive or unusually painful drug-induced skin conditions are rare, but often require fast action by health care providers to direct the patient to life-saving help. Many of these rashes are associated with high mortality, severe complications, and potential chronic disability. Awareness of the drugs that are most likely to cause a rash can help consultant pharmacists work with the clinical team to arrange appropriate care. PMID:23462025

  13. Remission-inducing drugs in rheumatoid arthritis.

    PubMed Central

    Anastassiades, T. P.

    1980-01-01

    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

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

    PubMed Central

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

    2014-01-01

    Neuroinflammation is a major risk factor in Parkinson 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 [11C](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

  15. [Drug induced psychosis and schizophrenia in youth].

    PubMed

    Bron, B

    1980-01-01

    Among 233 young drug abusers with different drug-induced psychotic syndroms there were 84 patients whose psychosis showed a character of their own. Their drug-history and behaviour, specialities in their former life, in some cases also premorbid personality signs, mainly, however, psychotic diseases in their families and the psychopathological diagnosis showed statistical significant differences to other patients. The time of development of young people is an especially relevant prepsychotic situation, if it is influenced by drugs. There are a number of unanswered questions yet, for example why some patients under similar or equal prerequisites become drug abusers, while others get a psychosis, having its own laws. The cause of a drug-induced psychosis of its own laws among young people needs to be considered in several dimensions: effects of the drug, the individual constitution, factors of the specific personality, psychodynamic, reactive aspects in situations, as well as specific and typical factors in a phase of time. Clinical observation shows essential connections between the effects of the drug and a psychosis, having its own laws. PMID:7414306

  16. Posttraumatic parkinsonism.

    PubMed

    Formisano, Rita; Zasler, Nathan D

    2014-01-01

    Amantadine hydrochloride is one of the most commonly used drugs in the pharmacotherapeutic treatment of disorders of consciousness (DOCs) following traumatic brain injury (TBI). Indeed, its actions as a pro-dopaminergic drug and as an N-methyl-D-aspartate antagonist makes amantadine an interesting candidate to improve consciousness and responsiveness in individuals with DOC, including vegetative state and minimally conscious state. Giacino et al (N Engl J Med. 2012;366(9):819-826) recently reported that amantadine was able to accelerate the functional recovery course of subjects after TBI with DOC, during a 4-week treatment period. Some patients with DOC following severe TBI have been reported to have parkinsonian symptoms. Severe TBI and posttraumatic parkinsonism may share a common midbrain network dysfunction. In fact, both vegetative state and minimally conscious state following severe TBI can include features of akinetic mutism and parkinsonism. Responsiveness to pro-dopaminergic agents in some patients and to deep brain stimulation in others, might depend, respectively, on the integrity, or lack thereof, of the dopaminergic postsynaptic receptors. We are of the strong opinion that more attention should be given to parkinsonian findings in persons with DOC after severe TBI and would advocate for multicenter, randomized, controlled trials to assess risk factors for parkinsonism following severe TBI. PMID:24695262

  17. Mechanistic review of drug-induced steatohepatitis.

    PubMed

    Schumacher, Justin D; Guo, Grace L

    2015-11-15

    Drug-induced steatohepatitis is a rare form of liver injury known to be caused by only a handful of compounds. These compounds stimulate the development of steatohepatitis through their toxicity to hepatocyte mitochondria; inhibition of beta-oxidation, mitochondrial respiration, and/or oxidative phosphorylation. Other mechanisms discussed include the disruption of phospholipid metabolism in lysosomes, prevention of lipid egress from hepatocytes, targeting mitochondrial DNA and topoisomerase, decreasing intestinal barrier function, activation of the adenosine pathway, increasing fatty acid synthesis, and sequestration of coenzyme A. It has been found that the majority of compounds that induce steatohepatitis have cationic amphiphilic structures; a lipophilic ring structure with a side chain containing a cationic secondary or tertiary amine. Within the last decade, the ability of many chemotherapeutics to cause steatohepatitis has become more evident coining the term chemotherapy-associated steatohepatitis (CASH). The mechanisms behind drug-induced steatohepatitis are discussed with a focus on cationic amphiphilic drugs and chemotherapeutic agents. PMID:26344000

  18. Salvianolic Acid B Attenuates Toxin-Induced Neuronal Damage via Nrf2-Dependent Glial Cells-Mediated Protective Activity in Parkinsonís Disease Models

    PubMed Central

    Li, Zhi-Yun; Wei-Ji; Liu, Qi; Ma, Yi-Hui; He, Jiao-Jiang

    2014-01-01

    Salvianolic acid B (SalB), a bioactive compound isolated from the plant-derived medicinal herb Danshen, has been shown to exert various anti-oxidative and anti-inflammatory activities in several neurological disorders. In this study, we sought to investigate the potential protective effects and associated molecular mechanisms of SalB in Parkinsonís disease (PD) models. To determine the neuroprotective effects of SalB in vitro, MPP+- or lipopolysaccharide (LPS)-induced neuronal injury was achieved using primary cultures with different compositions of neurons, microglia and astrocytes. Our results showed that SalB reduced both LPS- and MPP+-induced toxicity of dopamine neurons in a dose-dependent manner. Additionally, SalB treatment inhibited the release of microglial pro-inflammatory cytokines and resulted in an increase in the expression and release of glial cell line-derived neurotrophic factor (GDNF) from astrocytes. Western blot analysis illustrated that SalB increased the expression and nuclear translocation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2). The knockdown of Nrf2 using specific small interfering RNA (siRNA) partially reversed the SalB-induced GDNF expression and anti-inflammatory activity. Moreover, SalB treatment significantly attenuated dopaminergic (DA) neuronal loss, inhibited neuroinflammation, increased GDNF expression and improved the neurological function in MPTP-treated mice. Collectively, these findings demonstrated that SalB protects DA neurons by an Nrf-2 -mediated dual action: reducing microglia activation-mediated neuroinflammation and inducing astrocyte activation-dependent GDNF expression. Importantly the present study also highlights critical roles of glial cells as targets for developing new strategies to alter the progression of neurodegenerative disorders. PMID:24991814

  19. Drug-induced immune neutropenia/agranulocytosis.

    PubMed

    Curtis, Brian R

    2014-01-01

    Neutrophils are the most abundant white blood cell in blood and play a critical role in preventing infections as part of the innate immune system. Reduction in neutrophils below an absolute count of 500 cells/pL is termed severe neutropenia or agranulocytosis. Drug-induced immune neutropenia (DIIN) occurs when drug-dependent antibodies form against neutrophil membrane glycoproteins and cause neutrophil destruction. Affected patients have fever, chills, and infections; severe infections left untreated can result in death. Treatment with granulocyte colony-stimulating factor can hasten neutrophil recovery. Cumulative data show that severe neutropenia or agranulocytosis associated with exposure to nonchemotherapy drugs ranges from approximately 1.6 to 15.4 cases per million population per year. Drugs most often associated with neutropenia or agranulocytosis include dipyrone, diclofenac, ticlopidine, calcium dobesilate, spironolactone, antithyroid drugs (e.g., propylthiouracil), carbamazepine, sulfamethoxazole- trimethoprim, [3-lactam antibiotics, clozapine, levamisole, and vancomycin. Assays used for detection of neutrophil drug-dependent antibodies (DDAbs) include flow cytometry, monoclonal antibody immobilization of granulocyte antigens, enzyme-linked immunosorbent assay, immunoblotting, granulocyte agglutination, and granulocytotoxicity. However, testing for neutrophil DDAbs is rarely performed owing to its complexity and lack of availability. Mechanisms proposed for DIIN have not been rigorously studied, but those that have been studied include drug- or hapten-induced antibody formation and autoantibody production against drug metabolite or protein adducts covalently attached to neutrophil membrane proteins. This review will address acute, severe neutropenia caused by neutrophil-reactive antibodies induced by nonchemotherapy drugs-DIIN PMID:25247619

  20. Drug-induced valvulopathy: an update.

    PubMed

    Elangbam, Chandikumar S

    2010-10-01

    Drug-induced valvulopathy is a serious liability for certain compound classes in development and for some marketed drugs intended for human use. Reports of valvulopathy led to the withdrawal of fenfluramines (anorexigens) and pergolide (antiparkinson drug) from the United States market in 1997 and 2007, respectively. The mechanism responsible for the pathogenesis of valvulopathy by these drugs is likely a result of an "off-target" effect via activation of 5-hydroxytryptamine (5-HT) 2B receptor (5-HT2BR) expressed on heart valve leaflets. Microscopically, the affected valve leaflets showed plaques of proliferative myofibroblasts in an abundant extracellular matrix, composed primarily of glycosaminoglycans. However, the valvular effects caused by fenfluramines and pergolide were not initially predicted from routine preclinical toxicity studies, and to date there are no specific validated animal models or preclinical/toxicologic screens to accurately predict drug-induced valvulopathy. This review covers the structure and function of heart valves and highlights major advances toward understanding the 5-HT2BR-mediated pathogenesis of the lesion and subsequently, development of appropriate animal models using novel techniques/experiments, use of functional screens against 5-HT2BR, and more consistent sampling and pathologic evaluation of valves in preclinical studies that will aid in avoidance of future drug-induced valvulopathy in humans. PMID:20716786

  1. Drug-Induced Long QT Syndrome

    PubMed Central

    Kannankeril, Prince; Darbar, Dawood

    2010-01-01

    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

  2. Drug Induced Hypersensitivity and the HLA Complex

    PubMed Central

    Alfirevic, Ana; Pirmohamed, Munir

    2011-01-01

    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.

  3. GRK3 suppresses L-DOPA-induced dyskinesia in the rat model of Parkinsonís disease via its RGS homology domain

    PubMed Central

    Ahmed, Mohamed R.; Bychkov, Evgeny; Li, Lingyong; Gurevich, Vsevolod V.; Gurevich, Eugenia V.

    2015-01-01

    Degeneration of dopaminergic neurons causes Parkinsonís disease. Dopamine replacement therapy with L-DOPA is the best available treatment. However, patients develop L-DOPA-induced dyskinesia (LID). In the hemiparkinsonian rat, chronic L-DOPA increases rotations and abnormal involuntary movements modeling LID, via supersensitive dopamine receptors. Dopamine receptors are controlled by G protein-coupled receptor kinases (GRKs). Here we demonstrate that LID is attenuated by overexpression of GRK3 in the striatum, whereas knockdown of GRK3 by microRNA exacerbated it. Kinase-dead GRK3 and its separated RGS homology domain (RH) suppressed sensitization to L-DOPA, whereas GRK3 with disabled RH did not. RH alleviated LID without compromising anti-akinetic effect of L-DOPA. RH binds striatal Gq. GRK3, kinase-dead GRK3, and RH inhibited accumulation of ?FosB, a marker of LID. RH-dead mutant was ineffective, whereas GRK3 knockdown exacerbated ?FosB accumulation. Our findings reveal a novel mechanism of GRK3 control of the dopamine receptor signaling and the role of Gq in LID. PMID:26043205

  4. Risk of drug-induced congenital defects.

    PubMed

    De Santis, Marco; Straface, Gianluca; Carducci, Brigida; Cavaliere, Anna Franca; De Santis, Lidia; Lucchese, Angela; Merola, Anna Maria; Caruso, Alessandro

    2004-11-10

    Defects attributable to drug therapy represent about 1% of congenital defects of known aetiology. This means that a precautionary attitude and correct use of drugs in fertile, and especially pregnant, women is a feasible form of prevention. Drugs currently in use with proven teratogenic effect number approximately 25, but new pharmaceutical drugs are constantly in preparation. Recognition of a drug-induced teratogenic effect is a complex procedure taking into account not only experimental animal data but also experience in humans. Considering that 40% of pregnancies are not planned, it follows that any drug with known or suspected teratogenic potential must be used only under strict medical control. Also, adequate knowledge on potential teratogenicity of a drug permits modification of therapy before conception. It goes without saying that any drug should be used during pregnancy only if it is essential, and it would be prudent to use only those where adequate information is provided and prior clinical experience is available. Teratology Information Services can assist both physicians and patients when any doubt exists. PMID:15474237

  5. Adjunctive therapy in Parkinsonís disease: the role of rasagiline

    PubMed Central

    Gaines, Kathryn D; Hinson, Vanessa K

    2012-01-01

    Parkinsonís 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 Parkinsonís 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 Parkinsonís disease. Finally, we discuss potential side effects, drug interactions, and other practical aspects concerning the use of rasagiline in Parkinsonís disease. PMID:22802692

  6. Mechanisms of Drug Induced Liver Injury

    PubMed Central

    Yuan, Liyun; Kaplowitz, Neil

    2013-01-01

    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

  7. Contrasting gene expression patterns induced by levodopa and pramipexole treatments in the rat model of Parkinson's disease.

    PubMed

    Taravini, Irene R; Larramendy, Celia; Gomez, Gimena; Saborido, Mariano D; Spaans, Floor; Fresno, Cristůbal; GonzŠlez, GermŠn A; FernŠndez, Elmer; Murer, Mario G; Gershanik, Oscar S

    2016-02-01

    Whether the treatment of Parkinson's disease has to be initiated with levodopa or a D2 agonist like pramipexole remains debatable. Levodopa is more potent against symptoms than D2 agonists, but D2 agonists are less prone to induce motor complications and may have neuroprotective effects. Although regulation of plastic changes in striatal circuits may be the key to their different therapeutic potential, the gene expression patterns induced by de novo treatments with levodopa or D2 agonists are currently unknown. By studying the whole striatal transcriptome in a rodent model of early stage Parkinson's disease, we have identified the gene expression patterns underlying therapeutically comparable chronic treatments with levodopa or pramipexole. Despite the overall relatively small size of mRNA expression changes at the level of individual transcripts, our data show a robust and complete segregation of the transcript expression patterns induced by both treatments. Moreover, transcripts related to oxidative metabolism and mitochondrial function were enriched in levodopa-treated compared to vehicle-treated and pramipexole-treated animals, whereas transcripts related to olfactory transduction pathways were enriched in both treatment groups compared to vehicle-treated animals. Thus, our data reveal the plasticity of genetic striatal networks possibly contributing to the therapeutic effects of the most common initial treatments for Parkinson's disease, suggesting a role for oxidative stress in the long term complications induced by levodopa and identifying previously overlooked signaling cascades as potentially new therapeutic targets. PMID:25963416

  8. Drug-induced neurotoxicity in addiction medicine: From prevention to harm reduction.

    PubMed

    Mohammad Ahmadi Soleimani, S; Ekhtiari, Hamed; Cadet, Jean Lud

    2016-01-01

    Neurotoxicity is considered as a major cause of neurodegenerative disorders. Most drugs of abuse have nonnegligible neurotoxic effects many of which are primarily mediated by several dopaminergic and glutamatergic neurotransmitter systems. Although many researchers have investigated the medical and cognitive consequences of drug abuse, the neurotoxicity induced by these drugs still requires comprehensive attention. The science of neurotoxicity promises to improve preventive and therapeutic strategies for brain disorders such as Alzheimer disease and Parkinson's disease. However, its clinical applications for addiction medicine remain to be defined adequately. This chapter reviews the most commonly discussed mechanisms underlying neurotoxicity induced by common drugs of abuse including amphetamines, cocaine, opiates, and alcohol. In addition, the known factors that trigger and/or predispose to drug-induced neurotoxicity are discussed. These factors include drug-related, individual-related, and environmental insults. Moreover, we introduce some of the potential pharmacological antineurotoxic interventions deduced from experimental animal studies. These interventions involve various targets such as dopaminergic system, mitochondria, cell death signaling, and NMDA receptors, among others. We conclude the chapter with a discussion of addicted patients who might benefit from such interventions. PMID:26806769

  9. Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson's disease patients.

    PubMed

    Politis, Marios; Wu, Kit; Loane, Clare; Brooks, David J; Kiferle, Lorenzo; Turkheimer, Federico E; Bain, Peter; Molloy, Sophie; Piccini, Paola

    2014-03-01

    Levodopa-induced dyskinesias (LIDs) are the most common and disabling adverse motor effect of therapy in Parkinson's disease (PD) patients. In this study, we investigated serotonergic mechanisms in LIDs development in PD patients using 11C-DASB PET to evaluate serotonin terminal function and 11C-raclopride PET to evaluate dopamine release. PD patients with LIDs showed relative preservation of serotonergic terminals throughout their disease. Identical levodopa doses induced markedly higher striatal synaptic dopamine concentrations in PD patients with LIDs compared with PD patients with stable responses to levodopa. Oral administration of the serotonin receptor type 1A agonist buspirone prior to levodopa reduced levodopa-evoked striatal synaptic dopamine increases and attenuated LIDs. PD patients with LIDs that exhibited greater decreases in synaptic dopamine after buspirone pretreatment had higher levels of serotonergic terminal functional integrity. Buspirone-associated modulation of dopamine levels was greater in PD patients with mild LIDs compared with those with more severe LIDs. These findings indicate that striatal serotonergic terminals contribute to LIDs pathophysiology via aberrant processing of exogenous levodopa and release of dopamine as false neurotransmitter in the denervated striatum of PD patients with LIDs. Our results also support the development of selective serotonin receptor type 1A agonists for use as antidyskinetic agents in PD. PMID:24531549

  10. Foetal Cell Transplantation for Parkinson's Disease: Focus on Graft-Induced Dyskinesia

    PubMed Central

    Tronci, Elisabetta; Fidalgo, Camino; Carta, Manolo

    2015-01-01

    Transplantation of dopamine- (DA-) rich foetal ventral mesencephalic cells emerged as a promising therapy for Parkinson's disease (PD), as it allowed significant improvement of motor symptoms in several PD patients in open-label studies. However, double-blind clinical trials have been largely disappointing. The general agreement in the field is that the lack of standardization of tissue collection and preparation, together with the absence of postsurgical immunosuppression, played a key role in the failure of these studies. Moreover, a further complication that emerged in previous studies is the appearance of the so-called graft-induced dyskinesia (GID), in a subset of grafted patients, which resembles dyskinesia induced by L-DOPA but in the absence of medication. Preclinical evidence pointed to the serotonin neurons as possible players in the appearance of GID. In agreement, clinical investigations have shown that grafted tissue may contain a large number of serotonin neurons, in the order of half of the DA cells; moreover, the serotonin 5-HT1A receptor agonist buspirone has been found to produce significant dampening of GID in grafted patients. In this paper, we will review the recent preclinical and clinical studies focusing on cell transplantation for PD and on the mechanisms underlying GID. PMID:26881178

  11. BCG Vaccine-Induced Neuroprotection in a Mouse Model of Parkinson's Disease

    PubMed Central

    Yong, Jing; Lacan, Goran; Dang, Hoa; Hsieh, Terry; Middleton, Blake; Wasserfall, Clive; Tian, Jide; Melega, William P.; Kaufman, Daniel L.

    2011-01-01

    There is a growing interest in using vaccination with CNS antigens to induce autoreactive T cell responses that home to damaged areas in the CNS and ameliorate neurodegenerative disease. Neuroprotective vaccine studies have focused on administering oligodendrocyte antigens or Copaxoneģ in complete Freund's adjuvant (CFA). Theoretical considerations, however, suggest that vaccination with a neuronal antigen may induce more robust neuroprotective immune responses. We assessed the neuroprotective potential of vaccines containing tyrosine hydroxylase (a neuronal protein involved in dopamine synthesis) or Copaxoneģ in CFA in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Surprisingly, we observed that the main beneficial factor in these vaccines was the CFA. Since the major immunogenic component in CFA is Mycobacterium tuberculosis, which closely related to the bacille Calmette-Guťrin (BCG) that is used in human vaccines, we tested BCG vaccination in the MPTP mouse model. We observed that BCG vaccination partially preserved markers of striatal dopamine system integrity and prevented an increase in activated microglia in the substantia nigra of MPTP-treated mice. These results support a new neuroprotective vaccine paradigm in which general (nonself-reactive) immune stimulation in the periphery can limit potentially deleterious microglial responses to a neuronal insult and exert a neurorestorative effect in the CNS. Accordingly, BCG vaccination may provide a new strategy to augment current treatments for a wide range of neuropathological conditions. PMID:21304945

  12. BCG vaccine-induced neuroprotection in a mouse model of Parkinson's disease.

    PubMed

    Yong, Jing; Lacan, Goran; Dang, Hoa; Hsieh, Terry; Middleton, Blake; Wasserfall, Clive; Tian, Jide; Melega, William P; Kaufman, Daniel L

    2011-01-01

    There is a growing interest in using vaccination with CNS antigens to induce autoreactive T cell responses that home to damaged areas in the CNS and ameliorate neurodegenerative disease. Neuroprotective vaccine studies have focused on administering oligodendrocyte antigens or Copaxoneģ in complete Freund's adjuvant (CFA). Theoretical considerations, however, suggest that vaccination with a neuronal antigen may induce more robust neuroprotective immune responses. We assessed the neuroprotective potential of vaccines containing tyrosine hydroxylase (a neuronal protein involved in dopamine synthesis) or Copaxoneģ in CFA in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Surprisingly, we observed that the main beneficial factor in these vaccines was the CFA. Since the major immunogenic component in CFA is Mycobacterium tuberculosis, which closely related to the bacille Calmette-Guťrin (BCG) that is used in human vaccines, we tested BCG vaccination in the MPTP mouse model. We observed that BCG vaccination partially preserved markers of striatal dopamine system integrity and prevented an increase in activated microglia in the substantia nigra of MPTP-treated mice. These results support a new neuroprotective vaccine paradigm in which general (nonself-reactive) immune stimulation in the periphery can limit potentially deleterious microglial responses to a neuronal insult and exert a neurorestorative effect in the CNS. Accordingly, BCG vaccination may provide a new strategy to augment current treatments for a wide range of neuropathological conditions. PMID:21304945

  13. Ameliorative effects of baicalein in MPTP-induced mouse model of Parkinson's disease: A microarray study.

    PubMed

    Gao, Li; Li, Chao; Yang, Ran-Yao; Lian, Wen-Wen; Fang, Jian-Song; Pang, Xiao-Cong; Qin, Xue-Mei; Liu, Ai-Lin; Du, Guan-Hua

    2015-06-01

    Baicalein, a flavonoid from Scutellaria baicalensis Georgi, has been shown to possess neuroprotective properties. The purpose of this study was to explore the effects of baicalein on motor behavioral deficits and gene expression in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice model of Parkinson's disease (PD). The behavioral results showed that baicalein significantly improves the abnormal behaviors in MPTP-induced mice model of PD, as manifested by shortening the total time for climbing down the pole, prolonging the latent periods of rotarod, and increasing the vertical movements. Using cDNA microarray and subsequent bioinformatic analyses, it was found that baicalein significantly promotes the biological processes including neurogenesis, neuroblast proliferation, neurotrophin signaling pathway, walking and locomotor behaviors, and inhibits dopamine metabolic process through regulation of gene expressions. Based on analysis of gene co-expression networks, the results indicated that the regulation of genes such as LIMK1, SNCA and GLRA1 by baicalein might play central roles in the network. Our results provide experimental evidence for the potential use of baicalein in the treatment of PD, and revealed gene expression profiles, biological processes and pathways influenced by baicalein in MPTP-treated mice. PMID:25895692

  14. Neurosteroid allopregnanolone attenuates cognitive dysfunctions in 6-OHDA-induced rat model of Parkinson's disease.

    PubMed

    Nezhadi, Akram; Sheibani, Vahid; Esmaeilpour, Khadijeh; Shabani, Mohammad; Esmaeili-Mahani, Saeed

    2016-05-15

    Cognitive deficits have an extensive influence on the quality of life of the Parkinson's disease (PD) patients. Previous studies have shown that lack of steroid hormones have an important role in the development of PD. Therefore, in this study the effects of neurosteroid allopregnanolone (Allo) on the PD-induced cognitive disorders were assessed. To simulate PD, 6-hydroxydopamine (6-OHDA) was injected into the rat's substantia nigra. Allo (5 and 20mg/kg, orally) were administered on the day after the 6-OHDA injection and continued during the entire treatment period (two months). Cognitive behaviors were assessed by Moris water maze (MWM), novel object recognition (NOR) and object location tasks. The data indicated that Allo significantly improved the 6-OHDA-induced cognitive impairment which revealed by the reduction of time spent to find out platform (escape latency) and the increase of retention time in MWM test and also with increase in the exploration index in NOR and object location tasks. Present study strongly supports the pro-cognitive property of allopregnanolone in PD. PMID:26970579

  15. Revisiting oxidative stress and mitochondrial dysfunction in the pathogenesis of Parkinson disease--resemblance to the effect of amphetamine drugs of abuse.

    PubMed

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

    2012-11-01

    Parkinson disease (PD) is a chronic and progressive neurological disease associated with a loss of dopaminergic neurons. In most cases the disease is sporadic but genetically inherited cases also exist. One of the major pathological features of PD is the presence of aggregates that localize in neuronal cytoplasm as Lewy bodies, mainly composed of ?-synuclein (?-syn) and ubiquitin. The selective degeneration of dopaminergic neurons suggests that dopamine itself may contribute to the neurodegenerative process in PD. Furthermore, mitochondrial dysfunction and oxidative stress constitute key pathogenic events of this disorder. Thus, in this review we give an actual perspective to classical pathways involving these two mechanisms of neurodegeneration, including the role of dopamine in sporadic and familial PD, as well as in the case of abuse of amphetamine-type drugs. Mutations in genes related to familial PD causing autosomal dominant or recessive forms may also have crucial effects on mitochondrial morphology, function, and oxidative stress. Environmental factors, such as MPTP and rotenone, have been reported to induce selective degeneration of the nigrostriatal pathways leading to ?-syn-positive inclusions, possibly by inhibiting mitochondrial complex I of the respiratory chain and subsequently increasing oxidative stress. Recently, increased risk for PD was found in amphetamine users. Amphetamine drugs have effects similar to those of other environmental factors for PD, because long-term exposure to these drugs leads to dopamine depletion. Moreover, amphetamine neurotoxicity involves ?-syn aggregation, mitochondrial dysfunction, and oxidative stress. Therefore, dopamine and related oxidative stress, as well as mitochondrial dysfunction, seem to be common links between PD and amphetamine neurotoxicity. PMID:22967820

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

    PubMed

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

    2013-09-01

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

  17. Current approaches to the treatment of Parkinsonís disease

    PubMed Central

    Jankovic, Joseph; Aguilar, L Giselle

    2008-01-01

    Enormous progress has been made in the treatment of Parkinsonís 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 ďwearing offĒ 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

  18. Drug induced acute pancreatitis: Does it exist?

    PubMed Central

    Tenner, Scott

    2014-01-01

    As the incidence of acute pancreatitis continues to rise, establishing the etiology in order to prevent recurrence is important. Although the etiology of acute pancreatitis is not difficult in the majority of patients, almost a quarter of patients are initially labeled as having idiopathic acute pancreatitis. When confronted with a patient with acute pancreatitis and no clear etiology defined as an absence alcoholism, gallstones (ultrasound and/or MRI), a normal triglyceride level, and absence of tumor, it often appears reasonable to consider a drug as the cause of acute pancreatitis. Over 100 drugs have been implicated by case reports as causing acute pancreatitis. While some of these case reports are well written, many case reports represent poorly written experiences of the clinician simply implicating a drug without a careful evaluation. Over-reliance on case reports while ignoring randomized clinical trials and large pharmacoepidemiologic surveys has led to confusion about drug induced acute pancreatitis. This review will explain that drug induced acute pancreatitis does occur, but it is rare, and over diagnosis leads to misconceptions about the disease resulting in inappropriate patient care, increased litigation and a failure to address the true entity: idiopathic acute pancreatitis. PMID:25469020

  19. Drug-Induced Hyperglycaemia and Diabetes.

    PubMed

    Fathallah, Neila; Slim, Raoudha; Larif, Sofien; Hmouda, Houssem; Ben Salem, Chaker

    2015-12-01

    Drug-induced hyperglycaemia and diabetes is a global issue. It may be a serious problem, as it increases the risk of microvascular and macrovascular complications, infections, metabolic coma and even death. Drugs may induce hyperglycaemia through a variety of mechanisms, including alterations in insulin secretion and sensitivity, direct cytotoxic effects on pancreatic cells and increases in glucose production. Antihypertensive drugs are not equally implicated in increasing serum glucose levels. Glycaemic adverse events occur more frequently with thiazide diuretics and with certain beta-blocking agents than with calcium-channel blockers and inhibitors of the renin-angiotensin system. Lipid-modifying agents may also induce hyperglycaemia, and the diabetogenic effect seems to differ between the different types and daily doses of statins. Nicotinic acid may also alter glycaemic control. Among the anti-infectives, severe life-threatening events have been reported with fluoroquinolones, especially when high doses are used. Protease inhibitors and, to a lesser extent, nucleoside reverse transcriptase inhibitors have been reported to induce alterations in glucose metabolism. Pentamidine-induced hyperglycaemia seems to be related to direct dysfunction in pancreatic cells. Phenytoin and valproic acid may also induce hyperglycaemia. The mechanisms of second-generation antipsychotic-associated hyperglycaemia, diabetes mellitus and ketoacidosis are complex and are mainly due to insulin resistance. Antidepressant agents with high daily doses seem to be more frequently associated with an increased risk of diabetes. Ketoacidosis may occur in patients receiving beta-adrenergic stimulants, and theophylline may also induce hyperglycaemia. Steroid diabetes is more frequently associated with high doses of glucocorticoids. Some chemotherapeutic agents carry a higher risk of hyperglycaemia, and calcineurin inhibitor-induced hyperglycaemia is mainly due to a decrease in insulin secretion. Hyperglycaemia has been associated with oral contraceptives containing high doses of oestrogen. Growth hormone therapy and somatostatin analogues may also induce hyperglycaemia. Clinicians should be aware of medications that may alter glycaemia. Efforts should be made to identify and closely monitor patients receiving drugs that are known to induce hyperglycaemia. PMID:26370106

  20. Drug-induced glaucomas: mechanism and management.

    PubMed

    Tripathi, Ramesh C; Tripathi, Brenda J; Haggerty, Chris

    2003-01-01

    Glaucoma comprises a heterogeneous group of diseases that have in common a characteristic optic neuropathy and visual field defects, for which elevated intraocular pressure is the major risk factor. The level of intraocular pressure within the eye depends on the steady state of formation and drainage of the clear watery fluid, called the aqueous humour, in the anterior chamber of the eye. An obstruction in the circulatory pathway of aqueous humour causes an elevation in intraocular pressure. Because intraocular pressure is the most modifiable parameter, therapeutic measures (medical and surgical) are aimed at reducing the pressure to protect against optic nerve damage. Glaucomatous optic neuropathy results from degeneration of the axonal nerve fibres in the optic nerve and death of their cell bodies, the retinal ganglion cells. Clinical examination of the optic nerve head or disc and the peripapillary nerve fibre layer of the retina reveals specific changes, and the resulting visual field defects can be documented by perimetry. Glaucoma can be classified into four main groups: primary open-angle glaucoma; angle-closure glaucoma; secondary glaucoma; and developmental glaucoma. Drug-induced glaucoma should be considered as a form of secondary glaucoma because it is brought about by specific systemic or topical medications. Although there is a high prevalence of glaucoma worldwide, the incidence of drug-induced glaucoma is uncertain. Drugs that cause or exacerbate open-angle glaucoma are mostly glucocorticoids. Several classes of drugs, including adrenergic agonists, cholinergics, anticholinergics, sulpha-based drugs, selective serotonin reuptake inhibitors, tricyclic and tetracyclic antidepressants, anticoagulants and histamine H(1) and H(2) receptor antagonists, have been reported to induce or precipitate acute angle-closure glaucoma, especially in individuals predisposed with narrow angles of the anterior chamber. In some instances, bilateral involvement and even blindness have occurred. In this article, the mechanism and management of drug-induced glaucomatous disease of the eye are emphasised. Although the product package insert may mention glaucoma as a contraindication or as an adverse effect, the type of glaucoma is usually not specified. Clinicians should be mindful of the possibility of drug-induced glaucoma, whether or not it is listed as a contraindication and, if in doubt, consult an ophthalmologist. PMID:12908846

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

    PubMed Central

    Kim, Grace K.

    2010-01-01

    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

  2. Michael J. Fox Foundation for Parkinson's Research

    MedlinePLUS

    ... SEE WHAT HAPPENS Our single, urgent goal: Eliminate Parkinson's disease in our lifetime. Today we are the ... leaders in an article on the history of Parkinson's and the promise of drug development toward a ...

  3. Cyclosporine A and MnTMPyP Alleviate ?-Synuclein Expression and Aggregation in Cypermethrin-Induced Parkinsonism.

    PubMed

    Agrawal, Sonal; Dixit, Anubhuti; Singh, Ashish; Tripathi, Pratibha; Singh, Dhirendra; Patel, Devendra Kumar; Singh, Mahendra Pratap

    2015-12-01

    Cypermethrin induces the mitochondrial dysfunction and oxidative damage to the nigrostriatal dopaminergic neurons leading to Parkinsonism in rats. Despite ?-synuclein aggregation is reported to be critical in Parkinson's disease, its role and alliance with the mitochondrial dysfunction and oxidative damage leading to cypermethrin-induced Parkinsonism have not yet been deciphered. The present study aimed to examine the effect of cypermethrin on the expression and aggregation of ?-synuclein and its subsequent connection with oxidative damage and mitochondrial dysfunction leading to the nigrostriatal dopaminergic neurodegeneration in the presence or absence of a mitochondrial membrane transition pore opening inhibitor, cyclosporine A and a superoxide dismutase/catalase mimetic, manganese (III) tetrakis (1-methyl-4-pyridyl) porphyrin pentachloride (MnTMPyP). The expression of ?-synuclein, 3-nitrotyrosine (3-NT), 4-hydroxynonenal (4-HNE)-modified proteins, mitochondrial dysfunction-dependent apoptotic proteins, nitrite content, lipid peroxidation (LPO) and number of tyrosine hydroxylase (TH)-positive neurons were estimated in the substantia nigra and dopamine content in the striatum of control and treated rats employing standard procedures. Cypermethrin augmented the expression of ?-synuclein, 3-NT, 4-HNE-modified proteins, caspase-3, mitochondrial Bax and cytosolic cytochrome-c along with nitrite and LPO and reduced the expression of cytosolic Bax, mitochondrial cytochrome-c, dopamine and number of TH-positive neurons. Cyclosporine A or MnTMPyP alleviated the expression and aggregation of ?-synuclein along with indicators of the mitochondrial dysfunction, oxidative damage and dopaminergic neurodegeneration. The results demonstrate that cypermethrin induces ?-synuclein expression and aggregation while cyclosporine A or MnTMPyP rescues from ?-synuclein over-expression and aggregation along with the mitochondrial dysfunction and oxidative damage leading to Parkinsonism in rats. PMID:25370934

  4. Gadd45ő≤ ameliorates L-DOPA-induced dyskinesia in a Parkinson's disease mouse model.

    PubMed

    Park, Hye-Yeon; Ryu, Young-Kyoung; Kim, Yong-Hoon; Park, Tae-Shin; Go, Jun; Hwang, Jung Hwan; Choi, Dong-Hee; Rhee, Myungchull; Lee, Chul-Ho; Kim, Kyoung-Shim

    2016-05-01

    The dopamine precursor 3,4-dihydroxyphenyl-l-alanine (L-DOPA) is currently the most efficacious pharmacotherapy for Parkinson's disease (PD). However, long-term L-DOPA treatment leads to the development of abnormal involuntary movements (AIMs) in patients and animal models of PD. Recently, involvement of growth arrest and DNA damage-inducible 45ő≤ (Gadd45ő≤) was reported in neurological and neurobehavioral dysfunctions. However, little is known about the role of Gadd45ő≤ in the dopaminergic nigrostriatal pathway or L-DOPA-induced dyskinesia (LID). To address this issue, we prepared an animal model of PD using unilateral 6-hydroxydopamine (6-OHDA) lesions in the substantia nigra of Gadd45ő≤(+/+) and Gadd45ő≤(-/-) mice. Dyskinetic symptoms were triggered by repetitive administration of L-DOPA in these 6-OHDA-lesioned mice. Whereas dopamine denervation in the dorsal striatum decreased Gadd45ő≤ mRNA, chronic L-DOPA treatment significantly increased Gadd45ő≤ mRNA expression in the 6-OHDA-lesioned striatum of wild-type mice. Using unilaterally 6-OHDA-lesioned Gadd45ő≤(+/+) and Gadd45ő≤(-/-) mice, we found that mice lacking Gadd45ő≤ exhibited long-lasting increases in AIMs following repeated administration of L-DOPA. By contrast, adeno-associated virus-mediated expression of Gadd45ő≤ in the striatum reduced AIMs in Gadd45ő≤ knockout mice. The deficiency of Gadd45ő≤ in LID increased expression of őĒFosB and c-Fos in the lesioned striatum 90min after the last administration of L-DOPA following 11days of daily L-DOPA treatments. These data suggest that the increased expression of Gadd45ő≤ induced by repeated administration of L-DOPA may be beneficial in patients with PD. PMID:26875664

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

    PubMed

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

    2013-11-01

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

  6. Induced pluripotent stem cell-based studies of Parkinson's disease: challenges and promises.

    PubMed

    Sanchez-Danes, Adriana; Benzoni, Patrizia; Memo, Maurizio; Dell'Era, Patrizia; Raya, Angel; Consiglio, Antonella

    2013-12-01

    A critical step in the development of effective therapeutics to treat Parkinson's disease (PD) is the identification of molecular pathogenic mechanisms underlying this chronically progressive neurodegenerative disease. However, while animal models have provided valuable information about the molecular basis of PD, the lack of faithful cellular and animal models that recapitulate human pathophysiology is delaying the development of new therapeutics. The reprogramming of somatic cells to induced pluripotent stem cells (iPSC) using delivery of defined combinations of transcription factors is a groundbreaking discovery that opens great opportunities for modeling human diseases, including PD, since iPSC can be generated from patients and differentiated into disease-relevant cell types, which would capture the patients' genetic complexity. Furthermore, human iPSC-derived neuronal models offer unprecedented access to early stages of the disease, allowing the investigation of the events that initiate the pathologic process in PD. Recently, human iPSC-derived neurons from patients with familial and sporadic PD have been generated and importantly they recapitulate some PD-related cell phenotypes, including abnormal ?-synuclein accumulation in vitro, and alterations in the autophagy machinery. This review highlights the current PD iPSC-based models and discusses the potential future research directions of this field. PMID:24040813

  7. Lipoic acid protects dopaminergic neurons in LPS-induced Parkinson's disease model.

    PubMed

    Li, Yan-Hua; He, Qing; Yu, Jie-zhong; Liu, Chun-yun; Feng, Ling; Chai, Zhi; Wang, Qing; Zhang, Hong-zhen; Zhang, Guang-Xian; Xiao, Bao-guo; Ma, Cun-gen

    2015-10-01

    Parkinson's disease (PD) is a chronic neurodegenerative disease of the central nervous system (CNS), characterized by a loss of dopaminergic neurons, which is thought to be caused by both genetic and environmental factors. Recent findings suggest that neuroinflammation may be a pathogenic factor in the onset and progression of sporadic PD. Here we explore the potential therapeutic effect of lipoic acid (LA) on a lipolysaccharide (LPS)-induced inflammatory PD model. Our results for the first time showed that LA administration improved motor dysfunction, protected dopaminergic neurons loss, and decreased ?-synuclein accumulation in the substantia nigra (SN) area of brain. Further, LA inhibited the activation of nuclear factor-?B (NF-?B) and expression of pro-inflammatory molecules in M1 microglia. Taken together, these results suggest that LA may exert a profound neuroprotective effect and is thus a promising anti-neuroinflammatory and anti-oxidative agent for halting the progression of PD. Interventions aimed at either blocking microglia-derived inflammatory mediators or modulating the polarization of microglia may be potentially useful therapies that are worth further investigation. PMID:26084861

  8. p53 signalling mediates acupuncture-induced neuroprotection in Parkinson's disease.

    PubMed

    Park, Ji-Yeun; Choi, Hwan; Baek, Soonbong; Jang, Jaehwan; Lee, Ahreum; Jeon, Songhee; Kim, Jongpil; Park, Hi-Joon

    2015-05-01

    Parkinson's disease (PD) is a progressive neurodegenerative disorder associated with a selective loss of dopamine (DA) neurons in the substantia nigra of the midbrain. Recently, it has been demonstrated that acupuncture treatment has protective effects in PD. However, to date, the molecular mechanisms underlying acupuncture's effect on DA neuronal protection are largely unknown. In this study, we report that p53 signalling mediates the protective effects of acupuncture treatment in a mouse model of PD. We found that the acupuncture treatment in the mouse PD model results in significant recovery to the normal in the context of behaviour and molecular signatures. We found that the gene network associated with p53 signalling is closely involved in the protective effects of acupuncture treatment in PD. Consistent with this idea, we demonstrated that specific knockout of the p53 gene in the midbrain DA neurons abrogates the acupuncture induced protective effects in the mouse model of PD. Thus, these data suggest that p53 signalling mediates the protective effects of acupuncture treatment in PD. PMID:25827815

  9. Sigma-1 receptor deficiency reduces MPTP-induced parkinsonism and death of dopaminergic neurons

    PubMed Central

    Hong, J; Sha, S; Zhou, L; Wang, C; Yin, J; Chen, L

    2015-01-01

    Sigma-1 receptor (ŌÉ1R) has been reported to be decreased in nigrostriatal motor system of Parkinson's disease patients. Using heterozygous and homozygous ŌÉ1R knockout (ŌÉ1R+/‚ąí and ŌÉ1R‚ąí/‚ąí) mice, we investigated the influence of ŌÉ1R deficiency on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-impaired nigrostriatal motor system. The injection of MPTP for 5 weeks in wild-type mice (MPTP-WT mice), but not in ŌÉ1R+/‚ąí or ŌÉ1R‚ąí/‚ąí mice (MPTP-ŌÉ1R+/‚ąí or MPTP-ŌÉ1R‚ąí/‚ąí mice), caused motor deficits and ~40% death of dopaminergic neurons in substantia nigra pars compacta with an elevation of N-methyl-d-aspartate receptor (NMDAr) NR2B phosphorylation. The ŌÉ1R antagonist NE100 or the NR2B inhibitor Ro25-6981 could alleviate the motor deficits and the death of dopaminergic neurons in MPTP-WT mice. By contrast, MPTP-ŌÉ1R+/‚ąí mice treated with the ŌÉ1R agonist PRE084 or MPTP-ŌÉ1R‚ąí/‚ąí mice treated with the NMDAr agonist NMDA appeared to have similar motor deficits and loss of dopaminergic neurons as MPTP-WT mice. The pharmacological or genetic inactivation of ŌÉ1R suppressed the expression of dopamine transporter (DAT) in substantia nigra, which was corrected by NMDA. The activation of ŌÉ1R by PRE084 enhanced the DAT expression in WT mice or ŌÉ1R+/‚ąí mice. By contrast, the level of vesicular monoamine transporter 2 (VMAT2) in ŌÉ1R+/‚ąí mice or ŌÉ1R‚ąí/‚ąí mice had no difference from WT mice. Interestingly, MPTP-WT mice showed the reduction in the levels of DAT and VMAT2, but MPTP-ŌÉ1R‚ąí/‚ąí mice did not. The inactivation of ŌÉ1R by NE100 could prevent the reduction of VMAT2 in MPTP-WT mice. In addition, the activation of microglia cells in substantia nigra was equally enhanced in MPTP-WT mice and MPTP-ŌÉ1R‚ąí/‚ąí mice. The number of activated astrocytes in MPTP-ŌÉ1R‚ąí/‚ąí mice was less than that in MPTP-WT mice. The findings indicate that the ŌÉ1R deficiency through suppressing NMDAr function and DAT expression can reduce MPTP-induced death of dopaminergic neurons and parkinsonism. PMID:26203861

  10. [Iatrogenic and drug-induced hypertension].

    PubMed

    Mounier-Vehier, Claire; BoudghŤne, Fanny; Claisse, Gonzague; Delsart, Pascal

    2015-06-01

    Various toxic or drug agents can induce arterial hypertension, aggravate or limit the efficiency of anti-hypertensive drugs. Iatrogenic and drug-induced hypertension should be well known by the clinicians and the pharmacists, given the impact for driving the management of patients. In the food, an excessive alcohol consumption (more than 30 g per day) and more rarely glycerizine (active ingredient of the licorice) should be systematically looked for in front of a recent hypertension or do not respond to usual treatment. In the list of offending medicines, we must remember ethinyl estradiol contained in the contraception (oral, vaginal ring or transcutaneous patch), non steroidal anti-inflammatory drugs, immunosuppressants (cyclosporine, tacrolimus), vascular endothelial growth factor and its receptor R2 (avastin, inhibitors of receptor tyrosine kinases), recombinant human erythropoietin, sympathomimetics (nasal decongestants), anabolic steroids, bromocriptine (inhibitor of lactation), psychotropes (tricyclics antidepressants, monoamine oxydase inhibitors). The diagnosis of iatrogenic hypertensions should be systematically suspected in front of a suggestive clinical context with a meticulous food questioning because these hypertensions are partially or fully reversible after exposure stops. PMID:26298906

  11. Drug-induced mitochondrial dysfunction and cardiotoxicity.

    PubMed

    Varga, Zolt√°n V; Ferdinandy, Peter; Liaudet, Lucas; Pacher, P√°l

    2015-11-01

    Mitochondria has an essential role in myocardial tissue homeostasis; thus deterioration in mitochondrial function eventually leads to cardiomyocyte and endothelial cell death and consequent cardiovascular dysfunction. Several chemical compounds and drugs have been known to directly or indirectly modulate cardiac mitochondrial function, which can account both for the toxicological and pharmacological properties of these substances. In many cases, toxicity problems appear only in the presence of additional cardiovascular disease conditions or develop months/years following the exposure, making the diagnosis difficult. Cardiotoxic agents affecting mitochondria include several widely used anticancer drugs [anthracyclines (Doxorubicin/Adriamycin), cisplatin, trastuzumab (Herceptin), arsenic trioxide (Trisenox), mitoxantrone (Novantrone), imatinib (Gleevec), bevacizumab (Avastin), sunitinib (Sutent), and sorafenib (Nevaxar)], antiviral compound azidothymidine (AZT, Zidovudine) and several oral antidiabetics [e.g., rosiglitazone (Avandia)]. Illicit drugs such as alcohol, cocaine, methamphetamine, ecstasy, and synthetic cannabinoids (spice, K2) may also induce mitochondria-related cardiotoxicity. Mitochondrial toxicity develops due to various mechanisms involving interference with the mitochondrial respiratory chain (e.g., uncoupling) or inhibition of the important mitochondrial enzymes (oxidative phosphorylation, Szent-Györgyi-Krebs cycle, mitochondrial DNA replication, ADP/ATP translocator). The final phase of mitochondrial dysfunction induces loss of mitochondrial membrane potential and an increase in mitochondrial oxidative/nitrative stress, eventually culminating into cell death. This review aims to discuss the mechanisms of mitochondrion-mediated cardiotoxicity of commonly used drugs and some potential cardioprotective strategies to prevent these toxicities. PMID:26386112

  12. NMR Fingerprints of the Drug-like Natural-Product Space Identify Iotrochotazine A: A Chemical Probe to Study Parkinsonís Disease**

    PubMed Central

    Grkovic, Tanja; Pouwer, Rebecca H; Vial, Marie-Laure; Gambini, Luca; NoŽl, Alba; Hooper, John N A; Wood, Stephen A; Mellick, George D; Quinn, Ronald J

    2014-01-01

    The NMR spectrum of a mixture of small molecules is a fingerprint of all of its components. Herein, we present an NMR fingerprint method that takes advantage of the fact that fractions contain simplified NMR profiles, with minimal signal overlap, to allow the identification of unique spectral patterns. The approach is exemplified in the identification of a novel natural product, iotrochotazine A (1), sourced from an Australian marine sponge Iotrochota sp. Compound 1 was used as a chemical probe in a phenotypic assay panel based on human olfactory neurosphere-derived cells (hONS) from idiopathic Parkinsonís disease patients. Compound 1 at 1 ?m was not cytotoxic but specifically affected the morphology and cellular distribution of lysosomes and early endosomes. PMID:24737726

  13. The Pael-R gene does not mediate the changes in rotenone-induced Parkinson's disease model cells.

    PubMed

    Zou, Ting; Tang, Xiangqi; Huang, Zhiling; Xu, Niangui; Hu, Zhiping

    2014-02-15

    In this study, we established cell models for Parkinson's disease using rotenone. An RNA interference vector targeting Parkin-associated endothelin receptor-like receptor (Pael-R) was transfected into the model cells. The results of reverse-transcription polymerase chain reaction and western blot analysis showed that Pael-R expression was decreased after RNA interference compared with the control group (no treatment) and the model group (rotenone treatment), while the rate of apoptosis and survival of dopaminergic cells did not differ significantly between groups, as detected by flow cytometry and an MTT assay. These experimental findings indicate that the Pael-R gene has no role in the changes in rotenone-induced Parkinson's disease model cells. PMID:25206827

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

    PubMed

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

    2011-09-01

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

  15. Drug-induced fibrotic valvular heart disease.

    PubMed

    Bhattacharyya, Sanjeev; Schapira, Anthony H; Mikhailidis, Dimitri P; Davar, Joseph

    2009-08-15

    The initial association between the development of valvular heart disease and drugs stems from observations made during the use of methysergide and ergotamine for migraine prophylaxis in the 1960s. Since then, the appetite suppressants fenfluramine and dexfenfluramine, the dopamine agonists pergolide and cabergoline, and more recently, the recreational drug ecstasy (3,4 methylenedioxymethamphetamine; MDMA) have been implicated. Results from clinical trials show that drug dose and treatment duration affect both the risk of developing the disease and its severity. The natural history of the disease remains unclear, although regression of valvular lesions after the end of treatment has been reported. Interference with serotonin metabolism and its associated receptors and transporter gene seems a likely mechanism for development of the drug-induced valvular heart disease. Physicians need to balance the benefits of continued therapy with these drugs against possible risks. Further investigation is needed to assist with treatment decisions. Continued vigilance is necessary because several commonly prescribed treatments interact with serotonergic pathways. PMID:19683643

  16. Parkinson's disease-linked mutations in VPS35 induce dopaminergic neurodegeneration.

    PubMed

    Tsika, Elpida; Glauser, Liliane; Moser, Roger; Fiser, Aris; Daniel, Guillaume; Sheerin, Una-Marie; Lees, Andrew; Troncoso, Juan C; Lewis, Patrick A; Bandopadhyay, Rina; Schneider, Bernard L; Moore, Darren J

    2014-09-01

    Mutations in the vacuolar protein sorting 35 homolog (VPS35) gene at the PARK17 locus, encoding a key component of the retromer complex, were recently identified as a new cause of late-onset, autosomal dominant Parkinson's disease (PD). Here we explore the pathogenic consequences of PD-associated mutations in VPS35 using a number of model systems. VPS35 exhibits a broad neuronal distribution throughout the rodent brain, including within the nigrostriatal dopaminergic pathway. In the human brain, VPS35 protein levels and distribution are similar in tissues from control and PD subjects, and VPS35 is not associated with Lewy body pathology. The common D620N missense mutation in VPS35 does not compromise its protein stability or localization to endosomal and lysosomal vesicles, or the vesicular sorting of the retromer cargo, sortilin, SorLA and cation-independent mannose 6-phosphate receptor, in rodent primary neurons or patient-derived human fibroblasts. In yeast we show that PD-linked VPS35 mutations are functional and can normally complement VPS35 null phenotypes suggesting that they do not result in a loss-of-function. In rat primary cortical cultures the overexpression of human VPS35 induces neuronal cell death and increases neuronal vulnerability to PD-relevant cellular stress. In a novel viral-mediated gene transfer rat model, the expression of D620N VPS35 induces the marked degeneration of substantia nigra dopaminergic neurons and axonal pathology, a cardinal pathological hallmark of PD. Collectively, these studies establish that dominant VPS35 mutations lead to neurodegeneration in PD consistent with a gain-of-function mechanism, and support a key role for VPS35 in the development of PD. PMID:24740878

  17. An update on pharmacological, pharmacokinetic properties and drug-drug interactions of rotigotine transdermal system in Parkinson's disease and restless legs syndrome.

    PubMed

    Elshoff, Jan-Peer; Cawello, Willi; Andreas, Jens-Otto; Mathy, Francois-Xavier; Braun, Marina

    2015-04-01

    This narrative review reports on the pharmacological and pharmacokinetic properties of rotigotine, a non-ergolinic D‚āÉ/D‚āā/D‚āĀ dopamine receptor agonist approved for the treatment of early- and advanced-stage Parkinson's disease (PD) and moderate to severe restless legs syndrome (RLS). Rotigotine is formulated as a transdermal patch providing continuous drug delivery over 24 h, with a plasma concentration profile similar to that of administration via continuous intravenous infusion. Absolute bioavailability after 24 h transdermal delivery is 37 % of the applied rotigotine dose. Following a single administration of rotigotine transdermal system (24-h patch-on period), most of the absorbed drug is eliminated in urine and feces as sulphated and glucuronidated conjugates within 24 h of patch removal. The drug shows a high apparent volume of distribution (>2500 L) and a total body clearance of 300-600 L/h. Rotigotine transdermal system provides dose-proportional pharmacokinetics up to supratherapeutic dose rates of 24 mg/24 h, with steady-state plasma drug concentrations attained within 1-2 days of daily dosing. The pharmacokinetics of rotigotine transdermal patch are similar in healthy subjects, patients with early- or advanced-stage PD, and patients with RLS when comparing dose-normalized area under the plasma concentration-time curve (AUC) and maximum plasma drug concentration (Cmax), as well as half-life and other pharmacokinetic parameters. Also, it is not influenced in a relevant manner by age, sex, ethnicity, advanced renal insufficiency, or moderate hepatic impairment. No clinically relevant drug-drug interactions were observed following co-administration of rotigotine with levodopa/carbidopa, domperidone, or the CYP450 inhibitors cimetidine or omeprazole. Also, pharmacodynamics and pharmacokinetics of an oral hormonal contraceptive were not influenced by rotigotine co-administration. Rotigotine was generally well tolerated, with an adverse event profile consistent with dopaminergic stimulation and use of a transdermal patch. These observations, combined with the long-term efficacy demonstrated in clinical studies, support the use of rotigotine as a continuous non-ergot D‚āÉ/D‚āā/D‚āĀ dopamine receptor agonist in the treatment of PD and RLS. PMID:25795100

  18. Overground robot assisted gait trainer for the treatment of drug-resistant freezing of gait in Parkinson disease.

    PubMed

    Pilleri, Manuela; Weis, Luca; Zabeo, Letizia; Koutsikos, Konstantinos; Biundo, Roberta; Facchini, Silvia; Rossi, Simonetta; Masiero, Stefano; Antonini, Angelo

    2015-08-15

    Freezing of Gait (FOG) is a frequent and disabling feature of Parkinson disease (PD). Gait rehabilitation assisted by electromechanical devices, such as training on treadmill associated with sensory cues or assisted by gait orthosis have been shown to improve FOG. Overground robot assisted gait training (RGT) has been recently tested in patients with PD with improvement of several gait parameters. We here evaluated the effectiveness of RGT on FOG severity and gait abnormalities in PD patients. Eighteen patients with FOG resistant to dopaminergic medications were treated with 15 sessions of RGT and underwent an extensive clinical evaluation before and after treatment. The main outcome measures were FOG questionnaire (FOGQ) global score and specific tasks for gait assessment, namely 10 meter walking test (10 MWT), Timed Up and Go test (TUG) and 360į narrow turns (360 NT). Balance was also evaluated through Fear of Falling Efficacy Scale (FFES), assessing self perceived stability and Berg Balance Scale (BBS), for objective examination. After treatment, FOGQ score was significantly reduced (P=0.023). We also found a significant reduction of time needed to complete TUG, 10 MWT, and 360 NT (P=0.009, 0.004 and 0.04, respectively). By contrast the number of steps and the number of freezing episodes recorded at each gait task did not change. FFES and BBS scores also improved, with positive repercussions on performance on daily activity and quality of life. Our results indicate that RGT is a useful strategy for the treatment of drug refractory FOG. PMID:26048047

  19. Advances in understanding drug-induced neuropathies.

    PubMed

    Peltier, Amanda C; Russell, James W

    2006-01-01

    Many commonly used medications have neurotoxic adverse effects; the most common of these is peripheral neuropathy. Neuropathy can be a dose-limiting adverse effect for many medications used in life-threatening conditions, such as malignancy and HIV-related disease. Epidemiological evidence supports previous case reports of HMG-CoA reductase inhibitors (or 'statins') causing an axonal sensorimotor neuropathy or a purely small-fibre neuropathy in some patients. The neuropathy improves when the medication is withdrawn. Despite the association between HMG-CoA reductase inhibitors and neuropathy, the risk is low compared with the significant vascular protective benefits. Oxaliplatin, a new platinum chemotherapy agent designed to have fewer adverse effects than other such agents, has been shown to cause a transient initial dysaesthesia in addition to an axonal polyneuropathy. Thalidomide, an old therapy currently being utilised for new therapeutic indications (e.g. treatment of haematological malignancies), is associated with a painful, axonal sensorimotor neuropathy that does not improve on withdrawal of the drug. Nucleoside reverse transcriptase inhibitors are important components of highly active antiretroviral therapy, but are associated with a sensory neuropathy that is likely to be due to a direct effect of these drugs on mitochondrial DNA replication. New research demonstrates that lactate levels may help discriminate between neuropathy caused by nucleoside analogues and HIV-induced neuropathy. Understanding the mechanism of drug-induced neuropathy has led to advances in preventing this disabling condition. PMID:16454532

  20. Drug-induced myelosuppression : diagnosis and management.

    TOXLINE Toxicology Bibliographic Information

    Carey PJ

    2003-01-01

    Myelosuppression is a common and anticipated adverse effect of cytotoxic chemotherapy. It is a potential but rare idiosyncratic effect with any other drug, but there is a recognised association with a number of higher-risk agents which justify additional vigilance. Genetic risk factors are being identified which may predispose individuals to this reaction with particular drugs. As marker tests become available, dose adjustment or alternative treatment choices may help to avoid more severe reactions. Myelosuppression is potentially life threatening because of the infection and bleeding complications of neutropenia and thrombocytopenia. Strategies for monitoring, early detection, diagnostic confirmation and appropriate supportive care are well developed for cytotoxic therapy. Developments in antimicrobial chemotherapy, blood product transfusion support and growth factor therapy have improved outcomes. These advances are largely applicable to idiosyncratic drug-induced myelosuppression, reinforcing the importance of early recognition and referral to appropriate expertise. Many reactions will resolve on drug withdrawal with appropriate supportive care during the period of cytopenia. Prolonged marrow failure may require more specific treatment with intensive immunosuppression or consideration of bone marrow transplantation.

  1. Optimization of 6-Heterocyclic-2-(1H-pyrazol-1-yl)-N-(pyridin-2-yl)pyrimidin-4-amine as Potent Adenosine A2A Receptor Antagonists for the Treatment of Parkinsonís Disease

    PubMed Central

    2014-01-01

    Parkinsonís disease is a neurodegenerative disease characterized by the motor symptoms of bradykinesia, tremor, and rigidity. Current therapies are based mainly on dopaminergic replacement strategies by administration of either dopamine agonists or dopamine precursor levodopa (L-Dopa). These treatments provide symptomatic relief without slowing or stopping the disease progression, and long-term usage of these drugs is associated with diminished efficacy, motor fluctuation, and dyskinisia. Unfortunately, there had been few novel treatments developed in the past decades. Among nondopaminergic strategies for the treatment of Parkinsonís disease, antagonism of the adenosine A2A receptor has emerged to show great potential. Here we report the optimization of a new chemical scaffold, which achieved exceptional receptor binding affinity and ligand efficiency against adenosine A2A receptor. The leading compounds demonstrated excellent efficacy in the haloperidol induced catalepsy model for Parkinsonís disease. PMID:24922583

  2. Neuroprotective effects of aldehyde dehydrogenase 2 activation in rotenone-induced cellular and animal models of parkinsonism

    PubMed Central

    Chiu, Ching-Chi; Yeh, Tu-Hsueh; Lai, Szu-Chia; Wu-Chou, Yah-Huei; Chen, Che-Hong; Mochly-Rosen, Daria; Huang, Yin-Cheng; Chen, Yu-Jie; Chen, Chao-Lang; Chang, Ya-Ming; Wang, Hung-Li; Lu, Chin-Song

    2015-01-01

    Many studies have shown that mitochondrial aldehyde dehydrogenase 2 (ALDH2) functions as a cellular protector against oxidative stress by detoxification of cytotoxic aldehydes. Within dopaminergic neurons, dopamine is metabolized by monoamine oxidase to yield 3,4-dihydroxyphenylacetaldehyde (DOPAL) then converts to a less toxic acid product by ALDH. The highly toxic and reactive DOPAL has been hypothesized to contribute to the selective neurodegeneration in Parkinsonís disease (PD). In this study, we investigated the neuroprotective mechanism and therapeutic effect of ALDH2 in rotenone models for parkinsonism. Overexpression of wild-type ALDH2 gene, but not the enzymatically deficient mutant ALDH2*2 (E504K), reduced rotenone-induced cell death. Application of a potent activator of ALDH2, Alda-1, was effective in protecting against rotenone-induced apoptotic cell death in both SH-SY5Y cells and primary cultured substantia nigra (SN) dopaminergic neurons. In addition, intraperitoneal administration of Alda-1 significantly reduced rotenone- or MPTP-induced death of SN tyrosine hydroxylase (TH)-positive dopaminergic neurons. The attenuation of rotenone-induced apoptosis by Alda-1 resulted from decreasing ROS accumulation, reversal of mitochondrial membrane potential depolarization, and inhibition of activation of proteins related to mitochondrial apoptotic pathway. The present study demonstrates that ALDH2 plays a crucial role in maintaining normal mitochondrial function to protect against neurotoxicity and that Alda-1 is effective in ameliorating mitochondrial dysfunction and inhibiting mitochondria-mediated apoptotic pathway. These results indicate that ALDH2 activation could be a neuroprotective therapy for PD. PMID:25263579

  3. A Granulomatous Drug Eruption Induced by Entecavir

    PubMed Central

    Yoon, Jimi; Park, Donghwa

    2013-01-01

    Entecavir (Baracludeģ, 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

  4. Zhichan decoction induces differentiation of dopaminergic neurons in Parkinson's disease rats after neural stem cell transplantation

    PubMed Central

    Shi, Huifen; Song, Jie; Yang, Xuming

    2014-01-01

    The goal of this study was to increase the dopamine content and reduce dopaminergic metabolites in the brain of Parkinson's disease rats. Using high-performance liquid chromatography, we found that dopamine and dopaminergic metabolite (dihydroxyphenylacetic acid and homovanillic acid) content in the midbrain of Parkinson's disease rats was increased after neural stem cell transplantation + Zhichan decoction, compared with neural stem cell transplantation alone. Our genetic algorithm results show that dihydroxyphenylacetic acid and homovanillic acid levels achieve global optimization. Neural stem cell transplantation + Zhichan decoction increased dihydroxyphenylacetic acid levels up to 10-fold, while transplantation alone resulted in a 3-fold increment. Homovanillic acid levels showed no apparent change. Our experimental findings show that after neural stem cell transplantation in Parkinson's disease rats, Zhichan decoction can promote differentiation of neural stem cells into dopaminergic neurons. PMID:25206914

  5. Parkinson disease

    MedlinePLUS

    Parkinson disease causes certain brain cells to die. These are the cells that help control movement and ... called dopamine to help control muscle movement. With Parkinson disease, the brain cells that make dopamine slowly ...

  6. Parkinson's Disease

    MedlinePLUS

    ... some have been linked to specific gene mutations. Juvenile Parkinsonism In very rare cases, parkinsonian symptoms may ... the age of 20. This condition is called juvenile parkinsonism. It is most commonly seen in Japan ...

  7. Parkinson's Disease

    MedlinePLUS

    ... You may have seen the actor Michael J. Fox on TV talking about Parkinson's disease. He has ... and help find a cure. Mostly adults (like Fox and boxer Muhammad Ali) get Parkinson's disease. It's ...

  8. Drug-induced spatial dispersion of repolarization

    PubMed Central

    Antzelevitch, Charles

    2008-01-01

    Spatial dispersion of repolarization in the form of transmural, trans-septal and apico-basal dispersion of repolarization creates voltage gradients that inscribe the J wave and T wave of the ECG. Amplification of this spatial dispersion of repolarization (SDR) underlies the development of life-threatening ventricular arrhythmias associated with inherited or acquired ion channelopathies giving rise to the long QT, short QT and Brugada syndromes (BrS). This review focuses on the role of spatial dispersion of repolarization in drug-induced arrhythmogenesis associated with the long QT and BrS. In the long QT syndrome, drug-induced amplification of SDR is often secondary to preferential prolongation of the action potential duration (APD) of M cells, whereas in the BrS, it is thought to be due to selective abbreviation of the APD of right ventricular epicardium. Among the challenges ahead is the identification of a means to quantitate SDR non-invasively. This review also discusses the value of the interval between the peak and end of the T wave (TpeakĖTend, TpĖTe) as an index of SDR and transmural dispersion of repolarization, in particular. PMID:18651395

  9. Women use illicit drug to induce abortion.

    PubMed

    1993-09-15

    Citing information published in 2 Lancet articles (one by the research groups of Dr. Helena Coelho and Dr. Walter Fonseca and another by Sarah Costa and Martin Vessey), this article describes the misuse of the anti-ulcer prescription drug, misoprostol, which is actually obtainable over the counter, to induce abortion in Brazilian women. Its safety and efficacy are questionable. During a 2.5 year survey, Coelho found that 32% of the women admitted to the main obstetric hospital at Fortaleza had developed womb infections. Others hemorrhaged badly enough to require transfusions. Also, one-third of those who needed womb evacuations had used misoprostol or other illicit drugs to induce the miscarriage. Costa and Vessey discovered that 10% of the women studied who finished their pregnancies had initially attempted to use misoprostol as an abortifacient. Costa blames the lack of access to contraception for the rise in abortion attempts. Changes in prescription laws pertaining specifically to misoprostol have reduced its use in this manner. PMID:12179168

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

    PubMed

    Seeman, P; Tallerico, T

    1998-03-01

    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% of D2 receptors, as measured in patients by a variety of radioligands. It has recently been found, however, that the percent occupancy of a receptor by a drug depends on the radioligand used to measure that receptor. Based on this new finding, this review concludes that clozapine clinically occupies high levels of D2 receptors in the absence of any radioligand. This occupancy is estimated to be of the order of 70-80% in the dopamine-rich region of the human striatum, and even higher in the limbic D2-containing regions which are low in endogenous synaptic dopamine. This conclusion arises from two different approaches. One approach is to relate the reported clozapine occupancies in the human striatum with the dissociation constants of the various radioligands at the D2 receptor. This relation extrapolates to approximately 70-80% occupancy by clozapine when clozapine competes with endogenous dopamine at the D2 receptor. The second approach is to calculate the D2 occupancy of each antipsychotic drug, using the average spinal fluid concentration and the correct dissociation constant of the antipsychotic, thereby revealing that all antipsychotic drugs, including clozapine, occupy approximately 70-80% of dopamine D2 receptors in the human striatum, and possibly higher in the limbic regions. As determined by the new dissociation constants, antipsychotic drugs which elicit Parkinsonism (trifluperazine, chlorpromazine, raclopride, haloperidol, fluphenazine, risperidone) bind more tightly than dopamine to D2, while those antipsychotic drugs which elicit little or no Parkinsonism (melperone, seroquel, perlapine, clozapine, remoxipride, molindone, sulpiride, olanzapine, sertindole) bind more loosely than dopamine to D2 receptors. Compared to the tightly bound antipsychotic drugs, the more loosely bound antipsychotics generally require higher clinical doses, require fewer days for clinical adjustment, but may dissociate from the D2 receptor more rapidly and could lead to clinical relapse somewhat earlier than that found with the traditional tightly bound antipsychotic drugs. PMID:9577836

  11. Neurogenesis in Neurotoxin-induced Animal Models for Parkinson's Disease-A Review of the Current Status.

    PubMed

    He, Xi Jun; Nakayama, Hiroyuki

    2009-06-01

    Animal models for Parkinson's disease (PD) are essential for understanding its pathogenesis and for development and testing of new therapies. Discoveries of endogenous neurogenesis in the adult mammalian brain give new insight into the cell-based approach for treatment of neurodegenerative disorders, such as PD. Although a great deal of interest has been focused on endogenous neurogenesis in neurotoxin-induced animal models for PD, it still remains controversial whether neural stem cells migrate into the injured area and contribute to repopulation of depleted dopaminergic neurons in neurotoxin-injured adult brains. The purpose of this review is to examine the data available regarding neurogenesis in neurotoxin-induced animal models of PD. It is hoped that data from the animal investigations available in the literature will promote understanding of the neurotoxin-induced animal models for PD. PMID:22271983

  12. Co-occurrence of parkinsonism and dementia in clinical practice: relevant differential diagnoses.

    PubMed

    Liepelt-Scarfone, I; Jamour, M; Maetzler, W

    2012-01-01

    Co-occurrence of parkinsonism and dementia is commonly observed in the aging population. This narrative review gives an overview of disorders regularly presenting with these symptoms, e.g., idiopathic Parkinson disease with dementia, dementia with Lewy bodies, progressive supranuclear palsy, corticobasal degeneration syndrome, vascular cognitive impairment, drug-induced parkinsonism, and normal-pressure hydrocephalus. Both a thoroughly performed medical history and a comprehensive clinical examination can narrow down relevant differential diagnoses. Characteristic clinical and neuropsychological features are highlighted, including cognitive screening strategies. Neurophysiological and neuropathological aspects of the disorders are briefly discussed to give a better understanding of treatment options. PMID:22278003

  13. Neurotoxicant-induced animal models of Parkinson's disease: understanding the role of rotenone, maneb and paraquat in neurodegeneration.

    PubMed

    Uversky, Vladimir N

    2004-10-01

    The etiologic basis of Parkinson's disease (PD), the second most common age-related neurodegenerative disorder, is unknown. Recent epidemiological and experimental studies indicate that exposure to environmental agents, including a number of agricultural chemicals, may contribute to the pathogenesis of this disorder. Animal models are important tools in experimental medical science for studying the pathogenesis and therapeutic intervention strategies of human diseases. Since many human disorders do not arise spontaneously in animals, characteristic functional changes have to be mimicked by neurotoxic agents. Recently, agricultural chemicals, when administrated systemically, have been shown to reproduce specific features of PD in rodents, thus opening new routes for the development of animal models for this disorder. In addition to a brief historical overview of the toxin-induced PD models, this study provides a detailed description of exiting models in which Parkinsonism is initiated via the exposure of animals to such agricultural chemicals as rotenone, paraquat, and maneb. Suggested neurotoxicity mechanisms of these chemicals are considered, and the major lessons learned from the analysis of pesticide-induced PD models are discussed. PMID:15258850

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

    PubMed Central

    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

    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

  15. Drug-induced immune hemolytic anemia

    MedlinePLUS

    Immune hemolytic anemia secondary to drugs; Anemia - immune hemolytic - secondary to drugs ... In some cases, a drug can cause the immune system to mistake your own red blood cells for foreign substances. The body responds by making ...

  16. Effects of treadmill exercise on hippocampal neurogenesis in an MPTP /probenecid-induced Parkinson's disease mouse model.

    PubMed

    Sung, Yun-Hee

    2015-10-01

    [Purpose] This study aimed to investigate the effect of treadmill exercise on non-motor function, specifically long-term memory, in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid-induced Parkinson's disease mouse model. [Methods] A mouse model of Parkinson's disease was developed by injecting 20‚ÄÖmg/kg of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 250‚ÄÖmg/kg of probenecid (P). We divided in into four groups: probenecid group, probenecid-exercise group, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid group, and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid-exercise group. Mice in the exercise groups ran on treadmill for 30‚ÄÖmin/day, five times per week for 4 weeks. [Results] Latency in the passive avoidance test increased in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid-exercise group compared with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid group. In addition, the number of 5-bromo-2-deoxyuridine/NeuN-positive cells and 5-bromo-2-deoxyuridine/doublecortin-positive cells in the hippocampal dentate gyrus was higher in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid-exercise group than that in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/probenecid group. These changes were associated with the expression of brain-derived neurotrophic factor in the hippocampus. [Conclusion] Our results suggest that treadmill exercise may improve long-term memory in Parkinson's disease mice by facilitating neurogenesis via increased expression of neurotrophic factors. PMID:26644675

  17. Assessing drug-induced dyskinesia in the clinic, the laboratory and the natural environment of patients.

    PubMed

    Carignan, Benoit; Daneault, Jean-FranÁois; Duval, Christian

    2011-01-01

    The assessment of drug-induced dyskinesia (DID) in Parkinson's disease represents a formidable challenge for clinicians and researchers alike. The present review describes the current assessment tools used in the clinic, where different scales have been developed for monitoring levels of DID in patients. We also review laboratory tools used to assess the quantity and characteristics of DID. Finally, we review assessment methods currently in development for monitoring DID and voluntary mobility in the natural living environment of patients. Here, we discuss the strengths and weaknesses of these tools as it pertains to their efficacy in assessing the quantity of DID, its characteristics, as well as its impact on the quality of life of patients. Finally, we discuss ongoing challenges and research questions that may guide future development of assessment methods aimed at monitoring DID and its impact on daily lives of patients. PMID:23939342

  18. An update on risk factors for drug-induced arrhythmias.

    PubMed

    Vlachos, Konstantinos; Georgopoulos, Stamatis; Efremidis, Michael; Sideris, Antonios; Letsas, Konstantinos P

    2016-01-01

    A variety of drugs, either anti-arrhythmics or non-antiarrhythmics, have been associated with drug-induced arrhythmias. Drug-induced arrhythmias are usually observed in the presence of long QT interval or Brugada electrocardiographic pattern. Clinical risk factors, such as female gender, structural heart disease, metabolic and electrolyte abnormalities, bradycardia and conduction disease, increased drug bioavailability, and silent channelopathies act as ''effect amplifiers'' which can make an otherwise relatively safe drug dangerous with regard to risk for polymorphic ventricular tachycardia in the setting of QT interval prolongation. A drug-induced type 1 electrocardiographic pattern of Brugada syndrome is considered highly proarrhythmic. Specific electrocardiographic markers including the corrected QT interval, QRS duration, Tpeak-Tend/QT ratio, and others may predict the risk of arrhythmias in both situations. The present review highlights on the current clinical and electrocardiographic risk factors for prediction of drug-induced arrhythmias. PMID:26460585

  19. Clinically silent idiopathic Parkinson's disease unmasked by valproate use: a brief report.

    PubMed

    Athauda, Dilan; Batley, Robert; Ellis, Catherine

    2015-06-01

    Valproate is an important but uncommon cause of drug induced parkinsonism in the elderly. The development of symptoms after valproate onset is unpredictable, and severity of symptoms is unrelated to plasma levels. However, though the majority of cases improve after drug cessation, parkinsonian symptoms can persist and should prompt investigation into underlying degenerative parkinsonism, as valproate can unmask idiopathic Parkinson's disease in susceptible individuals. This case describes a patient on chronic valproate therapy developing a severely disabling akinetic-rigid syndrome, only partially reversed on stopping valproate. We hypothesise that an increase in valproate dosage unmasked clinically silent Parkinson's disease. The patient made an excellent recovery following cessation of valproate and commencement of dopaminergic therapy. PMID:25365950

  20. Treatment dilemma in comorbidity of schizophrenia and idiopathic Parkinson's disease.

    PubMed

    Lan, Chen-Chia; Su, Tung-Ping; Chen, Ying Sheue; Bai, Ya Mei

    2011-01-01

    Extrapyramidal symptoms are frequently found in patients with schizophrenia. Most are attributed as drug-induced parkinsonism, but comorbidity of idiopathic Parkinson's disease is also possible. We report a 59-year-old male with a diagnosis of schizophrenia for 32 years. Progressive hand tremor was noted from age 53; and then masked face, bradykinesia, dysphagia, sialorrhea; and unsteady shuffling gait became markedly exacerbated, even after discontinuing all antipsychotics for 6 months. The diagnosis of idiopathic Parkinson's disease was confirmed by Tc99m TRODAT SPECT. The dilemma of psychopharmacological treatment to control both disorders was encountered. Based on the review of treatment for Parkinson's disease psychosis (PDP), the recommended treatments suggest the utilization of quetiapine, clozapine, or aripiprazole. However, monotherapy with each of the three atypical antipsychotics failed due to poor efficacy or worsening of parkinsonism symptoms. After a 2-month cautious titration, a combination of quetiapine 50 mg/day and clozapine 37.5 mg/day finally achieved satisfactory efficacy. This case report illustrates the dilemma of treating a patient with schizophrenia and comorbid idiopathic Parkinson's disease, which differed from PDP and required more clinical data for a proper treatment recommendation. PMID:21762841

  1. Sleep alterations in an environmental neurotoxin-induced model of parkinsonism.

    PubMed

    McDowell, Kimberly A; Hadjimarkou, Maria M; Viechweg, Shaun; Rose, Avigail E; Clark, Sarah M; Yarowsky, Paul J; Mong, Jessica A

    2010-11-01

    Parkinson's disease (PD) is classically defined as a motor disorder resulting from decreased dopamine production in the basal ganglia circuit. In an attempt to better diagnose and treat PD before the onset of severe motor dysfunction, recent attention has focused on the early, non-motor symptoms, which include but are not limited to sleep disorders such as excessive daytime sleepiness (EDS) and REM behavioral disorder (RBD). However, few animal models have been able to replicate both the motor and non-motor symptoms of PD. Here, we present a progressive rat model of parkinsonism that displays disturbances in sleep/wake patterns. Epidemiological studies elucidated a link between the Guamanian variant of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) and the consumption of flour made from the washed seeds of the plant Cycas micronesica (cycad). Our study examined the effects of prolonged cycad consumption on sleep/wake activity in male, Sprague-Dawley rats. Cycad-fed rats exhibited an increase in length and/or number of bouts of rapid eye movement (REM) sleep and Non-REM (NREM) sleep at the expense of wakefulness during the active period when compared to control rats. This hypersomnolent behavior suggests an inability to maintain arousal. In addition, cycad-fed rats had significantly fewer orexin cells in the hypothalamus. Our results reveal a novel rodent model of parkinsonism that includes an EDS-like syndrome that may be associated with a dysregulation of orexin neurons. Further characterization of this early, non-motor symptom, may provide potential therapeutic interventions in the treatment of PD. PMID:20713046

  2. Myalgias and Myopathies: Drug-Induced Myalgias and Myopathies.

    PubMed

    Holder, Kathryn

    2016-01-01

    Drugs can cause myalgias and myopathies through a variety of mechanisms. Most drug-induced myopathies are potentially reversible if recognized early. Prescribers should be familiar with common drug-induced myopathies and drug-drug interactions. Clinical presentations can be subacute or acute, ranging from benign muscle pain with mild elevations of serum creatine kinase to fulminant rhabdomyolysis with high creatine kinase levels and potentially life-threatening acute kidney injury. Myalgias and proximal muscle weakness are typical symptoms; onset can be weeks to months after drug exposure. Endocrine disorders and inflammatory etiologies should be excluded because their management may differ from that of drug-induced myopathies. Statin drugs are prescribed widely, and statin-induced myopathy is one of the most commonly recognized and studied myopathies. Risk factors include dose and type of statin prescribed, older age, female sex, genetic predisposition, and concomitant use of other drugs metabolized by the cytochrome P450 system. Glucocorticoids, immunologic drugs, and antimicrobials, as well as other drugs and alcohol, can cause myopathies. Management typically involves discontinuing the drug and switching to an alternative drug or considering an alternative dosing schedule. Referral to a neuromuscular subspecialist is warranted if symptoms persist. PMID:26734833

  3. Role of serotoninergic pathways in drug-induced valvular heart disease and diagnostic features by echocardiography.

    PubMed

    Smith, Sakima A; Waggoner, Alan D; de las Fuentes, Lisa; Davila-Roman, Victor G

    2009-08-01

    Serotonin plays a significant role in the development of carcinoid heart disease, which primarily leads to fibrosis and contraction of right-sided heart valves. Recently, strong evidence has emerged that the use of specific drug classes, such as ergot alkaloids (for migraine headaches), 5-hydroxytryptamine (5-HT or serotonin) uptake regulators or inhibitors (for weight reduction), and ergot-derived dopamine agonists (for Parkinson's disease), can result in left-sided heart valve damage that resembles carcinoid heart disease. Recent studies have suggested that both right-sided and left-sided drug-induced heart valve disease involves increased serotoninergic activity and in particular activation of the 5-HT receptors, including the 5-HT2B receptor subtype, which mediate many of the central and peripheral functions of serotonin. G-proteins that inhibit adenylate cyclase activity mediate the activity of the 5-HT2B receptor subunit, which is widely expressed in a variety of tissues, including liver, lung, heart, and coronary and pulmonary arteries; it has also been reported in embryonic mouse heart, particularly on mouse heart valve leaflets. In this review, the authors discuss the salient features of serotoninergic manifestations of both carcinoid heart disease and drug-induced cardiac valvulopathy, with an emphasis on echocardiographic diagnosis. PMID:19553085

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

    PubMed

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

    2014-11-01

    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

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

    PubMed Central

    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

    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. PMID:25258574

  6. Parkinsonís Psychosis

    PubMed Central

    Zahodne, Laura B.

    2011-01-01

    Opinion statement Psychosis is a leading reason for nursing home placement of patients with Parkinsonís disease (PD). It may also be the single greatest stressor for caregivers of PD patients, it is generally persistent, and its presence markedly increases the risk of mortality. For these reasons, it is essential to recognize and appropriately treat psychosis in PD. Treatment of psychotic symptoms should be initiated after potential medical and environmental causes of delirium (eg, infection) have been eliminated or addressed. Initial pharmacologic changes should include limiting the patientís anti-PD medications to those that are necessary to preserve motor function (ie, eliminating adjunctive agents). Should that fail, an atypical antipsychotic agent is the treatment of choice. Clozapine is presently the gold standard, and quetiapine represents another option because of its ease of use and good tolerability profile. Emerging treatment options include the use of acetylcholinesterase inhibitors, antidepressants, and cognitive behavioral therapy. This article reviews what is currently known about treatment strategies in PD psychosis. PMID:20842582

  7. Pathways to relapse: the neurobiology of drug- and stress-induced relapse to drug-taking.

    PubMed Central

    Stewart, J

    2000-01-01

    Relapse is a major characteristic of drug addiction, and remains the primary problem in treating drug abuse. Without an understanding of the factors that determine renewed drug-seeking, the urge to use drugs, and the persistent craving for them, it is unlikely that health care professionals can provide effective treatment. Using an animal model of relapse, the author and her team are studying factors that induce reinstatement of drug-taking behaviour after short and long periods of abstinence, and they are exploring the neurobiological basis of these effects. In their experiments, rats are trained to self-administer drugs intravenously by pressing 1 of 2 levers. During a subsequent period, the drug is no longer available, but the rats are free to try to obtain the drug (a period of "extinction training"). After extinction of responding, the investigators test for the ability of various events to reinitiate drug-seeking. On this background of renewed drug-seeking or relapse, the investigators search for pharmacological and neurochemical manipulations that might block or attenuate such behaviour. They have found that the 2 most effective events for reinstating responding after both short and long drug-free periods are re-exposure to the drug itself and exposure to a brief period of stress. The critical neurochemical pathways mediating drug-induced relapse are not identical to those mediating stress-induced relapse. Relapse induced by "priming" injections of heroin or cocaine involves activation of the mesolimbic dopaminergic pathways, whereas relapse induced by stress involves actions of corticotropin-releasing factor (CRF) in the brain, and of brain noradrenergic (NE) systems. In addition, evidence shows that CRF and NE may interact at the level of the bed nucleus of the stria terminalis in stress-induced relapse. By contrast, relapse induced by "priming" injections of drugs is relatively unaffected by manipulation of CRF and NE systems of the brain. PMID:10740986

  8. Adverse outcome pathways and drug-induced liver injury testing

    PubMed Central

    Vinken, Mathieu

    2015-01-01

    Drug-induced liver injury is a prominent reason for premarketing and postmarketing drug withdrawal and can be manifested in a number of ways, such as cholestasis, steatosis and fibrosis. The mechanisms driving these toxicological processes have been well characterized and have been emdedded in adverse outcome pathway frameworks in recent years. This paper reviews these constructs and simultaneously illustrates their use in the preclinical testing of drug-induced liver injury. PMID:26119269

  9. Cutaneous drug eruption induced by antihistamines.

    PubMed

    ViŮas, M; Castillo, M J; HernŠndez, N; Ibero, M

    2014-12-01

    Topical application of antihistamines commonly leads to sensitization for patients, but systemic administration of antihistamines rarely induces allergic hypersensitivity, which is mainly linked to phenothiazine-derived and piperazine-derived compounds. We report a 70-year-old woman whose medical history included lichen planus, and who was referred by the dermatology department of our hospital for suspected allergy to corticosteroids. The reason for referral was that on the fourth day of treatment with prednisone and hydroxyzine, the patient presented a bilateral highly pruritic palmar erythema that evolved to a generalized morbilliform rash with subsequent complete desquamation. At a later time, she took cetirizine for a cold, and developed palmar erythema and desquamation. Skin tests (prick and intradermal tests) were performed with steroids, and patch tests (read after 48 and 96†h) with corticosteroids and antihistamines. Controlled oral challenge tests were performed with prednisone and with an alternative antihistamine. Skin tests were negative for all corticosteroids. Patch tests were negative for all corticosteroids, but the antihistamine test was positive for hydroxyzine. Oral challenge with prednisone and dexchlorpheniramine was negative. The patient was diagnosed with cutaneous drug eruption from hydroxyzine and cetirizine. We consider it is important to assess every patient whose skin condition worsens after treatment with antihistamines, especially hydroxyzine, because it is known that antihistamines are often not recognised as the culprit in cases of cutaneous eruption. PMID:25394293

  10. Antituberculosis drug-induced hepatotoxicity in children

    PubMed Central

    Donald, Peter R

    2011-01-01

    Recent increases in the dosages of the essential antituberculosis agents isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA) for use in children recommended by World Health Organization have raised concerns regarding the risk of hepatotoxicity. Published data relating to the incidence and pathogenesis of antituberculosis drug-induced hepatotoxicity (ADIH), particularly in children, is reviewed. Amongst 12,708 children receiving chemoprophylaxis, mainly with INH, but also other combinations of INH, RMP and PZA only 1 case (0.06%) of jaundice was recorded and abnormal liver functions documented in 110 (8%) of the 1225 children studied. Excluding tuberculous meningitis (TBM) 8984 were children treated for tuberculosis disease and jaundice documented in 75 (0.83%) and abnormal liver function tests in 380 (9.9%) of the 3855 children evaluated. Amongst 717 children treated for TBM, however, jaundice occurred in 72 (10.8%) and abnormal LFT were recorded in 174 (52.9%) of those studied. Case reports document the occurrence of ADIH in at least 63 children. Signs and symptoms of ADIH were frequently ignored in the recorded cases. ADIH can occur in children at any age or at any dosage of INH, RMP or PZA, but the incidence of.ADIH is is considerably lower in children than in adults. Children with disseminated forms of disease are at greater risk of ADIH. The use of the higher dosages of INH, RMP and PZA recently recommended by WHO is unlikely to result in a greater risk of ADIH in children. PMID:21772953

  11. N-acetylcysteine prevents rotenone-induced Parkinson's disease in rat: An investigation into the interaction of parkin and Drp1 proteins.

    PubMed

    Rahimmi, Arman; Khosrobakhsh, Farnoosh; Izadpanah, Esmael; Moloudi, Mohammad Raman; Hassanzadeh, Kambiz

    2015-04-01

    There are convincing evidences that oxidative stress has an important role in both the initiation and progression of Parkinson's disease. N-acetylcysteine (NAC) is shown to have antioxidant properties via fortifying glutathione which is one of the main endogenous antioxidant systems. Therefore our study was aimed to evaluate the effect of NAC in management of Parkinson's disease. To this aim, male Wistar rats (10-12 months) received rotenone 2.5mg/kg/48 h intraperitoneally (ip) to induce a Parkinson's disease model. Pretreatment with NAC (25 and 50mg/kg/48 h ip) was administered 1h before the rotenone injection. Three behavioral tests (rotarod, rearing and bar tests) were performed for motor function assessment. Dopamine levels of dopaminergic areas in rat brain including substantia nigra (SN) and striatum (ST) were assessed using high performance liquid chromatography analysis to measure the loss of dopamine. Western blot analysis was also done for parkin and Drp1 (dynamin related protein-1) proteins quantification in SN and ST. Our results indicated that NAC significantly ameliorated the rotenone-induced motor dysfunction and dopamine loss. Furthermore, NAC was able to prevent the rotenone-induced changes in parkin and Drp1 levels in the both studied areas. In conclusion we found that NAC delayed the Parkinson's disease induction by rotenone and this effect might be related to its proved antioxidant effect. PMID:25732239

  12. Drug-induced valvular heart disease: an update.

    PubMed

    Andrejak, Michel; Tribouilloy, Christophe

    2013-05-01

    Numerous reports have shown an unquestionable association between fibrotic valve disease and the following drugs: ergot alkaloids (such as methysergide and ergotamine), ergot-derived dopaminergic agonists (such as pergolide and cabergoline) and drugs metabolized into norfenfluramine (such as fenfluramine, dexfenfluramine and benfluorex). This review focuses on different aspects of drug-induced valvular heart disease: historical background; echocardiographic features; different drugs recognized as being responsible for valvular heart disease; and pathophysiology. PMID:23769407

  13. Biochanin A protects dopaminergic neurons against lipopolysaccharide-induced damage and oxidative stress in a rat model of Parkinson's disease.

    PubMed

    Wang, Jun; He, Can; Wu, Wang-Yang; Chen, Feng; Wu, Yang-Yang; Li, Wei-Zu; Chen, Han-Qing; Yin, Yan-Yan

    2015-11-01

    Parkinson's disease (PD) is the second most common neurodegenerative disease, which is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Accumulated evidences have suggested that oxidative stress is closely associated with the dopaminergic neurodegeneration of PD that can be protected by antioxidants. Biochanin A that is an O-methylated isoflavone in chickpea is investigated to explore its protective mechanism on dopaminergic neurons of the unilateral lipopolysaccharide (LPS)-injected rat. The results showed that biochanin A significantly improved the animal model's behavioral symptoms, prevented the loss of dopaminergic neurons and inhibited the deleterious microglia activation in the LPS-induced rats. Moreover, biochanin A inhibited nicotinamide adenine dinucleotide phosphate oxidase (NADPH oxidase) activation and malondialdehyde (MDA) production, increased superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities in the rat brain. These results suggested that biochanin A might be a natural candidate with protective properties on dopaminergic neurons against the PD. PMID:26394281

  14. A single intramuscular injection of rAAV-mediated mutant erythropoietin protects against MPTP-induced parkinsonism

    PubMed Central

    Dhanushkodi, A.; Akano, E. O.; Roguski, E. E.; Xue, Y.; Rao, S. K.; Matta, S. G.; Rex, T. S.; McDonald, M. P.

    2015-01-01

    Erythropoietin (Epo) is neuroprotective in a number of preparations, but can lead to unacceptably high and even lethal hematocrit levels. Recent reports show that modified Epo variants confer neuroprotection in models of glaucoma and retinal degeneration without raising hematocrit. In this study, neuroprotective effects of two Epo variants (EpoR76E and EpoS71E) were assessed in a model of Parkinsonís disease. The constructs were packaged in recombinant adeno-associated viral (rAAV) vectors and injected intramuscularly. After 3 weeks, mice received five daily injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and were killed 5 weeks later. The MPTP-lesioned mice pretreated with rAAV.eGFP (negative control) exhibited a 7- to 9-Hz tremor and slower latencies to move on a grid test (akinesia). Both of these symptomatic features were absent in mice pretreated with either modified Epo construct. The rAAV.eGFP-treated mice lesioned with MPTP exhibited a 41% reduction in tyrosine hydroxylase (TH)-positive neurons in the substantia nigra. The rAAV.EpoS71E construct did not protect nigral neurons, but neuronal loss in mice pretreated with rAAV.EpoR76E was only half that of rAAV.eGFP controls. Although dopamine levels were normal in all groups, 3,4-dihydroxyphenylacetic acid (DOPAC) was significantly reduced only in MPTP-lesioned mice pre-treated with rAAV.eGFP, indicating reduced dopamine turnover. Analysis of TH-positive fibers in the striatum showed normalized density in MPTP-lesioned mice pretreated with rAAV.EpoS71E, suggesting that enhanced sprouting induced by EpoS71E may have been responsible for normal behavior and dopaminergic tone in these mice. These results show that systemically administered rAAV-generated non-erythropoietic Epo may protect against MPTP-induced parkinsonism by a combination of neuroprotection and enhanced axonal sprouting. PMID:23190369

  15. Systems biology analysis of the proteomic alterations induced by MPP+, a Parkinson's disease-related mitochondrial toxin

    PubMed Central

    Monti, Chiara; Bondi, Heather; Urbani, Andrea; Fasano, Mauro; Alberio, Tiziana

    2015-01-01

    Parkinson's disease (PD) is a complex neurodegenerative disease whose etiology has not been completely characterized. Many cellular processes have been proposed to play a role in the neuronal damage and loss: defects in the proteosomal activity, altered protein processing, increased reactive oxygen species burden. Among them, the involvement of a decreased activity and an altered disposal of mitochondria is becoming more and more evident. The mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP+), an inhibitor of complex I, has been widely used to reproduce biochemical alterations linked to PD in vitro and its precursor, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP), to induce a Parkinson-like syndrome in vivo. Therefore, we performed a meta-analysis of the literature of all the proteomic investigations of neuronal alterations due to MPP+ treatment and compared it with our results obtained with a mitochondrial proteomic analysis of SH-SY5Y cells treated with MPP+. By using open-source bioinformatics tools, we identified the biochemical pathways and the molecular functions mostly affected by MPP+, i.e., ATP production, the mitochondrial unfolded stress response, apoptosis, autophagy, and, most importantly, the synapse funcionality. Eventually, we generated protein networks, based on physical or functional interactions, to highlight the relationships among the molecular actors involved. In particular, we identified the mitochondrial protein HSP60 as the central hub in the protein-protein interaction network. As a whole, this analysis clarified the cellular responses to MPP+, the specific mitochondrial proteome alterations induced and how this toxic model can recapitulate some pathogenetic events of PD. PMID:25698928

  16. Systems biology analysis of the proteomic alterations induced by MPP(+), a Parkinson's disease-related mitochondrial toxin.

    PubMed

    Monti, Chiara; Bondi, Heather; Urbani, Andrea; Fasano, Mauro; Alberio, Tiziana

    2015-01-01

    Parkinson's disease (PD) is a complex neurodegenerative disease whose etiology has not been completely characterized. Many cellular processes have been proposed to play a role in the neuronal damage and loss: defects in the proteosomal activity, altered protein processing, increased reactive oxygen species burden. Among them, the involvement of a decreased activity and an altered disposal of mitochondria is becoming more and more evident. The mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP(+)), an inhibitor of complex I, has been widely used to reproduce biochemical alterations linked to PD in vitro and its precursor, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP), to induce a Parkinson-like syndrome in vivo. Therefore, we performed a meta-analysis of the literature of all the proteomic investigations of neuronal alterations due to MPP(+) treatment and compared it with our results obtained with a mitochondrial proteomic analysis of SH-SY5Y cells treated with MPP(+). By using open-source bioinformatics tools, we identified the biochemical pathways and the molecular functions mostly affected by MPP(+), i.e., ATP production, the mitochondrial unfolded stress response, apoptosis, autophagy, and, most importantly, the synapse funcionality. Eventually, we generated protein networks, based on physical or functional interactions, to highlight the relationships among the molecular actors involved. In particular, we identified the mitochondrial protein HSP60 as the central hub in the protein-protein interaction network. As a whole, this analysis clarified the cellular responses to MPP(+), the specific mitochondrial proteome alterations induced and how this toxic model can recapitulate some pathogenetic events of PD. PMID:25698928

  17. Acute changes in mood induced by subthalamic deep brain stimulation in Parkinson disease are modulated by psychiatric diagnosis

    PubMed Central

    Eisenstein, Sarah A.; Dewispelaere, William B.; Campbell, Meghan C.; Lugar, Heather M.; Perlmutter, Joel S.; Black, Kevin J.; Hershey, Tamara

    2014-01-01

    Background Deep brain stimulation of the subthalamic nucleus (STN DBS) reduces Parkinson disease (PD) motor symptoms but has unexplained, variable effects on mood. Objective The study tested the hypothesis that pre-existing mood and/or anxiety disorders or increased symptom severity negatively affects mood response to STN DBS. Methods Thirty-eight PD participants with bilateral STN DBS and on PD medications were interviewed with Structured Clinical Interview for DSM-IV-TR Axis I Disorders (SCID) and completed Beck Depression Inventory (BDI) and Spielberger State Anxiety Inventory (SSAI) self-reports. Subsequently, during OFF and optimal ON (clinical settings) STN DBS conditions and while off PD medications, motor function was assessed with the United Parkinson Disease Rating Scale (UPDRS, part III), and participants rated their mood with Visual Analogue Scales (VAS), and again completed SSAI. VAS mood variables included anxiety, apathy, valence and emotional arousal. Results STN DBS improved UPDRS scores and mood. Unexpectedly, PD participants diagnosed with current anxiety or mood disorders experienced greater STN DBS-induced improvement in mood than those diagnosed with remitted disorders or who were deemed as having never met threshold criteria for diagnosis. BDI and SSAI scores did not modulate mood response to STN DBS, indicating that clinical categorical diagnosis better differentiates mood response to STN DBS than self-rated symptom severity. SCID diagnosis, BDI and SSAI scores did not modulate motor response to STN DBS. Conclusions PD participants diagnosed with current mood or anxiety disorders are more sensitive to STN DBS-induced effects on mood, possibly indicating altered basal ganglia circuitry in this group. PMID:25017671

  18. Striatal Signaling in L-DOPA-Induced Dyskinesia: Common Mechanisms with Drug Abuse and Long Term Memory Involving D1 Dopamine Receptor Stimulation

    PubMed Central

    Murer, Mario Gustavo; Moratalla, Rosario

    2011-01-01

    Parkinsonís disease is a common neurodegenerative disorder caused by the degeneration of midbrain substantia nigra dopaminergic neurons that project to the striatum. Despite extensive investigation aimed at finding new therapeutic approaches, the dopamine precursor molecule, 3,4-dihydroxyphenyl-l-alanine (l-DOPA), remains the most effective and commonly used treatment. However, chronic treatment and disease progression lead to changes in the brainís response to l-DOPA, resulting in decreased therapeutic effect and the appearance of dyskinesias. l-DOPA-induced dyskinesia (LID) interferes significantly with normal motor activity and persists unless l-DOPA dosages are reduced to below therapeutic levels. Thus, controlling LID is one of the major challenges in Parkinsonís disease therapy. LID is the result of intermittent stimulation of supersensitive D1 dopamine receptors located in the very severely denervated striatal neurons. Through increased coupling to G?olf, resulting in greater stimulation of adenylyl-cyclase, D1 receptors phosphorylate DARPP-32, and other protein kinase A targets. Moreover, D1 receptor stimulation activates extracellular signal-regulated kinase and triggers a signaling pathway involving mammalian target for rapamycin and modifications of histones that results in changes in translation, chromatin modification, and gene transcription. In turn, sensitization of D1 receptor signaling causes a widespread increase in the metabolic response to D1 agonists and changes in the activity of basal ganglia neurons that correlate with the severity of LID. Importantly, different studies suggest that dyskinesias may share mechanisms with drug abuse and long term memory involving D1 receptor activation. Here we review evidence implicating D1 receptor signaling in the genesis of LID, analyze mechanisms that may translate enhanced D1 signaling into dyskinetic movements, and discuss the possibility that the mechanisms underlying LID are not unique to the Parkinsonís disease brain. PMID:21886608

  19. Identification of Drugs Inducing Phospholipidosis by Novel in vitro Data

    PubMed Central

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

    2012-01-01

    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 bloodĖbrain barrier, and compounds that violate Lipinskiís rule of five. Furthermore, we were able to show that PLD-inducing compounds applied in combination additively induce PLD. PMID:22945602

  20. Differences between Drug-Induced and Contrast Media-Induced Adverse Reactions Based on Spontaneously Reported Adverse Drug Reactions

    PubMed Central

    Suh, JinUk; Yang, MyungSuk; Kang, WonKu; Kim, EunYoung

    2015-01-01

    Objective We analyzed differences between spontaneously reported drug-induced (not including contrast media) and contrast media-induced adverse reactions. Methods Adverse drug reactions reported by an in-hospital pharmacovigilance center (St. Mary‚Äôs teaching hospital, Daejeon, Korea) from 2010‚Äď2012 were classified as drug-induced or contrast media-induced. Clinical patterns, frequency, causality, severity, Schumock and Thornton‚Äôs preventability, and type A/B reactions were recorded. The trends among causality tools measuring drug and contrast-induced adverse reactions were analyzed. Results Of 1,335 reports, 636 drug-induced and contrast media-induced adverse reactions were identified. The prevalence of spontaneously reported adverse drug reaction-related admissions revealed a suspected adverse drug reaction-reporting rate of 20.9/100,000 (inpatient, 0.021%) and 3.9/100,000 (outpatients, 0.004%). The most common adverse drug reaction-associated drug classes included nervous system agents and anti-infectives. Dermatological and gastrointestinal adverse drug reactions were most frequently and similarly reported between drug and contrast media-induced adverse reactions. Compared to contrast media-induced adverse reactions, drug-induced adverse reactions were milder, more likely to be preventable (9.8% vs. 1.1%, p < 0.001), and more likely to be type A reactions (73.5% vs. 18.8%, p < 0.001). Females were over-represented among drug-induced adverse reactions (68.1%, p < 0.001) but not among contrast media-induced adverse reactions (56.6%, p = 0.066). Causality patterns differed between the two adverse reaction classes. The World Health Organization‚ÄďUppsala Monitoring Centre causality evaluation and Naranjo algorithm results significantly differed from those of the Korean algorithm version II (p < 0.001). Conclusions We found differences in sex, preventability, severity, and type A/B reactions between spontaneously reported drug and contrast media-induced adverse reactions. The World Health Organization‚ÄďUppsala Monitoring Centre and Naranjo algorithm causality evaluation afforded similar results. PMID:26544039

  1. Vascular parkinsonism.

    PubMed

    Sibon, Igor; Fenelon, Gilles; Quinn, Niall P; Tison, FranÁois

    2004-05-01

    The concept of vascular parkinsonism (VP) has been highly controversial since the initial paper by Critchley in 1929. This review tentatively delineates the extent of the spectrum of VP. Much confusion has arisen owing to the lack of clear definitions of parkinsonism, "atypical parkinsonism" and "pseudoparkinsonism", which we here attempt to define. Confusion has also arisen because incidental vascular lesions occurring in true idiopathic Parkinson's disease (IPD) are up to 10 times more common than parkinsonism due to cerebrovascular disease. VP is clinically heterogeneous. Most often VP is atypical and can be separated from IPD, on the basis of the presence of additional focal signs, and the absence of typical resting tremor in the upper limbs, of true akinesia (i. e.: with decrement and fatiguing of alternating movements), and of definite benefit from levodopa. Exceptionally, VP may mimic IPD or other degenerative diseases such as progressive supranuclear palsy or corticobasal degeneration. The lesions responsible for VP are mostly basal ganglia lacunes and/or subcortical white matter vasculopathy of the "Binswanger" type. Rarely, a single striatal infarct, striatal cribriform cavities or ischaemic changes in the substantia nigra have been described. Vascular "pseudo-parkinsonism" refers to isolated gait disorders called "lower body parkinsonism", "frontal-type gait disorders" or "gait ignition failure" that are reminiscent of, but distinct from, that found in IPD. The pathophysiology of VP is poorly understood. Why some patients develop parkinsonism and others do not, despite the same apparent lesion load, remains a mystery. PMID:15164182

  2. The Neuroprotective Role of Insulin Against MPP(+) -Induced Parkinson's Disease in Differentiated SH-SY5Y Cells.

    PubMed

    Ramalingam, Mahesh; Kim, Sung-Jin

    2016-04-01

    Parkinson's disease (PD) is a common chronic neurodegenerative disorder associated with aging that primarily caused by the death of dopaminergic neurons in the substantia nigra pars compacta (SN). Retinoic acid (RA)-differentiated human neuroblastoma SH-SY5Y cells (SH-SY5Y+RA) have been broadly utilized in studies of mechanisms of the pathogenesis underlying 1-Methyl-4-phenyl pyridinium (MPP(+) )-induced PD models. Here, we investigated the neuroprotective mechanisms of insulin on MPP(+) -induced neurotoxicity on SH-SY5Y+RA cells. Recent studies suggest that insulin has a protective effect against oxidative stress but not been elucidated for PD. In this study, pretreatment of insulin prevented the cell death in a dose dependent manner and lowered nitric oxide (NO) release, reactive oxygen species (ROS), and calcium ion (Ca(2+) ) influx induced by MPP(+) . Insulin also elevated tyrosine hydroxylase (TH) and insulin signaling pathways in dopaminergic neuron through activating PI3K/Akt/GSK-3 survival pathways which in turn inhibits MPP(+) -induced iNOS and ERK activation, and Bax to Bcl-2 ratio. These results suggest that insulin has a protective effect on MPP(+) -neurotoxicity in SH-SY5Y+RA cells. J. Cell. Biochem. 117: 917-926, 2016. © 2015 Wiley Periodicals, Inc. PMID:26364587

  3. Side effect profile of 5-HT treatments for Parkinson's disease and L-DOPA-induced dyskinesia in rats

    PubMed Central

    Lindenbach, D; Palumbo, N; Ostock, C Y; Vilceus, N; Conti, M M; Bishop, C

    2015-01-01

    BACKGROUND AND PURPOSE Treatment of Parkinson's disease (PD) with L-DOPA eventually causes abnormal involuntary movements known as dyskinesias in most patients. Dyskinesia can be reduced using compounds that act as direct or indirect agonists of the 5-HT1A receptor, but these drugs have been reported to worsen PD features and are known to produce Ď5-HT syndromeí, symptoms of which include tremor, myoclonus, rigidity and hyper-reflexia. EXPERIMENTAL APPROACH Sprague-Dawley rats were given unilateral nigrostriatal dopamine lesions with 6-hydroxydopamine. Each of the following three purportedly anti-dyskinetic 5-HT compounds were administered 15 min before L-DOPA: the full 5-HT1A agonist Ī-8-hydroxy-2-dipropylaminotetralin (Ī8-OH-DPAT), the partial 5-HT1A agonist buspirone or the 5-HT transporter inhibitor citalopram. After these injections, animals were monitored for dyskinesia, 5-HT syndrome, motor activity and PD akinesia. KEY RESULTS Each 5-HT drug dose-dependently reduced dyskinesia by relatively equal amounts (Ī8-OH-DPAT ? citalopram ? buspirone), but 5-HT syndrome was higher with Ī8-OH-DPAT, lower with buspirone and not present with citalopram. Importantly, with or without L-DOPA, all three compounds provided an additional improvement of PD akinesia. All drugs tempered the locomotor response to L-DOPA suggesting dyskinesia reduction, but vertical rearing was reduced with 5-HT drugs, potentially reflecting features of 5-HT syndrome. CONCLUSIONS AND IMPLICATIONS The results suggest that compounds that indirectly facilitate 5-HT1A receptor activation, such as citalopram, may be more effective therapeutics than direct 5-HT1A receptor agonists because they exhibit similar anti-dyskinesia efficacy, while possessing a reduced side effect profile. PMID:25175895

  4. Antitubercular drug-induced violent suicide of a hospitalised patient

    PubMed Central

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

    2014-01-01

    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

  5. Glutamate receptors as therapeutic targets for Parkinsonís disease

    PubMed Central

    Johnson, Kari A.; Conn, P. Jeffrey

    2010-01-01

    Parkinsonís 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

  6. Drug-induced impairment of renal function

    PubMed Central

    Pazhayattil, George Sunny; Shirali, Anushree C

    2014-01-01

    Pharmaceutical agents provide diagnostic and therapeutic utility that are central to patient care. However, all agents also carry adverse drug effect profiles. While most of these are clinically insignificant, some drugs may cause unacceptable toxicity that impacts negatively on patient morbidity and mortality. Recognizing adverse effects is important for administering appropriate drug doses, instituting preventive strategies, and withdrawing the offending agent due to toxicity. In the present article, we will review those drugs that are associated with impaired renal function. By focusing on pharmaceutical agents that are currently in clinical practice, we will provide an overview of nephrotoxic drugs that a treating physician is most likely to encounter. In doing so, we will summarize risk factors for nephrotoxicity, describe clinical manifestations, and address preventive and treatment strategies. PMID:25540591

  7. Atomistic Investigation of Cu-Induced Misfolding in the Onset of Parkinson's Disease

    NASA Astrophysics Data System (ADS)

    Rose, Francis; Hodak, Miroslav; Bernholc, Jerry

    2009-03-01

    A nucleation mechanism for the misfolding of ?-synuclein, the protein implicated in Parkinson's Disease (PD), is investigated using computer simulations. Through a combination of ab initio and classical simulation techniques, the conformational evolution of copper-ion-initiated misfolding of ?-synuclein is determined. Based on these investigations and available experimental evidence, an atomistic model detailing the nucleation-initiated pathogenesis of PD is proposed. Once misfolded, the proteins can assemble into fibrils, the primary structural components of the deleterious PD plaques. Our model identifies a process of structural modifications to an initially unfolded ?-synuclein that results in a partially folded intermediate with a well defined nucleation site as a precursor to the fully misfolded protein. The identified pathway can enable studies of reversal mechanisms and inhibitory agents, potentially leading to the development of effective therapies.

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

    PubMed

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

    2012-03-01

    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 a toxin-induced mouse model of PD and measured levels of nine sterol intermediates. We found that lanosterol is significantly (?50%) and specifically reduced in the nigrostriatal regions of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice, indicative of altered lanosterol metabolism during PD pathogenesis. Remarkably, exogenous addition of lanosterol rescued dopaminergic neurons from 1-methyl-4-phenylpyridinium (MPP+)-induced cell death in culture. Furthermore, we observed a marked redistribution of lanosterol synthase from the endoplasmic reticulum to mitochondria in dopaminergic neurons exposed to MPP+, suggesting that lanosterol might exert its survival effect by regulating mitochondrial function. Consistent with this model, we find that lanosterol induces mild depolarization of mitochondria and promotes autophagy. Collectively, our results highlight a novel sterol-based neuroprotective mechanism with direct relevance to PD. PMID:21818119

  9. Protective role of SIRT5 against motor deficit and dopaminergic degeneration in MPTP-induced mice model of Parkinson's disease.

    PubMed

    Liu, Lei; Peritore, Carina; Ginsberg, Jessica; Shih, Jennifer; Arun, Siddharth; Donmez, Gizem

    2015-03-15

    Parkinson's disease (PD) is characterized by progressive loss of nigrostriatal dopaminergic neurons that results in motor deficits including resting tremor, rigidity, bradykinesia, and postural instability. Despite decades of intensive study, the underlying molecular mechanisms are not fully understood. Multiple lines of evidence indicate that mitochondrial dysfunction and oxidative stress contribute to neuronal death, which is the key feature of neurodegeneration. Mitochondria are pivotal organelles that host essential functions in neuronal viability including energy production, oxidative phosphorylation, calcium buffering, redox homeostasis and apoptosis. SIRT5, which localizes in the mitochondrial matrix, is nicotinamide adenine dinucleotide (NAD(+))-dependent histone deacetylase. The physiological and pathophysiological functions of SIRT5 in vivo remain elusive although it is known to be an important energy sensor. Here, we investigated the role of SIRT5 in the pathogenesis of PD mice induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We present evidence that SIRT5 deficiency, by itself, does not affect motor and non-motor functions; however, lack of SIRT5 exacerbates MPTP-induced motor deficits. Consistently, MPTP-exposed SIRT5 knockout mice exhibited more severe nigrostriatal dopaminergic degeneration than that observed in wild-type controls. Furthermore, deletion of SIRT5 leads to a larger decrease, relative to control, in the expression level of manganese superoxide dismutase (SOD2), a mitochondria-specific antioxidant enzyme, after MPTP induction. These findings indicate that SIRT5 ameliorates MPTP-induced nigrostriatal dopaminergic degeneration via preserving mitochondrial antioxidant capacity. PMID:25541039

  10. Adalimumab-induced lichenoid drug eruption.

    PubMed

    El Habr, Constantin; Meguerian, Zarouwi; Sammour, Rita

    2014-01-01

    Tumor necrosis factor (TNF)-? inhibitors are being widely and increasingly used for the management of a spectrum of rheumatologic diseases that are refractory to conventional disease modifying anti-rheumatic drugs. Various cutaneous side effects have been reported after treatment with TNF-? inhibitors. We present a case report of a 26-year-old male patient who developed a lichenoid drug eruption few months after the initiation of adalimumab for the management of Crohn's disease. We also highlight the clinical and histopathologic differences between lichenoid drug eruptions and idiopathic lichen planus. PMID:25807724

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

    PubMed

    Thaler, S; Neumeier, C; Flury, G

    2013-04-01

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

  12. Electroconvulsive therapy in Parkinsonīs disease.

    PubMed

    Calderůn-Fajardo, Humberto; Cervantes-Arriaga, Amin; Llorens-Arenas, Rodrigo; RamŪrez-Bermudez, Jesķs; Ruiz-Chow, Ńngel; RodrŪguez-Violante, Mayela

    2015-10-01

    Purpose To analyze the effectiveness of electroconvulsive therapy for the management of depression and/or psychosis refractory to drug therapy in patients with Parkinson disease.Methods A retrospective study was carried out including patients treated with electroconvulsive therapy during the period between 2002 and 2013. A review of the literature was performed.Results A total of 27 patients were included. In regards to the neuropsychiatric diagnosis, 14 patients had major depression, 12 patients had both psychosis and depression, and only one patient had isolated psychosis. The mean number of electroconvulsive therapy sessions was 12 Ī 2.8. After electroconvulsive therapy, all patients showed a statistically significant improvement in the Brief Psychiatric Rating scale (reduction of 52% points) and Hamilton Depression Rating Scale (reduction of 50% points) independent of the presence of psychosis, depression or both.Conclusion Electroconvulsive therapy is effective for the treatment of refractory neuropsychiatric symptoms in Parkinson's disease. PMID:26331387

  13. Ursodeoxycholic acid induced generalized fixed drug eruption.

    PubMed

    Ozkol, Hatice Uce; Calka, Omer; Dulger, Ahmet Cumhur; Bulut, Gulay

    2014-09-01

    Fixed drug eruption (FDE) is a rare form of drug allergies that recur at the same cutaneous or mucosal site in every usage of drug. Single or multiple round, sharply demarcated and dusky red plaques appear soon after drug exposure. Ursodeoxycholic acid (UDCA: 3őĪ,7ő≤-dihydroxy-5ő≤-cholanic acid) is used for the treatment of cholestatic liver diseases. Some side effects may be observed, such as diarrhea, dyspepsia, pruritus and headaches. We encountered only three cases of lichenoid reaction regarding the use of UDCA among previous studies. In this article, we reported a generalized FDE case related to UDCA intake in a 59-year-old male patient with cholestasis for the first time in the literature. PMID:24147950

  14. 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.

  15. [Molecular mechanism of neuroprotective drugs against oxidative stress-induced neuronal cell death].

    PubMed

    Hara, Hirokazu

    2007-08-01

    NF-E2-related factor-2 (Nrf2), a basic leucine zipper transcription factor, is involved in the expression of numerous detoxifying and antioxidant genes via the antioxidant response element (ARE). Keap1, a cytoplasmic protein, sequesters Nrf2 in the cytoplasm under normal conditions. Various stimuli, including electrophiles and oxidative stress, liberate Nrf2 from Keap1, allowing Nrf2 to translocate into the nucleus and to bind to the ARE. Recently, there is increasing evidence that compounds that stimulate the activation of the Nrf2-ARE pathway may become useful therapeutic drugs for neurodegenerative diseases associated with oxidative stress. Apomorphine (Apo), a dopamine D(1)/D(2) receptor agonist, is used for clinical therapy of Parkinson's disease. On the other hand, Apo is a potent radical scavenger and has protective effects on oxidative stress-induced cell death. We previously reported that pretreatment of human neuroblastoma SH-SY5Y cells with Apo enhanced the protective effects. In addition, we have recently demonstrated that Apo stimulates the translocation of Nrf2 into the nucleus and the transactivation of the ARE. Our findings suggest that not only the function as a radical scavenger, but also the function as an Nrf2-ARE pathway activator may be involved in the neuroprotective effects of Apo on oxidative stress-induced neuronal cell death. In this review, our recent studies on the mechanism underlying Apo-induced neuroprotection are summarized. PMID:17666870

  16. Drug induced lung disease--amiodarone in focus.

    PubMed

    Vasi?, Nada R; Milenkovi?, Branislava A; Peöut, Dragica P; Stevi?, Ruěa S; Jovanovi?, Dragana M

    2014-01-01

    More than 380 medications are known to cause pulmonary toxicity. Selected drugs that are important causes of pulmonary toxicity fall into the following classes: cytotoxic, cardiovascular, anti-inflammatory, antimicrobial, illicit drugs, miscellaneous. The adverse reactions can involve the pulmonary parenchyma, pleura, the airways, pulmonary vascular system, and mediastinum. Drug-induced lung diseases have no pathognomonic clinical, laboratory, physical, radiographic or histological findings. A drug-induced lung disease is usually considered a diagnosis of exclusion of other diseases. The diagnosis of drug-mediated pulmonary toxicity is usually made based on clinical findings. In general, laboratory analyses do not help in establishing the diagnosis. High-resolution computed tomography scanning is more sensitive than chest radiography for defining radiographic abnormalities. The treatment of drug-induced lung disease consists of immediate discontinuation of the offending drug and appropriate management of the pulmonary symptoms. Glucocorticoids have been associated with rapid improvement in gas exchange and reversal of radiographic abnormalities. Before starting any medication, patients should be educated about the potential adverse effects of the drug. Amiodarone is an antiarrhythmic agent used in the treatment of many types of tachyarrhythmia. Amiodarone-caused pulmonary toxicity is a well-known side effect (complication) of this medication. The incidence of amiodarone-induced lung disease is approximately 5-7%. PMID:25546981

  17. Drug-Induced Ocular Hypertension and Angle-Closure Glaucoma.

    PubMed

    Badhu, Badri P; Bhattarai, Balkrishna; Sangraula, Himal P

    2013-01-01

    The objective of this study was to review the available literature on the drugs causing ocular hypertension and glaucoma. Electronic literature search was carried out using the Web sites www.pubmed.gov and www.google.com published through the year 2011. The search words were "drug induced ocular hypertension" and "drug induced glaucoma" used in combination. The articles published or translated into English were studied. Quite a significant number of drugs commonly prescribed by various physicians of different specialties can induce ocular hypertension or glaucoma. A brief account of various drugs that can induce ocular hypertension has been given in this article. Those drugs are parasympatholytics; steroids; anticholinergics, adrenergics, and antidepressants; cholinomimetics; antineoplastic agents; antipsychotic and antiparkinsonism agents; H1 and H2 receptor blockers; botulinum toxin, cardiac agents, and anticoagulants; silicone oil; sulfa drugs; and anesthetic agents. Rational use of these drugs and knowledge of their potential adverse effects can help prevent the devastating complications resulting in loss of vision and compromised quality of life. PMID:26108110

  18. Phenotype standardization for drug-induced kidney disease.

    PubMed

    Mehta, Ravindra L; Awdishu, Linda; Davenport, Andrew; Murray, Patrick T; Macedo, Etienne; Cerda, Jorge; Chakaravarthi, Raj; Holden, Arthur L; Goldstein, Stuart L

    2015-08-01

    Drug-induced kidney disease is a frequent cause of renal dysfunction; however, there are no standards to identify and characterize the spectrum of these disorders. We convened a panel of international, adult and pediatric, nephrologists and pharmacists to develop standardized phenotypes for drug-induced kidney disease as part of the phenotype standardization project initiated by the International Serious Adverse Events Consortium. We propose four phenotypes of drug-induced kidney disease based on clinical presentation: acute kidney injury, glomerular, tubular, and nephrolithiasis, along with the primary and secondary clinical criteria to support the phenotype definition, and a time course based on the KDIGO/AKIN definitions of acute kidney injury, acute kidney disease, and chronic kidney disease. Establishing causality in drug-induced kidney disease is challenging and requires knowledge of the biological plausibility for the specific drug, mechanism of injury, time course, and assessment of competing risk factors. These phenotypes provide a consistent framework for clinicians, investigators, industry, and regulatory agencies to evaluate drug nephrotoxicity across various settings. We believe that this is the first step to recognizing drug-induced kidney disease and developing strategies to prevent and manage this condition. PMID:25853333

  19. Annonacin, a lipophilic inhibitor of mitochondrial complex I, induces nigral and striatal neurodegeneration in rats: possible relevance for atypical parkinsonism in Guadeloupe.

    PubMed

    Champy, Pierre; HŲglinger, GŁnter U; Fťger, Jean; Gleye, Christophe; Hocquemiller, Reynald; Laurens, Alain; Guťrineau, Vincent; Laprťvote, Olivier; Medja, Fadia; LombŤs, Anne; Michel, Patrick P; Lannuzel, Annie; Hirsch, Etienne C; Ruberg, Merle

    2004-01-01

    In Guadeloupe, epidemiological data have linked atypical parkinsonism with fruit and herbal teas from plants of the Annonaceae family, particularly Annona muricata. These plants contain a class of powerful, lipophilic complex I inhibitors, the annonaceous acetogenins. To determine the neurotoxic potential of these substances, we administered annonacin, the major acetogenin of A. muricata, to rats intravenously with Azlet osmotic minipumps (3.8 and 7.6 mg per kg per day for 28 days). Annonacin inhibited complex I in brain homogenates in a concentration-dependent manner, and, when administered systemically, entered the brain parenchyma, where it was detected by matrix-associated laser desorption ionization-time of flight mass spectrometry, and decreased brain ATP levels by 44%. In the absence of evident systemic toxicity, we observed neuropathological abnormalities in the basal ganglia and brainstem nuclei. Stereological cell counts showed significant loss of dopaminergic neurones in the substantia nigra (-31.7%), and cholinergic (-37.9%) and dopamine and cyclic AMP-regulated phosphoprotein (DARPP-32)-immunoreactive GABAergic neurones (-39.3%) in the striatum, accompanied by a significant increase in the number of astrocytes (35.4%) and microglial cells (73.4%). The distribution of the lesions was similar to that in patients with atypical parkinsonism. These data are compatible with the theory that annonaceous acetogenins, such as annonacin, might be implicated in the aetiology of Guadeloupean parkinsonism and support the hypothesis that some forms of parkinsonism might be induced by environmental toxins. PMID:14675150

  20. Parkinson's Disease Dementia

    MedlinePLUS

    ... Find your local chapter Join our online community Parkinson's Disease Dementia Parkinson's disease dementia is an impairment ... disease. About Symptoms Diagnosis Causes & risks Treatments About Parkinson's disease dementia The brain changes caused by Parkinson's ...

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

    SciTech Connect

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

    2009-10-15

    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.

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

    PubMed Central

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

    2009-01-01

    Environmental exposure to neurotoxic metals through various sources including exposure to welding fumes has been linked to an increased incidence of Parkinson's disease (PD). Welding fumes contain many different metals including vanadium typically present as particulates containing vanadium pentoxide (V2O5). However, possible neurotoxic effects of this metal oxide on dopaminergic neuronal cells are not well studied. In the present study, we characterized vanadium-induced oxidative stress-dependent cellular events in cell culture models of PD. V2O5 was neurotoxic to dopaminergic neuronal cells including primary nigral dopaminergic neurons and the EC50 was determined to be 37 ?M in N27 dopaminergic neuronal cell model. The neurotoxic effect was accompanied by a time-dependent uptake of vanadium and upregulation of metal transporter proteins Tf and DMT1 in N27 cells. Additionally, vanadium resulted in a threefold increase in reactive oxygen species generation, followed by release of mitochondrial cytochrome c into cytoplasm and subsequent activation of caspase-9 (>fourfold) and caspase-3 (>ninefold). Interestingly, vanadium exposure induced proteolytic cleavage of native protein kinase Cdelta (PKC?, 72-74 kDa) to yield a 41 kDa catalytically active fragment resulting in a persistent increase in PKC? kinase activity. Co-treatment with pan-caspase inhibitor ZVAD-FMK significantly blocked vanadium-induced PKC? proteolytic activation, indicating that caspases mediate PKC? cleavage. Also, co-treatment with Z-VAD-FMK almost completely inhibited V2O5-induced DNA fragmentation. Furthermore, PKC? knockdown using siRNA protected N27 cells from V2O5-induced apoptotic cell death. Collectively, these results demonstrate vanadium can exert neurotoxic effects in dopaminergic neuronal cells via caspase-3-dependent PKC? cleavage, suggesting that metal exposure may promote nigral dopaminergic degeneration. PMID:19646462

  3. Improving Response Inhibition in Parkinsonís Disease with Atomoxetine

    PubMed Central

    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.; Rowe, James B.

    2015-01-01

    Background Dopaminergic drugs remain the mainstay of Parkinsonís disease therapy but often fail to improve cognitive problems such as impulsivity. This may be due to the loss of other neurotransmitters, including noradrenaline, which is linked to impulsivity and response inhibition. We therefore examined the effect of the selective noradrenaline reuptake inhibitor atomoxetine on response inhibition in a stop-signal paradigm. Methods This pharmacological functional magnetic resonance imaging study used a double-blinded randomized crossover design with low-frequency inhibition trials distributed among frequent Go trials. Twenty-one patients received 40 mg atomoxetine or placebo. Control subjects were tested on no-drug. The effects of disease and drug on behavioral performance, regional brain activity, and functional connectivity were analyzed using general linear models. Anatomical connectivity was examined using diffusion-weighted imaging. Results Patients with Parkinsonís disease had longer stop-signal reaction times, less stop-related activation in the right inferior frontal gyrus (RIFG), and weaker functional connectivity between the RIFG and striatum compared with control subjects. Atomoxetine enhanced stop-related RIFG activation in proportion to disease severity. Although there was no overall behavioral benefit from atomoxetine, analyses of individual differences revealed that enhanced response inhibition by atomoxetine was associated with increased RIFG activation and functional frontostriatal connectivity. Improved performance was more likely in patients with higher structural frontostriatal connectivity. Conclusions This study suggests that enhanced prefrontal cortical activation and frontostriatal connectivity by atomoxetine may improve response inhibition in Parkinsonís disease. These results point the way to new stratified clinical trials of atomoxetine to treat impulsivity in selected patients with Parkinsonís disease. PMID:24655598

  4. Neuroprotective Effects of A Standardized Flavonoid Extract of Safflower Against Neurotoxin-Induced Cellular and Animal Models of Parkinson's Disease.

    PubMed

    Ren, Rutong; Shi, Chunyan; Cao, Jing; Sun, Yi; Zhao, Xin; Guo, Yongfei; Wang, Chen; Lei, Hui; Jiang, Hanjie; Ablat, Nuramatjan; Xu, Jiamin; Li, Wan; Ma, Yingcong; Qi, Xianrong; Ye, Min; Pu, Xiaoping; Han, Hongbin

    2016-01-01

    Safflower has long been used to treat cerebrovascular diseases in China. We previously reported that kaempferol derivatives of safflower can bind DJ-1, a protein associated with Parkinson's disease (PD), and flavonoid extract of safflower exhibited neuroprotective effects in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of PD. In this study, a standardized safflower flavonoid extract (SAFE) was isolated from safflower and mainly contained flavonoids. Two marker compounds of SAFE, kaempferol 3-O-rutinoside and anhydrosafflor yellow B, were proven to suppress microtubule destabilization and decreased cell area, respectively. We confirmed that SAFE in dripping pill form could improve behavioural performances in a 6-hydroxydopamine (6-OHDA)-induced rat model of PD, partially via the suppression of ?-synuclein overexpression or aggregation, as well as the suppression of reactive astrogliosis. Using an MRI tracer-based method, we found that 6-OHDA could change extracellular space (ECS) diffusion parameters, including a decrease in tortuosity and the rate constant of clearance and an increase in the elimination half-life of the tracer in the 6-OHDA-lesioned substantia nigra. SAFE treatment could partially inhibit the changes in ECS diffusion parameters, which might provide some information about neuronal loss and astrocyte activation. Consequently, our results indicate that SAFE is a potential therapeutic herbal product for treatment of PD. PMID:26906725

  5. Evidence of an association between sleep and levodopa-induced dyskinesia in an animal model of Parkinson's disease.

    PubMed

    Galati, Salvatore; SalvadŤ, Agnese; Pace, Marta; Sarasso, Simone; Baracchi, Francesca; Bassetti, Claudio L; Kaelin-Lang, Alain; Stšdler, Claudio; Stanzione, Paolo; MŲller, Jens C

    2015-03-01

    Levodopa-induced dyskinesia (LID) represents a major challenge for clinicians treating patients affected by Parkinson's disease (PD). Although levodopa is the most effective treatment for PD, the remodeling effects induced by disease progression and the pharmacologic treatment itself cause a narrowing of the therapeutic window because of the development of LID. Although animal models of PD provide strong evidence that striatal plasticity underlies the development of dyskinetic movements, the pathogenesis of LID is not entirely understood. In recent years, slow homeostatic adjustment of intrinsic excitability occurring during sleep has been considered fundamental for network stabilization by gradually modifying plasticity thresholds. So far, how sleep affects on LID has not been investigated. Therefore, we measured synaptic downscaling across sleep episodes in a parkinsonian animal model showing dyskinetic movements similar to LID. Our electrophysiological, molecular, and behavioral results are consistent with an impaired synaptic homeostasis during sleep in animals showing dyskinesia. Accordingly, sleep deprivation causes an anticipation and worsening of LID supporting a link between sleep and the development of LID. PMID:25596726

  6. Parkinson's Disease

    MedlinePLUS

    Parkinson's disease (PD) is a type of movement disorder. It happens when nerve cells in the brain don't ... coordination As symptoms get worse, people with the disease may have trouble walking, talking, or doing simple ...

  7. Parkinson's Disease

    MedlinePLUS

    ... time, a person with Parkinson's may have trouble smiling, talking, or swallowing. Their faces may appear flat ... Maggie found out that Mrs. Barton couldn't smile as much on the outside anymore, but that ...

  8. Drug Induced Steatohepatitis: An Uncommon Culprit of a Common Disease.

    PubMed

    Rabinowich, Liane; Shibolet, Oren

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver disease in developed countries. Its frequency is increasing in the general population mostly due to the widespread occurrence of obesity and the metabolic syndrome. Although drugs and dietary supplements are viewed as a major cause of acute liver injury, drug induced steatosis and steatohepatitis are considered a rare form of drug induced liver injury (DILI). The complex mechanism leading to hepatic steatosis caused by commonly used drugs such as amiodarone, methotrexate, tamoxifen, valproic acid, glucocorticoids, and others is not fully understood. It relates not only to induction of the metabolic syndrome by some drugs but also to their impact on important molecular pathways including increased hepatocytes lipogenesis, decreased secretion of fatty acids, and interruption of mitochondrial ?-oxidation as well as altered expression of genes responsible for drug metabolism. Better familiarity with this type of liver injury is important for early recognition of drug hepatotoxicity and crucial for preventing severe forms of liver injury and cirrhosis. Moreover, understanding the mechanisms leading to drug induced hepatic steatosis may provide much needed clues to the mechanism and potential prevention of the more common form of metabolic steatohepatitis. PMID:26273591

  9. Drug Induced Steatohepatitis: An Uncommon Culprit of a Common Disease

    PubMed Central

    Rabinowich, Liane; Shibolet, Oren

    2015-01-01

    Nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver disease in developed countries. Its frequency is increasing in the general population mostly due to the widespread occurrence of obesity and the metabolic syndrome. Although drugs and dietary supplements are viewed as a major cause of acute liver injury, drug induced steatosis and steatohepatitis are considered a rare form of drug induced liver injury (DILI). The complex mechanism leading to hepatic steatosis caused by commonly used drugs such as amiodarone, methotrexate, tamoxifen, valproic acid, glucocorticoids, and others is not fully understood. It relates not only to induction of the metabolic syndrome by some drugs but also to their impact on important molecular pathways including increased hepatocytes lipogenesis, decreased secretion of fatty acids, and interruption of mitochondrial ő≤-oxidation as well as altered expression of genes responsible for drug metabolism. Better familiarity with this type of liver injury is important for early recognition of drug hepatotoxicity and crucial for preventing severe forms of liver injury and cirrhosis. Moreover, understanding the mechanisms leading to drug induced hepatic steatosis may provide much needed clues to the mechanism and potential prevention of the more common form of metabolic steatohepatitis. PMID:26273591

  10. Role of őĪ-synuclein in inducing innate and adaptive immunity in Parkinson disease

    PubMed Central

    Allen Reish, Heather E.; Standaert, David G.

    2015-01-01

    Alpha-synuclein (őĪ-syn) is central to the pathogenesis of Parkinson disease (PD). Gene duplications, triplications and point mutations in SNCA1, the gene encoding őĪ-syn, cause autosomal dominant forms of PD. Aggregated and post-translationally modified forms of őĪ-syn are present in Lewy bodies and Lewy neurites in both sporadic and familial PD, and recent work has emphasized the prion-like ability of aggregated őĪ-syn to produce spreading pathology. Accumulation of abnormal forms of őĪ-syn is a trigger for PD, but recent evidence suggests that much of the downstream neurodegeneration may result from inflammatory responses. Components of both the innate and adaptive immune systems are activated in PD, and influencing interactions between innate and adaptive immune components has been shown to modify the pathological process in animal models of PD. Understanding the relationship between őĪ-syn and subsequent inflammation may reveal novel targets for neuroprotective interventions. In this review, we examine the role of őĪ-syn and modified forms of this protein in the initiation of innate and adaptive immune responses. PMID:25588354

  11. Drug Induced Arousal and Fear Appeals.

    ERIC Educational Resources Information Center

    Deckner, C. William; Rogers, Ronald W.

    It is hypothesized that the drug, epinephrine, used in conjunction with a fear arousing film on the consquences of smoking would be more effective than either alone in increasing fear and negative attitudes toward smoking and, resultantly, in reducing cigarette consumption. The experimenters assigned 119 subjects to the four cells of a 2x2Ö

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

    PubMed Central

    Hung, Whitney Y; Abreu Lanfranco, Odaliz

    2014-01-01

    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

  13. Effects of intravenous human umbilical cord blood CD34+ stem cell therapy versus levodopa in experimentally induced Parkinsonism in mice

    PubMed Central

    Abo-Grisha, Noha; Abo-Elmatty, Dina M.; Abdel-Hady, Zenab

    2013-01-01

    Introduction Parkinsonism is a neurodegenerative disease with impaired motor function. The current research was directed to investigate the effect of CD34+ stem cells versus levodopa in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism. Material and methods Mice were divided into 4 groups; saline-injected, MPTP: received four MPTP injections (20 mg/kg, i.p.) at 2 h intervals, MPTP groups treated with levodopa/carbidopa (100/10 mg/kg/twice/day for 28 days) or single intravenous injection of 106 CD34+ stem cells/mouse at day 7 and allowed to survive until the end of week 5. Results Levodopa and stem cells improved MPTP-induced motor deficits; they abolished the difference in stride length, decreased percentage of foot slip errors and increased ambulation, activity factor and mobility duration in parkinsonian mice (p < 0.05). Further, they significantly (p < 0.05) increased striatal dopamine (85.3 Ī4.3 and 110.6 Ī5.3) and ATP levels (10.6 Ī1.1 and 15.5 Ī1.14) compared to MPTP (60.1 Ī3.9 pmol/g and 3.6 Ī0.09 mmol/g, respectively) (p < 0.05). Moreover, mitochondrial DNA from mice treated with levodopa or stem cells was in intact form; average concentration was (52.8 Ī3.01 and 107.8 Ī8.6) and no appreciable fragmentation of nuclear DNA was found compared to MPTP group. Regarding tyrosine hydroxylase (TH) immunostaining, stem cell group showed a marked increase of percentage of TH-immunopositive neurons (63.55 Ī5.2) compared to both MPTP (37.6 Ī3.1) and levodopa groups (41.6 Ī3.5). Conclusions CD34+ cells ameliorated motor, biochemical and histological deficits in MPTP-parkinsonian mice, these effects were superior to those produced by levodopa that would be promising for the treatment of PD. PMID:24482663

  14. Pentoxifylline stimulates drug-induced apoptosis in leukemic cells.

    PubMed

    Rauko, P; SedlŠk, J; Duraj, J; Szekeres, M F; Novotnż, L

    1998-01-01

    Camptothecin (CAM) and cisplatin (cis-diamminedichloroplatinum(II), cis-Pt) were used as inducers of apoptosis in the mouse leukemic L1210 cells. Relatively high concentrations of 50 micromol cis-Pt and 50 micromol CAM, respectively, were used to induce the apoptotic DNA ladder. The simultaneous treatment of L1210 cells by the drug and pentoxifylline (PTX) resulted in a decrease of drug concentrations necessary for the induction of apoptosis. This study revealed that a cell cycle G2 checkpoint inhibitor PTX reduces time intervals necessary for the onset of drug-induced apoptosis in these cells. This fact might be important as the earlier onset of programmed cell death may decrease a risk of tumor cells to become resistant to drug therapy. PMID:9921918

  15. Histopathological and immunohistochemical features of drug-induced exanthems.

    PubMed

    Lisi, P; Pelliccia, S; Bellini, V

    2014-04-01

    Exanthematic eruptions, together with urticaria-angioedema syndrome and fixed drug eruption, are the most frequent cutaneous adverse drug reactions. Among the drug-induced exanthems (DIEs), erythematous maculopapular eruptions are the most common. Their management, especially when retrospective, is often not easy, and it is based on the use of clinical criteria, history, results of some laboratory tests, drug elimination test, skin tests, and oral challenge test. The superficial perivascular and spongiotic dermatitis, which is the prevalent histopathological features of DIEs, is not very useful in the differential diagnosis with virus- and bacteria-induced exanthems (VBIEs). On the contrary, some immune-histochemical findings (interleukin-5 overexpression, concomitant enhancement of perforin, interleukin-5, and granzyme B production, positivity for fatty acid synthase-ligand-L in amoxicillin-induced exanthems) seem to be more important. These data justifie the inclusion of DIEs in the subtypes IVb and IVc of delayed hypersensitivity reactions. PMID:24819645

  16. Pulmonary and generalized lysosomal storage induced by amphiphilic drugs.

    PubMed Central

    Hruban, Z

    1984-01-01

    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

  17. Drug-Induced Torsade de Pointes and Implications for Drug Development

    PubMed Central

    Fenichel, Robert R.; Malik, Marek; Antzelevitch, Charles; Sanguinetti, Michael; Roden, Dan M.; Priori, Silvia G.; Ruskin, Jeremy N.; Lipicky, Raymond J.; Cantilena, Lou

    2006-01-01

    Torsade de pointes is a potentially lethal arrhythmia that occasionally appears as an adverse effect of pharmacotherapy. Recently-developed understanding of the underlying electrophysiology allows better estimation of the drug-induced risks, and explains the failures of older approaches through the surface electrocardiogram. The article expresses a consensus reached by an independent academic task force on the physiologic understanding of drug-induced repolarisation changes, on their preclinical and clinical evaluation, and on the risk-benefit interpretation of drug-induced torsade de pointes. The consensus of the task force includes suggestions on how to evaluate the risk of torsade within drug development program. Individual sections of the text discuss the techniques and limitations of methods directed at drug-related ion-channel phenomena, investigations aimed at action potentials changes, preclinical studies of phenomena seen only in the whole (or nearly whole) heart, and at interpretation of human electrocardiograms obtained in clinical studies. Final section of the text discusses drug-induced torsade within the larger evaluation of drug-related risks and benefits. PMID:15090000

  18. Coherence of neuronal firing of the entopeduncular nucleus with motor cortex oscillatory activity in the 6-OHDA rat model of Parkinson's disease with levodopa-induced dyskinesias.

    PubMed

    Jin, Xingxing; Schwabe, Kerstin; Krauss, Joachim K; Alam, Mesbah

    2016-04-01

    The pathophysiological mechanisms leading to dyskinesias in Parkinson's disease (PD) after long-term treatment with levodopa remain unclear. This study investigates the neuronal firing characteristics of the entopeduncular nucleus (EPN), the rat equivalent of the human globus pallidus internus and output nucleus of the basal ganglia, and its coherence with the motor cortex (MCx) field potentials in the unilateral 6-OHDA rat model of PD with and without levodopa-induced dyskinesias (LID). 6-hydroxydopamine-lesioned hemiparkinsonian (HP) rats, 6-OHDA-lesioned HP rats with LID (HP-LID) rats, and na√Įve controls were used for recording of single-unit activity under urethane (1.4¬†g/kg, i.p) anesthesia in the EPN "on" and "off" levodopa. Over the MCx, the electrocorticogram output was recorded. Analysis of single-unit activity in the EPN showed enhanced firing rates, burst activity, and irregularity compared to na√Įve controls, which did not differ between drug-na√Įve HP and HP-LID rats. Analysis of EPN spike coherence and phase-locked ratio with MCx field potentials showed a shift of low (12-19¬†Hz) and high (19-30¬†Hz) beta oscillatory activity between HP and HP-LID groups. EPN theta phase-locked ratio was only enhanced in HP-LID compared to HP rats. Overall, levodopa injection had no stronger effect in HP-LID rats than in HP rats. Altered coherence and changes in the phase lock ratio of spike and local field potentials in the beta range may play a role for the development of LID. PMID:26724931

  19. An In Vivo Microdialysis Study of FLZ Penetration through the Blood-Brain Barrier in Normal and 6-Hydroxydopamine Induced Parkinson's Disease Model Rats

    PubMed Central

    Hou, Jinfeng; Liu, Qian; Li, Yingfei; Sun, Hua; Zhang, Jinlan

    2014-01-01

    FLZ (N-[2-(4-hydroxy-phenyl)-ethyl]-2-(2,5-dimethoxy-phenyl)-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide) is a novel synthetic squamosamide derivative and a potential anti-Parkinson's disease (PD) agent. The objective of the present study was to investigate the penetration of free FLZ across the BBB and the effects of P-gp inhibition on FLZ transport in normal and 6-hydroxydopamine (6-OHDA) induced PD model rats. In vivo microdialysis was used to collect FLZ containing brain and blood dialysates following intravenous (i.v.) drug administration either with or without pretreatment with the specific P-gp inhibitor, zosuquidar trihydrochloride (zosuquidar·3HCl). A sensitive, rapid, and reliable ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) technique was developed and validated to quantitate free FLZ levels in the dialysates. No significant differences were observed in the brain/blood FLZ area under the concentration-time curve (AUC) ratio between normal and PD model rats. However, pretreatment with zosuquidar·3HCl markedly increased the AUC ratio in both rat models. In addition, FLZ penetration was similar in zosuquidar·3HCl-pretreated normal and PD rats. These results suggest that P-gp inhibition increases BBB permeability to FLZ, thereby supporting the hypothesis that P-gp normally restricts FLZ transfer to the brain. These findings could provide reference data for future clinical trials and may aid investigation of the BBB permeability of other CNS-active substances. PMID:25045708

  20. Oxicam structure in non-steroidal anti-inflammatory drugs is essential to exhibit Akt-mediated neuroprotection against 1-methyl-4-phenyl pyridinium-induced cytotoxicity.

    PubMed

    Tasaki, Yoshikazu; Yamamoto, Joe; Omura, Tomohiro; Noda, Toshihiro; Kamiyama, Naoya; Yoshida, Koichi; Satomi, Machiko; Sakaguchi, Tomoki; Asari, Masaru; Ohkubo, Tomoko; Shimizu, Keiko; Matsubara, Kazuo

    2012-02-15

    In the treatment of Parkinson's disease, potent disease-modifying drugs are still needed to halt progressive dopaminergic neurodegeneration. We have previously shown that meloxicam, an oxicam non-steroidal anti-inflammatory drug (NSAID), elicits a potent neuroprotective effect against 1-methyl-4-phenyl pyridinium (MPP(+))-induced toxicity in human dopaminergic SH-SY5Y neuroblastoma cells. This cyclooxygenase-independent neuroprotection of meloxicam is mediated via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway; however, the specific chemical structure involved in inducing neuroprotection remains unresolved. In this study, we therefore investigated the structure-specific for eliciting the neuroprotective effect by examining a series of NSAIDs against MPP(+) toxicity in SH-SY5Y cells. Three oxicam-bearing NSAIDs showed potent neuroprotective effects, although none of the other 10 oxicam-nonbearing NSAIDs (3 salicylates, 6 coxibs and 1 polyphenol) or 3 piroxicam analogs (including ampiroxicam, a precursor of piroxicam) exerted any neuroprotection. Tenoxicam and piroxicam prevented MPP(+)-induced reduction of phosphorylated Akt levels in cells: a protective mechanism similar to that of meloxicam. Therefore, the oxicam structure was likely to be responsible for exhibiting the neuroprotection by sustaining survival-signaling in dopaminergic cells. The present results raise the possibility that the oxicam-bearing NSAIDs may serve as potential therapeutic drugs to retard or terminate progression of Parkinson's disease via a novel mechanism. PMID:22182582

  1. Anticancer Drug Induced Palmar Plantar Erythrodysesthesia

    PubMed Central

    Srinivasamurthy, Sureshkumar; Dubashi, Biswajit; Chandrasekaran, Adithan

    2014-01-01

    Background: Palmar plantar erythrodysesthesia (PPE) is a dose limiting toxicity of anticancer agents. In some cases it may mandate for discontinuation of anticancer agents. Evaluation of data of PPE among reported adverse drug reactions (ADRs) from the Department of Medical Oncology could quantify the burden. Aim: To evaluate and analyse the PPE among reported ADRs from medical Oncology. Materials and Methods: The data of all cases of reported PPE were collected during January 2012 to September 2013 and were analysed with WHO causality assessment scale. The severity was clinically graded. The follow-up data regarding outcome of ADRs were also noted. Results: During the study period of 21 months a total of 1418 ADRs have been reported from 1076 patients. Among them PPE was reported from 31 cases (2.9%). Majority (32.2%) of these patients were on chemotherapy for breast cancer. Patientís age ranged from 17 to 68 y and the median age was 50 y. There were 18 female (58%) and 13 male patients (42%). Capecitabine was the leading drug involved in PPE, reported with 20 cases (64.5%), and followed by docetaxel with 5 cases (16.1%). Majority (67.7%) of the reactions was categorized as certain and 64.5% was grade II severity clinically. Conclusion: Our findings show that PPE accounts for 2.9% of total reported ADRs from Medical Oncology during 21 months. Majority of the reactions were classified as certain. Capecitabine is commonly implicated drug. PMID:25478366

  2. Comparison of Two Methods for Inducing Reflex Cough in Patients With Parkinson's Disease, With and Without Dysphagia.

    PubMed

    Hegland, Karen W; Troche, Michelle S; Brandimore, Alexandra; Okun, Michael S; Davenport, Paul W

    2016-02-01

    Aspiration pneumonia is a common cause of death in people with Parkinson's disease (PD). Dysfunctional swallowing occurs in the majority of people with PD, and research has shown that cough function is also impaired. Previous studies suggest that testing reflex cough by having participants inhale a cough-inducing stimulus through a nebulizer may be a reliable indicator of swallowing dysfunction, or dysphagia. The primary goal of this study was to determine the cough response to two different cough-inducing stimuli in people with and without PD. The second goal of this study was to compare the cough response to the two different stimuli in people with PD, with and without swallowing dysfunction. Seventy adults (49 healthy and 21 with PD) participated in the study. Aerosolized water (fog) and 200¬†őľM capsaicin were used to induce cough. Each substance was placed in a small, hand-held nebulizer, and presented to the participant. Each cough stimulus was presented three times. The total number of coughs produced to each stimulus trial was recorded. All participants coughed more to capsaicin versus fog (p¬†<¬†0.001). A categorical 'responder' and 'non-responder' variable for the fog stimulus, defined as whether or not the participant coughed at least two times to two of three presentations of the stimulus, yields sensitivity of 77.8¬†% and a specificity of 90.9¬†% for identifying PD participants with and without dysphagia. The data show a differential response of the PD participants to the capsaicin versus fog stimuli. Clinically, this finding may allow for earlier identification of people with PD who are in need of a swallowing evaluation. As well, there are implications for the neural control of cough in this patient population. PMID:26497650

  3. Neurological morphofunctional differentiation induced by REAC technology in PC12. A neuro protective model for Parkinson's disease.

    PubMed

    Maioli, Margherita; Rinaldi, Salvatore; Migheli, Rossana; Pigliaru, Gianfranco; Rocchitta, Gaia; Santaniello, Sara; Basoli, Valentina; Castagna, Alessandro; Fontani, Vania; Ventura, Carlo; Serra, Pier Andrea

    2015-01-01

    Research for the use of physical means, in order to induce cell differentiation for new therapeutic strategies, is one of the most interesting challenges in the field of regenerative medicine, and then in the treatment of neurodegenerative diseases, Parkinson's disease (PD) included. The aim of this work is to verify the effect of the radio electric asymmetric conveyer (REAC) technology on the PC12 rat adrenal pheochromocytoma cell line, as they display metabolic features of PD. PC12 cells were cultured with a REAC regenerative tissue optimization treatment (TO-RGN) for a period ranging between 24 and 192?hours. Gene expression analysis of specific neurogenic genes, as neurogenin-1, beta3-tubulin and Nerve growth factor, together with the immunostaining analysis of the specific neuronal protein beta3-tubulin and tyrosine hydroxylase, shows that the number of cells committed toward the neurogenic phenotype was significantly higher in REAC treated cultures, as compared to control untreated cells. Moreover, MTT and Trypan blue proliferation assays highlighted that cell proliferation was significantly reduced in REAC TO-RGN treated cells. These results open new perspectives in neurodegenerative diseases treatment, particularly in PD. Further studies will be needed to better address the therapeutic potential of the REAC technology. PMID:25976344

  4. Targeting the Intrinsically Disordered Structural Ensemble of ?-Synuclein by Small Molecules as a Potential Therapeutic Strategy for Parkinsonís Disease

    PubMed Central

    Tůth, Gergely; Gardai, Shyra J.; Zago, Wagner; Bertoncini, Carlos W.; Cremades, Nunilo; Roy, Susan L.; Tambe, Mitali A.; Rochet, Jean-Christophe; Galvagnion, Celine; Skibinski, Gaia; Finkbeiner, Steven; Bova, Michael; Regnstrom, Karin; Chiou, San-San; Johnston, Jennifer; Callaway, Kari; Anderson, John P.; Jobling, Michael F.; Buell, Alexander K.; Yednock, Ted A.; Knowles, Tuomas P. J.; Vendruscolo, Michele; Christodoulou, John; Dobson, Christopher M.; Schenk, Dale; McConlogue, Lisa

    2014-01-01

    The misfolding of intrinsically disordered proteins such as ?-synuclein, tau and the A? peptide has been associated with many highly debilitating neurodegenerative syndromes including Parkinsonís and Alzheimerís diseases. Therapeutic targeting of the monomeric state of such intrinsically disordered proteins by small molecules has, however, been a major challenge because of their heterogeneous conformational properties. We show here that a combination of computational and experimental techniques has led to the identification of a drug-like phenyl-sulfonamide compound (ELN484228), that targets ?-synuclein, a key protein in Parkinsonís disease. We found that this compound has substantial biological activity in cellular models of ?-synuclein-mediated dysfunction, including rescue of ?-synuclein-induced disruption of vesicle trafficking and dopaminergic neuronal loss and neurite retraction most likely by reducing the amount of ?-synuclein targeted to sites of vesicle mobilization such as the synapse in neurons or the site of bead engulfment in microglial cells. These results indicate that targeting ?-synuclein by small molecules represents a promising approach to the development of therapeutic treatments of Parkinsonís disease and related conditions. PMID:24551051

  5. The Sirtuin-2 Inhibitor AK7 Is Neuroprotective in Models of Parkinsonís Disease but Not Amyotrophic Lateral Sclerosis and Cerebral Ischemia

    PubMed Central

    Chen, Xiqun; Wales, Pauline; Quinti, Luisa; Zuo, Fuxing; Moniot, Sťbastien; Herisson, Fanny; Rauf, Nazifa Abdul; Wang, Hua; Silverman, Richard B.; Ayata, Cenk; Maxwell, Michelle M.; Steegborn, Clemens; Schwarzschild, Michael A.; Outeiro, Tiago F.; Kazantsev, Aleksey G.

    2015-01-01

    Sirtuin deacetylases regulate diverse cellular pathways and influence disease processes. Our previous studies identified the brain-enriched sirtuin-2 (SIRT2) deacetylase as a potential drug target to counteract neurodegeneration. In the present study, we characterize SIRT2 inhibition activity of the brain-permeable compound AK7 and examine the efficacy of this small molecule in models of Parkinsonís disease, amyotrophic lateral sclerosis and cerebral ischemia. Our results demonstrate that AK7 is neuroprotective in models of Parkinsonís disease; it ameliorates alpha-synuclein toxicity in vitro and prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine depletion and dopaminergic neuron loss in vivo. The compound does not show beneficial effects in mouse models of amyotrophic lateral sclerosis and cerebral ischemia. These findings underscore the specificity of protective effects observed here in models of Parkinsonís disease, and previously in Huntingtonís disease, and support the development of SIRT2 inhibitors as potential therapeutics for the two neurodegenerative diseases. PMID:25608039

  6. Parkinson's disease in 1984: an update.

    PubMed Central

    Lang, A E; Blair, R D

    1984-01-01

    This update reviews several important topics in the field of Parkinson's disease, including etiologic studies, the types and mechanisms of drug complications and their treatment, when and how to begin treatment, the association of dementia with Parkinson's disease, and the development of the newer research tools. The recent discovery of a highly selective neurotoxin (MPTP) that causes parkinsonism in humans and other primates and the use of positron emission tomography in living patients should improve our understanding of the cause of cell death in Parkinson's disease and assist in the development of more definitive treatment for this common, disabling neurologic condition. PMID:6388779

  7. Imaging of Drug-induced Complications in the Gastrointestinal System.

    PubMed

    McGettigan, Melissa J; Menias, Christine O; Gao, Zhenqiang J; Mellnick, Vincent M; Hara, Amy K

    2016-01-01

    Drug-induced injury commonly affects the gastrointestinal and hepatobiliary systems because of the mechanisms of absorption and metabolism. In pill esophagitis, injury is frequently related to direct contact with the esophageal mucosa, resulting in small superficial ulcers in the mid esophagus. Nonsteroidal anti-inflammatory drugs can lead to gastrointestinal tract ulcers and small bowel mucosal diaphragms (thin weblike strictures). Injury to the pancreatic and hepatobiliary systems can manifest as pancreatitis, acute or chronic hepatitis, cholestasis, or steatosis and steatohepatitis (which may progress to cirrhosis). Various drugs may also insult the hepatic vasculature, resulting in Budd-Chiari and sinusoidal obstructive syndromes. Focal lesions such as hepatic adenomas may develop after use of oral contraceptives or anabolic steroids. Ultrasonography, computed tomography, and magnetic resonance imaging can aid in diagnosis of drug-induced injuries and often are necessary to exclude other causes. (©)RSNA, 2015. PMID:26761532

  8. Drug induced osteonecrosis of the jaw.

    PubMed

    Hamadeh, Issam S; Ngwa, Bridget A; Gong, Yan

    2015-05-01

    Despite the widespread use of bisphosphonates and their unequivocal efficacy for the treatment of various disease states, osteonecrosis of the jaw remains one of the most feared complications associated with their use. Current evidence, however, suggests that there is also a relationship between occurrence of osteonecrosis of the jaw and use of other classes of pharmacotherapies namely RANKL inhibitors as well as angiogenesis inhibitors. Although these drugs have different mechanisms of action than bisphosphonates, they all seem to interfere with the bone remodeling process i.e. alter the balance between bone resorption and bone formation which may be the most plausible explanation for pathogenesis of osteonecrosis of the jaw. The main objective of this review is to introduce the readership to a number of relatively new medications that may cause osteonecrosis of the jaw. Accordingly, we will summarize latest findings from clinical studies, meta analyses and case reports published in medical literature on this topic. For some of these medications, the evidence may not appear as robust as that for bisphosphonates; yet, the possibility of this adverse event occurring with these non bisphosphonate drugs should never be precluded unless proven otherwise. Thus, it is imperative that health care providers implement preventive measures so as to circumvent the incidence of osteonecrosis of the jaw. In this day of age where medical care is becoming personalized, we will highlight some of significant findings from studies seeking to identify genetic markers that may potentially play a role in development of osteonecrosis of the jaw. PMID:25913713

  9. Heat shock protein 60: an endogenous inducer of dopaminergic cell death in Parkinson disease

    PubMed Central

    2014-01-01

    Background Increasing evidence suggests that inflammation associated with microglial cell activation in the substantia nigra (SN) of patients with Parkinson disease (PD) is not only a consequence of neuronal degeneration, but may actively sustain dopaminergic (DA) cell loss over time. We aimed to study whether the intracellular chaperone heat shock protein 60 (Hsp60) could serve as a signal of CNS injury for activation of microglial cells. Methods Hsp60 mRNA expression in the mesencephalon and the striatum of C57/BL6 mice treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and the Hsp60/TH mRNA ratios in the SN of PD patients and aged-matched subjects were measured. To further investigate a possible link between the neuronal Hsp60 response and PD-related cellular stress, Hsp60 immunoblot analysis and quantification in cell lysates from SH-SY5Y after treatment with 100†?M MPP+ (1-methyl-4-phenylpyridinium) at different time points (6, 12, 24 and 48†hours) compared to control cells were performed. Additional MTT and LDH assay were used. We next addressed the question as to whether Hsp60 influences the survival of TH+ neurons in mesencephalic neuron-glia cultures treated either with MPP+ (1†?M), hHsp60 (10†?g/ml) or a combination of both. Finally, we measured IL-1?, IL-6, TNF-? and NO-release by ELISA in primary microglial cell cultures following treatment with different hHsp60 preparations. Control cultures were exposed to LPS. Results In the mesencephalon and striatum of mice treated with MPTP and also in the SN of PD patients, we found that Hsp60 mRNA was up-regulated. MPP+, the active metabolite of MPTP, also caused an increased expression and release of Hsp60 in the human dopaminergic cell line SH-SY5Y. Interestingly, in addition to being toxic to DA neurons in primary mesencephalic cultures, exogenous Hsp60 aggravated the effects of MPP+. Yet, although we demonstrated that Hsp60 specifically binds to microglial cells, it failed to stimulate the production of pro-inflammatory cytokines or NO by these cells. Conclusions Overall, our data suggest that Hsp60 is likely to participate in DA cell death in PD but via a mechanism unrelated to cytokine release. PMID:24886419

  10. Identifying the Basal Ganglia Network Model Markers for Medication-Induced Impulsivity in Parkinson's Disease Patients

    PubMed Central

    Balasubramani, Pragathi Priyadharsini; Chakravarthy, V. Srinivasa; Ali, Manal; Ravindran, Balaraman; Moustafa, Ahmed A.

    2015-01-01

    Impulsivity, i.e. irresistibility in the execution of actions, may be prominent in Parkinson's disease (PD) patients who are treated with dopamine precursors or dopamine receptor agonists. In this study, we combine clinical investigations with computational modeling to explore whether impulsivity in PD patients on medication may arise as a result of abnormalities in risk, reward and punishment learning. In order to empirically assess learning outcomes involving risk, reward and punishment, four subject groups were examined: healthy controls, ON medication PD patients with impulse control disorder (PD-ON ICD) or without ICD (PD-ON non-ICD), and OFF medication PD patients (PD-OFF). A neural network model of the Basal Ganglia (BG) that has the capacity to predict the dysfunction of both the dopaminergic (DA) and the serotonergic (5HT) neuromodulator systems was developed and used to facilitate the interpretation of experimental results. In the model, the BG action selection dynamics were mimicked using a utility function based decision making framework, with DA controlling reward prediction and 5HT controlling punishment and risk predictions. The striatal model included three pools of Medium Spiny Neurons (MSNs), with D1 receptor (R) alone, D2R alone and co-expressing D1R-D2R. Empirical studies showed that reward optimality was increased in PD-ON ICD patients while punishment optimality was increased in PD-OFF patients. Empirical studies also revealed that PD-ON ICD subjects had lower reaction times (RT) compared to that of the PD-ON non-ICD patients. Computational modeling suggested that PD-OFF patients have higher punishment sensitivity, while healthy controls showed comparatively higher risk sensitivity. A significant decrease in sensitivity to punishment and risk was crucial for explaining behavioral changes observed in PD-ON ICD patients. Our results highlight the power of computational modelling for identifying neuronal circuitry implicated in learning, and its impairment in PD. The results presented here not only show that computational modelling can be used as a valuable tool for understanding and interpreting clinical data, but they also show that computational modeling has the potential to become an invaluable tool to predict the onset of behavioral changes during disease progression. PMID:26042675

  11. Drug-induced angioedema: experience of Italian emergency departments.

    PubMed

    Bertazzoni, G; Spina, M T; Scarpellini, M G; Buccelletti, F; De Simone, M; Gregori, M; Valeriano, V; Pugliese, F R; Ruggieri, M P; Magnanti, M; Susi, B; Minetola, L; Zulli, L; D'Ambrogio, F

    2014-06-01

    Acute angioedema represents a cause of admission to the emergency department requiring rapid diagnosis and appropriate management to prevent airway obstruction. Several drugs, including angiotensin-converting enzyme inhibitors (ACE-I), nonsteroidal anti-inflammatory drugs (NSAIDs) and oral antidiabetics, have been reported to induce angioedema. The aim of this prospective observational study conducted in a setting of routine emergency care was to evaluate the incidence and extent of drug-induced non-histaminergic angioedema in this specific clinical setting, and to identify the class of drugs possibly associated with angioedema. Patients admitted to seven different emergency departments (EDs) in Rome with the diagnosis of angioedema and urticaria were enrolled during a 6-month period. Of the 120,000 patients admitted at the EDs, 447 (0.37†%) were coded as having angioedema and 655 (0.5†%) as having urticaria. After accurate clinical review, 62 cases were defined as drug-induced, non-histaminergic angioedema. NSAIDs were the most frequent drugs (taken by 22 out of 62 patients) associated with the angioedema attack. Of the remaining patients, 15 received antibiotic treatment and 10 antihypertensive treatment. In addition, we observed in our series some cases of angioedema associated with drugs (such as antiasthmatics, antidiarrheal and antiepileptics) of which there are few descriptions in the literature. The present data, which add much needed information to the existing limited literature on drug-induced angioedema in the clinical emergency department setting, will provide more appropriate diagnosis and management of this potentially life-threatening adverse event. PMID:24214335

  12. In silico modeling to predict drug-induced phospholipidosis

    SciTech Connect

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

    2013-06-01

    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‚Äďactivity 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‚Äď81% concordance. Furthermore, the predictive performance characteristics include models with high sensitivity and specificity, in most cases above ‚Č• 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. - Highlights: ‚ÄĘ New in silico models for predicting drug-induced phospholipidosis (DIPL) are described. ‚ÄĘ The training set data in the models is derived from the FDA's phospholipidosis database. ‚ÄĘ We find excellent predictivity values of the models based on external validation. ‚ÄĘ The models can support drug screening and regulatory decision-making on DIPL.

  13. Hitler's parkinsonism.

    PubMed

    Boettcher, Lillian B; Bonney, Phillip A; Smitherman, Adam D; Sughrue, Michael E

    2015-07-01

    Of the multitude of medical and psychiatric conditions ascribed to Hitler both in his lifetime and since his suicide in April 1945, few are more substantiated than parkinsonism. While the timeline of the development of this condition, as well as its etiology, are debated, there is clear evidence for classic manifestations of the disease, most prominently a resting tremor but also stooped posture, bradykinesia, micrographia, and masked facial expressions, with progression steadily seen over his final years. Though ultimately speculation, some have suggested that Hitler suffered from progressive cognitive and mood disturbances, possibly due to parkinsonism, that affected the course of events in the war. Here, the authors discuss Hitler's parkinsonism in the context of the Third Reich and its eventual destruction, maintaining that ultimately his disease had little effect on the end result. PMID:26126407

  14. Generation of Naivetropic Induced Pluripotent Stem Cells from Parkinson's Disease Patients for High-Efficiency Genetic Manipulation and Disease Modeling.

    PubMed

    Hu, Zhixing; Pu, Jiali; Jiang, Houbo; Zhong, Ping; Qiu, Jingxin; Li, Feng; Wang, Xiaomin; Zhang, Baorong; Yan, Zhen; Feng, Jian

    2015-11-01

    The lack of robust Parkinson's disease (PD) phenotype in parkin knockout rodents and the identification of defective dopaminergic (DA) neurotransmission in midbrain DA neurons derived from induced pluripotent stem cells (iPSC) of PD patients with parkin mutations demonstrate the utility of patient-specific iPSCs as an effective system to model the unique vulnerabilities of midbrain DA neurons in PD. Significant efforts have been directed at developing efficient genomic engineering technologies in human iPSCs to study diseases such as PD. In the present study, we converted patient-specific iPSCs from the primed state to a naivetropic state by DOX-induced expression of transgenes (Oct4, Sox2, Klf4, c-Myc, and Nanog) and the use of 2iL (MEK inhibitor PD0325901, GSK3 inhibitor CHIR99021, and human LIF). These patient-specific naivetropic iPSCs were pluripotent in terms of marker expression, spontaneous differentiation in vitro, and teratoma formation in vivo. They exhibited morphological, proliferative, and clonogenic characteristics very similar to naive mouse embryonic stem cells (ESC). The high clonal efficiency and proliferation rate of naivetropic iPSCs enabled very efficient gene targeting of GFP to the PITX3 locus by transcription activator-like effector nuclease. The naivetropic iPSCs could be readily reverted to the primed state upon the withdrawal of DOX, 2iL, and the switch to primed-state hESC culture conditions. Midbrain DA neurons differentiated from the reverted iPSCs retained the original phenotypes caused by parkin mutations, attesting to the robustness of these phenotypes and the usefulness of genomic engineering in patient-specific naivetropic iPSCs for studying PD. PMID:26218671

  15. Generation of Naivetropic Induced Pluripotent Stem Cells from Parkinson's Disease Patients for High-Efficiency Genetic Manipulation and Disease Modeling

    PubMed Central

    Hu, Zhixing; Pu, Jiali; Jiang, Houbo; Zhong, Ping; Qiu, Jingxin; Li, Feng; Wang, Xiaomin; Zhang, Baorong; Yan, Zhen

    2015-01-01

    The lack of robust Parkinson's disease (PD) phenotype in parkin knockout rodents and the identification of defective dopaminergic (DA) neurotransmission in midbrain DA neurons derived from induced pluripotent stem cells (iPSC) of PD patients with parkin mutations demonstrate the utility of patient-specific iPSCs as an effective system to model the unique vulnerabilities of midbrain DA neurons in PD. Significant efforts have been directed at developing efficient genomic engineering technologies in human iPSCs to study diseases such as PD. In the present study, we converted patient-specific iPSCs from the primed state to a naivetropic state by DOX-induced expression of transgenes (Oct4, Sox2, Klf4, c-Myc, and Nanog) and the use of 2iL (MEK inhibitor PD0325901, GSK3 inhibitor CHIR99021, and human LIF). These patient-specific naivetropic iPSCs were pluripotent in terms of marker expression, spontaneous differentiation in vitro, and teratoma formation in vivo. They exhibited morphological, proliferative, and clonogenic characteristics very similar to naive mouse embryonic stem cells (ESC). The high clonal efficiency and proliferation rate of naivetropic iPSCs enabled very efficient gene targeting of GFP to the PITX3 locus by transcription activator-like effector nuclease. The naivetropic iPSCs could be readily reverted to the primed state upon the withdrawal of DOX, 2iL, and the switch to primed-state hESC culture conditions. Midbrain DA neurons differentiated from the reverted iPSCs retained the original phenotypes caused by parkin mutations, attesting to the robustness of these phenotypes and the usefulness of genomic engineering in patient-specific naivetropic iPSCs for studying PD. PMID:26218671

  16. Biomarkers to monitor drug-induced phospholipidosis

    SciTech Connect

    Baronas, Elizabeth Tengstrand; Lee, Ju-Whei; Alden, Carl; Hsieh, Frank Y. . E-mail: frank.hsieh@nextcea.com

    2007-01-01

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

  17. Drug Induced Gingival Overgrowth: A Rare Case Report

    PubMed Central

    Khatri, Rohit Kumar; Mathur, Ranjan; Srivastava, Rashi; Nag, B.P.

    2015-01-01

    Gingival overgrowth is well documented side effect associated with three major classes of drugs viz, anticonvulsants, calcium channel blockers, and immunosuppressants. Despite our greater understanding of pathogenesis of Drug induced Gingival Overgrowth (DIGO), its treatment still remains a challenge for the periodontists and treatment is still largely limited to maintenance of improved level of oral hygiene and surgical removal of overgrown tissue. Dental Surgeons need to discuss this issue with their medical colleagues and to practice care while prescribing the drugs associated with gingival overgrowth. The aim of present article is to report a rare case where even after extraction of all teeth; the enlargement did not subsided for one month. PMID:25738096

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

    PubMed Central

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

    2011-01-01

    Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60‚Äď70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the ‚ÄúRule of Three‚ÄĚ was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity. PMID:22194678

  19. Mechanism of laser-induced drug delivery in tumors

    NASA Astrophysics Data System (ADS)

    Esenaliev, Rinat O.; Larina, Irina V.; Larin, Kirill V.; Motamedi, Massoud; Evers, B. M.

    2000-06-01

    Penetration of anti-cancer drugs (especially macromolecular agents) from blood in tumor cells is limited due to the presence of physiological barriers: tumor capillary wall, slow diffusion in the interstitium, and cancer cell membrane. Interaction of exogenous nano- or microparticles with laser or ultrasonic radiation may enhance drug delivery in tumor cells due to laser- or ultrasound-induced cavitation. Our previous studies demonstrated enhanced delivery of model macromolecular anti-cancer drugs in tissues in vitro when laser or ultrasonic radiation is applied. In this paper, we studied laser-induced cavitation in suspension of strongly absorbing particles and laser-enhanced drug delivery in human colon tumors of nude mice in vivo. Cavitation kinetics and thresholds were measured for carbon and colored polystyrene particle suspensions. Histological examination of control and irradiated tumors with fluorescent microscopy demonstrated that Q-switched Nd:YAG laser irradiation enhances delivery of a model macromolecular drug (FITC-dextran) in tumor blood vessel and interstitium. Enhanced delivery of an anti-cancer drug (5-FU) that is currently used in clinics resulted in tumor necrosis and inhibited tumor growth. Results of our studies suggest that the drug delivery enhancement is due to cavitation produced by local heating of particles with pulsed laser radiation.

  20. Drug metabolism in drug-induced liver diseases: pathogenetic role of active metabolites.

    PubMed

    HorvŠth, T; Past, T; Nťmeth, A; KŠdas, I; Hoffmann-Traeger, A; Rechenbach, C; JŠvor, T

    1989-01-01

    Three cases with drug-induced liver diseases (hepatitis caused by hydralasine, steatosis caused by methimazole, choletasis caused by birth control pill) were investigated with respect to their drug metabolising ability. Clinical diagnoses were based on the exclusion of other pathogenetic factors, on histological findings of liver biopsy specimens and on the clinical chemical tests. Investigation of biotransforming ability was carried out using test materials (menthol loading, antipyrine, sulfadimidine, caffeine, indocyanine green kinetics) and measurement of D-glucaric acid excretion. In all cases the results show a defective capacity in some respect of drug metabolism. Possible pathogenetic role of reactive metabolites is discussed in the pathomechanism of genesis of drug-induced liver diseases. PMID:2596319

  1. An Update on Drug-induced Liver Injury.

    PubMed

    Devarbhavi, Harshad

    2012-09-01

    Idiosyncratic drug-induced liver injury (DILI) is an important cause of morbidity and mortality following drugs taken in therapeutic doses. Hepatotoxicity is a leading cause of attrition in drug development, or withdrawal or restricted use after marketing. No age is exempt although adults and the elderly are at increased risk. DILI spans the entire spectrum ranging from asymptomatic elevation in transaminases to severe disease such as acute hepatitis leading to acute liver failure. The liver specific Roussel Uclaf Causality Assessment Method is the most validated and extensively used for determining the likelihood that an implicated drug caused DILI. Asymptomatic elevation in liver tests must be differentiated from adaptation. Drugs producing DILI have a signature pattern although no single pattern is characteristic. Antimicrobial and central nervous system agents including antiepileptic drugs are the leading causes of DILI worldwide. In the absence of a diagnostic test or a biomarker, the diagnosis rests on the evidence of absence of competing causes such as acute viral hepatitis, autoimmune hepatitis and others. Recent studies show that antituberculosis drugs given for active or latent disease are still a major cause of drug-induced liver injury in India and the West respectively. Presence of jaundice signifies a severe disease and entails a worse outcome. The pathogenesis is unclear and is due to a mix of host, drug metabolite and environmental factors. Research has evolved from incriminating candidate genes to genome wide analysis studies. Immediate cessation of the drug is key to prevent or minimize progressive damage. Treatment is largely supportive. N-acetylcysteine is the antidote for paracetamol toxicity. Carnitine has been tried in valproate injury whereas steroids and ursodeoxycholic acid may be used in DILI associated with hypersensitivity or cholestatic features respectively. This article provides an overview of the epidemiology, the patterns of hepatotoxicity, the pathogenesis and associated risk factors besides its clinical management. PMID:25755441

  2. Inferior phrenic artery pseudoaneurysm complicating drug-induced acute pancreatitis

    PubMed Central

    Salem, Jean F; Haydar, Ali; Hallal, Ali

    2014-01-01

    Inferior phrenic artery (IPA) pseudoaneurysm is an extremely rare complication of chronic pancreatitis with only three cases reported in the literature so far. It is a serious condition that can be life-threatening if not diagnosed promptly. Recent advances in endovascular interventions made angiography with embolisation the modality of choice for diagnosis and treatment. We presented the first report of a case of ruptured IPA pseudoaneurysm complicating a drug-induced acute pancreatitis that was successfully treated by transcatheter arterial embolisation. Despite its rarity, rupture of pseudoaneurysm due to drug-induced pancreatitis should be suspected and included in the differential diagnosis when associated with haemodynamic instability. PMID:24385392

  3. Hypoxia-induced drug resistance: comparison to P-glycoprotein-associated drug resistance.

    PubMed Central

    Sakata, K.; Kwok, T. T.; Murphy, B. J.; Laderoute, K. R.; Gordon, G. R.; Sutherland, R. M.

    1991-01-01

    In this report, we investigate several examples of hypoxia-induced drug resistance and compare them with P-glycoprotein associated multidrug resistance (MDR). EMT6/Ro cells exposed to drugs in air immediately after hypoxic treatment developed resistance to adriamycin, 5-fluorouracil, and actinomycin D. However, these cells did not develop resistance to colchicine, vincristine or cisplatin. When the cells were returned to a normal oxygen environment, they lost resistance. There was no correlation between the content of adriamycin and the development of adriamycin resistance induced by hypoxia. There was no difference between the efflux of adriamycin from aerobic cells and that from hypoxia-treated cells. The mRNA for P-glycoprotein was not detected in the hypoxia-treated cells. These results suggest that hypoxia-induced drug resistance is different from P-glycoprotein associated multidrug resistance. PMID:1681885

  4. Drug-Induced Nephrotoxicity and Dose Adjustment Recommendations: Agreement Among Four Drug Information Sources

    PubMed Central

    Bicalho, Millena Drumond; Soares, Danielly Botelho; Botoni, Fernando Antonio; Reis, Adriano Max Moreira; Martins, Maria Auxiliadora Parreiras

    2015-01-01

    Hospitalized patients require the use of a variety of drugs, many of which individually or in combination have the potential to cause kidney damage. The use of potentially nephrotoxic drugs is often unavoidable, and the need for dose adjustment should be evaluated. This study is aimed at assessing concordance in information on drug-induced nephrotoxicity and dose adjustment recommendations by comparing four drug information sources (DRUGDEX¬ģ, UpToDate¬ģ, Medscape¬ģ and the Brazilian Therapeutic Formulary) using the formulary of a Brazilian public hospital. A total of 218 drugs were investigated. The global Fleiss‚Äô kappa coefficient was 0.265 for nephrotoxicity (p < 0.001; CI 95%, 0.211‚Äď0.319) and 0.346 for recommendations (p < 0.001; CI 95%, 0.292‚Äď0.401), indicating fair concordance among the sources. Anti-infectives and anti-hypertensives were the main drugs cited as nephrotoxic by the different sources. There were no clear definitions for qualitative data or quantitative values for dose adjustments among the four information sources. There was no advice for dosing for a large number of the drugs in the international databases. The National Therapeutic Formulary offered imprecise dose adjustment recommendations for many nephrotoxic drugs. Discrepancies among information sources may have a clinical impact on patient care and contribute to drug-related morbidity and mortality. PMID:26371029

  5. Blockade of metabotropic glutamate receptor 5 protects against DNA damage in a rotenone-induced Parkinson's disease model.

    PubMed

    Xia, Ning; Zhang, Qian; Wang, Shu Ting; Gu, Li; Yang, Hui Min; Liu, Li; Bakshi, Rachit; Yang, Hui; Zhang, Hong

    2015-12-01

    Glutamate excitotoxicity contributes to the development of Parkinson's disease (PD) and pharmacological blockade of metabotropic glutamate receptor 5 (mGluR5) has beneficial anti-akinetic effects in animal models of PD; however, the mechanism by which these antagonists alleviate PD symptoms is largely unknown. In our study, the effects of mGluR5 inhibition on DNA damage were investigated in a rotenone-induced model of PD. We first found that the selective mGluR5 antagonist, 2-methyl-6- (phenylethynyl) pyridine, prevented rotenone-induced DNA damage in MN9D dopaminergic neurons through a mechanism involving the downregulation of intracellular calcium release which was associated with a reduction in endoplasmic reticulum stress and reactive oxygen species (ROS)-related mitochondrial dysfunction. Interestingly, the ROS-related mitochondrial dysfunction was accompanied by an increase in expression of the antioxidant protein, Trx2. Treatment of cells with the calcium chelating agent 1,2-bis-(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid or the ROS scavenger N-acetyl-L-cysteine, also reduced rotenone-induced DNA damage, while transfection of a dominant-negative form of Trx2 increased it. In addition, mGluR5 inhibition altered the expression profiles of proteins involved in DNA repair activity. Specifically, the expression of phosphorylated ERK (p-ERK) and CREB, as well as APE1 and Rad51 were elevated after rotenone stimulation and were subsequently downregulated following blockade of mGluR5. These findings were confirmed in vivo in a rotenone-induced rat model of PD. Inhibition of mGluR5 protected against neurotoxicity by mitigating oxidative stress-related DNA damage associated with 8-hydroxy-2'-deoxyguanosine production and also reduced p-ERK activity and Trx2 expression. These findings provide a novel link between mGluR5 and DNA damage in a model of PD, and reveal a potential mechanism by which mGluR5 mediates DNA damage in neurodegenerative diseases. PMID:26454081

  6. Excessive S-Adenosyl-L-Methionine-Dependent Methylation Increases Levels of Methanol, Formaldehyde and Formic Acid in Rat Brain Striatal Homogenates: Possible role in S-adenosyl-L-methionine-induced Parkinsonís disease-like disorders

    PubMed Central

    Lee, Eun-Sook; Chen, Hongtao; Hardman, Chadwick; Simm, Anthony; Charlton, Clivel

    2009-01-01

    Aims Excessive methylation may be a precipitating factor for Parkinsonís disease (PD) since S-adenosylmethionine (SAM), the endogenous methyl donor, induces PD-like changes when injected into the rat brain. The hydrolysis of the methyl ester bond of the methylated proteins produces methanol. Since methanol is oxidized into formaldehyde, and formaldehyde into formic acid in the body, we investigated the effects of SAM on the production of methanol, formaldehyde and formic acid in rat brain striatal homogenates and the toxicity of these products in PC12 cells. Main methods radio-enzymatic and colorimetric assays, cell viability, Western blot. Key findings SAM increased the formation of methanol, formaldehyde and formic acid in a concentration and time-dependent manner. Concentrations of [3H-methyl]-SAM at 0.17, 0.33, 0.67 and 1.34 nM produced 3.8, 8.0, 18.3 and 34.4 fmol/mg protein/h of [3H] methanol in rat striatal homogenates, respectively. SAM also significantly generated formaldehyde and formic acid in striatal homogenates. Formaldehyde was the most toxic metabolite to differentiated PC12 pheochromocytoma cells in cell culture studies, indicating that formaldehyde formed endogenously may contribute to neuronal damage in excessive methylation conditions. Subtoxic concentration of formaldehyde decreased the expression of tyrosine hydroxylase, the limiting factor in dopamine synthesis. Formaldehyde was more toxic to catecholaminergic PC12 cells than C6 glioma cells, indicating that neurons are more vulnerable to formaldehyde than glia cells. Significance We suggest that excessive carboxylmethylation of proteins might be involved in the SAM-induced PD-like changes and in the aging process via the toxic effects of formaldehyde. PMID:18930743

  7. Induced Pluripotent Stem Cells for Disease Modeling and Drug Discovery in Neurodegenerative Diseases.

    PubMed

    Cao, Lei; Tan, Lan; Jiang, Teng; Zhu, Xi-Chen; Yu, Jin-Tai

    2015-08-01

    Although most neurodegenerative diseases have been closely related to aberrant accumulation of aggregation-prone proteins in neurons, understanding their pathogenesis remains incomplete, and there is no treatment to delay the onset or slow the progression of many neurodegenerative diseases. The availability of induced pluripotent stem cells (iPSCs) in recapitulating the phenotypes of several late-onset neurodegenerative diseases marks the new era in in vitro modeling. The iPSC collection represents a unique and well-characterized resource to elucidate disease mechanisms in these diseases and provides a novel human stem cell platform for screening new candidate therapeutics. Modeling human diseases using iPSCs has created novel opportunities for both mechanistic studies as well as for the discovery of new disease therapies. In this review, we introduce iPSC-based disease modeling in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. In addition, we discuss the implementation of iPSCs in drug discovery associated with some new techniques. PMID:25146848

  8. Effects of non-steroidal antiinflammatory drugs on D-serine-induced oxidative stress in vitro.

    PubMed

    Armagan, Guliz; Kanit, Lutfiye; Yalcin, Ayfer

    2012-10-01

    Inflammation is deleterious for organs with reduced capacity of regeneration, such as the brain. Recently, studies have focused on investigating the therapeutic effects of nonsteroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. Excitotoxicity is the pathological process when receptors for the excitatory neurotransmitter glutamate, such as the N-methyl-D-aspartate (NMDA), receptors are overactivated. This process may be involved in neurodegenerative diseases. D-serine is one of the coagonist of NMDA receptors, and increased levels of D-serine are associated with excitotoxicity. In our study, the potential neuroprotective effects of mefenamic acid, acetaminophen, and naproxen sodium were investigated against D-serine-induced oxidative stress in the rat brain in vitro. To show their potential neuroprotective properties, NSAIDs were incubated with D-serine and reactive oxygen species (ROS), malondialdehyde, and protein carbonyl content of the brain after different treatments were measured. Our results demostrate that NSAIDs used in the present study significantly reduced ROS production, lipid peroxidation, and protein oxidation against D-serine treatment. PMID:22486999

  9. Non-Steroidal Anti-Inflammatory Drug-Induced Enteropathy

    PubMed Central

    Lim, Yun Jeong

    2012-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly prescribed drugs in the world. NSAID-induced lower gastrointestinal (GI) complications are increasing while upper GI complications are decreasing. Lower GI events accounted for 40% of all serious GI events in patients on NSAIDs. Capsule endoscopy and device assisted enteroscopy are available for detection of small intestinal lesions. Capsule endoscopy studies have demonstrated that NSAIDs use in healthy volunteers raised the incidence (55% to 75%) of intestinal damage. It appears that selective cyclooxygenase-2 inhibitors (coxibs) improved upper and lower GI safety based on results of clinical trials. Selective coxibs are still capable of triggering GI adverse events and cardiovascular toxicity issues were the main focus of concerns. Unfortunately, definite strategies are not available to prevent or heal NSAID-induced intestinal injuries. Thus, there is still a strong clinical need for effective drugs with improved safety profiles than the existing NSAIDs. PMID:22866254

  10. A 2015 focus on preventing drug-induced arrhythmias.

    PubMed

    Bossu, A; van der Heyden, Mag; de Boer, T P; Vos, M A

    2016-02-01

    Drug-induced Torsade de Pointes arrhythmia is a life-threatening adverse effect feared by pharmaceutical companies. For the last decade, the cardiac safety guidelines have imposed human ether-a-go-go-related gene channel blockade and prolongation of QT interval as surrogates for proarrhythmic risk propensity of a new chemical entity. Suffering from a lack of specificity, this assessment strategy led to a great amount of false positive outcomes. Therefore, this review will discuss new pharmaceutical strategies: the cardiac safety proposal that recently emerged, the Comprehensive in vitro Proarrhythmia Assay, combining in vitro assays that integrate effects on main cardiac ion channels, with computational models of human ventricular action potential as well as assays using human stem cell-derived cardiomyocytes for an improved prediction of drug's proarrhythmic liability, alternative pharmacological perspectives as well as the current treatment of drug-induced long QT syndrome. PMID:26560188

  11. ACETAMINOPHEN-INDUCED CELLULITIS-LIKE FIXED DRUG ERUPTION

    PubMed Central

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

    2011-01-01

    Acetaminophen is a widely used analgesic drug. Its adverse reactions are rare but severe. An 89-year-old man developed an indurated edematous and erythematous plaque on his left arm 1 day after acetaminophen ingestion. Cellulitis was suspected and antibiotictherapy was started but there was no improvement of the rash; there was a spectacular extension of the lesion with occurrence of flaccid vesicles and blisters in the affected sites. The diagnosis of generalized-bullous-fixed drug eruption induced by acetaminophen was considered especially with a reported history of a previous milder reaction occurring in the same site. Acetaminophen was withdrawn and the rash improved significantly. According to the Naranjo probability scale, the eruption experienced by the patient was probably due to acetaminophen. Clinicians should be aware of the ability of acetaminophen to induce fixed drug eruption that may clinically take several aspects and may be misdiagnosed. PMID:21716550

  12. Drug-induced hepatitis with hepatic granuloma due to saridon.

    PubMed

    Abe, Masanori; Kumagi, Teru; Nakanishi, Seiji; Yamagami, Takashi; Michitaka, Kojiro; Abe, Kayo; Okura, Izumi; Yamashita, Haruhiko; Horiike, Norio; Onji, Morikazu

    2002-01-01

    A 38-year-old Japanese woman with no past history of liver disease developed liver dysfunction associated with fever, anorexia, and general malaise following the prolonged administration of saridon. A liver biopsy demonstrated multiple noncaseating epithelioid granulomas within hepatic lobules, with an inflammatory cell infiltrate of the lobular parenchyma and portal tracts. Viral markers and autoantibodies were negative. Lymphocyte stimulation tests for saridon and for isopropylantipyrine, one of the constituents of saridon, were positive, and therefore a diagnosis of drug-induced hepatitis due to administration of saridon was made. Her symptoms resolved and liver function test results returned to normal following discontinuation of the drug. The possibility of drug-induced hepatitis must be considered when liver dysfunction or systemic symptomatology develops during saridon therapy. PMID:12522541

  13. Drug-induced liver injury: Is it somehow foreseeable?

    PubMed Central

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

    2009-01-01

    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

  14. No association between akathisia or Parkinsonism and suicidality in treatment-resistant Schizophrenia.

    PubMed

    Hansen, Lars; Jones, Roland Morgan; Kingdon, David

    2004-09-01

    Akathisia and drug-induced Parkinsonism have traditionally been associated with depression and suicidality based on case study evidence. In this subanalysis, patients with treatment resistant schizophrenia were rated on the Comprehensive Psychopathological Rating Scale, Barnes Akathisia Scale and Simpson-Angus extrapyramidal side-effect scale at two time points (n=86 at first assessment; n=67 at second assessment). At no time point was there any significant relationship between akathisia and depression/suicidality or distress associated with akathisia and Parkinsonism with suicidality. These preliminary findings warrant further investigation. PMID:15358982

  15. Indirect application of near infrared light induces neuroprotection in a mouse model of parkinsonism - an abscopal neuroprotective effect.

    PubMed

    Johnstone, D M; el Massri, N; Moro, C; Spana, S; Wang, X S; Torres, N; Chabrol, C; De Jaeger, X; Reinhart, F; Purushothuman, S; Benabid, A-L; Stone, J; Mitrofanis, J

    2014-08-22

    We have previously shown near infrared light (NIr), directed transcranially, mitigates the loss of dopaminergic cells in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated mice, a model of parkinsonism. These findings complement others suggesting NIr treatment protects against damage from various insults. However one puzzling feature of NIr treatment is that unilateral exposure can lead to a bilateral healing response, suggesting NIr may have 'indirect' protective effects. We investigated whether remote NIr treatment is neuroprotective by administering different MPTP doses (50-, 75-, 100-mg/kg) to mice and treating with 670-nm light directed specifically at either the head or body. Our results show that, despite no direct irradiation of the damaged tissue, remote NIr treatment produces a significant rescue of tyrosine hydroxylase-positive cells in the substantia nigra pars compacta at the milder MPTP dose of 50-mg/kg (?30% increase vs sham-treated MPTP mice, p<0.05). However this protection did not appear as robust as that achieved by direct irradiation of the head (?50% increase vs sham-treated MPTP mice, p<0.001). There was no quantifiable protective effect of NIr at higher MPTP doses, irrespective of the delivery mode. Astrocyte and microglia cell numbers in substantia nigra pars compacta were not influenced by either mode of NIr treatment. In summary, the findings suggest that treatment of a remote tissue with NIr is sufficient to induce protection of the brain, reminiscent of the 'abscopal effect' sometimes observed in radiation treatment of metastatic cancer. This discovery has implications for the clinical translation of light-based therapies, providing an improved mode of delivery over transcranial irradiation. PMID:24857852

  16. Drug-induced liver injury: the role of drug metabolism and transport.

    PubMed

    Corsini, Alberto; Bortolini, Michele

    2013-05-01

    Many studies have pinpointed the significant contribution of liver-mediated drug metabolism and transport to the complexity of drug-induced liver injury (DILI). Phase I cytochrome P450 (CYP450) enzymes can lead to altered drug metabolism and formation of toxic metabolites, whilst Phase II enzymes are also associated with DILI. The emerging role of hepatic transporters in regulating the movement of endogenous and exogenous chemicals (e.g., bile acids and drugs) across cellular and tissue membranes is critical in determining the pathophysiology of liver disease as well as drug toxicity and efficacy. Genetic and environmental factors can have a significant impact on drug metabolism and transporter proteins, consequently increasing the risk of DILI in susceptible individuals. The assessment of these factors therefore represents an important approach for predicting and preventing DILI, by better understanding the pharmacological profile of a specific drug. This review focuses on the mechanisms of DILI associated with drug metabolism and hepatic transport, and how they can be influenced by underlying factors. PMID:23436293

  17. Neuroprotective effects of piperine on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinson's disease mouse model.

    PubMed

    Yang, Wei; Chen, Yu-Hua; Liu, Hao; Qu, Hong-Dang

    2015-11-01

    Parkinson's disease (PD) is second only to Alzheimer's disease as the most common and debilitating age-associated neurodegenerative disorder. Currently, no therapy has been shown to unequivocally retard or arrest the progression of the disease. The aim of the present study was to investigate the protective effect of piperine on the 1-methyl-4-phenyl-1,2,3,6?tetrahydropyridine (MPTP)-induced Parkinson's mouse model. For MPTP treatment, the animals received repeated intraperitoneal injections (i.p.) of MPTP (30†mg/kg) solution for 7†days. Piperine (10†mg/kg) was administered orally for 15†days including 8†days of pretreatment. Motor behavior analysis was conducted with the rotarod test. The Morris water maze (MWM) was used to assess the cognitive learning ability of the mice. A histological examination was subsequently conducted. The results ddemonstrate that piperine treatment attenuated MPTP-induced deficits in motor coordination and cognitive functioning. Piperine also prevented MPTP-induced decreases in the number of tyrosine hydroxylase-positive cells in the substantia nigra. Additionally, piperine reduced the number of activated microglia, expression of cytokine IL-1?, and oxidative stress following MPTP treatment. An anti-apoptotic property of piperine was identified by maintaining the balance of Bcl-2/Bax. In conclusion, the results show that piperine exerts a protective effect on dopaminergic neurons via antioxidant, anti-apoptotic, and anti-inflammatory mechanisms in an MPTP-induced mouse model of PD. Thus, piperine is a potential therapeutic treatment for PD. PMID:26648012

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

    PubMed Central

    de Ara√ļjo, Dayane Pessoa; De Sousa, Caren N√°dia Soares; Ara√ļjo, Paulo Victor Pontes; Menezes, Carlos Eduardo de Souza; Sousa Rodrigues, Francisca Taciana; Escudeiro, Sarah Souza; Lima, Nicole Brito Cortez; Patroc√≠nio, Manoel Cla√ļdio Azevedo; Aguiar, Lissiana Magna Vasconcelos; Viana, Glauce Socorro de Barros; Vasconcelos, Silv√Ęnia Maria Mendes

    2013-01-01

    This study aimed to investigate behavioral and neurochemical effects of őĪ-lipoic acid (100‚ÄČmg/kg or 200‚ÄČmg/kg) alone or associated with L-DOPA using an animal model of Parkinson's disease induced by stereotaxic injection of 6-hydroxydopamine (6-OHDA) in rat striatum. Motor behavior was assessed by monitoring body rotations induced by apomorphine, open field test and cylinder test. Oxidative stress was accessed by determination of lipid peroxidation using the TBARS method, concentration of nitrite and evaluation of catalase activity. őĪ-Lipoic acid decreased body rotations induced by apomorphine, as well as caused an improvement in motor performance by increasing locomotor activity in the open field test and use of contralateral paw (in the opposite side of the lesion produced by 6-OHDA) at cylinder test. őĪ-lipoic acid showed antioxidant effects, decreasing lipid peroxidation and nitrite levels and interacting with antioxidant system by decreasing of endogenous catalase activity. Therefore, őĪ-lipoic acid prevented the damage induced by 6-OHDA or by chronic use of L-DOPA in dopaminergic neurons, suggesting that őĪ-lipoic could be a new therapeutic target for Parkinson's disease prevention and treatment. PMID:24023579

  19. Cytotoxic?based assays in delayed drug hypersensitivity reactions induced by antiepileptic drugs.

    PubMed

    Por?bski, Grzegorz; Czarnobilska, Ewa; Bosak, Magdalena

    2015-11-27

    Introduction Cytotoxic mechanisms are present in the majority of delayed drug hypersensitivity reactions, but are not used as a diagnostic tool. Objectives The aim of the study was to compare cytotoxic?based assays with a proliferation assay and drug patch tests in patients with maculopapular eruptions induced by antiepileptic drugs. Patient s and methods Peripheral blood mononuclear cells of 23 patients and 24 controls exposed to the drugs were cultured under defined conditions. A drug?specific response was assessed by measuring granzyme B (GrB) release with an enzyme?linked immunospot assay, intracellular expression of granulysin (Grl) in CD3-NKp46+ cells with flow cytometry, perforin concentrations in cell culture supernatants with an enzyme?linked immunosorbent assay, and using the lymphocyte proliferation test. Patch tests with culprit drugs were done in all patients. Result s Lymphocyte proliferation, GrB release, and Grl expression were significantly higher in patients than in controls, while perforin concentrations were not elevated. The sensitivities were 30.4%, 55%, 39.1%, and 17.4% for proliferation, GrB, Grl, and perforin?based assays, respectively. A significantly higher rate of positive results was observed when assays were done within 2 years after a drug?induced reaction. The specificities of all assays remained in the range of 95.8% to 100%. The results of patch tests were positive only in 3 patients (sensitivity, 14.3%) and negative in all controls. Conclusions In vitro assays based on the detection of Grl, and in particular of GrB, are superior to routine diagnostic tests in patients with hypersensitivity to antiepileptic drugs. They can detect a low?level response that might be overlooked by standard techniques. In the remission phase, drug?specific cells are more easily detectable directly in the circulation than in the skin. PMID:26445768

  20. Homers regulate drug-induced neuroplasticity: Implications for addiction

    PubMed Central

    Szumlinski, Karen K.; Ary, Alexis W.; Lominac, Kevin D.

    2008-01-01

    Drug addiction is a chronic, relapsing disorder, characterized by an uncontrollable motivation to seek and use drugs. Converging clinical and preclinical observations implicate pathologies within the corticolimbic glutamate system in the genetic predisposition to, and the development of, an addicted phenotype. Such observations pose cellular factors regulating glutamate transmission as likely molecular candidates in the etiology of addiction. Members of the Homer family of proteins regulate signal transduction through, and the trafficking of, glutamate receptors, as well as maintain and regulate extracellular glutamate levels in corticolimbic brain regions. This review summarizes the existing data implicating the Homer family of protein in acute behavioral and neurochemical sensitivity to drugs of abuse, the development of drug-induced neuroplasticity, as well as other behavioral and cognitive pathologies associated with an addicted state. PMID:17765204

  1. Deep Learning for Drug-Induced Liver Injury.

    PubMed

    Xu, Youjun; Dai, Ziwei; Chen, Fangjin; Gao, Shuaishi; Pei, Jianfeng; Lai, Luhua

    2015-10-26

    Drug-induced liver injury (DILI) has been the single most frequent cause of safety-related drug marketing withdrawals for the past 50 years. Recently, deep learning (DL) has been successfully applied in many fields due to its exceptional and automatic learning ability. In this study, DILI prediction models were developed using DL architectures, and the best model trained on 475 drugs predicted an external validation set of 198 drugs with an accuracy of 86.9%, sensitivity of 82.5%, specificity of 92.9%, and area under the curve of 0.955, which is better than the performance of previously described DILI prediction models. Furthermore, with deep analysis, we also identified important molecular features that are related to DILI. Such DL models could improve the prediction of DILI risk in humans. The DL DILI prediction models are freely available at http://www.repharma.cn/DILIserver/DILI_home.php. PMID:26437739

  2. Acceleration stress-induced Wolff-Parkinson-White Syndrome with marked ST-segment depression.

    PubMed

    Whinnery, J E

    1981-11-01

    Exercise can affect preexcitation in several ways. The possible presence of catecholamine-sensitive bypass, stimulated during periods of high stress, was recently reported. In addition to a direct effect on the preexcitation, when the preexcitation pattern exists, exercise-induced ST-segment changes may occur which preclude stress testing for coronary artery disease detection. Current high-performance fighter pilots, flying new generation aircraft, are under severe stress during aerial combat maneuvering when they are exposed to high sustained +Gz (head-to-foot) acceleration stress. We report the occurrence of a +Gz acceleration-induced episode of preexcitation with marked ST-segment depression in a healthy asymptomatic aircrewman. Autonomic imbalance, with high catecholamine levels developed during +Gz stress, may be the etiology of this preexcitation episode. PMID:7305792

  3. Highly specific changes in antioxidant levels and lipid peroxidation in Parkinson's disease and its progression: Disease and staging biomarkers and new drug targets.

    PubMed

    de Farias, Carine Coneglian; Maes, Michael; Bonif√°cio, Kamila Landucci; Bortolasci, Chiara Cristina; de Souza Nogueira, Andr√©; Brinholi, Francis Fregonesi; Matsumoto, Andressa Keiko; do Nascimento, Matheus Amarante; de Melo, L√ļcio Baena; Nixdorf, Suzana Lucy; Lavado, Edson Lopes; Moreira, Estef√Ęnia Gastaldello; Barbosa, D√©cio Sabbatini

    2016-03-23

    There is evidence that immune-inflammatory, stress of reactive oxygen and nitrogen species (IO&NS) processes play a role in the neurodegenerative processes observed in Parkinson's disease (PD). The aim of the present study was to investigate peripheral IO&NS biomarkers in PD. We included 56 healthy individuals and 56 PD patients divided in two groups: early PD stage and late PD stage. Plasma lipid hydroperoxides (LOOH), malondialdehyde (MDA), nitric oxide metabolites (NOx), sulfhydryl (SH) groups, catalase (CAT) activity, superoxide dismutase (SOD) activity, paraoxonase (PON)1 activity, total radical trapping antioxidant parameter (TRAP) and C-reactive protein (CRP) were measured. PD is characterized by increased LOOH, MDA and SOD activity and lowered CAT activity. A combination of five O&NS biomarkers highly significantly predicts PD with a sensitivity of 94.5% and a specificity of 86.8% (i.e., MDA, SOD activity, TRAP, SH-groups and CAT activity). The single best biomarker of PD is MDA, while LOOH and SOD activity are significantly associated with late PD stage, but not early PD stage. Antiparkinson drugs did not affect O&NS biomarkers, but levodopa+carbidopa significantly increased CRP. It is suggested that MDA may serve as a disease biomarker, while LOOH and SOD activity are associated with late PD stage characteristic. New treatments for PD should not only target dopamine but also lipid peroxidation. PMID:26861200

  4. Multiple Targets for Drug-Induced Mitochondrial Toxicity.

    PubMed

    Wallace, Kendall B

    2015-01-01

    Mitochondrial toxicity is rapidly gaining the interest of researchers and practitioners as a prominent liability in drug discovery and development, accounting for a growing proportion of preclinical drug attrition and post-market withdrawals or black box warnings by the U.S. FDA. To date, the focus of registries of drugs that elicit mitochondrial toxicity has been largely restricted to those that either inhibit the mitochondrial electron transport chain (ETC) or uncouple mitochondrial oxidative phosphorylation. Less appreciated are the toxicities that are secondary to the drug affecting either the molecular regulation, assembly or incorporation of the ETC into the inner mitochondrial membrane or those that limit substrate availability. The current article describes the complexities of molecular events and biochemical pathways required to sustain mitochondrial fidelity and substrate homeostasis with examples of drugs that interfere which the various pathways. The principal objective of this review is to shed light on the broader scope of drug-induced mitochondrial toxicities and how these secondary targets may account for a large portion of drug failures. PMID:25973981

  5. Drug-induced proarrhythmia: risk factors and electrophysiological mechanisms.

    PubMed

    Frommeyer, Gerrit; Eckardt, Lars

    2016-01-01

    Drug-induced ventricular tachyarrhythmias can be caused by cardiovascular drugs, noncardiovascular drugs, and even nonprescription agents. They can result in arrhythmic emergencies and sudden cardiac death. If a new arrhythmia or aggravation of an existing arrhythmia develops during therapy with a drug at a concentration usually considered not to be toxic, the situation can be defined as proarrhythmia. Various cardiovascular and noncardiovascular drugs can increase the occurrence of polymorphic ventricular tachycardia of the 'torsade de pointes' type. Antiarrhythmic drugs, antimicrobial agents, and antipsychotic and antidepressant drugs are the most important groups. Age, female sex, and structural heart disease are important risk factors for the occurrence of torsade de pointes. Genetic predisposition and individual pharmacodynamic and pharmacokinetic sensitivity also have important roles in the generation of arrhythmias. An increase in spatial or temporal dispersion of repolarization and a triangular action-potential configuration have been identified as crucial predictors of proarrhythmia in experimental models. These studies emphasized that sole consideration of the QT interval is not sufficient to assess the proarrhythmic risk. In this Review, we focus on important triggers of proarrhythmia and the underlying electrophysiological mechanisms that can enhance or prevent the development of torsade de pointes. PMID:26194552

  6. Drug Repositioning for Cancer Therapy Based on Large-Scale Drug-Induced Transcriptional Signatures

    PubMed Central

    Lee, Haeseung; Kang, Seungmin; Kim, Wankyu

    2016-01-01

    An in silico chemical genomics approach is developed to predict drug repositioning (DR) candidates for three types of cancer: glioblastoma, lung cancer, and breast cancer. It is based on a recent large-scale dataset of ~20,000 drug-induced expression profiles in multiple cancer cell lines, which provides i) a global impact of transcriptional perturbation of both known targets and unknown off-targets, and ii) rich information on drug’s mode-of-action. First, the drug-induced expression profile is shown more effective than other information, such as the drug structure or known target, using multiple HTS datasets as unbiased benchmarks. Particularly, the utility of our method was robustly demonstrated in identifying novel DR candidates. Second, we predicted 14 high-scoring DR candidates solely based on expression signatures. Eight of the fourteen drugs showed significant anti-proliferative activity against glioblastoma; i.e., ivermectin, trifluridine, astemizole, amlodipine, maprotiline, apomorphine, mometasone, and nortriptyline. Our DR score strongly correlated with that of cell-based experimental results; the top seven DR candidates were positive, corresponding to an approximately 20-fold enrichment compared with conventional HTS. Despite diverse original indications and known targets, the perturbed pathways of active DR candidates show five distinct patterns that form tight clusters together with one or more known cancer drugs, suggesting common transcriptome-level mechanisms of anti-proliferative activity. PMID:26954019

  7. Symptoms of Parkinson's

    MedlinePLUS

    ... Patient Advocates Sign Up for Funding News npj Parkinson's Disease Scientific Advisory Board Understanding Parkinson's Coping with a Diagnosis What is Parkinson’s Disease? National HelpLine Educational Publications Online Seminars Parkinson's News ...

  8. Managing Your Parkinson's Disease

    MedlinePLUS

    ... Patient Advocates Sign Up for Funding News npj Parkinson's Disease Scientific Advisory Board Understanding Parkinson's Coping with a Diagnosis What is Parkinson’s Disease? National HelpLine Educational Publications Online Seminars Parkinson's News ...

  9. What Causes Parkinson's?

    MedlinePLUS

    ... National HelpLine Educational Publications Online Seminars Parkinson's News Parkinson's HelpLine Learn More Educational Materials Do you want ... more. Order Free Materials Today Causes What Causes Parkinson's? To date, despite decades of intensive study, the ...

  10. Progression of Parkinson's Disease

    MedlinePLUS

    ... National HelpLine Educational Publications Online Seminars Parkinson's News Parkinson's HelpLine Learn More Educational Materials Do you want ... out daily activities, and treatment complications. Severity of Parkinson's Below are some descriptions of mild, moderate and ...

  11. What Is Parkinson's Disease?

    MedlinePLUS

    ... National HelpLine Educational Publications Online Seminars Parkinson's News Parkinson's HelpLine Learn More Educational Materials Do you want ... resources & more. Order Free Materials Today What is Parkinson’s Disease? Parkinson's disease (PD) is a chronic and ...

  12. Angioedema induced by cardiovascular drugs: new players join old friends.

    PubMed

    Bas, M; Greve, J; Strassen, U; Khosravani, F; Hoffmann, T K; Kojda, G

    2015-10-01

    During the last years, two new cardiovascular drug classes, namely inhibitors of DPP IV or neprilysin, have been developed. In both cases, there is clinical evidence for their potential to induce angioedema as known already from blockers of the renin-angiotensin-aldosterone system (RAAS). The majority of angioedema induced by DPP IV inhibitors occurs during concomitant treatment with ACEi and is therefore likely mediated by overactivation of bradykinin type 2 receptors (B2). In striking contrast, the molecular pathways causing angioedema induced by neprilysin inhibitors, that is, sacubitril, are unclear, although a contribution of bradykinin appears likely. Nevertheless, there is no clinical evidence suggesting that inhibition of B2 might relieve the symptoms and/or prevent invasive treatment including coniotomy or tracheotomy in angioedema caused by these drugs. Therefore, the risk of angioedema should always be considered, especially in ambulatory care situations where patients have no rapid access to intensive care. PMID:26119220

  13. N-acetyl-L-methionyl-L-Dopa-methyl ester as a dual acting drug that relieves L-Dopa-induced oxidative toxicity.

    PubMed

    Minelli, Alba; Conte, Carmela; Prudenzi, Elvira; Cacciatore, Ivana; Cornacchia, Catia; Taha, Elena; Pinnen, Francesco

    2010-07-01

    Initiation and progression of Parkinson's disease seem to be linked to oxidative stress, closely related to decreased mitochondrial functions and ubiquitin proteasome system dysfunction. To date, L-Dopa is the most effective medication , although long-term treatment can enhance oxidative stress and accelerate the degenerative process of residual cells. Therefore the inhibition of oxidation of L-Dopa/dopamine and the inhibition of reactive oxygen species formation are important strategies for neuroprotective therapy. Recently, several dual acting drugs, in which L-Dopa/dopamine are covalently linked to antioxidant molecules, were shown to induce sustained delivery of both L-Dopa/dopamine in rat plasma and striatum, suggesting that these compounds might be proposed as useful agents against Parkinson's disease. Here, by analyzing GSH levels and heme oxygenase-1 expression, we investigated in primary mesencephalic neuron cultures and in newborn mice the effects of the treatment with Ac-Met-LD-OMe. Moreover, by using proteasome inhibitor-treated mice as Parkinson's disease animal model, we demonstrated the beneficial effects of the systemic administration of this novel codrug. PMID:20307650

  14. Adenosine A2A receptor-mediated control of pilocarpine-induced tremulous jaw movements is Parkinson's disease-associated GPR37 receptor-dependent.

    PubMed

    GandŪa, Jorge; Moratů, Xavier; Stagljar, Igor; FernŠndez-DueŮas, VŪctor; Ciruela, Francisco

    2015-07-15

    GPR37, also known as parkin associated endothelin-like receptor (Pael-R), is an orphan GPCR that aggregates intracellularly in a juvenile form of Parkinson's disease. However, little is known about the function of this orphan receptor. Here, using a model for parkisonian tremor, the pilocarpine-induced tremulous jaw movements (TJMs), we show that the deletion of GPR37 attenuated the TJMs in response to this cholinomimetic. Interestingly, the control that adenosine A2A receptor exerted over TJMs was lost in the absence of GPR37, thus pointing to a pivotal role of this orphan receptor in the adenosinergic control of parkinsonian tremor. PMID:25862943

  15. [The causative gene of Parkinsonism and its medical treatment strategy].

    PubMed

    Inden, Masatoshi

    2014-01-01

    Parkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability. The neurodegenerative condition of Parkinson's disease (PD) is the most common cause of parkinsonism. PD is classified as sporadic PD and familial PD. Whereas idiopathic PD is caused by a number of complex factors, familial PD is a result of mutations in PD-associated genes. Unraveling the mechanisms surrounding familial PD will offer pivotal clues in understanding etiology of not only familial PD but also sporadic PD. We have demonstrated neuroprotective effects with particular focus on DJ-1. On the other hand, idiopathic basal ganglia calcification, also known as Fahr disease (FD) is another condition characterized by parkinsonism. In 2012, solute carrier family 20A2 (SLC20A2) was identified as the causative gene for familial FD. Our analysis of patient samples revealed a novel mutation in SLC20A2. Type-III sodium-dependent phosphate transporter 2 (PiT-2), the protein encoded by SLC20A2, plays an important role in phosphate homeostasis. However, PiT-2's role in the pathology of FD remains largely unclear. We have established induced pluripotent stem (iPS) cells from FD patients and are investigating their usefulness in drug development. Here, we present some of our latest research findings. PMID:25452235

  16. Trigger medications and patient-related risk factors for Parkinson disease psychosis requiring anti-psychotic drugs: a retrospective cohort study

    PubMed Central

    2013-01-01

    Background Psychoses such as hallucinations are a frequent non-motor problem in patients with Parkinson disease (PD) and serious psychosis requires anti-psychotic medications that worsen Parkinsonism. Although psychosis could be associated with patient-related or biological factors such as cognition, age, and severity of PD, it can also be associated with medications. Therefore we aimed to investigate patient-related and medication-related risks of psychosis requiring anti-psychotic medications (serious psychosis). Methods A retrospective cohort of 331 PD patients was followed for 2†years. Patient-related factors associated with risk of psychosis were identified by a survival time analysis. In patients who developed psychosis, medications during the hazard period (1-14†days before psychosis) were contrasted with those during the control periods (1 and 3†months before psychosis) using a caseĖcrossover analysis to identify medication-related risks of psychosis. Results Serious psychosis was detected in 52 patients and the incidence was estimated to be 116 (95% confidence interval [CI], 85-148) per 1,000 person-years. Analyses of baseline characteristics revealed the risk to be higher in patients with a modified HoehnĖYahr stage of ?4 (hazard ratio [HR], 2.22; 95% CI, 1.11-4.40), those with a longer duration of PD (HR, 1.25; 95% CI, 1.00-1.55, per 5†years) and those with Mini-Mental State Examination scores of ?24 (HR, 2.66; 95% CI, 1.37-5.16). The case-crossover analysis revealed that anti-cholinergics use (HR, 19.7; 95% CI, 2.39-162) elevated the risk, while donepezil use reduced it (HR, 0.48; 95% CI, 0.27-0.85). Conclusions Risk of psychosis was elevated by increasing severity of PD, cognitive dysfunction and duration of the disease. It was elevated by use of anti-cholinergic drugs and reduced by use of donepezil. The medication-related risk was higher in patients aged???70†years. In contrast, there was no significant medication-related risk in younger patients, suggesting different pathomechanisms between young and old patients. PMID:24119306

  17. Light induced cytosolic drug delivery from liposomes with gold nanoparticles.

    PubMed

    Lajunen, Tatu; Viitala, Lauri; Kontturi, Leena-Stiina; Laaksonen, Timo; Liang, Huamin; Vuorimaa-Laukkanen, Elina; Viitala, Tapani; Le Guťvel, Xavier; Yliperttula, Marjo; Murtomški, Lasse; Urtti, Arto

    2015-04-10

    Externally triggered drug release at defined targets allows site- and time-controlled drug treatment regimens. We have developed liposomal drug carriers with encapsulated gold nanoparticles for triggered drug release. Light energy is converted to heat in the gold nanoparticles and released to the lipid bilayers. Localized temperature increase renders liposomal bilayers to be leaky and triggers drug release. The aim of this study was to develop a drug releasing system capable of releasing its cargo to cell cytosol upon triggering with visible and near infrared light signals. The liposomes were formulated using either heat-sensitive or heat- and pH-sensitive lipid compositions with star or rod shaped gold nanoparticles. Encapsulated fluorescent probe, calcein, was released from the liposomes after exposure to the light. In addition, the pH-sensitive formulations showed a faster drug release in acidic conditions than in neutral conditions. The liposomes were internalized into human retinal pigment epithelial cells (ARPE-19) and human umbilical vein endothelial cells (HUVECs) and did not show any cellular toxicity. The light induced cytosolic delivery of calcein from the gold nanoparticle containing liposomes was shown, whereas no cytosolic release was seen without light induction or without gold nanoparticles in the liposomes. The light activated liposome formulations showed a controlled content release to the cellular cytosol at a specific location and time. Triggering with visual and near infrared light allows good tissue penetration and safety, and the pH-sensitive liposomes may enable selective drug release in the intracellular acidic compartments (endosomes, lysosomes). Thus, light activated liposomes with gold nanoparticles are an attractive option for time- and site-specific drug delivery into the target cells. PMID:25701610

  18. Risk factors for drug-induced long-QT syndrome

    PubMed Central

    Paulussen, A.D.C.; Aerssens, J.

    2005-01-01

    Congenital long-QT syndrome (cLQTS) is a ventricular arrhythmia that is characterised by a prolonged QT interval on the surface electro-cardiogram (ECG). Clinical symptoms include sudden loss of consciousness (syncopes), seizures, cardiac arrest and sudden death. The prevalence of this inherited disease is approximately one in 10,000 in Caucasians. Over the last decade, more than 200 different diseases causing mutations have been identified in five genes that encode ion channels involved in the delicate balance of inward and outward K/Ca currents during the cardiac action potential. A prolonged QT interval accompanied by very similar clinical symptoms as in cLQTS can also occur in otherwise healthy individuals after the intake of specific drug(s). This phenomenon is known as 'acquired' or 'drug-induced' long-QT syndrome. Because the clinical symptoms of the two forms are very similar, the question arises whether a common underlying genetic basis also exists. Several studies indicate that only a minority (approximately 10%) of the drug-induced LQTS cases can be explained by a mutation or polymorphism in one of the known LQTS genes. Even though the disease can often at least partially be explained by environmental factors, mutations or polymorphisms in other genes are also expected to be involved, including genes encoding drug-metabolising enzymes, adrenergic receptors, hormone-related genes and mitochondrial genes. This article reviews the current knowledge on risk factors for drug-induced LQTS, with a special emphasis on the role of genetic determinants. ImagesFigure 1AFigure 2Figure 3 PMID:25696450

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

    ERIC Educational Resources Information Center

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

    2013-01-01

    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…

  20. Mechanism of Nanotization-Mediated Improvement in the Efficacy of Caffeine Against 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Induced Parkinsonism.

    PubMed

    Singhal, Naveen Kumar; Agarwal, Swati; Bhatnagar, Priyanka; Tiwari, Manindra Nath; Tiwari, Shashi Kant; Srivastava, Garima; Kumar, Pradeep; Brashket, Seth; Patel, Devendra Kumar; Chaturvedi, Rajnish Kumar; Singh, Mahendra Pratap; Gupta, Kailash Chand

    2015-12-01

    The study aimed to measure the neuroprotective efficacy of caffeine-encapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles over bulk and to delineate the mechanism of improvement in efficacy both in vitro and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of Parkinsonism. Caffeine-encapsulated PLGA nanoparticles exhibited more pronounced increase in the endurance of dopaminergic neurons, fibre outgrowth and expression of tyrosine hydroxylase (TH) and growth-associated protein-43 (GAP-43) against 1-methyl-4-phenylpyridinium (MPP+)-induced alterations in vitro. Caffeine-encapsulated PLGA nanoparticles also inhibited MPP(+)-mediated nuclear translocation of nuclear factor-kappa B (NF-őļB) and augmented protein kinase B phosphorylation more potentially than bulk counterpart. Conversely, MPTP reduced the striatal dopamine and its metabolites and nigral TH immunoreactivity whereas augmented the nigral microglial activation and nigrostriatal lipid peroxidation and nitrite content, which were shifted towards normalcy by caffeine. The modulations were more evident in caffeine-encapsulated PLGA nanoparticles treated animals as compared with bulk. Moreover, the striatal caffeine and its metabolites were found to be significantly higher in caffeine-encapsulated PLGA nanoparticles-treated mice as compared with bulk. The results thus suggest that nanotization improves the protective efficacy of caffeine against MPTP-induced Parkinsonism owing to enhanced bioavailability, inhibition of the nuclear translocation of NF-őļB and activation of protein kinase B phosphorylation. PMID:26510314

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

    PubMed

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

    2012-03-31

    The generation of disease-specific induced pluripotent stem cell (iPSC) lines from patients with incurable diseases is a promising approach for studying disease mechanisms and drug screening. Such innovation enables to obtain autologous cell sources in regenerative medicine. Herein, we report the generation and characterization of iPSCs from fibroblasts of patients with sporadic or familial diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), juvenile-onset, type I diabetes mellitus (JDM), and Duchenne type muscular dystrophy (DMD), as well as from normal human fibroblasts (WT). As an example to modeling disease using disease-specific iPSCs, we also discuss the previously established childhood cerebral adrenoleukodystrophy (CCALD)- and adrenomyeloneuropathy (AMN)-iPSCs by our group. Through DNA fingerprinting analysis, the origins of generated disease-specific iPSC lines were identified. Each iPSC line exhibited an intense alkaline phosphatase activity, expression of pluripotent markers, and the potential to differentiate into all three embryonic germ layers: the ectoderm, endoderm, and mesoderm. Expression of endogenous pluripotent markers and downregulation of retrovirus-delivered transgenes [OCT4 (POU5F1), SOX2, KLF4, and c-MYC] were observed in the generated iPSCs. Collectively, our results demonstrated that disease-specific iPSC lines characteristically resembled hESC lines. Furthermore, we were able to differentiate PD-iPSCs, one of the disease-specific-iPSC lines we generated, into dopaminergic (DA) neurons, the cell type mostly affected by PD. These PD-specific DA neurons along with other examples of cell models derived from disease-specific iPSCs would provide a powerful platform for examining the pathophysiology of relevant diseases at the cellular and molecular levels and for developing new drugs and therapeutic regimens. PMID:22179105

  2. Suspected drug-induced destructive cholangitis in a young dog.

    PubMed

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

    2006-06-01

    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

  3. [Talc-induced pulmonary granulomas in drug addicts].

    PubMed

    Latartseva, L N; Kryvenko, O N

    2013-01-01

    Among the diseases accompanied by granuloma formation in the lung, there is so-called granulomatosis developing in injection drug users who have been long injecting suspensions of oral medications containing talc and other water insoluble fillers. 102 deaths of chronic intravenous drug users were examined; 12 of whom showed pulmonary talc-induced granulomatosis. Their morphology was studied using polarized light microscopy. The main mechanisms of thanatogenesis in lethal cases within the first hours after intravenous injection of talc-containing oral medication suspensions are explained. PMID:24313188

  4. Methamphetamine and Parkinson's Disease

    PubMed Central

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

    2013-01-01

    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

  5. Structure-based Methods for Predicting Target Mutation-induced Drug Resistance and Rational Drug Design to Overcome the Problem

    PubMed Central

    Hao, Ge-Fei; Yang, Guang-Fu; Zhan, Chang-Guo

    2012-01-01

    Drug resistance has become one of the biggest challenges in drug discovery/development and attracted great research interests worldwide. During the last decade, computational strategies have been developed to predict target mutation-induced drug resistance. Meanwhile, various molecular design strategies, including targeting protein backbone, targeting highly conserved residues, and dual/multiple targeting, have been used to design novel inhibitors for combating the drug resistance. This is a brief review of recent advances in development of computational methods for target mutation-induced drug resistance prediction and strategies for rational design of novel inhibitors that could be effective also against the possible drug-resistant mutants of the target. PMID:22789991

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

    PubMed

    Grossman, Ehud; Messerli, Franz H

    2012-01-01

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

  7. Psychiatric care in Parkinson's disease.

    TOXLINE Toxicology Bibliographic Information

    Quelhas R

    2013-03-01

    OBJECTIVE: Parkinson's disease (PD) is a degenerative and disabling disease in which medical providers focus mainly on ameliorating problems in day-to-day functioning. This review summarizes current knowledge about the efficacy and tolerability of psychopharmacological agents in the treatment of depression, anxiety, psychosis, and insomnia in patients with PD. Recommended or promising nonpharmacological interventions are also reviewed.METHOD: Studies were identified using computerized searches, with further references obtained from the bibliographies of the reviewed articles.RESULT: Findings in the research literature provide growing evidence concerning the antidepressant treatment of patients with PD. Psychoeducational interventions for managing depression and anxiety symptoms also appear promising. Music therapy has proven to be particularly effective for patients with PD. Psychosis is common in patients with PD. When psychosis is induced by antiparkinson drugs, a dose reduction can be considered, but it is seldom successful. Patients with PD do not generally tolerate conventional antipsychotic medications, justifying evaluation of newer atypical agents in this population. Cholinesterase inhibitors have also become increasingly important in the treatment of PD in recent years. Finally, insomnia is a very frequent complaint in patients with PD and may also contribute to the development of depression. Patients should be encouraged to improve sleep hygiene and use behavioral interventions. Definitive trials of treatments for sleep disorders in this population are also warranted.CONCLUSION: Therapeutic approaches to the treatment of PD and its associated psychiatric symptoms must be individualized and may involve a combination of antiparkinson drugs, psychopharmacological treatment, and/or psychotherapeutic interventions.

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

    ERIC Educational Resources Information Center

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

    2007-01-01

    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 theseÖ

  9. Dual target strategy: combining distinct non-dopaminergic treatments reduces neuronal cell loss and synergistically modulates L-DOPA-induced rotational behavior in a rodent model of Parkinson's disease.

    PubMed

    Fuzzati-Armentero, Marie-Therese; Cerri, Silvia; Levandis, Giovanna; Ambrosi, Giulia; Montepeloso, Elena; Antoninetti, Gianfilippo; Blandini, Fabio; Baqi, Younis; M√ľller, Christa E; Volpini, Rosaria; Costa, Giulia; Simola, Nicola; Pinna, Annalisa

    2015-08-01

    The glutamate metabotropic receptor 5 (mGluR5) and the adenosine A2A receptor (A2A R) represent major non-dopaminergic therapeutic targets in Parkinson's disease (PD) to improve motor symptoms and slow down/revert disease progression. The 6-hydroxydopamine rat model of PD was used to determine/compare the neuroprotective and behavioral impacts of single and combined administration of one mGluR5 antagonist, 2-methyl-6-(phenylethynyl)pyridine (MPEP), and two A2A R antagonists, (E)-phosphoric acid mono-[3-[8-[2-(3-methoxyphenyl)vinyl]-7-methyl-2,6-dioxo-1-prop-2-ynyl-1,2,6,7-tetrahydropurin-3-yl]propyl] (MSX-3) and 8-ethoxy-9-ethyladenine (ANR 94). Chronic treatment with MPEP or MSX-3 alone, but not with ANR 94, reduced the toxin-induced loss of dopaminergic neurons in the substantia nigra pars compacta. Combining MSX-3 and MPEP further improved the neuroprotective effect of either antagonists. At the behavioral level, ANR 94 and MSX-3 given alone significantly potentiated L-DOPA-induced turning behavior. Combination of either A2A R antagonists with MPEP synergistically increased L-DOPA-induced turning. This effect was dose-dependent and required subthreshold drug concentration, which per se had no motor stimulating effect. Our findings suggest that co-treatment with A2A R and mGluR5 antagonists provides better therapeutic benefits than those produced by either drug alone. Our study sheds some light on the efficacy and advantages of combined non-dopaminergic PD treatment using low drug concentration and establishes the basis for in-depth studies to identify optimal doses at which these drugs reach highest efficacy. Combined treatment with low concentrations of known adenosine A2A receptor (A2A R) and metabotropic glutamate receptor (mGluR5) antagonists results in a therapeutic benefit and provides better results than those produced by either drug given alone, both in terms of motor performance and neuroprotection. Future trials should involve careful optimization of drug combinations and concentrations that may avoid the emergence of debilitating side effects and slow-down/revert disease progression. PMID:25962878

  10. A case of severe psychosis induced by novel recreational drugs

    PubMed Central

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

    2014-01-01

    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

  11. Drug target validation: Lethal infection blocked by inducible peptide

    NASA Astrophysics Data System (ADS)

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

    2000-01-01

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

  12. Troponin leak associated with drug-induced methemoglobinemia.

    PubMed

    Cannon, Robert D; Wagner, Michael; Jacoby, Jeanne L

    2014-10-01

    Drug-induced methemoglobinemia is a well-described entity but has not been previously associated with elevated troponins in the absence of cardiac symptoms. We report a case of a patient presenting to the emergency department (ED) with complaints related to an exacerbation of her long-standing cystitis. A low pulse oximetry reading prompted an evaluation, revealing a troponin leak, which peaked at 10 hours. Her methemoglobin level was found to be elevated at 11.4%, but a preexisting anemia apparently prevented the clinical recognition of cyanosis. The methemoglobinemia was determined to be secondary to her ingestion of phenazopyridine and trimethoprim-sulfa methoxizole. Although phenazopyridine and sulfa agents have long been known to cause methemoglobinemia, our patient exhibited an asymptomatic troponin leak that has not been previously reported as a complication of drug-induced methemoglobinemia. Clinicians should be aware of this potential association. PMID:24686024

  13. Homogeneous generation of iDA neurons with high similarity to bona fide DA neurons using a drug inducible system.

    PubMed

    Park, Hanseul; Kim, Hongwon; Yoo, Junsang; Lee, Jaekwang; Choi, Hwan; Baek, Soonbong; Lee, C Justin; Kim, Janghwan; Lengner, Christopher J; Sung, Jung-Suk; Kim, Jongpil

    2015-12-01

    Recent work generating induced dopaminergic (iDA) neurons using direct lineage reprogramming potentially provides a novel platform for the study and treatment Parkinson's disease (PD). However, one of the most important issues for iDA-based applications is the degree to which iDA neurons resemble the molecular and functional properties of their endogenous DA neuron counterparts. Here we report that the homogeneity of the reprogramming gene expression system is critical for the generation of iDA neuron cultures that are highly similar to endogenous DA neurons. We employed an inducible system that carries iDA-inducing factors as defined transgenes for direct lineage reprogramming to iDA neurons. This system circumvents the need for viral transduction, enabling a more efficient and reproducible reprogramming process for the generation of genetically homogenous iDA neurons. We showed that this inducible system generates iDA neurons with high similarity to their bona fide in†vivo counterparts in comparison to direct infection methods. Thus, our results suggest that homogenous expression of exogenous genes in direct lineage reprogramming is critical for the generation of high quality iDA neuron cultures, making such culture systems a valuable resource for iDA-based drug screening and, ultimately, potential therapeutic intervention in PD. PMID:26370928

  14. Drug induced hypertension--An unappreciated cause of secondary hypertension.

    PubMed

    Grossman, Alon; Messerli, Franz H; Grossman, Ehud

    2015-09-15

    Most patients with hypertension have essential hypertension or well-known forms of secondary hypertension, such as renal disease, renal artery stenosis, or common endocrine diseases (hyperaldosteronism or pheochromocytoma). Physicians are less aware of drug induced hypertension. A variety of therapeutic agents or chemical substances may increase blood pressure. When a patient with well controlled hypertension is presented with acute blood pressure elevation, use of drug or chemical substance which increases blood pressure should be suspected. Drug-induced blood pressure increases are usually minor and short-lived, although rare hypertensive emergencies associated with use of certain drugs have been reported. Careful evaluation of prescription and non-prescription medications is crucial in the evaluation of the hypertensive individual and may obviate the need for expensive and unnecessary evaluations. Discontinuation of the offending agent will usually achieve adequate blood pressure control. When use of a chemical agent which increases blood pressure is mandatory, anti-hypertensive therapy may facilitate continued use of this agent. We summarize the therapeutic agents or chemical substances that elevate blood pressure and their mechanisms of action. PMID:26096556

  15. Drug-induced immune thrombocytopenia due to moxifloxacin

    PubMed Central

    Coker, Timothy J

    2013-01-01

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

  16. Targeting the D1-N-methyl-d-aspartate receptor complex reduces l-dopa-induced dyskinesia in 6-hydroxydopamine-lesioned Parkinson's rats.

    PubMed

    Song, Lu; Zhang, Zhanzhao; Hu, Rongguo; Cheng, Jie; Li, Lin; Fan, Qinyi; Wu, Na; Gan, Jing; Zhou, Mingzhu; Liu, Zhenguo

    2016-01-01

    L-3,4-dihydroxyphenylalanine (l-dopa) remains the most effective therapy for Parkinson's disease (PD), but its long-term administration is associated with the development of debilitating motor complications known as l-dopa-induced dyskinesia (LID). Enhanced function of dopamine D1 receptor (D1R) and N-methyl-d-aspartate receptor (NMDAR) is believed to participate in the pathogenesis of LID. Given the existence of physical and functional interactions between D1R and NMDAR, we explored the effects of uncoupling D1R and NMDA GluN1 (GluN1) interaction on LID by using the Tat-conjugated interfering peptide (Tat-D1-t2). In this study, we demonstrated in 6-hydroxydopamine (6-OHDA)-lesioned PD rat model that intrastriatal injection of Tat-D1-t2 alleviated dyskinetic behaviors and downregulated the phosphorylation of DARPP-32 at Thr34 induced by levodopa. Moreover, we also showed intrastriatal administration of Tat-D1-t2 elicited alterations in membranous GluN1 and D1R expression. These findings indicate that D1R/GluN1 complexes may be a molecular target with therapeutic potential for the treatment of dyskinesia in Parkinson's patients. PMID:26893543

  17. Beneficial effects of dietary omega-3 polyunsaturated fatty acid on toxin-induced neuronal degeneration in an animal model of Parkinson's disease.

    PubMed

    Bousquet, M; Saint-Pierre, M; Julien, C; Salem, N; Cicchetti, F; Calon, F

    2008-04-01

    In this study, we examined whether omega-3 (n-3) polyunsaturated fatty acids (PUFAs) may exert neuroprotective action in Parkinson's disease, as previously shown in Alzheimer's disease. We exposed mice to either a control or a high n-3 PUFA diet from 2 to 12 months of age and then treated them with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP; 140 mg/kg in 5 days). High n-3 PUFA dietary consumption completely prevented the MPTP-induced decrease of tyrosine hydroxylase (TH)-labeled nigral cells (P<0.01 vs. MPTP mice on control diet), Nurr1 mRNA (P<0.01 vs. MPTP mice on control diet), and dopamine transporter mRNA levels (P<0.05 vs. MPTP mice on control diet) in the substantia nigra. Although n-3 PUFA dietary treatment had no effect on striatal dopaminergic terminals, the high n-3 PUFA diet protected against the MPTP-induced decrease in dopamine (P<0.05 vs. MPTP mice on control diet) and its metabolite dihydroxyphenylacetic acid (P<0.05 vs. MPTP mice on control diet) in the striatum. Taken together, these data suggest that a high n-3 PUFA dietary intake exerts neuroprotective actions in an animal model of Parkinsonism. PMID:18032633

  18. 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

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

    2008-01-01

    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

  19. 6-OHDA-Induced Changes in Parkinson`s Disease-Related Gene Expression are not Affected by the Overexpression of PGAM5 in In Vitro Differentiated Embryonic Mesencephalic Cells.

    PubMed

    St?pkowski, Tomasz Maciej; Wasyk, Iwona; Grzelak, Agnieszka; Kruszewski, Marcin

    2015-11-01

    LUHMES cells, a recently established line of immortalized embryonic mesencephalic cells, are the novel in vitro model for studying Parkinson's disease (PD) and dopaminergic neuron biology. Phosphoglyceromutase 5 (PGAM5) is a mitochondrial protein involved in mitophagy, mitochondria dynamics, and other processes important for PD pathogenesis. We tested the impact of lentiviral overexpression of PGAM5 protein in LUHMES cells on their differentiation and expression of 84 PD-related genes. LUHMES cells were transduced with PGAM5 or mock and treated with 100†?M 6-hydroxydopamine (6-OHDA), a model PD neurotoxin. Real-Time PCR analysis revealed that the treatment with 6-OHDA-induced changes in expression of 44 PD-related genes. PGAM5 transduction alone did not cause alternations in PD-related genes expression, nor it affected changes in gene expression mediated by 6-OHDA. The 6-OHDA-induced PD-related gene expression profile of LUHMES cells is presented for the first time and widely discussed. PMID:25986246

  20. Pregnane X receptor and drug-induced liver injury

    PubMed Central

    Wang, Yue-Ming; Chai, Sergio C.; Brewer, Christopher T; Chen, Taosheng

    2014-01-01

    Introduction The liver plays a central role in transforming and clearing foreign substances. The continuous exposure of the liver to xenobiotics sometimes leads to impaired liver function, referred to as drug-induced liver injury (DILI). The pregnane X receptor (PXR) tightly regulates the expression of genes in the hepatic drug-clearance system and its undesired activation plays a role in DILI. Areas covered This review focuses on the recent progress in understanding PXR-mediated DILI and highlights the efforts made to assess and manage PXR-mediated DILI during drug development. Expert opinion Future efforts are needed to further elucidate the mechanisms of PXR-mediated liver injury, including the epigenetic regulation and polymorphisms of PXR. Novel in vitro models containing functional PXR could improve our ability to predict and assess DILI during drug development. PXR inhibitors may provide chemical tools to validate the potential of PXR as a therapetic target and to develop drugs to be used in the clinic to manage PXR-mediated DILI. PMID:25252616

  1. Cytokine expression and signaling in drug-induced cellular senescence.

    PubMed

    Novakova, Z; Hubackova, S; Kosar, M; Janderova-Rossmeislova, L; Dobrovolna, J; Vasicova, P; Vancurova, M; Horejsi, Z; Hozak, P; Bartek, J; Hodny, Z

    2010-01-14

    Cellular senescence guards against cancer and modulates aging; however, the underlying mechanisms remain poorly understood. Here, we show that genotoxic drugs capable of inducing premature senescence in normal and cancer cells, such as 5-bromo-2'-deoxyuridine (BrdU), distamycin A (DMA), aphidicolin and hydroxyurea, persistently activate Janus kinase-signal transducer and activator of transcription (JAK/STAT) signaling and expression of interferon-stimulated genes (ISGs), such as MX1, OAS, ISG15, STAT1, PML, IRF1 and IRF7, in several human cancer cell lines. JAK1/STAT-activating ligands, interleukin 10 (IL10), IL20, IL24, interferon gamma (IFNgamma), IFNbeta and IL6, were also expressed by senescent cells, supporting autocrine/paracrine activation of JAK1/STAT. Furthermore, cytokine genes, including proinflammatory IL1, tumor necrosis factor and transforming growth factor families, were highly expressed. The strongest inducer of JAK/STAT signaling, cytokine production and senescence was BrdU combined with DMA. RNA interference-mediated knockdown of JAK1 abolished expression of ISGs, but not DNA damage signaling or senescence. Thus, although DNA damage signaling, p53 and RB activation, and the cytokine/chemokine secretory phenotype are apparently shared by all types of senescence, our data reveal so far unprecedented activation of the IFNbeta-STAT1-ISGs axis, and indicate a less prominent causative role of IL6-JAK/STAT signaling in genotoxic drug-induced senescence compared with reports on oncogene-induced or replicative senescence. These results highlight shared and unique features of drug-induced cellular senescence, and implicate induction of cancer secretory phenotype in chemotherapy. PMID:19802007

  2. AC-186, a Selective Nonsteroidal Estrogen Receptor ? Agonist, Shows Gender Specific Neuroprotection in a Parkinsonís Disease Rat Model

    PubMed Central

    2013-01-01

    Drugs that selectively activate estrogen receptor ? (ER?) are potentially safer than the nonselective estrogens currently used in hormonal replacement treatments that activate both ER? and ER?. The selective ER? agonist AC-186 was evaluated in a rat model of Parkinsonís disease induced through bilateral 6-hydroxydopamine lesions of the substantia nigra. In this model, AC-186 prevented motor, cognitive, and sensorimotor gating deficits and mitigated the loss of dopamine neurons in the substantia nigra, in males, but not in females. Furthermore, in male rats, 17?-estradiol, which activates ER? and ER? with equal potency, did not show the same neuroprotective benefits as AC-186. Hence, in addition to a beneficial safety profile for use in both males and females, a selective ER? agonist has a differentiated pharmacological profile compared to 17?-estradiol in males. PMID:23898966

  3. Drug-induced expression of intercellular adhesion molecule-1 on lesional keratinocytes in fixed drug eruption.

    PubMed Central

    Teraki, Y.; Moriya, N.; Shiohara, T.

    1994-01-01

    The mechanism(s) and the factor(s) that contribute to preferential localization of fixed drug eruption (FDE) lesions to certain skin sites remain speculative. Previous studies suggested that populations of T cells residing in the lesional epidermis may be involved in selective destruction of the epidermis in FDE. In this study, to define the earliest cellular and molecular events with potential relevance to activation of the epidermal T cells, expression of adhesion molecules on keratinocytes (KC) and vascular endothelium was examined sequentially in the lesional skin of FDE patients after challenge with the causative drug. Rapid and intense intercellular adhesion molecule-1 (ICAM-1) expression was induced on the vascular endothelium and KC as early as 1.5 hours after challenge, at which time E-selectin and vascular cell adhesion molecule-1 (VCAM-1) were not up-regulated. In vitro studies using skin organ culture showed that the lesional KC and endothelium responded more rapidly and intensely to express ICAM-1 to tumor necrosis factor-alpha or interferon-gamma compared with those in the nonlesional skin. Surprisingly, such selective induction of KC ICAM-1 restricted to the lesional skin was also observed after exposure to the causative drug alone in skin organ culture. Pretreatment of the lesional skin with anti-tumor necrosis factor completely abrogated in vitro induction of KC ICAM-1 expression by the drug. Drug-induced, TNF-alpha-dependent KC ICAM-1 expression in the lesional skin suggests that induction of ICAM-1 expression by the lesional KC after ingestion of the drug would probably provide a localized initiating stimulus for activation of the disease-associated epidermal T cells. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 PMID:7915886

  4. The role of natural products in the discovery of new drug candidates for the treatment of neurodegenerative disorders I: Parkinson's disease.

    PubMed

    Campos, Helineide Cristina; da Rocha, Miguel Divino; Viegas, Flávia Pereira Dias; Nicastro, Patrícia Carolina; Fossaluzza, Poliana Calve; Fraga, Carlos Alberto Manssour; Barreiro, Eliezer J; Viegas, Claudio

    2011-03-01

    Neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS) are currently incurable pathologies with huge social and economic impacts closely related to the increasing of life expectancy in modern times. Although the clinical and neuropathological aspects of these debilitating disorders are distinct, they share a pattern of neurodegeneration in anatomically or functionally related regions. For each disease, presently available treatments only address symptoms and do not alter the course or progression of the underlying diseases. In this context, the search for new effective chemical entities, capable of acting on diverse biochemical targets, with new mechanisms of action and low toxicity are genuine challenges to research groups and the pharmaceutical industry. This medical need has led to the reemerging of modern natural products chemistry that has yielded sophisticated and complex new lead molecules for drug discovery and development. In this review we discuss some of the main contributions of the natural products chemistry that covers multiple and varied plant species. Advances in the discovery of active constituents of plants, herbs, and extracts prescribed by traditional medicine practices for the treatment of senile neurodegenerative disorders, especially for PD, in the period after the 2000s is reviewed. The most important contributions from the 1990s are also discussed. The review also focuses on the pharmacological mechanisms of action that might underlie the purported beneficial improvements in memory and cognition, neurovascular function, and in neuroprotection. It is concluded that natural product chemistry brings tremendous diversity and historical precedent to a huge area of unmet medical need. PMID:20874702

  5. Redox Imbalance in Parkinsonís Disease

    PubMed Central

    Chinta, Shankar J.; Andersen, Julie K.

    2008-01-01

    Parkinsonís disease (PD) is an adult-onset neurodegenerative disorder characterized by preferential loss of dopaminergic neurons in an area of the midbrain called the substantia nigra (SN) along with occurrence of intraneuronal inclusions called Lewy bodies. The majority of cases of PD are sporadic in nature with late onset (95% of patients); however a few PD cases (5%) are seen in familial clusters with generally earlier onset. Although PD has been heavily researched, so far the exact cause of the rather selective cell death is unknown. Multiple lines of evidence suggest an important role for oxidative stress. Dopaminergic neurons (DA) are particularly prone to oxidative stress due to DA metabolism and auto-oxidation combined with increased iron, decreased total glutathione levels and mitochondrial complex I inhibition-induced ROS production in the SN which can lead to cell death by exceeding the oxidative capacity of DA-containing cells in the region. Enhancing antioxidant capabilities and chelating labile iron pools in this region therefore constitutes a rational approach to prevent or slow ongoing damage of DA neurons. In this review, we summarize the various sources of reactive oxygen species that may cause redox imbalance in PD as well as potential therapeutic targets for attenuation of oxidative stress associated with PD. PMID:18358848

  6. Mechanisms of drug-induced diarrhoea in the elderly.

    PubMed

    Ratnaike, R N; Jones, T E

    1998-09-01

    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

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

    PubMed Central

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

    2013-01-01

    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

  8. Ocular changes induced by drugs commonly used in dermatology.

    PubMed

    Turno-Krńôcicka, Anna; Grzybowski, Andrzej; Misiuk-HojŇāo, Marta; Patryn, Eliza; Czajor, Karolina; Nita, MaŇāgorzata

    2016-01-01

    The use of many drugs in dermatologic diseases may cause ocular side effects. Some may regress after discontinuation of the therapy, but others persist or progress even after the cessation of treatment. This review presents four groups of commonly prescribed drugs-antimalarial medicines, glucocorticoids, retinoids, and psoralens + ultraviolet A (UVA) therapy-and discusses their possible ocular side effects. The most significant complication of antimalarial drugs is retinopathy with the risk of permanent visual impairment. There are different recommendations for screening for this drug-related retinopathy. The most important ocular manifestations of steroid management are irreversible optic nerve damage in "steroid responders" (steroid glaucoma) and cataract. Some other side effects may disappear after discontinuation of the therapy. Retinoid-induced ocular side effects include ocular surface disease as well as retinal dysfunction. It is recommended to modify the therapy when night blindness occurs or after the decrease of color vision. Protective eyewear is sufficient to avoid ocular surface problems during psoralen + UVA therapy. The knowledge of screening schemes and closer cooperation between physicians may decrease the risk of serious or irreversible ocular side effects. PMID:26903180

  9. Nicotine as a potential neuroprotective agent for Parkinsonís disease

    PubMed Central

    Quik, Maryka; Perez, Xiomara A.; Bordia, Tanuja

    2012-01-01

    Converging research efforts suggest that nicotine and other drugs that act at nicotinic acetylcholine receptors (nAChRs) may be beneficial in the management of Parkinsonís disease. This idea initially stemmed from the results of epidemiological studies which demonstrate that smoking is associated with a decreased incidence of Parkinsonís disease. The subsequent finding that nicotine administration protected against nigrostriatal damage in parkinsonian animal models led to the idea that nicotine in tobacco products may contribute to this apparent protective action. Nicotine most likely exerts its effects by interacting at nAChRs. Accumulating research indicates that multiple subtypes, including ?4?2, ?6?2 and/or ?7 containing nAChRs, may be involved. Stimulation of nAChRs initially activates various intracellular transduction pathways primarily via alterations in calcium signaling. Consequent adaptations in immune responsiveness and trophic factors may ultimately mediate nicotineís ability to reduce/halt the neuronal damage that arises in Parkinsonís disease. In addition to a potential neuroprotective action, nicotine also has anti-depressant properties and improves attention/cognition. Altogether, these findings suggest that nicotine and nAChR drugs represent promising therapeutic agents for the management of Parkinsonís disease. PMID:22693036

  10. Elevated ?-synuclein caused by SNCA gene triplication impairs neuronal differentiation and maturation in Parkinson's patient-derived induced pluripotent stem cells.

    PubMed

    Oliveira, L M A; Falomir-Lockhart, L J; Botelho, M G; Lin, K-H; Wales, P; Koch, J C; Gerhardt, E; Taschenberger, H; Outeiro, T F; Lingor, P; SchŁle, B; Arndt-Jovin, D J; Jovin, T M

    2015-01-01

    We have assessed the impact of ?-synuclein overexpression on the differentiation potential and phenotypic signatures of two neural-committed induced pluripotent stem cell lines derived from a Parkinson's disease patient with a triplication of the human SNCA genomic locus. In parallel, comparative studies were performed on two control lines derived from healthy individuals and lines generated from the patient iPS-derived neuroprogenitor lines infected with a lentivirus incorporating a small hairpin RNA to knock down the SNCA mRNA. The SNCA triplication lines exhibited a reduced capacity to differentiate into dopaminergic or GABAergic neurons and decreased neurite outgrowth and lower neuronal activity compared with control cultures. This delayed maturation phenotype was confirmed by gene expression profiling, which revealed a significant reduction in mRNA for genes implicated in neuronal differentiation such as delta-like homolog 1 (DLK1), gamma-aminobutyric acid type B receptor subunit 2 (GABABR2), nuclear receptor related 1 protein (NURR1), G-protein-regulated inward-rectifier potassium channel 2 (GIRK-2) and tyrosine hydroxylase (TH). The differentiated patient cells also demonstrated increased autophagic flux when stressed with chloroquine. We conclude that a two-fold overexpression of ?-synuclein caused by a triplication of the SNCA gene is sufficient to impair the differentiation of neuronal progenitor cells, a finding with implications for adult neurogenesis and Parkinson's disease progression, particularly in the context of bioenergetic dysfunction. PMID:26610207

  11. Bee Venom Phospholipase A2, a Novel Foxp3+ Regulatory T Cell Inducer, Protects Dopaminergic Neurons by Modulating Neuroinflammatory Responses in a Mouse Model of Parkinson's Disease.

    PubMed

    Chung, Eun Sook; Lee, Gihyun; Lee, Chanju; Ye, Minsook; Chung, Hwan-suck; Kim, Hyunseong; Bae, Sung-joo S; Hwang, Deok-Sang; Bae, Hyunsu

    2015-11-15

    Foxp3-expressing CD4(+) regulatory T cells (Tregs) are vital for maintaining immune tolerance in animal models of various immune diseases. In the present study, we demonstrated that bee venom phospholipase A2 (bvPLA2) is the major BV compound capable of inducing Treg expansion and promotes the survival of dopaminergic neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. We associated this neuroprotective effect of bvPLA2 with microglial deactivation and reduction of CD4(+) T cell infiltration. Interestingly, bvPLA2 had no effect on mice depleted of Tregs by injecting anti-CD25 Ab. This finding indicated that Treg-mediated modulation of peripheral immune tolerance is strongly involved in the neuroprotective effects of bvPLA2. Furthermore, our results showed that bvPLA2 directly bound to CD206 on dendritic cells and consequently promoted the secretion of PGE2, which resulted in Treg differentiation via PGE2 (EP2) receptor signaling in Foxp3(-)CD4(+) T cells. These observations suggest that bvPLA2-CD206-PGE2-EP2 signaling promotes immune tolerance through Treg differentiation and contributes to the prevention of various neurodegenerative diseases, including Parkinson's disease. PMID:26453752

  12. Elevated őĪ-synuclein caused by SNCA gene triplication impairs neuronal differentiation and maturation in Parkinson's patient-derived induced pluripotent stem cells

    PubMed Central

    Oliveira, L M A; Falomir-Lockhart, L J; Botelho, M G; Lin, K-H; Wales, P; Koch, J C; Gerhardt, E; Taschenberger, H; Outeiro, T F; Lingor, P; Sch√ľle, B; Arndt-Jovin, D J; Jovin, T M

    2015-01-01

    We have assessed the impact of őĪ-synuclein overexpression on the differentiation potential and phenotypic signatures of two neural-committed induced pluripotent stem cell lines derived from a Parkinson's disease patient with a triplication of the human SNCA genomic locus. In parallel, comparative studies were performed on two control lines derived from healthy individuals and lines generated from the patient iPS-derived neuroprogenitor lines infected with a lentivirus incorporating a small hairpin RNA to knock down the SNCA mRNA. The SNCA triplication lines exhibited a reduced capacity to differentiate into dopaminergic or GABAergic neurons and decreased neurite outgrowth and lower neuronal activity compared with control cultures. This delayed maturation phenotype was confirmed by gene expression profiling, which revealed a significant reduction in mRNA for genes implicated in neuronal differentiation such as delta-like homolog 1 (DLK1), gamma-aminobutyric acid type B receptor subunit 2 (GABABR2), nuclear receptor related 1 protein (NURR1), G-protein-regulated inward-rectifier potassium channel 2 (GIRK-2) and tyrosine hydroxylase (TH). The differentiated patient cells also demonstrated increased autophagic flux when stressed with chloroquine. We conclude that a two-fold overexpression of őĪ-synuclein caused by a triplication of the SNCA gene is sufficient to impair the differentiation of neuronal progenitor cells, a finding with implications for adult neurogenesis and Parkinson's disease progression, particularly in the context of bioenergetic dysfunction. PMID:26610207

  13. Drug-Induced Liver Injury: Pattern Recognition and Future Directions.

    PubMed

    Haque, Tanvir; Sasatomi, Eizaburo; Hayashi, Paul H

    2016-01-23

    Drug-induced liver injury (DILI) remains a significant clinical challenge and is the leading cause of acute liver failure in most countries. An aging population that uses more medications, a constant influx of newly developed drugs and a growing risk from unfamiliar herbal and dietary supplements will make DILI an increasing part of clinical practice. Currently, the most effective strategy for disease management is rapid identification, withholding the inciting agents, supportive care and having a firm understanding of the expected natural history. There are resources available to aid the clinician, including a new online "textbook" as well as causality assessment tools, but a heightened awareness of risk and the disease's varying phenotypes and good history-taking remain cornerstones to diagnosis. Looking ahead, growing registries of cases, pharmacoepidemiology studies and translational research into the mechanisms of injury may produce better diagnostic tools, markers for risk and disease, and prevention and therapeutics. PMID:26696029

  14. Drug-Induced Liver Injury: Pattern Recognition and Future Directions

    PubMed Central

    Haque, Tanvir; Sasatomi, Eizaburo; Hayashi, Paul H.

    2016-01-01

    Drug-induced liver injury (DILI) remains a significant clinical challenge and is the leading cause of acute liver failure in most countries. An aging population that uses more medications, a constant influx of newly developed drugs and a growing risk from unfamiliar herbal and dietary supplements will make DILI an increasing part of clinical practice. Currently, the most effective strategy for disease management is rapid identification, withholding the inciting agents, supportive care and having a firm understanding of the expected natural history. There are resources available to aid the clinician, including a new online ‚Äútextbook‚ÄĚ as well as causality assessment tools, but a heightened awareness of risk and the disease‚Äôs varying phenotypes and good history-taking remain cornerstones to diagnosis. Looking ahead, growing registries of cases, pharmacoepidemiology studies and translational research into the mechanisms of injury may produce better diagnostic tools, markers for risk and disease, and prevention and therapeutics. PMID:26696029

  15. Drug-induced liver injury with autoimmune features.

    PubMed

    deLemos, Andrew S; Foureau, David M; Jacobs, Carl; Ahrens, Will; Russo, Mark W; Bonkovsky, Herbert L

    2014-05-01

    Drug-induced liver injury (DILI) with features of autoimmunity (AI) represents an important category of hepatotoxicity due to medication exposure. Drugs repeatedly associated with AI-DILI include diclofenac, ?-methyl DOPA, hydralazine, nitrofurantoin, minocycline, and more recently statins and anti-TNF-? agents. Usually, symptoms of acute liver injury occur within a few months after initiation of a culprit medication, but a longer latency period is possible. Like idiopathic autoimmune hepatitis, circulating autoantibodies and a hypergammaglobulinemia are frequently present in sera from patients with AI-DILI. If performed, a liver biopsy should demonstrate interface hepatitis with a prominent plasma cell infiltrate. The severity of AI-DILI is variable, but a complete resolution after withdrawal of the offending medication is the expectation. A response to corticosteroid therapy supports the diagnosis, whereas a lack of recurrence of symptoms or signs following corticosteroid cessation distinguishes AI-DILI from idiopathic autoimmune hepatitis. PMID:24879983

  16. Drug-Induced Acute Interstitial Nephritis with Nifedipine

    PubMed Central

    Golbin, Léonard; Dolley-Hitze, Thibault; Lorcy, Nolwenn; Rioux-Leclercq, Nathalie; Vigneau, Cécile

    2016-01-01

    Background. Acute interstitial nephritis (AIN) is a frequent cause of Acute Kidney Injury (AKI). Drug hypersensitivity is the most common etiology and the list of drugs that can induce AIN is not exhaustive yet. Case Report. Here, we describe the case of a 43-year-old man who was treated with nifedipine (Adalate¬ģ) for Raynaud's syndrome. After nifedipine introduction, serum creatininemia progressively increased from 91 to 188‚ÄČőľmol/L in a few months and AKI was diagnosed. Laboratory work-up results indicated the presence of tubular proteinuria and nonspecific inflammatory syndrome. Histological analysis found granulomatous interstitial nephropathy without necrosis in 20% of the kidney biopsy without immunofluorescent deposit. Nifedipine was stopped and corticosteroid treatment was started with a rapid but incomplete reduction of serum creatininemia level to 106‚ÄČőľmol/L. Conclusion. This is the first case of AIN caused by nifedipine. PMID:26955492

  17. Models of drug-induced epileptiform synchronization in vitro.

    PubMed

    Avoli, Massimo; Jefferys, John G R

    2016-02-15

    Models of epileptiform activity in vitro have many advantages for recording and experimental manipulation. Neural tissues can be maintained in vitro for hours, and in neuronal or organotypic slice cultures for several weeks. A variety of drugs and other agents increase activity in these in vitro conditions, in many cases resulting in epileptiform activity, thus providing a direct model of symptomatic seizures. We review these preparations and the experimental manipulations used to induce epileptiform activity. The most common of drugs used are GABAA receptor antagonists and potassium channel blockers (notably 4-aminopyridine). Muscarinic agents also can induce epileptiform synchronization in vitro, and include potassium channel inhibition amongst their cellular actions. Manipulations of extracellular ions are reviewed in another paper in this special issue, as are ex vivo slices prepared from chronically epileptic animals and from people with epilepsy. More complex slices including extensive networks and/or several connected brain structures can provide insights into the dynamics of long range connections during epileptic activity. Visualization of slices also provides opportunities for identification of living neurons and for optical recording/stimulation and manipulation. Overall, the analysis of the epileptiform activity induced in brain tissue in vitro has played a major role in advancing our understanding of the cellular and network mechanisms of epileptiform synchronization, and it is expected to continue to do so in future. PMID:26484784

  18. Targeting impulsivity in Parkinsonís disease using atomoxetine

    PubMed Central

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

    2014-01-01

    Noradrenergic dysfunction may play a significant role in cognition in Parkinsonís 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 Parkinsonís disease (12 female /13 male; 64.4 Ī 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 Parkinsonís 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

  19. Invariant NKT cells increase drug-induced osteosarcoma cell death

    PubMed Central

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

    2012-01-01

    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‚Äď40% 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 (VőĪ24Vő≤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

  20. Early monitoring for detection of antituberculous drug-induced hepatotoxicity

    PubMed Central

    Lee, Chang Min; Lee, Sang Soo; Lee, Jeong Mi; Cho, Hyun Chin; Kim, Wan Soo; Kim, Hong Jun; Ha, Chang Yoon; Kim, Hyun Jin; Kim, Tae Hyo; Jung, Woon Tae; Lee, Ok Jae

    2016-01-01

    Background/Aims: We investigated the time of onset of antituberculous drug-induced hepatotoxicity (ADIH) and related characteristics. Methods: Adult patients (n = 1,031) treated with first-line antituberculous drugs between February 2009 and January 2013 were enrolled. Results: Of the 1,031 patients, 108 patients (10.5%) developed ADIH a mean of 39.6 Ī 43.7 days after treatment initiation. Twenty-eight patients (25.9%) developed ADIH within 7 days, 73 (67.6%) within 30 days, and the rest after 30 days. The ? 30-day group was characterized by higher peak alanine aminotransferase (ALT) level and a high proportion of patients with maintenance of first-line antituberculous drugs compared to the > 30-day group. In subgroup analysis, the ? 7-day group was characterized by higher baseline aspartate aminotransferase and ALT, high proportion of patients with maintenance of first-line antituberculous drugs, and high proportion of patients with extrapulmonary tuberculosis compared to patients with ADIH that developed beyond 7 days. In multivariate analysis, serum ALT > 40 IU/L (odds ratio [OR], 2.995; 95% confidence interval [CI], 1.580 to 5.680; p = 0.001) and presence of anti-hepatitis C virus (OR, 4.204; 95% CI, 1.822 to 9.700, p = 0.001) were independent risk factors for development of ADIH. Conclusions: Approximately 70% of the cases of ADIH occurred in the first month of antituberculous treatment, and were associated with continuation of the first-line drug regimen. PMID:26767859

  1. Drug-induced liver injury: the dawn of biomarkers?

    PubMed Central

    Weiler, Stefan; Merz, Michael

    2015-01-01

    Drug-induced liver injury (DILI) is a potentially fatal adverse event with significant medical and economic impact. Many drugs, especially anti-infective, neurologic or pain-modifying substances, act as hepatotoxins. With cardiovascular toxicity, liver toxicity is one of the two leading causes for drug withdrawal from the market. The liver can be affected directly, in a predictable and dose-dependent manner, or idiosyncratically, independent of the dose and therefore unpredictable. Currently DILI is a diagnosis of exclusion that physicians have to bear in mind in patients with an unexplained increase of liver enzymes. The type of injury is categorized into hepatocellular, cholestatic, or mixed by the respective enzyme pattern of injury. Symptoms of affected patients can mimic any other liver disease. Therefore, new diagnostic and prognostic biomarkers for early liver injury are currently being evaluated in multi-centre clinical trials that are conducted by international consortia and other initiatives. Pharmacogenetic testing, next-generation sequencing, proteomics, metabolomics and mechanistic markers can help to preselect susceptible patient populations and tailor drug therapy to individual patients. Proposed DILI indicators that are under investigation include microRNAs, cytokeratin-18 (CK18), high mobility group box protein 1 (HMGB-1), and several other biomarkers. These developments can change clinical practice, and improve patients' safety and management. However, they have not been translated into clinical practice or approved for routine use yet. Management of DILI usually consists of initial withdrawal of the suspected drug andóif applicableóadministration of specific antidotes, such as N-acetylcysteine. However, the overall management of DILI could change in the near future with the advent of novel diagnostic and prognostic DILI markers. PMID:25926985

  2. DRUG INDUCED PHOSPHOLIPIDOSIS: AN ACQUIRED LYSOSOMAL STORAGE DISORDER

    PubMed Central

    Shayman, James A.; Abe, Akira

    2012-01-01

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

  3. Detection of preclinical Parkinson's disease with PET

    SciTech Connect

    Brooks, D.J. )

    1991-08-01

    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.

  4. Polyhydroxylated fullerene derivative C(60)(OH)(24) prevents mitochondrial dysfunction and oxidative damage in an MPP(+) -induced cellular model of Parkinson's disease.

    PubMed

    Cai, Xiaoqing; Jia, Haiqun; Liu, Zhongbo; Hou, Bei; Luo, Cheng; Feng, Zhihui; Li, Wenxin; Liu, Jiankang

    2008-12-01

    To find effective agents for Parkinson's disease (PD) prevention and therapy, we examined the protective effects of the polyhydroxylated fullerene derivative C(60)(OH)(24) in a 1-methyl-4-phenylpyridinium (MPP(+)) -induced acute cellular PD model in human neuroblastoma cells and the free radical scavenging effects in this model with an electron spin resonance (ESR) spectrometer. Pretreatment with C(60)(OH)(24) at concentrations greater than 20 microM showed significant protective effects on MPP(+) -induced loss in cell viability, decreases in mitochondrial function (including mitochondrial membrane potential and activities of complex I and II), and increases in the levels of reactive oxygen species and oxidative damage to DNA and proteins. In addition, C(60)(OH)(24) acts as a phase 2 enzyme inducer to protect cells from MPP(+) -induced decreases in expression of nuclear factor-E2-related factor 2, expression and activity of gamma-glutamyl cysteine ligase and level of glutathione. The ESR study showed that C(60)(OH)(24) is a powerful radical scavenger for superoxide, hydroxyl, and lipid radicals. These data suggest that C(60)(OH)(24) is a mitochondrial protective antioxidant with direct radical scavenging activity and indirect antioxidant inducing activity. PMID:18709653

  5. Over-Pressure Suppresses Ultrasonic-Induced Drug Uptake

    PubMed Central

    Stringham, S. Briant; Viskovska, Maria A.; Richardson, Eric S.; Ohmine, Seiga; Husseini, Ghaleb A.; Murray, Byron K.; Pitt, William G.

    2012-01-01

    Ultrasound (US) is used to enhance and target delivery of drugs and genes to cancer tissues. The present study further examines the role of acoustic cavitation in US-induced permeabilization of cell membranes and subsequent drug or gene uptake by the cell. Rat colon cancer cells were exposed to ultrasound at various static pressures to examine the hypothesis that oscillating bubbles, also known as cavitating bubbles, permeabilize cells. Increasing pressure suppresses bubble cavitation activity; thus if applied pressure were to reduce drug uptake, cell permeabilization would be strongly linked to bubble cavitation activity. Cells were exposed to 476 kHz pulsed ultrasound at average intensities of 2.75 W/cm2 and 5.5 W/cm2 at various pressures and times in an isothermal chamber. Cell fractions with reversible membrane damage (calcein uptake) and irreversible damage (propidium iodide uptake) were analyzed by flow cytometry. Pressurization to 3 atm nearly eliminated the biological effect of US in promoting calcein uptake. Data also showed a linear increase in membrane permeability based upon increased time and intensity. This research shows that US-mediated cell membrane permeability is likely linked to cavitation bubble activity. PMID:19056161

  6. [Drug-induced liver damage and the problem of its pharmacological correction].

    PubMed

    Somova, M N; Muzalevskaia, E N; Nikolaevski?, V A; Buzlama, A V; Batishcheva, G A; Chernov, Iu N

    2013-01-01

    This review summarizes data on the pathogenesis and diagnostics of drug-induced liver damage. Special attention is paid to the role of individual genetically determined characteristics of drug metabolism in the development of this pathology. Results of experimental and clinical studies of the efficacy of hepatoprotectors in the treatment and prevention of the drug-induced hepatotoxicity are generalized. PMID:24432568

  7. Drug-induced secretory diarrhea: A role for CFTR.

    PubMed

    Moon, Changsuk; Zhang, Weiqiang; Sundaram, Nambirajan; Yarlagadda, Sunitha; Reddy, Vadde Sudhakar; Arora, Kavisha; Helmrath, Michael A; Naren, Anjaparavanda P

    2015-12-01

    Many medications induce diarrhea as a side effect, which can be a major obstacle to therapeutic efficacy and also a life-threatening condition. Secretory diarrhea can be caused by excessive fluid secretion in the intestine under pathological conditions. The cAMP/cGMP-regulated cystic fibrosis transmembrane conductance regulator (CFTR) is the primary chloride channel at the apical membrane of intestinal epithelial cells and plays a major role in intestinal fluid secretion and homeostasis. CFTR forms macromolecular complexes at discreet microdomains at the plasma membrane, and its chloride channel function is regulated spatiotemporally through protein-protein interactions and cAMP/cGMP-mediated signaling. Drugs that perturb CFTR-containing macromolecular complexes in the intestinal epithelium and upregulate intracellular cAMP and/or cGMP levels can hyperactivate the CFTR channel, causing excessive fluid secretion and secretory diarrhea. Inhibition of CFTR chloride-channel activity may represent a novel approach to the management of drug-induced secretory diarrhea. PMID:26429773

  8. Cerebral hemosiderosis as a causative factor of vascular parkinsonism.

    PubMed

    Hsieh, Cheng-Fang; Tung, Chin-Sung; Shih, Pang-Ying; Lin, Wei-Chen

    2005-12-01

    Secondary parkinsonism has comprised about 20 to 40 percent of all parkinsonism patients in movement disorders clinic. Most of them are induced by certain medications. About 5 to 10 percent of these patients are caused by sudden vascular events, who suffer from their parkinsonism abruptly, and usually of aged people with quite apparent stroke risk factors. Hemosiderosis was only occasionally reported as a causative factor in patients with parkinsonism, who presented with an insidious onset parkinsonism and a progressive supranuclear palsy-like clinical picture. We encountered two patients with stroke-related parkinsonism, whose high resolution MRI image showed apparent cortical or intraparenchymal hemosiderosis, although Binswanger type white matter change was also noted. Intracerebral hemosiderosis that manifests clinically as vascular parkinsonism might be much more frequent than we thought. PMID:16425548

  9. RUCAM in Drug and Herb Induced Liver Injury: The Update.

    PubMed

    Danan, Gaby; Teschke, Rolf

    2015-01-01

    RUCAM (Roussel Uclaf Causality Assessment Method) or its previous synonym CIOMS (Council for International Organizations of Medical Sciences) is a well established tool in common use to quantitatively assess causality in cases of suspected drug induced liver injury (DILI) and herb induced liver injury (HILI). Historical background and the original work confirm the use of RUCAM as single term for future cases, dismissing now the term CIOMS for reasons of simplicity and clarity. RUCAM represents a structured, standardized, validated, and hepatotoxicity specific diagnostic approach that attributes scores to individual key items, providing final quantitative gradings of causality for each suspect drug/herb in a case report. Experts from Europe and the United States had previously established in consensus meetings the first criteria of RUCAM to meet the requirements of clinicians and practitioners in care for their patients with suspected DILI and HILI. RUCAM was completed by additional criteria and validated, assisting to establish the timely diagnosis with a high degree of certainty. In many countries and for more than two decades, physicians, regulatory agencies, case report authors, and pharmaceutical companies successfully applied RUCAM for suspected DILI and HILI. Their practical experience, emerging new data on DILI and HILI characteristics, and few ambiguous questions in domains such alcohol use and exclusions of non-drug causes led to the present update of RUCAM. The aim was to reduce interobserver and intraobserver variability, to provide accurately defined, objective core elements, and to simplify the handling of the items. We now present the update of the well accepted original RUCAM scale and recommend its use for clinical, regulatory, publication, and expert purposes to validly establish causality in cases of suspected DILI and HILI, facilitating a straightforward application and an internationally harmonized approach of causality assessment as a common basic tool. PMID:26712744

  10. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Induced Dyspepsia.

    PubMed

    Yap, Paul Ray-Yee; Goh, Khean-Lee

    2015-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are the most prescribed group of drugs in the world. They are used primarily for pain relief in chronic inflammatory joint disease and act by inhibiting enzymes COX1 and COX2 and ultimately preventing the production of active prostanoids which are required for the innate inflammatory pathway. The use of NSAIDs have been associated with the development of gastrointestinal (GI) symptoms ranging from simple dyspepsia to life threatening GI bleeds and perforations. The definition of dyspepsia has evolved over the years and this has hampered accurate studies on the prevalence of dyspepsia as different studies used varying criteria to define dyspepsia. It is now known that NSAIDs significantly increase the risk of dyspepsia.The risk of developing peptic ulcer disease vary with specific NSAIDs and dosages but there is no correlation between the symptoms of dyspepsia and underlying peptic ulcers. The pathogenesis of dyspepsia with NSAIDs is not completely understood. Peptic ulceration alone is not able to account for the majority of dyspepsia symptoms encountered by NSAIDs users. Erosive oesophagitis secondary to NSAIDs may be contributing factor to the prevalence of dyspepsia in NSAIDs users. Altered gut permeability and changes in gastric mechanosensory function due to NSAIDs may also be a contributory factor. Management of NSAID induced dyspepsia is involves a multipronged approach. Drug avoidance if possible would be ideal. Other options include using the lowest effective dose, changing to an NSAIDs with a safer GI risk profile, avoiding concurrent use with other NSAIDs or if the patient has a previous history of peptic ulcer disease, and co-prescribing with anti-secretory medications such as proton pump inhibitors. Eradication of Helicobacter pylori has a protective role against developing peptic ulcers and may also improve symptoms of NSAIDs induced dyspepsia. PMID:26369685

  11. RUCAM in Drug and Herb Induced Liver Injury: The Update

    PubMed Central

    Danan, Gaby; Teschke, Rolf

    2015-01-01

    RUCAM (Roussel Uclaf Causality Assessment Method) or its previous synonym CIOMS (Council for International Organizations of Medical Sciences) is a well established tool in common use to quantitatively assess causality in cases of suspected drug induced liver injury (DILI) and herb induced liver injury (HILI). Historical background and the original work confirm the use of RUCAM as single term for future cases, dismissing now the term CIOMS for reasons of simplicity and clarity. RUCAM represents a structured, standardized, validated, and hepatotoxicity specific diagnostic approach that attributes scores to individual key items, providing final quantitative gradings of causality for each suspect drug/herb in a case report. Experts from Europe and the United States had previously established in consensus meetings the first criteria of RUCAM to meet the requirements of clinicians and practitioners in care for their patients with suspected DILI and HILI. RUCAM was completed by additional criteria and validated, assisting to establish the timely diagnosis with a high degree of certainty. In many countries and for more than two decades, physicians, regulatory agencies, case report authors, and pharmaceutical companies successfully applied RUCAM for suspected DILI and HILI. Their practical experience, emerging new data on DILI and HILI characteristics, and few ambiguous questions in domains such alcohol use and exclusions of non-drug causes led to the present update of RUCAM. The aim was to reduce interobserver and intraobserver variability, to provide accurately defined, objective core elements, and to simplify the handling of the items. We now present the update of the well accepted original RUCAM scale and recommend its use for clinical, regulatory, publication, and expert purposes to validly establish causality in cases of suspected DILI and HILI, facilitating a straightforward application and an internationally harmonized approach of causality assessment as a common basic tool. PMID:26712744

  12. [Parkinson's disease and psychoses].

    PubMed

    Bizzarri, Jacopo Vittoriano; Giupponi, Giancarlo; Maniscalco, Ignazio; Schroffenegger, Patrizia; Conca, Andreas; Kapfhammer, Hans Peter

    2015-01-01

    Psychotic symptoms are common in Parkinson's disease (PD) and are associated with increased disability, worsened quality of life, and poor long-term prognosis. In this article, clinical features, hypotheses on pathogenesis, and current treatment strategies for Parkinson's disease psychosis (PDP) are reviewed. According to epidemiological studies, the prevalence of PDP is between 20 to 40†%. Complex visual hallucinations are the most common psychotic symptoms and are present in 17-72†% of the patients. Other sensory disturbances encompass tactile hallucinations and minor hallucinatory phenomena, such as sense of presence and visual illusions. Hallucinations are often accompanied by delusions, whose most frequent themes are persecution and jealousy. The pathophysiology of PDP remains unclear. Different factors have been implicated, including Levo-dopa and dopaminergic medications, neurotransmitter imbalances, neuroanatomic alterations, abnormal visuospatial processes, and genetic predisposition. The first-line strategy in the treatment of persistent and problematic PDP is represented by reduction in anti-PD medications. Second-generation antipsychotics are the treatment of choice, with clozapine being demonstrated as the most effective and tolerable drug for PD patients. PMID:25586068

  13. Phytic acid attenuates inflammatory responses and the levels of NF-?B and p-ERK in MPTP-induced Parkinson's disease model of mice.

    PubMed

    Lv, Yuqiang; Zhang, Zheng; Hou, Lin; Zhang, Li; Zhang, Jinyu; Wang, Yuehua; Liu, Cun; Xu, Pingping; Liu, Lu; Gai, Xiaoying; Lu, Tingxiu

    2015-06-15

    Phytic acid (PA) is a naturally occurring constituent which exhibits protective action in Parkinson's disease (PD). Inflammation in the central nervous system (CNS) is strongly associated with neuronal death in PD. However, the molecular mechanism of the protective effect of PA in PD has not been fully elucidated. In this study, we tried to testify the protection of PA on neuron and inflammatory responses in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD model of mice and investigated the mechanism involved in them. Motor behavior test and tyrosine hydroxylase (TH) immunohistochemistry method showed PA significantly inhibited MPTP-induced dopaminergic cell loss in the substantia nigra (SN). Moreover, using immunohistochemistry method and quantitative polymerase chain reaction (qPCR), microglial activation and inducible nitric oxide synthase (iNOS) were found to be markedly repressed by PA. Via western blot assay, expressions of nuclear factor ?B (NF-?B) and phosphorylated extracellular signal-regulated kinase (p-ERK) were significantly attenuated by PA. In conclusion, it is suggested that PA has a neuroprotective effect in MPTP-induced PD model and the neuroprotection is correlated with its anti-inflammatory effect which may be associated with suppression of pathways that involved in NF-?B and p-ERK. PMID:25929185

  14. Ginsenoside Rg1 attenuates motor impairment and neuroinflammation in the MPTP-probenecid-induced parkinsonism mouse model by targeting őĪ-synuclein abnormalities in the substantia nigra.

    PubMed

    Heng, Yang; Zhang, Qiu-Shuang; Mu, Zheng; Hu, Jin-Feng; Yuan, Yu-He; Chen, Nai-Hong

    2016-01-22

    Parkinson's disease (PD) is pathologically characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the accumulation of aggregated őĪ-synuclein in specific central nervous system (CNS) regions. Disease development is attributed to őĪ-synuclein abnormalities, particularly aggregation and phosphorylation. The ginsenoside Rg1, an active component of ginseng, possesses neuroprotective and anti-inflammatory effects. The purpose of the present study was to evaluate these activities of Rg1 in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/probenecid (MPTP/p)-induced PD mouse model for the first time and to elucidate the underlying mechanisms. Oral treatment with Rg1 significantly attenuated the high MPTP-induced mortality, behavior defects, loss of dopamine neurons and abnormal ultrastructure changes in the SNpc. Other assays indicated that the protective effect of Rg1 may be mediated by its anti-neuroinflammatory properties. Rg1 regulated MPTP-induced reactive astrocytes and microglia and decreased the release of cytokines such as tumor necrosis factor-őĪ (TNF-őĪ) and interleukin-1ő≤ (IL-1ő≤) in the SNpc. Rg1 also alleviated the unusual MPTP-induced increase in oligomeric, phosphorylated and disease-related őĪ-synuclein in the SNpc. In conclusion, Rg1 protects dopaminergic neurons, most likely by reducing aberrant őĪ-synuclein-mediated neuroinflammation, and holds promise for PD therapeutics. PMID:26723869

  15. 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

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

    2014-01-01

    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

  16. Abnormal Bidirectional Plasticity-Like Effects in Parkinson's Disease

    ERIC Educational Resources Information Center

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

    2011-01-01

    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 thatÖ

  17. Abnormal Bidirectional Plasticity-Like Effects in Parkinson's Disease

    ERIC Educational Resources Information Center

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

    2011-01-01

    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…

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

    ERIC Educational Resources Information Center

    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

    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 analysedÖ

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

    ERIC Educational Resources Information Center

    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

    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…

  20. Parkinsonism in Spinocerebellar Ataxia

    PubMed Central

    Park, Hyeyoung; Kim, Han-Joon; Jeon, Beom S.

    2015-01-01

    Spinocerebellar ataxia (SCA) presents heterogeneous clinical phenotypes, and parkinsonism is reported in diverse SCA subtypes. Both levodopa responsive Parkinson disease (PD) like phenotype and atypical parkinsonism have been described especially in SCA2, SCA3, and SCA17 with geographic differences in prevalence. SCA2 is the most frequently reported subtype of SCA related to parkinsonism worldwide. Parkinsonism in SCA2 has unique genetic characteristics, such as low number of expansions and interrupted structures, which may explain the sporadic cases with low penetrance. Parkinsonism in SCA17 is more remarkable in Asian populations especially in Korea. In addition, an unclear cutoff of the pathologic range is the key issue in SCA17 related parkinsonism. SCA3 is more common in western cohorts. SCA6 and SCA8 have also been reported with a PD-like phenotype. Herein, we reviewed the epidemiologic, clinical, genetic, and pathologic features of parkinsonism in SCAs. PMID:25866756

  1. Parkinson's Disease Foundation

    MedlinePLUS

    ... Video: How Your Donations Make a Difference Ending Parkinson's PDF is increasing investment in research, health care ... the disease. Learn More A New Home for Parkinson's Science An open access journal, enabling professionals and ...

  2. 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 ...

  3. Young-Onset Parkinson's

    MedlinePLUS

    ... can help make life better for people with Parkinson's General Gift Tribute Gift Moving Day ¬ģ Team Hope ... can help make life better for people with Parkinson's General Gift Tribute Gift Moving Day ¬ģ Team Hope ...

  4. 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 ...

  5. Parkinson disease - resources

    MedlinePLUS

    Resources - Parkinson disease ... The following organizations are good resources for information on Parkinson disease : The Michael J. Fox Foundation -- www.michaeljfox.org National Institute of Neurological Disorders and Stroke -- www. ...

  6. National Parkinson Foundation, Inc.

    MedlinePLUS

    ... the Power of Exercise During Parkinson’s Disease Awareness Month March 21, 2016 The National Parkinson Foundation (NPF) ... Learn More Upcoming Events Upcoming Events Parkinson's Awareness Month! Friday, April 1 - April 30 Learn More Moving ...

  7. Lupus in a patient with cystinosis: is it drug induced?

    PubMed

    Eroglu, F K; Besbas, N; Ozaltin, F; Topaloglu, R; Ozen, S

    2015-11-01

    A 9-year-old girl with a diagnosis of cystinosis since 2 years of age, on cysteamine therapy, presented with complaints of serositis and arthritis, and laboratory tests revealed high antinuclear antibody titers with hypocomplementemia. Kidney biopsy was not consistent with lupus nephritis. With prednisolone treatment her complaints resolved and creatinine level decreased, but on follow-up, serological features of systemic lupus erythematosus (SLE) continued. Six years after cessation of prednisolone, lupus features were reactivated, with positive antihistone antibodies and ANCA. Coincidence of cystinosis and SLE is very rare, and to the best of our knowledge this is the fourth case reported in the literature. Physicians should be aware that cystinosis patients may have some autoimmune manifestations with features of true or drug-induced lupus. In the light of this case, pathophysiology and treatment are discussed. PMID:26223294

  8. Drug-induced thrombocytopenia secondary to natalizumab treatment.

    PubMed

    Cachia, David; Izzy, Saef; Berriosmorales, Idanis; Ionete, Carolina

    2014-01-01

    A 52-year-old woman with a 10-year history of relapsing-remitting multiple sclerosis (RRMS) was started on natalizumab after she developed side effects for interferon ?-1a and glatiramer acetate. The patient presented with acute severe infusion reaction after the third treatment with natalizumab, developing whole-body purpura. Laboratory testing revealed progressive worsening thrombocytopenia up to 3?weeks following natalizumab discontinuation. Platelet antibodies to platelet-specific antigen as well as antibodies against natalizumab were positive. Bone marrow biopsy was negative. The patient was diagnosed with drug-induced immune thrombocytopenia (DITP) as a rare case of natalizumab side effect which was treated with intravenous methylprednisolone followed by rituximab with successful resolution of thrombocytopenia. The patient had a stable course of RRMS with no relapses and no brain MRI changes at 2?years after initiation of rituximab. PMID:24879724

  9. Possibly drug-induced palpable migratory arciform erythema*

    PubMed Central

    Dantas, Fernando Luiz Teixeira; Valente, Neusa Yuriko Sakai; Veronez, Isis Suga; Kakizaki, Priscila; Leit„o, Juliana Ribeiro; Fraga, Rafael Cavanellas

    2015-01-01

    Palpable migratory arciform erythema is an entity of unknown etiology, with few published cases in the literature. The clinical and histopathological features of this disease are difficult to be distinguished from those of Jessnerís lymphocytic infiltration of the skin, lupus erythematous tumidus and the deep erythema annulare centrifugum. We describe here the first two Brazilian cases of palpable migratory arciform erythema. The patients presented with infiltrated annular plaques and erythematous arcs without scales. These showed centrifugal growth before disappearing without scarring or residual lesions after a few days. They had a chronic course with repeated episodes for years. In addition, these cases provide evidence of a drug-induced etiology. PMID:26312680

  10. Current Concepts of Mechanisms in Drug-Induced Hepatotoxicity

    PubMed Central

    Russmann, Stefan; Kullak-Ublick, Gerd A; Grattagliano, Ignazio

    2009-01-01

    Drug-induced liver injury (DILI) has become a leading cause of severe liver disease in Western countries and therefore poses a major clinical and regulatory challenge. Whereas previously drug-specific pathways leading to initial injury of liver cells were the main focus of mechanistic research and classifications, current concepts see these as initial upstream events and appreciate that subsequent common downstream pathways and their attenuation by drugs and other environmental and genetic factors also have a profound impact on the risk of an individual patient to develop overt liver disease. This review summarizes current mechanistic concepts of DILI in a 3-step model that limits its principle mechanisms to three main ways of initial injury, i.e. direct cell stress, direct mitochondrial impairment, and specific immune reactions. Subsequently, initial injury initiates further downstream events, i.e. direct and death receptor-mediated pathways leading to mitochondrial permeability transition, which then results in apoptotic or necrotic cell death. For all mechanisms, mitochondria play a central role in events leading to apoptotic vs. necrotic cell death. New treatment targets consequently focus on interference with downstream pathways that mediate injury and therefore determine the ultimate outcome of DILI. Genome wide and targeted pharmacogenetic as well as metabonomic approaches are now used in order to reach the key goals of a better understanding of mechanisms in hepatotoxicity, and to develop new strategies for its prediction and treatment. However, the complexity of interactions between genetic and environmental risk factors is considerable, and DILI therefore currently remains unpredictable for most hepatotoxins. PMID:19689281

  11. Drug-sensing hydrogels for the inducible release of biopharmaceuticals

    NASA Astrophysics Data System (ADS)

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

    2008-10-01

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

  12. Gauging reactive metabolites in drug-induced toxicity.

    PubMed

    Eno, Marsha R; Cameron, Michael D

    2015-01-01

    Over the past decades, it has become abundantly clear that enzymes evolved to detoxify and eliminate foreign chemicals from the body, occasionally generate highly reactive metabolites which have toxicological implications. To decrease the probability of late clinical failure or market withdrawal, there has been an increased prioritization on understanding key metabolic processes that might cause drug interactions or toxicities. Significant advances have been made in the detection of reactive metabolites and in understanding the structure activity relationship. It is now widely accepted that compounds with certain functional groups such as anilines, quinones, hydrazines, thiophenes, furans, acylpropionic acids, and alkynes have a much greater associated risk towards formation of reactive metabolites than compounds that do not contain such "structural alerts". Detection of reactive metabolites is usually done with in vitro assays, which have become more sensitive with advances in mass spectrometry. As an increasingly large number of compounds that form reactive metabolites have been identified, much of the focus has shifted from detection to evaluation of toxicological implication. While there is a disproportionate number of compounds metabolized to reactive metabolites that are associated with drug-induced hepatotoxicity and serious skin toxicities such as toxic endothelial necrolysis and Steven's Johnson syndrome, attempts to predict toxicity based on in vitro testing have been discouraging. In this review we attempt to summarize the experimental options available to evaluate reactive metabolites. PMID:25174933

  13. Salivary Secretory Disorders, Inducing Drugs, and Clinical Management

    PubMed Central

    Miranda-Rius, Jaume; Brunet-Llobet, Lluís; Lahor-Soler, Eduard; Farré, Magí

    2015-01-01

    Background: Salivary secretory disorders can be the result of a wide range of factors. Their prevalence and negative effects on the patient's quality of life oblige the clinician to confront the issue. Aim: To review the salivary secretory disorders, inducing drugs and their clinical management. Methods: In this article, a literature search of these dysfunctions was conducted with the assistance of a research librarian in the MEDLINE/PubMed Database. Results: Xerostomia, or dry mouth syndrome, can be caused by medication, systemic diseases such as Sjögren's Syndrome, glandular pathologies, and radiotherapy of the head and neck. Treatment of dry mouth is aimed at both minimizing its symptoms and preventing oral complications with the employment of sialogogues and topical acting substances. Sialorrhea and drooling, are mainly due to medication or neurological systemic disease. There are various therapeutic, pharmacologic, and surgical alternatives for its management. The pharmacology of most of the substances employed for the treatment of salivary disorders is well-known. Nevertheless, in some cases a significant improvement in salivary function has not been observed after their administration. Conclusion: At present, there are numerous frequently prescribed drugs whose unwanted effects include some kind of salivary disorder. In addition, the differing pathologic mechanisms, and the great variety of existing treatments hinder the clinical management of these patients. The authors have designed an algorithm to facilitate the decision making process when physicians, oral surgeons, or dentists face these salivary dysfunctions. PMID:26516310

  14. Round Window Membrane Intracochlear Drug Delivery Enhanced by Induced Advection

    PubMed Central

    Borkholder, David A.; Zhu, Xiaoxia; Frisina, Robert D.

    2014-01-01

    Delivery of therapeutic compounds to the inner ear via absorption through the round window membrane (RWM) has advantages over direct intracochlear infusions; specifically, minimizing impact upon functional hearing measures. However, previous reports show that significant basal-to-apical concentration gradients occur, with the potential to impact treatment efficacy. Here we present a new approach to inner ear drug delivery with induced advection aiding distribution of compounds throughout the inner ear in the murine cochlea. Polyimide microtubing was placed near the RWM niche through a bullaostomy into the middle ear cavity allowing directed delivery of compounds to the RWM. We hypothesized that a posterior semicircular canalostomy would induce apical flow from the patent cochlear aqueduct to the canalostomy due to influx of cerebral spinal fluid. To test this hypothesis, young adult CBA/CaJ mice were divided into two groups: bullaostomy approach only (BA) and bullaostomy + canalostomy (B+C). Cochlear function was evaluated by distortion product otoacoustic emission (DPOAE) and auditory brainstem response (ABR) thresholds during and after middle ear infusion of salicylate in artificial perilymph (AP), applied near the RWM. The mice recovered for 1 week, and were re-tested. The results demonstrate there was no significant impact on auditory function utilizing the RWM surgical procedure with or without the canalostomy, and DPOAE thresholds were elevated reversibly during the salicylate infusion. Comparing the threshold shifts for both methods, the B+C approach had more of a physiological effect than the BA approach, including at lower frequencies representing more apical cochlear locations. Unlike mouse cochleostomies, there was no deleterious auditory functional impact after 1 week recovery from surgery. The B+C approach had more drug efficacy at lower frequencies, underscoring potential benefits for more precise control of delivery of inner ear therapeutic compounds. PMID:24291333

  15. The Parkinson-associated human P5B-ATPase ATP13A2 protects against the iron-induced cytotoxicity.

    PubMed

    Rinaldi, Débora E; Corradi, Gerardo R; Cuesta, Lucía Martínez; Adamo, Hugo P; de Tezanos Pinto, Felicitas

    2015-08-01

    P-type ion pumps are membrane transporters that have been classified into five subfamilies termed P1-P5. The ion transported by the P5-ATPases is not known. Five genes named ATP13A1-ATP13A5 that belong to the P5-ATPase group are present in humans. Loss-of-function mutations in the ATP13A2 gene (PARK9, OMIM 610513) underlay a form of Parkinson's disease (PD) known as the Kufor-Rakeb syndrome (KRS), which belongs to the group of syndromes of neurodegeneration with brain iron accumulation (NBIA). Here we report that the cytotoxicity induced by iron exposure was two-fold reduced in CHO cells stably expressing the ATP13A2 recombinant protein (ATP13A2). Moreover, the iron content in ATP13A2 cells was lower than control cells stably expressing an inactive mutant of ATP13A2. ATP13A2 expression caused an enlargement of lysosomes and late endosomes. ATP13A2 cells exhibited a reduced iron-induced lysosome membrane permeabilization (LMP). These results suggest that ATP13A2 overexpression improves the lysosome membrane integrity and protects against the iron-induced cell damage. PMID:25912790

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

    SciTech Connect

    Wu Shaoping; Fu Ailing; Wang Yuxia; Yu Leiping; Jia Peiyuan; Li Qian; Jin Guozhang; Sun Manji . E-mail: Sunmj@nic.bmi.ac.cn

    2006-07-21

    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.

  17. A partial lesion model of Parkinson's disease in mice--characterization of a 6-OHDA-induced medial forebrain bundle lesion.

    PubMed

    Boix, Jordi; Padel, Thomas; Paul, Gesine

    2015-05-01

    The most frequently used animal models for Parkinson's disease (PD) utilize unilateral injection of 6-hydroxydopamine (6-OHDA) in the medial forebrain bundle (MFB), which results in total denervation of the dopaminergic nigrostriatal pathway. However, neuroprotective interventions in PD require models resembling earlier stages of PD, where some dopaminergic cells and fibres remain. The aim of the present study was therefore to establish a MFB partial lesion model in mice. We tested four different 6-OHDA doses, and our results show a dose-dependent loss of nigral dopaminergic cells and striatal fibres that correlated with behavioural impairment in several behavioural tests. Specifically, doses of 0.7 ?g and 1 ?g of 6-OHDA induced a partial denervation of the nigrostriatal pathway, associated with a mild but quantifiable behavioural impairment. We identified the amphetamine-induced rotation, stepping, corridor and cylinder test to be sensitive enough to select partial lesion animals. Based on our data, we proposed a range of cut-off values for these different behavioural tests to select partial lesion mice. Using a statistical prediction model we identified two behavioural tests (the stepping test and amphetamine-induced rotation test) that with a high sensitivity and specificity predict the extent of nigral dopaminergic cell loss and select mice with a partial nigrostriatal lesion prior to further interventions. This model can serve as an important tool to study neuroprotective therapies for PD in mouse models, especially when the treatment targets the substantia nigra and/or the striatum. PMID:25698603

  18. The possible mechanism of Parkinson's disease progressive damage and the preventive effect of GM1 in the rat model induced by 6-hydroxydopamine.

    PubMed

    Xu, Renshi; Zhou, Yiyi; Fang, Xin; Lu, Yi; Li, Jiao; Zhang, Jie; Deng, Xia; Li, Shujuan

    2014-12-10

    The progressive pathogenesis and prevention of Parkinson's disease (PD) remains unknown at present. Therefore, the present study aimed to investigate the possible progressive pathogenesis and prevention of PD. Our study investigated the content of glutamate, mitochondria calcium, calmodulin, malonaldehyde and trace elements in striatum, cerebral cortex and hippocampus tissues; and the expression of bcl-2, bax and neuronal nitric oxide synthase (nNOS) in substantia nigra and striatum; and the change of apomorphine induced rotation behavior; and the treatmental effect of monosialotetrahexosylganglioside (GM1) intraperitoneal administration for 14 days in a PD rat model induced by 6-hydroxydopamine. The results revealed that the content of glutamate significantly decreased, and that of mitochondria calcium, calmodulin, malonaldehyde and ferrum significantly increased in striatum, cerebral cortex and hippocampus tissues; the content of magnesium significantly decreased, and that of cuprum and zinc significantly increased in cerebral cortex; the expression of bcl-2 significantly decreased, and that of bax and nNOS significantly increased in substantia nigra and striatum in PD rat. GM1 can partially improve the apomorphine induced rotation behavior and changes of glutamate, mitochondria calcium, calmodulin content in striatum of PD rat. Data suggested that dysfunction of excitatory amino acids neurotransmitter, calcium homeostasis disorder, abnormal metabolism of oxygen free radicals, abnormal trace elements distribution and/or deposition and excessive apoptosis participated in the progressive process of PD, and that GM1 could partially prevent the progressive damage. PMID:25285892

  19. [Parkinson's disease. Perioperative management and anesthesia].

    PubMed

    WŁllner, U; Standop, J; Kaut, O; Coenen, V; Kalenka, A; Wappler, F

    2012-02-01

    Approximately 10,000-15,000 Parkinson's disease (PD) patients per year undergo surgery in Germany. The demographic developments along with further surgical progress and procedural refinements will lead to increasing numbers of PD patients in the operating theatre (OR). There are several perioperative risk factors for PD patients, they more often require prolonged intensive care treatment and warrant particular anesthesiological attention with regard to the choice of drugs and equipment. Careful evaluation of concomitant diseases, maintenance of oral Parkinson therapeutic drugs up to the time of surgery and continuous perioperative dopaminergic therapy are key factors for reducing postoperative morbidity in PD patients undergoing surgery. PMID:22354395

  20. Parkinson's disease as a result of aging

    PubMed Central

    Rodriguez, Manuel; Rodriguez-Sabate, Clara; Morales, Ingrid; Sanchez, Alberto; Sabate, Magdalena

    2015-01-01

    It is generally considered that Parkinson's disease is induced by specific agents that degenerate a clearly defined population of dopaminergic neurons. Data commented in this review suggest that this assumption is not as clear as is often thought and that aging may be critical for Parkinson's disease. Neurons degenerating in Parkinson's disease also degenerate in normal aging, and the different agents involved in the etiology of this illness are also involved in aging. Senescence is a wider phenomenon affecting cells all over the body, whereas Parkinson's disease seems to be restricted to certain brain centers and cell populations. However, reviewed data suggest that Parkinson's disease may be a local expression of aging on cell populations which, by their characteristics (high number of synaptic terminals and mitochondria, unmyelinated axons, etc.), are highly vulnerable to the agents promoting aging. The development of new knowledge about Parkinson's disease could be accelerated if the research on aging and Parkinson's disease were planned together, and the perspective provided by gerontology gains relevance in this field. PMID:25677794

  1. Drug-Induced Liver Injury Network (DILIN) Prospective Study

    PubMed Central

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

    2013-01-01

    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

  2. Prediction of drug-induced immediate hypersensitivity in guinea pigs.

    PubMed

    Chazal, I; Verdier, F; Virat, M; Descotes, J

    1994-10-01

    This study was undertaken to evaluate an assay to assess the risk for drug-induced immediate hypersensitivity reactions. Groups of five to 10 guinea-pigs were given six ip injections of the test compound on days 1, 3, 5, 8, 10 and 12. Aluminium hydroxide was also given in the first injection. At day 33, the animals were given an iv injection of the test compound and the response was recorded by grading the severity of clinical symptoms. Cutaneous passive anaphylaxis was also evaluated in six naive guinea pigs using Evans blue and sera collected from treated animals on day 26. A panel of six positive model compounds (ovalbumin, aprotinin, chymopapain, tetracosactide, cyanocobalamin and procaine), and the negative compound Ribomunyl were tested. Positive systemic and/or cutaneous anaphylactic responses were observed with ovalbumin, aprotinin, chymopapain and tetracosactide whereas no responses were noted with cyanocobalamin, procaine and Ribomunyl. Our results suggest that this protocol can help differentiate positive model compounds (known to induce reactions in man) from negative model compounds, provided that their molecular weight is large enough, but that it is not applicable to substances of low molecular weight. PMID:20693069

  3. Activin A Protects Midbrain Neurons in the 6-Hydroxydopamine Mouse Model of Parkinsonís Disease

    PubMed Central

    Li, Kong M.; Vissel, Bryce

    2015-01-01

    Parkinsonís disease (PD) is a chronic neurodegenerative disease characterized by a significant loss of dopaminergic neurons within the substantia nigra pars compacta (SNpc) and a subsequent loss of dopamine (DA) within the striatum. Despite advances in the development of pharmacological therapies that are effective at alleviating the symptoms of PD, the search for therapeutic treatments that halt or slow the underlying nigral degeneration remains a particular challenge. Activin A, a member of the transforming growth factor ? superfamily, has been shown to play a role in the neuroprotection of midbrain neurons against 6-hydroxydopamine (6-OHDA) in vitro, suggesting that activin A may offer similar neuroprotective effects in in vivo models of PD. Using robust stereological methods, we found that intrastriatal injections of 6-OHDA results in a significant loss of both TH positive and NeuN positive populations in the SNpc at 1, 2, and 3 weeks post-lesioning in drug naÔve mice. Exogenous application of activin A for 7 days, beginning the day prior to 6-OHDA administration, resulted in a significant survival of both dopaminergic and total neuron numbers in the SNpc against 6-OHDA-induced toxicity. However, we found no corresponding protection of striatal DA or dopamine transporter (DAT) expression levels in animals receiving activin A compared to vehicle controls. These results provide the first evidence that activin A exerts potent neuroprotection in a mouse model of PD, however this neuroprotection may be localized to the midbrain. PMID:25902062

  4. Functionalized nanoparticles for AMF-induced gene and drug delivery

    NASA Astrophysics Data System (ADS)

    Biswas, Souvik

    The properties and broad applications of nano-magnetic colloids have generated much interest in recent years. Specially, Fe3O4 nanoparticles have attracted a great deal of attention since their magnetic properties can be used for hyperthermia treatment or drug targeting. For example, enhanced levels of intracellular gene delivery can be achieved using Fe3O4 nano-vectors in the presence of an external magnetic field, a process known as 'magnetofection'. The low cytotoxicity, tunable particle size, ease of surface functionalization, and ability to generate thermal energy using an external alternating magnetic field (AMF) are properties have propelled Fe3O4 research to the forefront of nanoparticle research. The strategy of nanoparticle-mediated, AMF-induced heat generation has been used to effect intracellular hyperthermia. One application of this 'magnetic hyperthermia' is heat activated local delivery of a therapeutic effector (e.g.; drug or polynucleotide). This thesis describes the development of a magnetic nano-vector for AMF-induced, heat-activated pDNA and small molecule delivery. The use of heat-inducible vectors, such as heat shock protein ( hsp) genes, is a promising mode of gene therapy that would restrict gene expression to a local region by focusing a heat stimulus only at a target region. We thus aimed to design an Fe3O4 nanoparticle-mediated gene transfer vehicle for AMF-induced localized gene expression. We opted to use 'click' oximation techniques to assemble the magnetic gene transfer vector. Chapter 2 describes the synthesis, characterization, and transfection studies of the oxime ether lipid-based nano-magnetic vectors MLP and dMLP. The synthesis and characterization of a novel series of quaternary ammonium aminooxy reagents (2.1--2.4) is described. These cationic aminooxy compounds were loaded onto nanoparticles for ligation with carbonyl groups and also to impart a net positive charge on the nanoparticle surface. Our studies indicated that the non-toxic magnetoplexes (magnetic nanoparticle + pDNA complex) derived from dMLP deliver pDNA into mammalian cells even without external magnetic assistance. To date, dMLP is the only polymer-free magnetic gene delivery system that can deliver pDNA without any magnetic assistance. Chapter 3 of this thesis outlines the synthesis and characterization of other oxime ether lipids and details studies using derived-lipoplexes. These lipids were evaluated in pDNA and siRNA transfection studies in various mammalian cell lines. This work constitutes the first use of an oxime ether as the linking domain in cationic transfection lipids. These biocompatible oxime ether lipids can be readily assembled by click chemistry through ligation of hydrophobic aldehydes with quaternary ammonium aminooxy salts. Our studies showed that the oxime ether lipids transfected pDNA and siRNA efficiently in MCF-7, H 1792, and in PAR C10 cells comparable to and in some cases better than commercial transfection lipids. Chapter 4 describes the design and characterization of a nano-magnetic delivery system for AMF-induced drug (doxorubicin) release. In efforts to develop a magnetic formulation free from thermosensitive materials, such as hydrogels, we synthesized three nanoparticle-based doxorubicin formulations using charge interactions as the key associative force. To do so, we synthesized and characterized a novel cationic oxime ether conjugate at C-13 of doxorubicin. Our investigation indicated that the positive charge of the oxime ether drug conjugate tended to bind better to the negatively charged nanoparticle than did the other formulations prepared in stepwise manner. Our findings show that the nano-magnetic formulations remained essestially inactive at body temperature (37.5 ¬įC) and released a majority of the cargo only when exposed to an external AMF. Our designed magnetic drug delivery platform is the first example of an AMF-inducible system that does not depend on the inclusion of thermosensitive materials. Finally, we have developed a bioanalytical application of the highly chemoselective oximation chemistry using aminooxy reagent 2.1. Chapter 5 describes a silica microchip containing micropillars coated with cationic aminooxy reagent 2.1. The microchip captures gaseous ketones and aldehydes from exhaled human breath. A brief description of microchip fabricated breath analyzer and breath analysis is described in Chapter 5. Our studies showed that the acetone capture efficiency of the aminooxy-loaded microchip was 98%.

  5. Dopaminergic modulation of motor coordinaton in Parkinsonís disease

    PubMed Central

    Park, Jaebum; Lewis, Mechelle M.; Huang, Xuemei; Latash, Mark L.

    2013-01-01

    Background We applied the idea of synergies and the framework of the uncontrolled manifold hypothesis to explore the effects of dopamine replacement therapy on finger interaction and coordination in patients with early-stage Parkinsonís disease (PD). Methods Eight patients performed single-finger and multi-finger force production tasks with both the dominant and non-dominant hand before (off-drug) and after (on-drug) taking their dopaminergic medications. Synergy indices were defined as co-varied adjustments of commands to fingers that stabilized the total force produced by the hand. Results PD patients showed significantly lower maximal finger forces off-drug compared to the on-drug condition, while indices of finger individuation (enslaving) were unchanged. The synergy indices were weaker during steady-state force production off-drug compared to on-drug. Anticipatory adjustments of synergies prior to the quick force pulse initiation were delayed and reduced off-drug as compared to the on-drug condition. These drug effects were observed in both the symptomatic and asymptomatic hands of the patients whose symptoms were limited to one side of the body. Conclusions The study demonstrates dopaminergic modulation of motor coordination in PD and supports that the analysis of different components of multi-finger synergies offers a set of indices sensitive to the effects of dopamine replacement therapy in early-stage PD. The results suggest an important role of the basal ganglia in synergy formation and in feed-forward synergy adjustments. Future studies using these methods may yield more objective, quantitative biomarker(s) of motor coordination impairments in PD, and better understanding of subcortical involvement in the neural control of natural actions. PMID:24090949

  6. (1)H NMR-based metabolomics study on a goldfish model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).

    PubMed

    Lu, Zhaoguang; Wang, Junsong; Li, Minghui; Liu, Qingwang; Wei, Dandan; Yang, Minghua; Kong, Lingyi

    2014-09-19

    A goldfish (Carassius auratus) model of Parkinson's disease (PD) was constructed by a single dose of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) according to previously reported methods. Global metabolite changes in brain of the MPTP induced goldfish model of PD were investigated. (1)H NMR-based metabolomics combined with various statistical methods such as orthogonal partial least squares discriminant analysis (OPLS-DA) and two-dimensional statistical total correlation spectroscopy (2D-STOCSY) found significant increase of leucine, isoleucine, valine, alanine, alanylalanine, creatinine, myo-inositol, 18:2 fatty acid, total fatty acids, arachic alcohol, taurine and significant decrease of N-acetylaspartate, (phospho)creatine, (phospho)choline, betaine, glutamine, 3-hexenedioate, acetamide, malonate, isocitrate, scyllo-inositol, phosphatidylcholines, cholesterols, n-3 fatty acids, polyunsaturated fatty acids (PUFAs) in brain of MPTP induced PD goldfish. These disturbed metabolite levels were involved in oxidative stress, energy failure, neuronal cell injury and death, consistent with those observed in clinical PD patients, and rodents and primates model of PD, indicating that the acute MPTP model of goldfish was an ideal and valuable model for PD research. In addition, several unusual metabolites in brain were significantly changed between MPTP induced PD and control goldfish, which might also play an important role in the pathogenesis of PD. This study also demonstrated the applicability and potential of (1)H NMR-based metabolomics approach for evaluation of animal models of disease induced by chemicals, such as MPTP-induced PD goldfish. PMID:25242684

  7. őĪ-Synuclein-induced dopaminergic neurodegeneration in a rat model of Parkinson's disease occurs independent of ATP13A2 (PARK9).

    TOXLINE Toxicology Bibliographic Information

    Daniel G; Musso A; Tsika E; Fiser A; Glauser L; Pletnikova O; Schneider BL; Moore DJ

    2015-01-01

    Mutations in the ATP13A2 (PARK9) gene cause early-onset, autosomal recessive Parkinson's disease (PD) and Kufor-Rakeb syndrome. ATP13A2 mRNA is spliced into three distinct isoforms encoding a P5-type ATPase involved in regulating heavy metal transport across vesicular membranes. Here, we demonstrate that three ATP13A2 mRNA isoforms are expressed in the normal human brain and are modestly increased in the cingulate cortex of PD cases. ATP13A2 can mediate protection toward a number of stressors in mammalian cells and can protect against őĪ-synuclein-induced toxicity in cellular and invertebrate models of PD. Using a primary cortical neuronal model combined with lentiviral-mediated gene transfer, we demonstrate that human ATP13A2 isoforms 1 and 2 display selective neuroprotective effects toward toxicity induced by manganese and hydrogen peroxide exposure through an ATPase-independent mechanism. The familial PD mutations, F182L and G504R, abolish the neuroprotective effects of ATP13A2 consistent with a loss-of-function mechanism. We further demonstrate that the AAV-mediated overexpression of human ATP13A2 is not sufficient to attenuate dopaminergic neurodegeneration, neuropathology, and striatal dopamine and motoric deficits induced by human őĪ-synuclein expression in a rat model of PD. Intriguingly, the delivery of an ATPase-deficient form of ATP13A2 (D513N) to the substantia nigra is sufficient to induce dopaminergic neuronal degeneration and motor deficits in rats, potentially suggesting a dominant-negative mechanism of action. Collectively, our data demonstrate a distinct lack of ATP13A2-mediated protection against őĪ-synuclein-induced neurotoxicity in the rat nigrostriatal dopaminergic pathway, and limited neuroprotective capacity overall, and raise doubts about the potential of ATP13A2 as a therapeutic target for PD.

  8. Alterations in primary motor cortex neurotransmission and gene expression in hemi-parkinsonian rats with drug-induced dyskinesia.

    PubMed

    Lindenbach, D; Conti, M M; Ostock, C Y; Dupre, K B; Bishop, C

    2015-12-01

    Treatment of Parkinson's disease (PD) with dopamine replacement relieves symptoms of poverty of movement, but often causes drug-induced dyskinesias. Accumulating clinical and pre-clinical evidence suggests that the primary motor cortex (M1) is involved in the pathophysiology of PD and that modulating cortical activity may be a therapeutic target in PD and dyskinesia. However, surprisingly little is known about how M1 neurotransmitter tone or gene expression is altered in PD, dyskinesia or associated animal models. The present study utilized the rat unilateral 6-hydroxydopamine (6-OHDA) model of PD/dyskinesia to characterize structural and functional changes taking place in M1 monoamine innervation and gene expression. 6-OHDA caused dopamine pathology in M1, although the lesion was less severe than in the striatum. Rats with 6-OHDA lesions showed a PD motor impairment and developed dyskinesia when given l-DOPA or the D1 receptor agonist, SKF81297. M1 expression of two immediate-early genes (c-Fos and ARC) was strongly enhanced by either l-DOPA or SKF81297. At the same time, expression of genes specifically involved in glutamate and GABA signaling were either modestly affected or unchanged by lesion and/or treatment. We conclude that M1 neurotransmission and signal transduction in the rat 6-OHDA model of PD/dyskinesia mirror features of human PD, supporting the utility of the model to study M1 dysfunction in PD and the elucidation of novel pathophysiological mechanisms and therapeutic targets. PMID:26363150

  9. Garcinia Cambogia-Induced Acute Hepatitis; Varenicline-Induced Parkinsonism; Resistant Hypocalcemia After Zoledronic Acid Administration; Zonisamide-Induced Acute Kidney Injury; Psychosis Associated with Guanfacine.

    PubMed

    Mancano, Michael A

    2015-07-01

    The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration's (FDA's) Med Watch program (800-FDA-1088). If you have reported an interesting, preventable ADR to Med Watch, please consider sharing the account with our readers. Write to Dr. Mancano at ISMP, 200 Lakeside Drive, Suite 200, Horsham, PA 19044 (phone: 215-707-4936; e-mail: mmancano@temple.edu). Your report will be published anonymously unless otherwise requested. This feature is provided by the Institute for Safe Medication Practices (ISMP) in cooperation with the FDA's Med Watch program and Temple University School of Pharmacy. ISMP is an FDA Med Watch partner. PMID:26448666

  10. 5-HT1A receptor-dependent control of nigrostriatal dopamine neurotransmission in the pharmacotherapy of Parkinson's disease and schizophrenia.

    PubMed

    Haleem, Darakhshan J

    2015-02-01

    Dysfunctions of the basal ganglia are associated with a number of neurological and psychiatric conditions including Parkinson's disease and schizophrenia. Current treatments of these disorders are mostly symptomatic and inadequate, and are often associated with a number of unwanted side-effects. The striatum, the terminal region of the nigrostriatal dopamine pathway, is the main input nucleus of the basal ganglia, and dopamine neurotransmission through the nigrostriatal pathway plays a crucial role in the modulation of basal ganglia output and mediated behaviors. Evidence suggests a role of 5-hydroxytryptamine (5-HT; serotonin)-1A receptors in the modulation of dopamine neurotransmission and in improving pharmacotherapy in schizophrenia and Parkinson's disease. This review concerns the role of 5-HT1A receptors in the modulation of nigrostriatal dopamine neurotransmission, with the aim of providing guidelines for future research to improve pharmacotherapy. The current state of knowledge suggests that drugs simultaneously targeting dopamine D2 and 5-HT1A receptors may improve pharmacotherapy for schizophrenia and Parkinson's disease. Activation of somatodendritic 5-HT1A receptors in the dorsal raphe nucleus has an important role in the alleviation of extrapyramidal symptoms and levodopa-induced dyskinesia induced by antipsychotic treatment. Drugs acting exclusively through dopamine D2 and 5-HT1A receptors are highly needed to validate the potential role of 5-HT1A receptors in improving therapeutics for Parkinson's disease and schizophrenia. PMID:25503261

  11. Inflammatory Animal Model for Parkinson's Disease: The Intranigral Injection of LPS Induced the Inflammatory Process along with the Selective Degeneration of Nigrostriatal Dopaminergic Neurons

    PubMed Central

    Machado, A.; Herrera, A. J.; Venero, J. L.; Santiago, M.; de Pablos, R. M.; VillarŠn, R. F.; Espinosa-Oliva, A. M.; ArgŁelles, S.; Sarmiento, M.; Delgado-Cortťs, M. J.; MauriŮo, R.; Cano, J.

    2011-01-01

    We have developed an animal model of degeneration of the nigrostriatal dopaminergic neurons, the neuronal system involved in Parkinson's disease (PD). The implication of neuroinflammation on this disease was originally established in 1988, when the presence of activated microglia in the substantia nigra (SN) of parkinsonians was reported by McGeer et al. Neuroinflammation could be involved in the progression of the disease or even has more direct implications. We injected 2??g of the potent proinflammatory compound lipopolysaccharide (LPS) in different areas of the CNS, finding that SN displayed the highest inflammatory response and that dopaminergic (body) neurons showed a special and specific sensitivity to this process with the induction of selective dopaminergic degeneration. Neurodegeneration is induced by inflammation since it is prevented by anti-inflammatory compounds. The special sensitivity of dopaminergic neurons seems to be related to the endogenous dopaminergic content, since it is overcome by dopamine depletion. Compounds that activate microglia or induce inflammation have similar effects to LPS. This model suggest that inflammation is an important component of the degeneration of the nigrostriatal dopaminergic system, probably also in PD. Anti-inflammatory treatments could be useful to prevent or slow down the rate of dopaminergic degeneration in this disease. PMID:22389821

  12. Neurodegenerative Shielding by Curcumin and Its Derivatives on Brain Lesions Induced by 6-OHDA Model of Parkinson's Disease in Albino Wistar Rats.

    PubMed

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

    2012-01-01

    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 (D(2)) 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 D(2) 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

  13. MPTP-induced parkinsonism in mice alters striatal and nigral xCT expression but is unaffected by the genetic loss of xCT.

    PubMed

    Bentea, Eduard; Sconce, Michelle D; Churchill, Madeline J; Van Liefferinge, Joeri; Sato, Hideyo; Meshul, Charles K; Massie, Ann

    2015-04-23

    Nigral cell loss in Parkinson's disease (PD) is associated with disturbed glutathione (GSH) and glutamate levels, leading to oxidative stress and excitotoxicity, respectively. System xc- is a plasma membrane antiporter that couples cystine import (amino acid that can be further used for the synthesis of GSH) with glutamate export to the extracellular environment, and can thus affect both oxidative stress and glutamate excitotoxicity. In the current study, we evaluated the involvement of system xc- in a progressive 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Our results indicate that the expression of xCT (the specific subunit of system xc-) undergoes region-specific changes in MPTP-treated mice, with increased expression in the striatum, and decreased expression in the substantia nigra. Furthermore, mice lacking xCT were equally sensitive to the neurotoxic effects of MPTP compared to wild-type (WT) mice, as they demonstrate similar decreases in striatal dopamine content, striatal tyrosine hydroxylase (TH) expression, nigral TH immunopositive neurons and forelimb grip strength, five weeks after commencing MPTP treatment. Altogether, our data indicate that progressive lesioning with MPTP induces striatal and nigral dysregulation of system xc-. However, loss of system xc- does not affect MPTP-induced nigral dopaminergic neurodegeneration and motor impairment in mice. PMID:25766755

  14. 76 FR 4918 - Drug-Induced Liver Injury: Are We Ready to Look?; Public Conference; Request for Comments

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-01-27

    ... for industry entitled ``Drug-Induced Liver Injury: Premarketing Clinical Evaluation'' (see 74 FR 38035... HUMAN SERVICES Food and Drug Administration Drug-Induced Liver Injury: Are We Ready to Look?; Public... conference entitled ``Drug-Induced Liver Injury: Are We Ready to Look?'' The public conference will...

  15. Drug-Induced Gingival Overgrowth: The Genetic Dimension

    PubMed Central

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

    2014-01-01

    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 patientsí 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

  16. Adaptive down-regulation of the serotonin transporter in the 6-hydroxydopamine-induced rat model of preclinical stages of Parkinson's disease and after chronic pramipexole treatment.

    PubMed

    Berghauzen-Maciejewska, K; Wardas, J; Kosmowska, B; Domin, H; ŇömiaŇāowska, M; GŇāowacka, U; Ossowska, K

    2016-02-01

    Our recent study has indicated that a moderate lesion induced by bilateral 6-hydroxydopamine (6-OHDA) injections into the ventrolateral region of the caudate-putamen (CP) in rats, modeling preclinical stages of Parkinson's disease, induces a "depressive-like" behavior which is reversed by chronic treatment with pramipexole (PRA). The aim of the present study was to examine the influence of the above lesion and chronic PRA treatment on binding to the serotonin transporter (SERT) in different brain regions. As before, 6-OHDA (15őľg/2.5őľl) was administered bilaterally into the CP. PRA (1mg/kg) was injected subcutaneously twice a day for 2weeks. Serotonergic and dopaminergic neurons of the dorsal raphe (DR) were immunostained for tryptophan hydroxylase and tyrosine hydroxylase, respectively, and were counted stereologically. Binding of [(3)H]GBR 12,935 to the dopamine transporter (DAT) and [(3)H]citalopram to SERT was analyzed autoradiographically. Intrastriatal 6-OHDA injections decreased the number of dopaminergic, but not serotonergic neurons in the DR. 6-OHDA reduced the DAT binding in the CP, and SERT binding in the nigrostriatal system (CP, substantia nigra (SN)), limbic system (ventral tegmental area (VTA), nucleus accumbens (NAC), amygdala, prefrontal cortex (PFCX), habenula, hippocampus) and DR. A significant positive correlation was found between DAT and SERT binding in the CP. Chronic PRA did not influence DAT binding but reduced SERT binding in the above structures, and deepened the lesion-induced losses in the core region of the NAC, SN, VTA and PFCX. The present study indicates that both the lesion of dopaminergic neurons and chronic PRA administration induce adaptive down-regulation of SERT binding. Moreover, although involvement of stimulation of dopaminergic transmission by chronic PRA in its "antidepressant" effect seems to be prevalent, additional contribution of SERT inhibition cannot be excluded. PMID:26628402

  17. PEP-1-SOD fusion protein efficiently protects against paraquat-induced dopaminergic neuron damage in a Parkinson disease mouse model.

    PubMed

    Choi, Hee Soon; An, Jae Jin; Kim, So Young; Lee, Sun Hwa; Kim, Dae Won; Yoo, Ki-Yeon; Won, Moo Ho; Kang, Tae-Cheon; Kwon, Hyung Joo; Kang, Jung Hoon; Cho, Sung-Woo; Kwon, Oh-Shin; Park, Jinseu; Eum, Won Sik; Choi, Soo Young

    2006-10-01

    Parkinson disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN). However, the mechanism of the pathology of PD still remains poorly understood. Because the administration of the herbicide paraquat triggers selective dopaminergic neuronal cell death, exposure of mice to this herbicide is one valuable model for studying the pathological aspects of PD. In this study, we investigated the protective effects of PEP-1-SOD in vitro and in vivo under exposure to the herbicide paraquat. The viability of neuronal cells treated with paraquat was markedly increased by transduced PEP-1-SOD. When the PEP-1-SOD fusion protein was injected intraperitoneally into mice, a completely protective effect against dopaminergic neuronal cell death in the SN was observed. This protective effect was synergistically increased when the PEP-1-SOD was cotransduced with Tat-alpha-synuclein. These results suggest that PEP-1-SOD provides a strategy for therapeutic delivery in various human diseases related to reactive oxygen species, including PD. PMID:16962931

  18. Tat-fused recombinant human SAG prevents dopaminergic neurodegeneration in a MPTP-induced Parkinson's disease model.

    PubMed

    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

    2014-03-01

    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

  19. Neuroprotective effects of 5-(4-hydroxy-3-dimethoxybenzylidene)-thiazolidinone in MPTP induced Parkinsonism model in mice.

    PubMed

    Ren, Zhili; Yang, Nan; Ji, Chao; Zheng, Ji; Wang, Tao; Liu, Yanyong; Zuo, Pingping

    2015-06-01

    Parkinson's disease (PD) is a neurological disorder characterized by degeneration of nigrostriatal dopaminergic (DAergic) system. Present treatment targeting to DAergic system solely ameliorated the symptoms but failed to retard the DAergic neuron degeneration, therefore new therapeutic methods aiming at preventing or delaying the neurodegenerative process are urgently needed. In the present study, we found that 5-(4-hydroxy-3-dimethoxybenzylidene)-2-thioxo-4-thiazolidinone (RD-1), a compound derived from rhodanine, protected DAergicneurons from neurotoxicity of MPTP/MPP(+). Firstly, RD-1 significantly improved the locomotor ability in the MPTP mice model, and elevated the tyrosine hydroxylase (TH) positive cell numbers in substantianigra pars compacta (SNpc) and the integrated optical density (IOD) of TH-positive nerve fibers in striatum respectively. Since mitochondrial dysfunction plays an important role in pathogenesis of PD, thereby we investigated the molecular mechanisms of RD-1 against MPTP/MPP(+) neurotoxicity, focusing on its effects on the mitochondrial dysfunction. Immunoblotting analysis showed that RD-1 significantly elevated the Parkin and Miro2 expression levels in acute MPTP treated mice, and improved mitochondrial membrane potential and ATP synthesis in MPP(+)-treated Neuro-2a cells. Moreover, RD-1attenuated impaired mitochondrial transport and vesicle release dysfunction evoked by MPP(+) cytotoxicity in cultured primary mesencephalic neurons. Taken together, these results indicate that improving the mitochondrial dysfunction may be a good choice to delay the neurodegenerative progression commonly associated with PD. PMID:25680233

  20. Reactive oxygen species assay-based risk assessment of drug-induced phototoxicity: classification criteria and application to drug candidates.

    PubMed

    Onoue, Satomi; Kawamura, Kiyoshi; Igarashi, Naoko; Zhou, Yu; Fujikawa, Masaaki; Yamada, Hiroshi; Tsuda, Yoshiko; Seto, Yoshiki; Yamada, Shizuo

    2008-08-01

    We have previously demonstrated that the phototoxic potential of chemicals could be partly predicted by the determination of reactive oxygen species (ROS) from photo-irradiated compounds. In this study, ROS assay strategy was applied to 39 marketed drugs and 210 drug candidates in order to establish provisional classification criteria for risk assessment of drug-induced phototoxicity. The photosensitizing properties of 39 model compounds consisting of phototoxic and non-phototoxic chemicals, as well as ca. 210 drug candidates including 11 chemical series were evaluated using ROS assay and the 3T3 neutral red uptake phototoxicity test (NRU PT). With respect to marketed drugs, most phototoxic drugs tended to cause type I and/or II photochemical reactions, resulting in generation of singlet oxygen and superoxide. There seemed to be a clear difference between phototoxic drugs and non-phototoxic compounds in their abilities to induce photochemical reactions. A plot analysis of ROS data on the marked drugs provided classification criteria to discriminate the photosensitizers from non-phototoxic substances. Of all drug candidates tested, 35.2% compounds were identified as phototoxic or likely phototoxic on the basis of the 3T3 NRU PT, and all ROS data for these phototoxic compounds were found to be over the threshold value. Furthermore, 46.3% of non-phototoxic drug candidates were found to be in the subthreshold region. These results verify the usefulness of the ROS assay for understanding the phototoxicity risk of pharmaceutical substances, and the ROS assay can be used for screening purposes in the drug discovery stage. PMID:18455898

  1. 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

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

    2011-11-15

    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.

  2. The History of Parkinson's Disease: Early Clinical Descriptions and Neurological Therapies

    PubMed Central

    Goetz, Christopher G.

    2011-01-01

    Although components of possible Parkinson's disease can be found in very early documents, the first clear medical description was written in 1817 by James Parkinson. In the mid-1800s, Jean-Martin Charcot was particularly influential in refining and expanding this early description and in disseminating information internationally about Parkinson's disease. He separated Parkinson's disease from multiple sclerosis and other disorders characterized by tremor, and he recognized cases that later would likely be classified among the Parkinsonism-plus syndromes. Early treatments of Parkinson's disease were based on empirical observation, and anticholinergic drugs were used as early as the nineteenth century. The discovery of dopaminergic deficits in Parkinson's disease and the synthetic pathway of dopamine led to the first human trials of levodopa. Further historically important anatomical, biochemical, and physiological studies identified additional pharmacological and neurosurgical targets for Parkinson's disease and allow modern clinicians to offer an array of therapies aimed at improving function in this still incurable disease. PMID:22229124

  3. The history of Parkinson's disease: early clinical descriptions and neurological therapies.

    PubMed

    Goetz, Christopher G

    2011-09-01

    Although components of possible Parkinson's disease can be found in very early documents, the first clear medical description was written in 1817 by James Parkinson. In the mid-1800s, Jean-Martin Charcot was particularly influential in refining and expanding this early description and in disseminating information internationally about Parkinson's disease. He separated Parkinson's disease from multiple sclerosis and other disorders characterized by tremor, and he recognized cases that later would likely be classified among the Parkinsonism-plus syndromes. Early treatments of Parkinson's disease were based on empirical observation, and anticholinergic drugs were used as early as the nineteenth century. The discovery of dopaminergic deficits in Parkinson's disease and the synthetic pathway of dopamine led to the first human trials of levodopa. Further historically important anatomical, biochemical, and physiological studies identified additional pharmacological and neurosurgical targets for Parkinson's disease and allow modern clinicians to offer an array of therapies aimed at improving function in this still incurable disease. PMID:22229124

  4. Drug-induced thrombocytopenia for the hospitalist physician with a focus on heparin-induced thrombocytopenia.

    PubMed

    Rondina, Matthew T; Walker, Amanda; Pendleton, Robert C

    2010-04-01

    Acute thrombocytopenia occurs commonly in hospitalized patients. For most, the etiology of an acutely declining platelet count is obvious and includes sepsis with disseminated intravascular coagulation, large-volume crystalloid infusion, or the administration of cytotoxic therapies, such as chemotherapeutic agents. For others, however, the etiology may be less apparent. In these cases, drug-induced thrombocytopenia (DIT), including heparin-induced thrombocytopenia (HIT), must be a diagnostic consideration. The approach to the hospitalized patient with thrombocytopenia, without an obvious cause, includes a careful medication history to identify potential culprits, such as glycoprotein IIb/IIIa inhibitors, vancomycin, linezolid, beta-lactam antibiotics, quinine, antiepileptic drugs, or heparin/low-molecular-weight heparin. Usually, discontinuation of the offending medication is all that is necessary for resolution of thrombocytopenia. Heparin-induced thrombocytopenia, however, is an exception to this general rule given its unique pathogenesis and propensity for thrombotic complications and death. Differentiating between HIT and DIT due to nonheparin medications may prove challenging. Through a careful clinical assessment, consideration of the pre-test probability for HIT, and the thoughtful application of laboratory testing, HIT can be accurately diagnosed. Because patients with HIT have a high risk of thrombosis and bleeding is uncommon, the prompt initiation of an alternative anticoagulant (e.g., a direct thrombin inhibitor) is warranted in these patients. PMID:20469610

  5. Genetics Home Reference: Parkinson disease

    MedlinePLUS

    ... PubMed Recent literature OMIM Genetic disorder catalog Conditions > Parkinson disease On this page: Description Genetic changes Inheritance ... names Glossary definitions Reviewed May 2012 What is Parkinson disease? Parkinson disease is a progressive disorder of ...

  6. Cannabinoid Hyperemesis Syndrome: An Emerging Drug-Induced Disease.

    PubMed

    Woods, J Andrew; Wright, Nicholas J D; Gee, Jonathan; Scobey, Martin W

    2016-01-01

    Cannabinoid hyperemesis is a relatively rare but significant adverse effect of chronic marijuana use characterized by severe, cyclic nausea, vomiting, and abdominal pain and marked by compulsive hot-water bathing for temporary symptom relief. A 37-year-old African American male with no significant medical history other than the habitual abuse of marijuana was admitted for intractable nausea, vomiting, and abdominal pain. With the exception of abdominal skin hyperpigmentation and scarring secondary to the direct application of heat through a heating pad, physical examination of the abdomen was unremarkable. Laboratory studies revealed a mild leukocytosis and acute renal dysfunction. All diagnostic examinations were found to be unremarkable or noncontributory to the patient's presenting state. Consistent with previous admissions, the patient's urine toxicology screening was found to be positive for marijuana. After several days of aggressive IV fluid hydration and as needed antiemetics and pain management, all laboratory studies and vital signs returned to baseline and the patient was subsequently discharged. Symptoms of cannabinoid hyperemesis resolve with cannabis cessation and recur when cannabis use is reinitiated, supporting an association between chronic use and cyclic vomiting. A Naranjo algorithm score of 5 revealed a probable incidence of cyclic vomiting associated with chronic cannabis abuse in our patient. Marijuana use, both legal and illegal, is becoming more prevalent in the United States. Given the nationwide increase in marijuana use for recreational and medical reasons, pharmacists and other health care providers should be aware of this interesting drug-induced phenomenon. PMID:24413371

  7. Acetaldehyde and parkinsonism: role of CYP450 2E1

    PubMed Central

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

    2013-01-01

    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

  8. Modulation of non steroidal anti-inflammatory drug induced membrane fusion by copper coordination of these drugs: anchoring effect.

    PubMed

    Majumdar, Anupa; Chakraborty, Sreeja; Sarkar, Munna

    2014-12-01

    Membrane fusion, an integral event in several biological processes, is characterized by several intermediate steps guided by specific energy barriers. Hence, it requires the aid of fusogens to complete the process. Common fusogens, such as proteins/peptides, have the ability to overcome theses barriers by their conformational reorganization, an advantage not shared by small drug molecules. Hence, drug induced fusion at physiologically relevant drug concentrations is rare and occurs only in the case of the oxicam group of non steroidal anti-inflammatory drugs (NSAIDs). To use drugs to induce and control membrane fusion in various biochemical processes requires the understanding of how different parameters modulate fusion. Also, fusion efficacy needs to be enhanced. Here we have synthesized and used Cu(II) complexes of fusogenic oxicam NSAIDs, Meloxicam and Piroxicam, to induce fusion in model membranes monitored by using DSC, TEM, steady-state, and time-resolved spectroscopy. The ability of the complexes to anchor apposing model membranes to initiate/facilitate fusion has been demonstrated. This results in better fusion efficacy compared to the bare drugs. These complexes can take the fusion to its final step. Unlike other designed membrane anchors, the role of molecular recognition and strength of interaction between molecular partners is obliterated for these preformed Cu(II)-NSAIDs. PMID:25380501

  9. Rotenone-induced parkinsonism elicits behavioral impairments and differential expression of parkin, heat shock proteins and caspases in the rat.

    PubMed

    Sonia Angeline, M; Chaterjee, P; Anand, K; Ambasta, R K; Kumar, P

    2012-09-18

    Rotenone is a pesticide that inhibits mitochondrial complex I activity, thus creating an environment of oxidative stress in the cell. Many studies have employed rotenone to generate an experimental animal model of Parkinson's disease (PD) that mimics and elicits PD-like symptoms, such as motor and cognitive decline. Cytoprotective proteins including parkin and heat shock proteins (HSPs) play major roles in slowing PD progression. Moreover, evidence suggests that mitochondrial dysfunction and oxidative stress-dependent apoptotic pathways contribute to dopaminergic neuron degeneration in PD. Here, rats were chronically exposed to rotenone to confirm that it causes a debilitating phenotype and various behavioral defects. We also performed histopathological examinations of nigrostriatal, cortical and cerebellar regions of rotenone-treated brain to elucidate a plausible neurodegenerative mechanism. The results of silver, tyrosine hydroxylase (TH), parkin, ubiquitin and caspase staining of brain tissue sections further validated our findings. The stress response is known to trigger HSP in response to pharmacological insult. These protective proteins help maintain cellular homeostasis and may be capable of rescuing cells from death. Therefore, we assessed the levels of different HSPs in the rotenone-treated animals. Collectively, our studies indicated the following findings in the striatum and substantia nigra following chronic rotenone exposure in an experimental PD model: (i) behavioral deficit that correlated with histopathological changes and down regulation of TH signaling, (ii) decreased levels of the cytoprotective proteins parkin, DJ1 and Hsp70 and robust expression of mitochondrial chaperone Hsp60 according to Western blot, (iii) increased immunoreactivity for caspase 9, caspase 3 and ubiquitin and decreased parkin immunoreactivity. PMID:22710069

  10. Heat Shock Protein-70 (Hsp-70) Suppresses Paraquat-Induced Neurodegeneration by Inhibiting JNK and Caspase-3 Activation in Drosophila Model of Parkinson's Disease

    PubMed Central

    Shukla, Arvind Kumar; Pragya, Prakash; Chaouhan, Hitesh Singh; Tiwari, Anand Krishna; Patel, Devendra Kumar; Abdin, Malik Zainul; Chowdhuri, Debapratim Kar

    2014-01-01

    Parkinson's disease (PD) is one of the most common neurodegenerative disorders with limited clinical interventions. A number of epidemiological as well as case-control studies have revealed an association between pesticide exposure, especially of paraquat (PQ) and occurrence of PD. Hsp70, a molecular chaperone by function, has been shown as one of the modulators of neurological disorders. However, paucity of information regarding the protective role of Hsp70 on PQ-induced PD like symptoms led us to hypothesize that modulation of hsp70 expression in the dopaminergic neurons would improve the health of these cells. We took advantage of Drosophila, which is a well-established model for neurological research and also possesses genetic tools for easy manipulation of gene expression with limited ethical concern. Over-expression of hsp70 was found to reduce PQ-induced oxidative stress along with JNK and caspase-3 mediated dopaminergic neuronal cell death in exposed organism. Further, anti-apoptotic effect of hsp70 was shown to confer better homeostasis in the dopaminergic neurons of PQ-exposed organism as evidenced by their improved locomotor performance and survival. The study has merit in the context of human concern since we observed protection of dopaminergic neurons in PQ-exposed organism by over-expressing a human homologue of hsp70, HSPA1L, in these cells. The effect was parallel to that observed with Drosophila hsp70. These findings reflect the potential therapeutic applicability of hsp70 against PQ-induced PD like symptoms in an organism. PMID:24887138

  11. Allogeneic/xenogeneic transplantation of peptide-labeled mitochondria in Parkinson's disease: restoration of mitochondria functions and attenuation of 6-hydroxydopamine-induced neurotoxicity.

    PubMed

    Chang, Jui-Chih; Wu, Shey-Lin; Liu, Ko-Hung; Chen, Ya-Hui; Chuang, Chieh-Sen; Cheng, Fu-Chou; Su, Hong-Lin; Wei, Yau-Huei; Kuo, Shou-Jen; Liu, Chin-San

    2016-04-01

    Although restoration of mitochondrial function in mitochondrial diseases through peptide-mediated allogeneic mitochondrial delivery (PMD) has been demonstrated in vitro, the in vivo therapeutic efficacy of PMD in Parkinson's disease (PD) has yet to be determined. In this study, we compared the functionality of mitochondrial transfer with or without Pep-1 conjugation in neurotoxin (6-hydroxydopamine, 6-OHDA)-induced PC12 cells and PD rat models. We injected mitochondria into the medial forebrain bundle (MFB) of the PD rats after subjecting the nigrostriatal pathway to a unilateral 6-OHDA lesion for 21 days, and we verified the effectiveness of the mitochondrial graft in enhancing mitochondrial function in the soma of the substantia nigra (SN) neuron through mitochondrial transport dynamics in the nigrostriatal circuit. The result demonstrated that only PMD with allogeneic and xenogeneic sources significantly sustained mitochondrial function to resist the neurotoxin-induced oxidative stress and apoptotic death in the rat PC12 cells. The remaining cells exhibited a greater capability of neurite outgrowth. Furthermore, allogeneic and xenogeneic transplantation of peptide-labeled mitochondria after 3 months improved the locomotive activity in the PD rats. This increase was accompanied by a marked decrease in dopaminergic neuron loss in the substantia nigra pars compacta (SNc) and consistent enhancement of tyrosine hydroxylase-positive immunoreaction of dopaminergic neurons in the SNc and striatum. We also observed that in the SN dopaminergic neuron in the treated PD rats, mitochondrial complex I protein and mitochondrial dynamics were restored, thus ameliorating the oxidative DNA damage. Moreover, we determined signal translocation of graft allogeneic mitochondria from the MFB to the calbindin-positive SN neuron, which demonstrated the regulatory role of mitochondrial transport in alleviating 6-OHDA-induced degeneration of dopaminergic neurons. PMID:26730494

  12. Naringin treatment induces neuroprotective effects in a mouse model of Parkinson's disease in vivo, but not enough to restore the lesioned dopaminergic system.

    PubMed

    Kim, Heung Deok; Jeong, Kyoung Hoon; Jung, Un Ju; Kim, Sang Ryong

    2016-02-01

    We recently reported that treatment with naringin, a major flavonoid found in grapefruit and citrus fruits, attenuated neurodegeneration in a rat model of Parkinson's disease (PD) in vivo. In order to investigate whether its effects are universally applied to a different model of PD and whether its treatment induces restorative effects on the lesioned nigrostriatal dopaminergic (DA) projection, we observed the effects of pre-treatment or post-treatment with naringin in a mouse model of PD. For neuroprotective effects, 6-hydroxydopamine (6-OHDA) was unilaterally injected into the striatum of mouse brains for a neurotoxin model of PD in the presence or absence of naringin by daily intraperitoneal injection. Our results showed that naringin protected the nigrostriatal DA projection from 6-OHDA-induced neurotoxicity. Moreover, similar to the effects in rat brains, this treatment induced the activation of mammalian target of rapamycin complex 1 (mTORC1), which is well known as an important survival factor for DA neurons, and inhibited microglial activation in the substantia nigra (SN) of mouse brains treated with 6-OHDA. However, there was no significant change of DA phenotypes in the SN and striatum post-treated with naringin compared with 6-OHDA-lesioned mice, despite the treatment being continued for 12 weeks. These results suggest that post-treatment with naringin alone may not be enough to restore the nigrostriatal DA projection in a mouse model of PD. However, our results apparently suggest that naringin is a beneficial natural product to prevent DA degeneration, which is involved in PD. PMID:26878791

  13. Neuroprotective Effects of ő≤-Asarone Against 6-Hydroxy Dopamine-Induced Parkinsonism via JNK/Bcl-2/Beclin-1 Pathway.

    PubMed

    Zhang, Sheng; Gui, Xue-Hong; Huang, Li-Ping; Deng, Min-Zhen; Fang, Ruo-Ming; Ke, Xue-Hong; He, Yu-Ping; Li, Ling; Fang, Yong-Qi

    2016-01-01

    ő≤-asarone, a major component of Acorus tatarinowii Schott, has positive effects in neurodegeneration disease, however, its effect on the Parkinson's disease (PD) remains unclear. In this study, the effects of ő≤-asarone on behavioral tests, neurotransmitters, tyrosine hydroxylase (TH), and őĪ-synuclein (őĪ-syn) were investigated in 6-hydroxydopamine (6-OHDA) induced rats. Furthermore, the JNK/Bcl-2/Beclin-1 autophagy pathway was also studied. The results showed that ő≤-asarone improved the behavioral symptoms of rats in the open field, rotarod test, initiation time, and stepping time. And it increased the HVA, Dopacl, and 5-HIAA levels in striatum but not the DA and 5-HT levels. After administration of ő≤-asarone, the TH level was elevated but the őĪ-syn was declined in rats. It inhibited the expressions of LC3-II, but increased the p62 expression in SN4741 cells. Moreover, it affected the expressions of Beclin-1, Bcl-2, JNK, and p-JNK in vivo. We deduced that ő≤-asarone may firstly downregulate expressions of JNK and p-JNK, and then indirectly increase the expression of Bcl-2. And the function of Beclin-1 could be inhibited, which could inhibit autophagy activation. Collectively, all data indicated that ő≤-asarone may be explored as a potential therapeutic agent in PD therapy. PMID:25404088

  14. Protective effects of a polysaccharide from Spirulina platensis on dopaminergic neurons in an MPTP-induced Parkinson's disease model in C57BL/6J mice.

    PubMed

    Zhang, Fang; Lu, Jian; Zhang, Ji-Guo; Xie, Jun-Xia

    2015-02-01

    The present study aimed to determine whether a polysaccharide obtained from Spirulina platensis shows protective effects on dopaminergic neurons. A Parkinson's disease model was established through the intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57BL/6J mice. Prior to the MPTP injection, some mice were pretreated with intraperitoneal injections of a polysaccharide derived from Spirulina platensis once daily for 10 days. The results showed that the immunoreactive staining and mRNA expression of the dopamine transporter and tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, in the substantia nigra, were significantly increased in mice pretreated with 800 mg/kg of the polysaccharide compared with those in MPTP-treated mice. The activities of superoxide dismutase and glutathione peroxidase in the serum and midbrain were also increased significantly in mice injected with MPTP after pretreatment with the polysaccharide from Spirulina platensis. By contrast, the activity of monoamine oxidase B in serum and midbrain maintained unchanged. These experimental findings indicate that the polysaccharide obtained from Spirulina platensis plays a protective role against the MPTP-induced loss of dopaminergic neurons in C57BL/6J mice, and that the antioxidative properties of this polysaccharide likely underlie its neuroprotective effect. PMID:25883632

  15. Protective effects of a polysaccharide from Spirulina platensis on dopaminergic neurons in an MPTP-induced Parkinson's disease model in C57BL/6J mice

    PubMed Central

    Zhang, Fang; Lu, Jian; Zhang, Ji-guo; Xie, Jun-xia

    2015-01-01

    The present study aimed to determine whether a polysaccharide obtained from Spirulina platensis shows protective effects on dopaminergic neurons. A Parkinson's disease model was established through the intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in C57BL/6J mice. Prior to the MPTP injection, some mice were pretreated with intraperitoneal injections of a polysaccharide derived from Spirulina platensis once daily for 10 days. The results showed that the immunoreactive staining and mRNA expression of the dopamine transporter and tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis, in the substantia nigra, were significantly increased in mice pretreated with 800 mg/kg of the polysaccharide compared with those in MPTP-treated mice. The activities of superoxide dismutase and glutathione peroxidase in the serum and midbrain were also increased significantly in mice injected with MPTP after pretreatment with the polysaccharide from Spirulina platensis. By contrast, the activity of monoamine oxidase B in serum and midbrain maintained unchanged. These experimental findings indicate that the polysaccharide obtained from Spirulina platensis plays a protective role against the MPTP-induced loss of dopaminergic neurons in C57BL/6J mice, and that the antioxidative properties of this polysaccharide likely underlie its neuroprotective effect. PMID:25883632

  16. Microglia-Mediated Neuroinflammation and Neurotrophic Factor-Induced Protection in the MPTP Mouse Model of Parkinson's Disease-Lessons from Transgenic Mice.

    PubMed

    Machado, Venissa; ZŲller, Tanja; Attaai, Abdelraheim; Spittau, BjŲrn

    2016-01-01

    Parkinson's disease (PD) is a neurodegenerative disease characterised by histopathological and biochemical manifestations such as loss of midbrain dopaminergic (DA) neurons and decrease in dopamine levels accompanied by a concomitant neuroinflammatory response in the affected brain regions. Over the past decades, the use of toxin-based animal models has been crucial to elucidate disease pathophysiology, and to develop therapeutic approaches aimed to alleviate its motor symptoms. Analyses of transgenic mice deficient for cytokines, chemokine as well as neurotrophic factors and their respective receptors in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD have broadened the current knowledge of neuroinflammation and neurotrophic support. Here, we provide a comprehensive review that summarises the contribution of microglia-mediated neuroinflammation in MPTP-induced neurodegeneration. Moreover, we highlight the contribution of neurotrophic factors as endogenous and/or exogenous molecules to slow the progression of midbrain dopaminergic (mDA) neurons and further discuss the potential of combined therapeutic approaches employing neuroinflammation modifying agents and neurotrophic factors. PMID:26821015

  17. Non-Amyloid-ő≤ Component of Human őĪ-Synuclein Oligomers Induces Formation of New Aő≤ Oligomers: Insight into the Mechanisms That Link Parkinson's and Alzheimer's Diseases.

    PubMed

    Atsmon-Raz, Yoav; Miller, Yifat

    2016-01-20

    Parkinson's disease (PD) is characterized by the formation of Lewy bodies (LBs), of which their major component is the non-amyloid-ő≤ component (NAC) of őĪ-synuclein (AS). Clinical studies have identified a link between PD and Alzheimer's disease (AD), but the question of why PD patients are at risk to develop various types of dementia, such as AD, is still elusive. In vivo studies have shown that Aő≤ can act as a seed for NAC/AS aggregation, promoting NAC/AS aggregation and thus contributing to the etiology of PD. However, the mechanisms by which NAC/AS oligomers interact with Aő≤ oligomers are still elusive. This work presents the interactions between NAC oligomers and Aő≤ oligomers at atomic resolution by applying extensive molecular dynamics simulations for an ensemble of cross-seeded NAC-Aő≤1-42 oligomers. The main conclusions of this study are as follows: first, the cross-seeded NAC-Aő≤1-42 oligomers represent polymorphic states, yet NAC oligomers prefer to interact with Aő≤1-42 oligomers to form double-layer over single-layer conformations due to electrostatic/hydrophobic interactions; second, among the single-layer conformations, the NAC oligomers induce formation of new ő≤-strands in Aő≤1-42 oligomers, thus leading to new Aő≤ oligomer structures; and third, NAC oligomers stabilize the cross-ő≤ structure of Aő≤ oligomers, i.e., yielding compact Aő≤ fibril-like structures. PMID:26479553

  18. Mitochondrial dysfunction in Parkinson's disease.

    PubMed

    Winklhofer, Konstanze F; Haass, Christian

    2010-01-01

    Mitochondria are highly dynamic organelles which fulfill a plethora of functions. In addition to their prominent role in energy metabolism, mitochondria are intimately involved in various key cellular processes, such as the regulation of calcium homeostasis, stress response and cell death pathways. Thus, it is not surprising that an impairment of mitochondrial function results in cellular damage and is linked to aging and neurodegeneration. Many lines of evidence suggest that mitochondrial dysfunction plays a central role in the pathogenesis of Parkinson's disease (PD), starting in the early 1980s with the observation that an inhibitor of complex I of the electron transport chain can induce parkinsonism. Remarkably, recent research indicated that several PD-associated genes interface with pathways regulating mitochondrial function, morphology, and dynamics. In fact, sporadic and familial PD seem to converge at the level of mitochondrial integrity. PMID:19733240

  19. Bacopa monnieri Phytochemicals Mediated Synthesis of Platinum Nanoparticles and Its Neurorescue Effect on 1-Methyl 4-Phenyl 1,2,3,6 Tetrahydropyridine-Induced Experimental Parkinsonism in Zebrafish

    PubMed Central

    Nellore, Jayshree; Pauline, Cynthia; Amarnath, Kanchana

    2013-01-01

    Current discovery demonstrates the rapid formation of platinum nanoparticles using leaf extract of a neurobeneficial plant, Bacopa monnieri (BmE). The nanoparticles (BmE-PtNPs) were stabilized and then coated with varied phytochemicals present within the leaf extract. These nanoparticles demonstrated the same activity of Complex I, as that of oxidizing NADH to NAD+ using a spectrophotometric method. This suggests that BmE-PtNPs are a potential medicinal substance for oxidative stress mediated disease with suppressed mitochondrial complex I, namely, Parkinson's disease (PD). Hence, the neuroprotective potentials of the phytochemical coated nanoparticle were explored in 1-methyl 4-phenyl 1,2,3,6 tetrahydropyridine- (MPTP-)induced experimental Parkinsonism in zebrafish model. BmE-PtNPs pretreatment significantly reversed toxic effects of MPTP by increasing the levels of dopamine, its metabolites, GSH and activities of GPx, catalase, SOD and complex I, and reducing levels of MDA along with enhanced locomotor activity. Taken together, these findings suggest that BmE-PtNPs have protective effect in MPTP-induced neurotoxicity in this model of Parkinson's disease via their dual functions as mitochondrial complex I and antioxidant activity. PMID:26317003

  20. The Difference between Anxiolytic and Anxiogenic Effects Induced by Acute and Chronic Alcohol Exposure and Changes in Associative Learning and Memory Based on Color Preference and the Cause of Parkinson-Like Behaviors in Zebrafish

    PubMed Central

    Zhang, Yuan; Chen, Di; Sun, Ming-Zhu; Zhao, Xin; Chen, Dong-Yan; Feng, Xi-Zeng

    2015-01-01

    We describe an interdisciplinary comparison of the effects of acute and chronic alcohol exposure in terms of their disturbance of light, dark and color preferences and the occurrence of Parkinson-like behavior in zebrafish through computer visual tracking, data mining, and behavioral and physiological analyses. We found that zebrafish in anxiolytic and anxious states, which are induced by acute and chronic repeated alcohol exposure, respectively, display distinct emotional reactions in light/dark preference tests as well as distinct learning and memory abilities in color-enhanced conditional place preference (CPP) tests. Additionally, compared with the chronic alcohol (1.0%) treatment, acute alcohol exposure had a significant, dose-dependent effect on anxiety, learning and memory (color preference) as well as locomotive activities. Acute exposure doses (0.5%, 1.0%, and 1.5%) generated an ‚Äúinverted V‚ÄĚ dose-dependent pattern in all of the behavioral parameters, with 1.0% having the greatest effect, while the chronic treatment had a moderate effect. Furthermore, by measuring locomotive activity, learning and memory performance, the number of dopaminergic neurons, tyrosine hydroxylase expression, and the change in the photoreceptors in the retina, we found that acute and chronic alcohol exposure induced varying degrees of Parkinson-like symptoms in zebrafish. Taken together, these results illuminated the behavioral and physiological mechanisms underlying the changes associated with learning and memory and the cause of potential Parkinson-like behaviors in zebrafish due to acute and chronic alcohol exposure. PMID:26558894

  1. Deep brain stimulation for Parkinson's disease - patient selection.

    PubMed

    Pollak, Pierre

    2013-01-01

    Proper selection of patients who will reliably benefit from deep brain stimulation (DBS) is critical to its success. This requires careful evaluation that should be delivered by an expert multidisciplinary team involving a movement disorder neurologist, a neurosurgeon, a neuropsychologist, and a psychiatrist. The most suitable candidates for DBS suffer from Parkinson's disease with motor fluctuations and/or dyskinesias that are not adequately controlled with optimized medical therapy, or with medication-refractory tremor. During the best on-motor periods, gait difficulties, instability, and speech problems should be minimal, reflecting an excellent response to levodopa in the ideal candidate. The cognitive, psychiatric, and behavioral status must be normal or minimally affected, with the exception of dopamine agonist drug-induced impulse control disorders, which are usually improved after successful surgery and drug withdrawal. Moreover, the patients have no serious comorbidities. Most patients corresponding to this profile suffer from a relatively young onset of Parkinson's disease, and are aged less than 70 years at the time of surgery. Indeed, most patients fall outside this ideal description, and the medical art is to appreciate for each patient the extent to which the alterations of these features can be accepted. Eventually, patients make their own decision from detailed information of their individualized risks and benefits of DBS. Patient expectations, cooperation, and familial support are also important considerations. PMID:24112888

  2. 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

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

    2013-11-01

    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

  3. Drug bioactivation and protein adduct formation in the pathogenesis of drug-induced toxicity.

    PubMed

    Park, B K; Laverty, H; Srivastava, A; Antoine, D J; Naisbitt, D; Williams, D P

    2011-06-30

    Adverse drug reactions (ADRs) remain a major complication of drug therapy and can be classified as 'on-target' or 'off-target' (idiosyncratic) reactions. On-target reactions can be predicted from the known primary or secondary pharmacology of the drug and often represent an exaggeration of the pharmacological effect of the drug. In contrast, off-target adverse reactions cannot be predicted from knowledge of the basic pharmacology of the drug. The exact mechanisms of idiosyncratic drug reactions are still unclear; however it is believed that they can be initiated by chemically reactive drug metabolites. It is well known that xenobiotics can undergo metabolic bioactivation reactions which have the potential to cause cellular stress and damage. Bioactivation of drugs is thought to have the potential of initiating covalent linkages between cellular protein and drugs which can be recognised by the adaptive immune system in the absence of detectable cellular stress. This process cannot yet be predicted in pre-clinical models or discovered in clinical trials. Because of this hazard perception, the formation of chemically reactive metabolites in early drug discovery remains a serious impediment to the development of new medicines and can lead to withdrawal of an otherwise effective therapeutic agent. The fear of such reactions occurring at the post-licensing stage - when such problems first become evident - is a major contribution to drug attrition. The first step towards such methodology has been the development of chemically reactive metabolite screens. The chemical basis of drug bioactivation can usually be rationalised and synthetic strategies put in place to prevent such bioactivation. However, there is no simple correlation between drug bioactivation in vitro and adverse drug reactions in the clinic. Such a chemical approach is clearly limited by the facts that (a) not all drugs that can undergo bioactivation by human drug-metabolising enzymes are associated with hypersensitivity in the clinic and (b) drug bioactivation may not always be a mandatory step in drug hypersensitivity. To predict such reactions in early drug development, it will require an integrated understanding of the chemical, immunological and genetic basis of adverse drug reactions in patients, which in turn will depend on the development of novel in vitro experimental systems. PMID:20846520

  4. 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

    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

    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

  5. Drug-induced interstitial lung disease: mechanisms and best diagnostic approaches

    PubMed Central

    2012-01-01

    Drug-induced interstitial lung disease (DILD) is not uncommon and has many clinical patterns, ranging from benign infiltrates to life-threatening acute respiratory distress syndrome. There are two mechanisms involved in DILD, which are probably interdependent: one is direct, dose-dependent toxicity and the other is immune-mediated. Cytotoxic lung injury may result from direct injury to pneumocytes or the alveolar capillary endothelium. Drugs can induce all types of immunological reactions described by Gell and Coombs; however, most reactions in immune-mediated DILD may be T cell-mediated. DILD can be difficult to diagnose; diagnosis is often possible by exclusion alone. Identifying the causative drug that induces an allergy or cytotoxicity is essential for preventing secondary reactions. One method to confirm the diagnosis of a drug-induced disease is re-exposure or re-test of the drug. However, clinicians are reluctant to place patients at further risk of illness, particularly in cases with severe drug-induced diseases. Assessment of cell-mediated immunity has recently increased, because verifying the presence or absence of drug-sensitized lymphocytes can aid in confirmation of drug-induced disease. Using peripheral blood samples from drug-allergic patients, the drug-induced lymphocyte stimulation test (DLST) and the leukocyte migration test (LMT) can detect the presence of drug-sensitized T cells. However, these tests do not have a definite role in the diagnosis of DILD. This study explores the potential of these new tests and other similar tests in the diagnosis of DILD and provides a review of the relevant literature on this topic. PMID:22651223

  6. Bullous Fixed Drug Eruption Probably Induced by Paracetamol

    PubMed Central

    Agarwala, Manoj Kumar; Mukhopadhyay, Sramana; Sekhar, M Raja; Peter, CV Dincy

    2016-01-01

    We report a case of a 42-year-old male who presented with second episode of bullous eruptions after ingestion of paracetamol. There were no systemic complaints. The temporal correlation with the drug, history of a similar episode and the quick improvement led us to a diagnosis of bullous fixed drug due to paracetamol. Applying Naranjo's algorithm, a causality score of 8 was obtained and was categorized as probable reaction to paracetamol. Clinicians should be vigilant of the possible adverse reactions to drugs with robust safety profiles. Drug alert cards could play an important role in preventing recurrences.

  7. Drug-induced lesions of the oesophageal mucosa.

    PubMed

    2015-09-01

    Lesions of the oesophageal mucosa are observed in various situations: most often with gastrooesophageal reflux disease, but also with infections, cancer, contact with a toxic substance, etc. When they are symptomatic, these lesions provoke burning sensations, dysphagia, regurgitation and sometimes dorsal pain. The changes to the oesophageal mucosa may take various forms: inflammation, erosion, ulceration or necrosis. Serious or even fatal complications can develop but are rare; they include oesophageal perforation, stricture and haemorrhage. Some oral drugs damage the oesophageal mucosa through direct contact. The symptoms often develop several hours after ingestion. The pain is of sudden onset. The resulting lesions are solitary or multiple ulcers that vary in depth and usually occur in the upper portion of the oesophagus. Various factors prolong contact between a drug and the oesophageal mucosa, in particular: swallowing the drug with insufficient liquid or just before lying down; capsule forms; and oesophageal abnormalities. The drugs most frequently implicated are tetracyclines, particularly doxycycline, bisphosphonates and various nonsteroidal anti-inflammatory drugs (NSAIDs). Many drugs, used in various situations, provoke gastro-oesophageal reflux disease, sometimes causing mucosal lesions in the lower oesophagus: calcium-channel blockers, nitrates, exenatide and liraglutide, drugs with antimuscarinic effects, theophylline, etc. Some drugs affect all mucous membranes in the body, including the oesophageal mucosa, irrespective of their route of administration: cancer drugs, isotretinoin, and nicorandil. PMID:26417631

  8. Controlled striatal DOPA production from a gene delivery system in a rodent model of Parkinsonís disease

    PubMed Central

    Cederfjšll, Erik; Broom, Lauren; Kirik, Deniz

    2015-01-01

    Conventional symptomatic treatment for Parkinsonís disease (PD) with long term L-DOPA is complicated with development of drug-induced side effects. In vivo viral vector-mediated gene expression encoding tyrosine hydroxylase (TH) and GTP cyclohydrolase 1 (GCH1) provides a drug delivery strategy of DOPA with distinct advantages over pharmacotherapy. Since the brain alterations made with current gene transfer techniques are irreversible, the therapeutic approaches taken to the clinic should preferably be controllable to match the needs of each individual during the course of their disease. We used a recently described tunable gene expression system based on the use of destabilized dihydrofolate reductase (DD) and generated a N-terminally coupled GCH1 enzyme (DD-GCH1) while the TH enzyme was constitutively expressed, packaged in adeno-associated viral (AAV) vectors. Expression of DD-GCH1 was regulated by the activating ligand trimethoprim (TMP) that crosses the blood-brain barrier. We show that the resulting intervention provides a TMP-dose dependent regulation of DOPA synthesis that is closely linked to the magnitude of functional effects. Our data constitutes the first proof of principle for controlled reconstitution of dopamine capacity in the brain and suggests that such next generation gene therapy strategies are now mature for pre-clinical development towards use in patients with PD. PMID:25592335

  9. Protective Effects of Streblus asper Leaf Extract on H2O2-Induced ROS in SK-N-SH Cells and MPTP-Induced Parkinson's Disease-Like Symptoms in C57BL/6 Mouse

    PubMed Central

    Singsai, Kanathip; Akaravichien, Tarinee; Kukongviriyapan, Veerapol; Sattayasai, Jintana

    2015-01-01

    This study investigated the effects of Streblus asper leaf extract (SA) on reactive oxygen species (ROS) in SK-N-SH cell culture and on motor functions and behaviors in MPTP-treated C57BL/6 mice. SK-N-SH cell viability after incubation with SA for 24‚ÄČh was measured by MTT assay. Intracellular ROS levels of SK-N-SH cells were quantified after pretreatment with SA (0, 200, 600, and 1000‚ÄȬĶg/mL) in the presence of H2O2 (300‚ÄȬĶM). Male C57BL/6 mice were force-fed with water or 200‚ÄČmg/kg/day SA for 32 days. Intraperitoneal injection of MPTP was used to induce Parkinson's disease-like symptoms. Catalepsy, beam balance ability, olfactory discrimination, social recognition, and spontaneous locomotor activity were assessed on days 19, 21, 23, 26, and 32, respectively. In cell culture, SA at 200, 600, and 1000‚ÄȬĶg/mL significantly decreased ROS levels in H2O2-treated SK-N-SH cells. MPTP-treated C57BL/6 mice showed a significant change in all parameters tested when compared to the control group. Pretreatment and concurrent treatment with 200‚ÄČmg/kg/day SA could antagonize the motor and cognitive function deficits induced by MPTP. The results show that SA possesses anti-Parkinson effects in MPTP-treated C57BL/6 mice and that reduction in ROS levels might be one of the mechanisms. PMID:26798403

  10. Identification of drug-specific pathways based on gene expression data: application to drug induced lung injury.

    PubMed

    Melas, Ioannis N; Sakellaropoulos, Theodore; Iorio, Francesco; Alexopoulos, Leonidas G; Loh, Wei-Yin; Lauffenburger, Douglas A; Saez-Rodriguez, Julio; Bai, Jane P F

    2015-08-01

    Identification of signaling pathways that are functional in a specific biological context is a major challenge in systems biology, and could be instrumental to the study of complex diseases and various aspects of drug discovery. Recent approaches have attempted to combine gene expression data with prior knowledge of protein connectivity in the form of a PPI network, and employ computational methods to identify subsets of the protein-protein-interaction (PPI) network that are functional, based on the data at hand. However, the use of undirected networks limits the mechanistic insight that can be drawn, since it does not allow for following mechanistically signal transduction from one node to the next. To address this important issue, we used a directed, signaling network as a scaffold to represent protein connectivity, and implemented an Integer Linear Programming (ILP) formulation to model the rules of signal transduction from one node to the next in the network. We then optimized the structure of the network to best fit the gene expression data at hand. We illustrated the utility of ILP modeling with a case study of drug induced lung injury. We identified the modes of action of 200 lung toxic drugs based on their gene expression profiles and, subsequently, merged the drug specific pathways to construct a signaling network that captured the mechanisms underlying Drug Induced Lung Disease (DILD). We further demonstrated the predictive power and biological relevance of the DILD network by applying it to identify drugs with relevant pharmacological mechanisms for treating lung injury. PMID:25932872

  11. Identifying clinically relevant drug resistance genes in drug-induced resistant cancer cell lines and post- chemotherapy tissues

    PubMed Central

    Tong, Mengsha; Zheng, Weicheng; Lu, Xingrong; Ao, Lu; Li, Xiangyu; Guan, Qingzhou; Cai, Hao; Li, Mengyao; Yan, Haidan; Guo, You; Chi, Pan; Guo, Zheng

    2015-01-01

    Until recently, few molecular signatures of drug resistance identified in drug-induced resistant cancer cell models can be translated into clinical practice. Here, we defined differentially expressed genes (DEGs) between pre-chemotherapy colorectal cancer (CRC) tissue samples of non-responders and responders for 5-fluorouracil and oxaliplatin-based therapy as clinically relevant drug resistance genes (CRG5-FU/L-OHP). Taking CRG5-FU/L-OHP as reference, we evaluated the clinical relevance of several types of genes derived from HCT116 CRC cells with resistance to 5-fluorouracil and oxaliplatin, respectively. The results revealed that DEGs between parental and resistant cells, when both were treated with the corresponding drug for a certain time, were significantly consistent with the CRG5-FU/L-OHP as well as the DEGs between the post-chemotherapy CRC specimens of responders and non-responders. This study suggests a novel strategy to extract clinically relevant drug resistance genes from both drug-induced resistant cell models and post-chemotherapy cancer tissue specimens. PMID:26515599

  12. Carnosic acid protects against 6-hydroxydopamine-induced neurotoxicity in in vivo and in vitro model of Parkinson's disease: involvement of antioxidative enzymes induction.

    PubMed

    Wu, Chi-Rei; Tsai, Chia-Wen; Chang, Shu-Wei; Lin, Chia-Yuan; Huang, Li-Chun; Tsai, Chia-Wen

    2015-01-01

    The neuroprotective effects of carnosic acid (CA), a phenolic diterpene isolated from rosemary (Rosmarinus officinalis), have been widely investigated in recent years, however, its protection in in vivo still unclear. In this study, we investigated the behavioral activity and neuroprotective effects of CA in a rat model of Parkinson's disease (PD) induced by 6-hydroxydopamine (6-OHDA). Rats were treated with 20mg/kg body weight of CA for 3 weeks before 6-OHDA exposure. Results indicated that CA improved the locomotor activity and reduced the apomorphine-caused rotation in 6-OHDA-stimulated rats. Significant protection against lipid peroxidation and GSH reduction was observed in the 6-OHDA rats pretreated with CA. Pretreatment with CA increased the protein expression of ő≥-glutamate-cysteine ligase catalytic subunit, ő≥-glutamate-cysteine ligase modifier subunit, superoxide dismutase, and glutathione reductase compared with 6-OHDA-stimulated rats and SH-SY5Y cells. Immunoblots showed that the reduction of the Bcl-2/Bax ratio, the induction of caspase 3 cleavage, and the induction of poly(ADP-ribose) polymerase (PARP) cleavage by 6-OHDA was reversed in the presence of SB203580 (a p38 inhibitor) or SP600125 (a JNK inhibitor) in SH-SY5Y cells. Rats treated with CA reversed the 6-OHDA-mediated the activation of c-Jun NH2-terminal kinase and p38, the down-regulation of the Bcl-2/Bax ratio, the up-regulation of cleaved caspase 3/caspase 3 and cleaved PARP/PARP ratio, and the down-regulation of tyrosine hydroxylase protein. However, BAM7, an activator of Bax, attenuated the effect of CA on apoptosis in SH-SY5Y cells. These results suggest that CA protected against 6-OHDA-induced neurotoxicity is attributable to its anti-apoptotic and anti-oxidative action. The present findings may help to clarify the possible mechanisms of rosemary in the neuroprotection of PD. PMID:25446857

  13. Predicting beneficial effects of atomoxetine and citalopram on response inhibition in Parkinson's disease with clinical and neuroimaging measures.

    PubMed

    Ye, Zheng; Rae, Charlotte L; Nombela, Cristina; Ham, Timothy; Rittman, Timothy; Jones, Peter Simon; Rodríguez, Patricia Vázquez; Coyle-Gilchrist, Ian; Regenthal, Ralf; Altena, Ellemarije; Housden, Charlotte R; Maxwell, Helen; Sahakian, Barbara J; Barker, Roger A; Robbins, Trevor W; Rowe, James B

    2016-03-01

    Recent studies indicate that selective noradrenergic (atomoxetine) and serotonergic (citalopram) reuptake inhibitors may improve response inhibition in selected patients with Parkinson's disease, restoring behavioral performance and brain activity. We reassessed the behavioral efficacy of these drugs in a larger cohort and developed predictive models to identify patient responders. We used a double-blind randomized three-way crossover design to investigate stopping efficiency in 34 patients with idiopathic Parkinson's disease after 40 mg atomoxetine, 30 mg citalopram, or placebo. Diffusion-weighted and functional imaging measured microstructural properties and regional brain activations, respectively. We confirmed that Parkinson's disease impairs response inhibition. Overall, drug effects on response inhibition varied substantially across patients at both behavioral and brain activity levels. We therefore built binary classifiers with leave-one-out cross-validation (LOOCV) to predict patients' responses in terms of improved stopping efficiency. We identified two optimal models: (1) a "clinical" model that predicted the response of an individual patient with 77-79% accuracy for atomoxetine and citalopram, using clinically available information including age, cognitive status, and levodopa equivalent dose, and a simple diffusion-weighted imaging scan; and (2) a "mechanistic" model that explained the behavioral response with 85% accuracy for each drug, using drug-induced changes of brain activations in the striatum and presupplementary motor area from functional imaging. These data support growing evidence for the role of noradrenaline and serotonin in inhibitory control. Although noradrenergic and serotonergic drugs have highly variable effects in patients with Parkinson's disease, the individual patient's response to each drug can be predicted using a pattern of clinical and neuroimaging features. Hum Brain Mapp 37:1026-1037, 2016. © 2016 Wiley Periodicals, Inc. PMID:26757216

  14. Ambroxol-induced rescue of defective glucocerebrosidase is associated with increased LIMP-2 and saposin C levels in GBA1 mutant Parkinson's disease cells.

    PubMed

    Ambrosi, Giulia; Ghezzi, Cristina; Zangaglia, Roberta; Levandis, Giovanna; Pacchetti, Claudio; Blandini, Fabio

    2015-10-01

    Heterozygous mutations in GBA1 gene, encoding for lysosomal enzyme glucocerebrosidase (GCase), are a major risk factor for sporadic Parkinson's disease (PD). Defective GCase has been reported in fibroblasts of GBA1-mutant PD patients and pharmacological chaperone ambroxol has been shown to correct such defect. To further explore this issue, we investigated GCase and elements supporting GCase function and trafficking in fibroblasts from sporadic PD patients - with or without heterozygous GBA1 mutations - and healthy subjects, in basal conditions and following in vitro exposure to ambroxol. We assessed protein levels of GCase, lysosomal integral membrane protein-2 (LIMP-2), which mediates GCase trafficking to lysosomes, GCase endogenous activator saposin (Sap) C and parkin, which is involved in degradation of defective GCase. We also measured activities of GCase and cathepsin D, which cleaves Sap C from precursor prosaposin. GCase activity was reduced in fibroblasts from GBA1-mutant patients and ambroxol corrected this defect. Ambroxol increased cathepsin D activity, GCase and Sap C protein levels in all groups, while LIMP-2 levels were increased only in GBA1-mutant PD fibroblasts. Parkin levels were slightly increased only in the PD group without GBA1 mutations and were not significantly modified by ambroxol. Our study confirms that GCase activity is deficient in fibroblasts of GBA1-mutant PD patients and that ambroxol corrects this defect. The drug increased Sap C and LIMP-2 protein levels, without interfering with parkin. These results confirm that chemical chaperone ambroxol modulates lysosomal markers, further highlighting targets that may be exploited for innovative PD therapeutic strategies. PMID:26094596

  15. Nonsteroidal antiinflammatory drug-induced intestinal inflammation in humans

    SciTech Connect

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

    1987-09-01

    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.

  16. Unusual case of drug-induced cholestasis due to glucosamine and chondroitin sulfate.

    PubMed

    Ip, Stephen; Jeong, Rachel; Schaeffer, David F; Yoshida, Eric M

    2015-10-28

    Glucosamine (GS) and chondroitin sulfate (CS) are common over-the-counter (OTC) supplements used in the treatment of osteoarthritis. These medications are seemingly safe, but there are increasing reports of hepatotoxicity with these supplements. We reported a unique case of drug-induced cholestasis caused by GS and CS in a combination tablet. The etiology of the jaundice was overlooked despite extensive investigations over a three-month period. Unlike drug-induced hepatocellular injury, drug-induced cholestatic jaundice with GS and CS has only been reported twice before. This case emphasizes the importance of a complete medication history, especially OTC supplements, in the assessment of cholestasis. PMID:26527309

  17. Unusual case of drug-induced cholestasis due to glucosamine and chondroitin sulfate

    PubMed Central

    Ip, Stephen; Jeong, Rachel; Schaeffer, David F; Yoshida, Eric M

    2015-01-01

    Glucosamine (GS) and chondroitin sulfate (CS) are common over-the-counter (OTC) supplements used in the treatment of osteoarthritis. These medications are seemingly safe, but there are increasing reports of hepatotoxicity with these supplements. We reported a unique case of drug-induced cholestasis caused by GS and CS in a combination tablet. The etiology of the jaundice was overlooked despite extensive investigations over a three-month period. Unlike drug-induced hepatocellular injury, drug-induced cholestatic jaundice with GS and CS has only been reported twice before. This case emphasizes the importance of a complete medication history, especially OTC supplements, in the assessment of cholestasis. PMID:26527309

  18. Prime-, Stress- and Cue-Induced Reinstatement of Extinguished Drug-Reinforced Responding in Rats: Cocaine as the Prototypical Drug of Abuse

    PubMed Central

    Beardsley, Patrick M.; Shelton, Keith L.

    2012-01-01

    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

  19. Drug-induced skin reactions: a pathologist viewpoint.

    PubMed

    Hussein, Mahmoud Rezk Abdelwahed

    2016-03-01

    Cutaneous drug reactions are common adverse effects that occur in about 2-3% of the hospitalized patients. They have both immunologic and non-immunologic underlying mechanisms. These reactions are clinically and histologically similar to dermatoses. Their significant clinical indicators include: history of drug intake, atypical clinical features and improvement after cessation of the offending drugs. Their diagnostic histological clues include the presence of mixed histological patterns, apoptotic keratinocytes, eosinophils (dermis and epidermis), papillary dermal edema and extravasations of erythrocytes. However, no single clinical or histological feature is specific of drug eruptions. This work attempts to classify the histomorphologic reactions to various drugs in defined categories for assistance in morphologic diagnosis. PMID:26113029

  20. Oxidation-Induced Trapping of Drugs in Porous Silicon Microparticles

    PubMed Central

    2015-01-01

    An approach for the preparation of an oxidized porous silicon microparticle drug delivery system that can provide efficient trapping and sustained release of various drugs is reported. The method uses the contraction of porous siliconís mesopores, which occurs during oxidation of the silicon matrix, to increase the loading and retention of drugs within the particles. First, a porous Si (pSi) film is prepared by electrochemical etching of p-type silicon with a resistivity of >0.65 ? cm in a 1:1 (v/v) HF/ethanol electrolyte solution. Under these conditions, the pore walls are sufficiently thin to allow for complete oxidation of the silicon skeleton under mild conditions. The pSi film is then soaked in an aqueous solution containing the drug (cobinamide or rhodamine B test molecules were used in this study) and sodium nitrite. Oxidation of the porous host by nitrite results in a shrinking of the pore openings, which physically traps the drug in the porous matrix. The film is subsequently fractured by ultrasonication into microparticles. Upon comparison with commonly used oxidizing agents for pSi such as water, peroxide, and dimethyl sulfoxide, nitrite is kinetically and thermodynamically sufficient to oxidize the pore walls of the pSi matrix, precluding reductive (by Si) or oxidative (by nitrite) degradation of the drug payload. The drug loading efficiency is significantly increased (by up to 10-fold), and the release rate is significantly prolonged (by 20-fold) relative to control samples in which the drug is loaded by infiltration of pSi particles postoxidation. We find that it is important that the silicon skeleton be completely oxidized to ensure the drug is not reduced or degraded by contact with elemental silicon during the particle dissolutionĖdrug release phase. PMID:25678746

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

    PubMed Central

    Shalev, Uri; Erb, Suzanne; Shaham, Yavin

    2009-01-01

    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 ‚ÄúThe role of neuropeptides in stress and addiction‚ÄĚ, 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

  2. Glial-Mediated Inflammation Underlying Parkinsonism

    PubMed Central

    Barcia, Carlos

    2013-01-01

    The interest in studying neuroimmune interactions is increasing in the scientific community, and for many researchers, immunity is becoming a crucial factor in the understanding of the physiology of the normal brain as well as the biology underlying neurodegenerative diseases. Mounting data over the last two decades point toward immune and inflammatory alterations as important mediators of the progressive dopaminergic degeneration in Parkinson's disease. The purpose of this review is to address, under a historical perspective, as well as in the light of recent reports, the glial-mediated inflammatory and immune responses that occur in Parkinsonism. In line with this, this review also evaluates and highlights available anti-inflammatory drugs and putative targets for Parkinson's disease therapy for the near future. PMID:24278772

  3. Safinamide for symptoms of Parkinson's disease.

    PubMed

    MŁller, T

    2015-11-01

    Chronic and slow progression of neuronal death in Parkinson's disease is responsible for an altered neurotransmission of various biogenic amines, such as dopamine. Therefore, an individually different pronounced heterogeneity of motor and nonmotor symptoms characterizes each Parkinson's disease patient. Ideal candidates for the balance of these neurotransmitter deficits are compounds like safinamide with broad mechanisms of action such as reversible monoamine oxidase type B inhibition, blockage of voltage-dependent sodium channels, modulation of calcium channels and of glutamate release. Safinamide is administered one time daily with oral doses ranging from 50 to 100 mg. Safinamide was well tolerated and safe, ameliorated motor symptoms when combined with dopamine agonist only or additional levodopa in clinical trials. Safinamide is a novel instrument for the drug therapy of Parkinson's disease with better safety and tolerability particularly concerning diarrhea than inhibitors of catechol-O-methyltransferase, like entacapone, according to an indirect comparison within a meta-analysis with entacapone. PMID:26744740

  4. Quantifying Drug-Induced Nanomechanics and Mechanical Effects to Single Cardiomyocytes for Optimal Drug Administration To Minimize Cardiotoxicity.

    PubMed

    Yue, Tao; Park, Ki Ho; Reese, Benjamin E; Zhu, Hua; Lyon, Seth; Ma, Jianjie; Mohler, Peter J; Zhang, Mingjun

    2016-02-23

    Contrary to the well-studied dynamics and mechanics at organ and tissue levels, there is still a lack of good understanding for single cell dynamics and mechanics. Single cell dynamics and mechanics may act as an interface to provide unique information reflecting activities at the organ and tissue levels. This research was aimed at quantifying doxorubicin- and dexrazoxane-induced nanomechanics and mechanical effects to single cardiomyocytes, to reveal the therapeutic effectiveness of drugs at the single cell level and to optimize drug administration for reducing cardiotoxicity. This work employed a nanoinstrumentation platform, including a digital holographic microscope combined with an atomic force microscope, which can characterize cell stiffness and beating dynamics in response to drug exposures in real time and obtain time-dose-dependent effects of cardiotoxicity and protection. Through this research, an acute increase and a delayed decrease of surface beating force induced by doxorubicin was characterized. Dexrazoxane treated cells maintained better beating force and mechanical functions than cells without any treatment, which demonstrated cardioprotective effects of dexrazoxane. In addition, combined drug effects were quantitatively evaluated following various drug administration protocols. Preadministration of dexrazoxane was demonstrated to have protective effects against doxorubicin, which could lead to better strategies for cardiotoxicity prevention and anticancer drug administration. This study concluded that quantification of nanomechanics and mechanical effects at the single cell level could offer unique insights of molecular mechanisms involved in cellular activities influencing organ and tissue level responses to drug exposure, providing a new opportunity for the development of effective and time-dose-dependent strategies of drug administration. PMID:26738425

  5. Role of corticostriatal circuits in context-induced reinstatement of drug seeking.

    PubMed

    Marchant, Nathan J; Kaganovsky, Konstantin; Shaham, Yavin; Bossert, Jennifer M

    2015-12-01

    Drug addiction is characterized by persistent relapse vulnerability during abstinence. In abstinent drug users, relapse is often precipitated by re-exposure to environmental contexts that were previously associated with drug use. This clinical scenario is modeled in preclinical studies using the context-induced reinstatement procedure, which is based on the ABA renewal procedure. In these studies, context-induced reinstatement of drug seeking is reliably observed in laboratory animals that were trained to self-administer drugs abused by humans. In this review, we summarize neurobiological findings from preclinical studies that have focused on the role of corticostriatal circuits in context-induced reinstatement of heroin, cocaine, and alcohol seeking. We also discuss neurobiological similarities and differences in the corticostriatal mechanisms of context-induced reinstatement across these drug classes. We conclude by briefly discussing future directions in the study of context-induced relapse to drug seeking in rat models. Our main conclusion from the studies reviewed is that there are both similarities (accumbens shell, ventral hippocampus, and basolateral amygdala) and differences (medial prefrontal cortex and its projections to accumbens) in the neural mechanisms of context-induced reinstatement of cocaine, heroin, and alcohol seeking. This article is part of a Special Issue entitled SI:Addiction circuits. PMID:25199590

  6. EFFECT OF OZONE ON DRUG-INDUCED SLEEPING TIME IN MICE PRETREATED WITH MIXED-FUNCTION OXIDASE INDUCERS AND INHIBITORS

    EPA Science Inventory

    Studies were conducted to investigate the effect of ozone in prolonging pentobarbital (PEN)-induced sleeping time (S.T.). Since ozone is a common air pollutant, an ozone-induced alteration of mechanisms of drug action could have public health implications. It was shown that a 5-h...

  7. An Overview on the Proposed Mechanisms of Antithyroid Drugs-Induced Liver Injury

    PubMed Central

    Heidari, Reza; Niknahad, Hossein; Jamshidzadeh, Akram; Eghbal, Mohammad Ali; Abdoli, Narges

    2015-01-01

    Drug-induced liver injury (DILI) is a major problem for pharmaceutical industry and drug development. Mechanisms of DILI are many and varied. Elucidating the mechanisms of DILI will allow clinicians to prevent liver failure, need for liver transplantation, and death induced by drugs. Methimazole and propylthiouracil (PTU) are two convenient antithyroid agents which their administration is accompanied by hepatotoxicity as a deleterious side effect. Although several cases of antithyroid drugs-induced liver injury are reported, there is no clear idea about the mechanism(s) of hepatotoxicity induced by these medications. Different mechanisms such as reactive metabolites formation, oxidative stress induction, intracellular targets dysfunction, and immune-mediated toxicity are postulated to be involved in antithyroid agents-induced hepatic damage. Due to the idiosyncratic nature of antithyroid drugs-induced hepatotoxicity, it is impossible to draw a specific conclusion about the mechanisms of liver injury. However, it seems that reactive metabolite formation and immune-mediated toxicity have a great role in antithyroids liver toxicity, especially those caused by methimazole. This review attempted to discuss different mechanisms proposed to be involved in the hepatic injury induced by antithyroid drugs. PMID:25789213

  8. [Demand for abortion. Special aspects of drug-induced abortion].

    PubMed

    Champion, J; Cailleux-Kreitmann, J

    1994-03-01

    Since 1990, 180 to 200 abortions annually representing 8 to 9% of the total at the Center for Social Gynecology in Marseilles have been performed with RU-486. Experience with RU-486 since 1986 has led to some reflections concerning the tasks of the physician, the client, and the health team. Because of the need to begin proceedings before the forty-second day of amenorrhea, the physician must attach some urgency to these cases, and must somehow establish priorities among the different pressing medical needs of patients. The physician must diagnose extrauterine pregnancy at very early stages, and must decide whether endovaginal sonography is justified. Evaluation of the uterus ten to twelve days after RU-486 administration to determine the success of the procedure is also difficult. The physician's decisions about needed tests and procedures must take into account the patient's medical condition but also her psychological reactions. The woman must take action within the first 15 days of amenorrhea in order to arrange an RU-486 abortion. The one-week waiting period is probably necessary to allow her to reflect on her reasons for choosing RU-486 and perhaps to change her mind. Among all women who requested drug- induced abortions at the Center for Social Gynecology, 10% had spontaneous abortions, 10% decided to continue their pregnancies, and 25% preferred other types of abortion. The health care team must explain the procedure to the woman, who is often nervous and agitated. The behavior of the health workers can help reduce anxiety and de-dramatize the experience for the woman. During the morning of monitoring after administration of prostaglandins, the patient must be prepared to leave the service. In half of cases, the expulsion will occur after the woman has left the hospital. Information must be provided about expulsion at home, possible method failure, significant bleeding, and other side effects and complications. The necessity for the follow-up appointment must be stressed, and information about contraception must be given. PMID:8009395

  9. Drug-induced long QT syndrome increases the risk of drowning.

    PubMed

    Vincenzi, Frank F

    2016-02-01

    There is strong evidence linking inherited long QT syndromes with an increased risk of drowning due to fatal arrhythmias in the water. Drug-induced long QT syndrome (DILQTS) is hypothesized to increase the risk of drowning by similar mechanisms. It is suggested that QT prolongation caused by a drug or drugs, when combined with the autonomic conflict associated with the mammalian dive reflex and/or the cold shock reflex, sets up conditions that may result in a sudden fatal arrhythmia while in water - thus an increased risk of drowning related to a drug-induced prolongation of the QT interval. Many widely used drugs prolong the QT interval thus raising a drug safety issue that needs confirmation or refutation. PMID:26826633

  10. 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.

  11. Levetiracetam induced psoriasiform drug eruption: a rare case report

    PubMed Central

    Gencler, Onur Serdar; Gencler, Bilgen; Altunel, Cemile Tugba; Arslan, Nur

    2015-01-01

    Levetiracetam (LEV) is an established second generation anti-epileptic drug and LEV associated severe cutaneous reactions are rare. Here we report the case of psoriasiform drug eruption in a patient with newly diagnosed epilepsy who had been treated with levetiracetam. To our knowledge this is the first report of a patient with a psoriasiform eruption that appeared after the administration of LEV. PMID:26702269

  12. Localized Epidermal Drug Delivery Induced by Supramolecular Solvent Structuring.

    PubMed

    Benaouda, F; Jones, S A; Martin, G P; Brown, M B

    2016-01-01

    The preferential localization of drug molecules in the epidermis of human skin is considered advantageous for a number of agents, but achieving such a delivery profile can be problematic. The aim of the present study was to assess if the manipulation of solvent supramolecular structuring in the skin could be used to promote drug residence in the epidermal tissue. Skin deposition studies showed that a 175-fold increase in the epidermal loading of a model drug diclofenac (138.65 ¬Ī 11.67 őľg¬∑cm(-2)), compared to a control (0.81 ¬Ī 0.13 őľg¬∑cm(-2)), could be achieved by colocalizing the drug with a high concentration of propylene glycol (PG) in the tissue. For such a system at 1 h postdose application, the PG flux into the skin was 9.3 mg¬∑cm(2)¬∑h(-1) and the PG-water ratio in the epidermis was 76:24 (v/v). At this solvent ratio infrared spectroscopy indicated that PG rich supramolecular structures, which displayed a relatively strong physical affinity for the drug, were formed. Encouraging the production of the PG-rich supermolecular structures in the epidermis by applying diclofenac to the skin using a high PG loading dose (240 őľg¬∑cm(-2)) produced an epidermal-transdermal drug distribution of 6.8:1. However, generating water-rich solvent supermolecular structures in the epidermis by applying diclofenac using a low PG loading dose (2.2 őľg¬∑cm(-2)) led to a loss of preferential epidermal localization of diclofenac in the tissue (0.7:1 epidermal-transdermal drug distribution). This change in diclofenac skin deposition profile in response to PG variations and the accompanying FTIR data supported the notion that supramolecular solvent structures could control drug accumulation in the human epidermis. PMID:26593153

  13. Are cyclooxygenase-2 and nitric oxide involved in the dyskinesia of Parkinson's disease induced by L-DOPA?

    PubMed

    Bortolanza, Mariza; Padovan-Neto, Fernando E; Cavalcanti-Kiwiatkoski, Roberta; Dos Santos-Pereira, Maurício; Mitkovski, Miso; Raisman-Vozari, Rita; Del-Bel, Elaine

    2015-07-01

    Inflammatory mechanisms are proposed to play a role in L-DOPA-induced dyskinesia. Cyclooxygenase-2 (COX2) contributes to inflammation pathways in the periphery and is constitutively expressed in the central nervous system. Considering that inhibition of nitric oxide (NO) formation attenuates L-DOPA-induced dyskinesia, this study aimed at investigating if a NO synthase (NOS) inhibitor would change COX2 brain expression in animals with L-DOPA-induced dyskinesia. To this aim, male Wistar rats received unilateral 6-hydroxydopamine microinjection into the medial forebrain bundle were treated daily with L-DOPA (21 days) combined with 7-nitroindazole or vehicle. All hemi-Parkinsonian rats receiving l-DOPA showed dyskinesia. They also presented increased neuronal COX2 immunoreactivity in the dopamine-depleted dorsal striatum that was directly correlated with dyskinesia severity. Striatal COX2 co-localized with choline-acetyltransferase, calbindin and DARPP-32 (dopamine-cAMP-regulated phosphoprotein-32), neuronal markers of GABAergic neurons. NOS inhibition prevented L-DOPA-induced dyskinesia and COX2 increased expression in the dorsal striatum. These results suggest that increased COX2 expression after L-DOPA long-term treatment in Parkinsonian-like rats could contribute to the development of dyskinesia. PMID:26009769

  14. Drug-induced morphology switch in drug delivery systems based on poly(2-oxazoline)s.

    PubMed

    Schulz, Anita; Jaksch, Sebastian; Schubel, Rene; Wegener, Erik; Di, Zhenyu; Han, Yingchao; Meister, Annette; Kressler, JŲrg; Kabanov, Alexander V; Luxenhofer, Robert; Papadakis, Christine M; Jordan, Rainer

    2014-03-25

    Defined aggregates of polymers such as polymeric micelles are of great importance in the development of pharmaceutical formulations. The amount of drug that can be formulated by a drug delivery system is an important issue, and most drug delivery systems suffer from their relatively low drug-loading capacity. However, as the loading capacities increase, i.e., promoted by good drug-polymer interactions, the drug may affect the morphology and stability of the micellar system. We investigated this effect in a prominent system with very high capacity for hydrophobic drugs and found extraordinary stability as well as a profound morphology change upon incorporation of paclitaxel into micelles of amphiphilic ABA poly(2-oxazoline) triblock copolymers. The hydrophilic blocks A comprised poly(2-methyl-2-oxazoline), while the middle blocks B were either just barely hydrophobic poly(2-n-butyl-2-oxazoline) or highly hydrophobic poly(2-n-nonyl-2-oxazoline). The aggregation behavior of both polymers and their formulations with varying paclitaxel contents were investigated by means of dynamic light scattering, atomic force microscopy, (cryogenic) transmission electron microscopy, and small-angle neutron scattering. While without drug, wormlike micelles were present, after incorporation of small amounts of drugs only spherical morphologies remained. Furthermore, the much more hydrophobic poly(2-n-nonyl-2-oxazoline)-containing triblock copolymer exhibited only half the capacity for paclitaxel than the poly(2-n-butyl-2-oxazoline)-containing copolymer along with a lower stability. In the latter, contents of paclitaxel of 8 wt % or higher resulted in a raspberry-like micellar core. PMID:24548260

  15. Drug-Induced Morphology Switch in Drug Delivery Systems Based on Poly(2-oxazoline)s

    PubMed Central

    2015-01-01

    Defined aggregates of polymers such as polymeric micelles are of great importance in the development of pharmaceutical formulations. The amount of drug that can be formulated by a drug delivery system is an important issue, and most drug delivery systems suffer from their relatively low drug-loading capacity. However, as the loading capacities increase, i.e., promoted by good drugĖpolymer interactions, the drug may affect the morphology and stability of the micellar system. We investigated this effect in a prominent system with very high capacity for hydrophobic drugs and found extraordinary stability as well as a profound morphology change upon incorporation of paclitaxel into micelles of amphiphilic ABA poly(2-oxazoline) triblock copolymers. The hydrophilic blocks A comprised poly(2-methyl-2-oxazoline), while the middle blocks B were either just barely hydrophobic poly(2-n-butyl-2-oxazoline) or highly hydrophobic poly(2-n-nonyl-2-oxazoline). The aggregation behavior of both polymers and their formulations with varying paclitaxel contents were investigated by means of dynamic light scattering, atomic force microscopy, (cryogenic) transmission electron microscopy, and small-angle neutron scattering. While without drug, wormlike micelles were present, after incorporation of small amounts of drugs only spherical morphologies remained. Furthermore, the much more hydrophobic poly(2-n-nonyl-2-oxazoline)-containing triblock copolymer exhibited only half the capacity for paclitaxel than the poly(2-n-butyl-2-oxazoline)-containing copolymer along with a lower stability. In the latter, contents of paclitaxel of 8 wt % or higher resulted in a raspberry-like micellar core. PMID:24548260

  16. Effects of L-arginine pre-treatment in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonís diseases in Balb/c mice

    PubMed Central

    Hami, Javad; Hosseini, Mehran; Shahi, Sekineh; Lotfi, Nassim; Talebi, Abolfazl; Afshar, Mohammad

    2015-01-01

    Background: Parkinsonís disease (PD) is a common neurodegenerative disease resulting from the degeneration of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc). Increasing evidence demonstrated that mice treated intranasally with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) suffered impairments in motor functions associated with disruption of DA neurons in SNc conceivably analogous to those observed in PD. L-arginine has been proposed as a novel neuroprotective agent that plays protective roles in several models of neuronal cellular damage. This study aimed to evaluate the effects of L-arginine on the numerical density of dark neurons (DNs) in the SNc of Balb/c mice subjected to MPTP administration. Methods: In the present study, we demonstrated that repeated treatment with L-arginine (300 mg/kg, i.p.) during 7 consecutive days attenuated the production of DNs in SNc of adult male Balb/c mice infused with a single intranasal administration of MPTP (1 mg/nostril). Results: Pre-treatment with L-arginine significantly decreased the numerical density of DNs in SNc of mice 21 days after intranasal MPTP administration. Conclusion: This investigation provides new insights in experimental models of PD, indicating that L-arginine represents a potential neuroprotective agent for the prevention of DA neuron degeneration in SNc observed in PD patients. PMID:26885338

  17. Conditional depletion of intellectual disability and Parkinsonism candidate gene ATP6AP2 in fly and mouse induces cognitive impairment and neurodegeneration.

    PubMed

    Dubos, Aline; Castells-Nobau, Anna; Meziane, Hamid; Oortveld, Merel A W; Houbaert, Xander; Iacono, Giovanni; Martin, Christelle; Mittelhaeuser, Christophe; Lalanne, Valťrie; Kramer, Jamie M; Bhukel, Anuradha; Quentin, Christine; Slabbert, Jan; Verstreken, Patrik; Sigrist, Stefan J; Messaddeq, Nadia; Birling, Marie-Christine; Selloum, Mohammed; Stunnenberg, Henk G; Humeau, Yann; Schenck, Annette; Herault, Yann

    2015-12-01

    ATP6AP2, an essential accessory component of the vacuolar H+ ATPase (V-ATPase), has been associated with intellectual disability (ID) and Parkinsonism. ATP6AP2 has been implicated in several signalling pathways; however, little is known regarding its role in the nervous system. To decipher its function in behaviour and cognition, we generated and characterized conditional knockdowns of ATP6AP2 in the nervous system of Drosophila and mouse models. In Drosophila, ATP6AP2 knockdown induced defective phototaxis and vacuolated photoreceptor neurons and pigment cells when depleted in eyes and altered short- and long-term memory when depleted in the mushroom body. In mouse, conditional Atp6ap2 deletion in glutamatergic neurons (Atp6ap2(Camk2aCre/0) mice) caused increased spontaneous locomotor activity and altered fear memory. Both Drosophila ATP6AP2 knockdown and Atp6ap2(Camk2aCre/0) mice presented with presynaptic transmission defects, and with an abnormal number and morphology of synapses. In addition, Atp6ap2(Camk2aCre/0) mice showed autophagy defects that led to axonal and neuronal degeneration in the cortex and hippocampus. Surprisingly, axon myelination was affected in our mutant mice, and axonal transport alterations were observed in Drosophila. In accordance with the identified phenotypes across species, genome-wide transcriptome profiling of Atp6ap2(Camk2aCre/0) mouse hippocampi revealed dysregulation of genes involved in myelination, action potential, membrane-bound vesicles and motor behaviour. In summary, ATP6AP2 disruption in mouse and fly leads to cognitive impairment and neurodegeneration, mimicking aspects of the neuropathology associated with ATP6AP2 mutations in humans. Our results identify ATP6AP2 as an essential gene for the nervous system. PMID:26376863

  18. EMG activity and neuronal activity in the internal globus pallidus (GPi) and their interaction are different between hemiballismus and apomorphine induced dyskinesias of Parkinson's disease (AID).

    PubMed

    Zhao, L; Verhagen-Metman, L; Kim, J H; Liu, C C; Lenz, F A

    2015-04-01

    The nature of electromyogram (EMG) activity and its relationship to neuronal activity in the internal globus pallidus (GPi) have not previously been studied in hyperkinetic movement disorders. We now test the hypothesis that GPi spike trains are cross-correlated with EMG activity during apomorphine-induced dyskinesias of Parkinson's disease (AID), and Hemiballism. We have recorded these two signals during awake stereotactic pallidal surgeries and analyzed them by cross-correlation of the raw signals and of peaks of activity occurring in those signals. EMG signals in Hemiballism usually consist of 'sharp' activity characterized by peaks of activity with low levels of activity between peaks, and by co-contraction between antagonistic muscles. Less commonly, EMG in Hemiballism shows 'non-sharp' EMG activity with substantial EMG activity between peaks; 'non-sharp' EMG activity is more common in AID. Therefore, these hyperkinetic disorders show substantial differences in peripheral (EMG) activity, although both kinds of activity can occur in both disorders. Since GPi spike◊EMG spectral and time domain functions demonstrated inconsistent cross-correlation in both disorders, we studied peaks of activity in GPi neuronal and in EMG signals. The peaks of GPi activity commonly show prolonged cross-correlation with peaks of EMG activity, which suggests that GPi peaks are related to the occurrence of EMG peaks, perhaps by transmission of GPi activity to the periphery. In Hemiballism, the presence of direct GPi peak◊EMG peak cross-correlations at the site where lesions relieve these disorders is evidence that gradual changes in peak GPi neuronal activity are directly involved in Hemiballism. PMID:25656789

  19. Conditional depletion of intellectual disability and Parkinsonism candidate gene ATP6AP2 in fly and mouse induces cognitive impairment and neurodegeneration

    PubMed Central

    Dubos, Aline; Castells-Nobau, Anna; Meziane, Hamid; Oortveld, Merel A.W.; Houbaert, Xander; Iacono, Giovanni; Martin, Christelle; Mittelhaeuser, Christophe; Lalanne, Valérie; Kramer, Jamie M.; Bhukel, Anuradha; Quentin, Christine; Slabbert, Jan; Verstreken, Patrik; Sigrist, Stefan J.; Messaddeq, Nadia; Birling, Marie-Christine; Selloum, Mohammed; Stunnenberg, Henk G.; Humeau, Yann; Schenck, Annette; Herault, Yann

    2015-01-01

    ATP6AP2, an essential accessory component of the vacuolar H+ ATPase (V-ATPase), has been associated with intellectual disability (ID) and Parkinsonism. ATP6AP2 has been implicated in several signalling pathways; however, little is known regarding its role in the nervous system. To decipher its function in behaviour and cognition, we generated and characterized conditional knockdowns of ATP6AP2 in the nervous system of Drosophila and mouse models. In Drosophila, ATP6AP2 knockdown induced defective phototaxis and vacuolated photoreceptor neurons and pigment cells when depleted in eyes and altered short- and long-term memory when depleted in the mushroom body. In mouse, conditional Atp6ap2 deletion in glutamatergic neurons (Atp6ap2Camk2aCre/0 mice) caused increased spontaneous locomotor activity and altered fear memory. Both Drosophila ATP6AP2 knockdown and Atp6ap2Camk2aCre/0 mice presented with presynaptic transmission defects, and with an abnormal number and morphology of synapses. In addition, Atp6ap2Camk2aCre/0 mice showed autophagy defects that led to axonal and neuronal degeneration in the cortex and hippocampus. Surprisingly, axon myelination was affected in our mutant mice, and axonal transport alterations were observed in Drosophila. In accordance with the identified phenotypes across species, genome-wide transcriptome profiling of Atp6ap2Camk2aCre/0 mouse hippocampi revealed dysregulation of genes involved in myelination, action potential, membrane-bound vesicles and motor behaviour. In summary, ATP6AP2 disruption in mouse and fly leads to cognitive impairment and neurodegeneration, mimicking aspects of the neuropathology associated with ATP6AP2 mutations in humans. Our results identify ATP6AP2 as an essential gene for the nervous system. PMID:26376863

  20. Depressive-like behaviors alterations induced by intranigral MPTP, 6-OHDA, LPS and rotenone models of Parkinson's disease are predominantly associated with serotonin and dopamine.

    PubMed

    Santiago, Ronise M; Barbieiro, Janaína; Lima, Marcelo M S; Dombrowski, Patrícia A; Andreatini, Roberto; Vital, Maria A B F

    2010-08-16

    Depression is a frequently encountered non-motor feature of Parkinson's disease (PD) and it can have a significant impact on patient's quality of life. Considering the differential pathophysiology of depression in PD, it prompts the idea that a degenerated nigrostriatal system plays a role in depressive-like behaviors, whilst animal models of PD are employed. Therefore, we addressed the question of whether dopamine (DA) depletion, promoted by the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 6-hydroxydopamine (6-OHDA), lipopolysaccharide (LPS) and rotenone are able to induce depressive-like behaviors and neurotransmitters alterations similarly that encountered in PD. To test this rationale, we performed intranigral injections of each neurotoxin, followed by motor behavior, depressive-like behaviors, histological and neurochemical tests. After the motor recovery period, MPTP, 6-OHDA and rotenone were able to produce anhedonia and behavioral despair. These altered behavioral responses were accompanied by reductions of striatal DA, homovanillic acid (HVA) and 3,4-dihydroxyphenylacetic acid (DOPAC) restricted to the 6-OHDA group. Additionally, decreases on the hippocampal serotonin (5-HT) content were detected for the MPTP, 6-OHDA and rotenone groups. Notably, strong correlations were detected among the groups when 5-HT and DA were correlated with swimming (r=+0.97; P=0.001) and immobility (r=-0.90; P=0.012), respectively. Our data indicate that MPTP, 6-OHDA and rotenone, but not LPS were able to produce depressive-like behaviors accompanied primarily by hippocampal 5-HT reductions. Moreover, DA and 5-HT strongly correlated with "emotional" impairments suggesting an important participation of these neurotransmitters in anhedonia and behavioral despair after nigral lesions promoted by the neurotoxins. PMID:20547199

  1. Therapeutic potential of natural products in Parkinson's disease.

    PubMed

    Mythri, Rajeswara B; Harish, Gangadharappa; Bharath, M M

    2012-09-01

    The central objective in treating patients with Parkinson's disease (PD) is two-fold (i) to increase the striatal dopamine content and (ii) to prevent further degeneration of the surviving dopaminergic neurons in the substantia nigra region of the ventral midbrain. Most of the current PD drugs contribute to the former and provide symptomatic relief. Although compounds such as Levodopa (L-DOPA) improve the striatal dopamine content, their long-term usage is associated with progressive decrease in drug response, motor fluctuations, dyskinesias and drug-induced toxicity. In addition, these drugs fail to prevent the progression of the degenerative process. This has shifted the focus onto alternative therapeutic approaches involving natural products that could provide independent therapy or offer neuroprotective support to the existing drugs. The current review describes the neuroprotective and therapeutic utility of such natural products including herbal extracts, phytochemicals and bioactive ingredients from other natural sources either in isolation or in combination, with potential application in PD, highlighting the relevant patents. PMID:22827714

  2. Adenosine A2A receptors in Parkinsonís disease treatment

    PubMed Central

    Cie?lak, Marek; Wojtczak, Andrzej

    2008-01-01

    Latest results on the action of adenosine A2A receptor antagonists indicate their potential therapeutic usefulness in the treatment of Parkinsonís disease. Basal ganglia possess high levels of adenosine A2A receptors, mainly on the external surfaces of neurons located at the indirect tracts between the striatum, globus pallidus, and substantia nigra. Experiments with animal models of Parkinsonís disease indicate that adenosine A2A receptors are strongly involved in the regulation of the central nervous system. Co-localization of adenosine A2A and dopaminergic D2 receptors in striatum creates a milieu for antagonistic interaction between adenosine and dopamine. The experimental data prove that the best improvement of mobility in patients with Parkinsonís disease could be achieved with simultaneous activation of dopaminergic D2 receptors and inhibition of adenosine A2A receptors. In animal models of Parkinsonís disease, the use of selective antagonists of adenosine A2A receptors, such as istradefylline, led to the reversibility of movement dysfunction. These compounds might improve mobility during both monotherapy and co-administration with L-DOPA and dopamine receptor agonists. The use of adenosine A2A receptor antagonists in combination therapy enables the reduction of the L-DOPA doses, as well as a reduction of side effects. In combination therapy, the adenosine A2A receptor antagonists might be used in both moderate and advanced stages of Parkinsonís disease. The long-lasting administration of adenosine A2A receptor antagonists does not decrease the patient response and does not cause side effects typical of L-DOPA therapy. It was demonstrated in various animal models that inhibition of adenosine A2A receptors not only decreases the movement disturbance, but also reveals a neuroprotective activity, which might impede or stop the progression of the disease. Recently, clinical trials were completed on the use of istradefylline (KW-6002), an inhibitor of adenosine A2A receptors, as an anti-Parkinson drug. PMID:18438720

  3. miR-155 mediates drug resistance in osteosarcoma cells via inducing autophagy

    PubMed Central

    CHEN, LU; JIANG, KE; JIANG, HUA; WEI, PENG

    2014-01-01

    Frequent acquisition of drug resistance is often associated with the chemotherapy of malignant tumors, including osteosarcoma. A number of studies have demonstrated a critical role for autophagy in osteosarcoma development, therapy and drug resistance. However, the molecular mechanisms underlying the autophagy-mediated chemotherapy resistance of osteosarcoma cells remain largely unknown. In the present study, we determined the autophagy and microRNA-155 (miR-155) expression induced by chemotherapeutic drugs in osteosarcoma cells. Then we determined the promotory role of miR-155 to the chemotherapy-induced autophagy. Our results demonstrated that microRNA-155 (miR-155) expression was highly induced during chemotherapy of osteosarcoma cells, and this was accompanied by upregulated autophagy. The increased miR-155 expression levels upregulated anticancer drug-induced autophagy in osteosarcoma cells and ameliorated the anticancer drug-induced cell proliferation and viability decrease. Therefore, the results of the present study demonstrated that miR-155 mediated drug-resistance in osteosarcoma cells by inducing autophagy. The present study recognized a novel mechanism of chemoresistance in osteosarcoma cancers. PMID:25009614

  4. Stress-Induced Reinstatement of Drug Seeking: 20 Years of Progress.

    PubMed

    Mantsch, John R; Baker, David A; Funk, Douglas; Lê, Anh D; Shaham, Yavin

    2016-01-01

    In human addicts, drug relapse and craving are often provoked by stress. Since 1995, this clinical scenario has been studied using a rat model of stress-induced reinstatement of drug seeking. Here, we first discuss the generality of stress-induced reinstatement to different drugs of abuse, different stressors, and different behavioral procedures. We also discuss neuropharmacological mechanisms, and brain areas and circuits controlling stress-induced reinstatement of drug seeking. We conclude by discussing results from translational human laboratory studies and clinical trials that were inspired by results from rat studies on stress-induced reinstatement. Our main conclusions are (1) The phenomenon of stress-induced reinstatement, first shown with an intermittent footshock stressor in rats trained to self-administer heroin, generalizes to other abused drugs, including cocaine, methamphetamine, nicotine, and alcohol, and is also observed in the conditioned place preference model in rats and mice. This phenomenon, however, is stressor specific and not all stressors induce reinstatement of drug seeking. (2) Neuropharmacological studies indicate the involvement of corticotropin-releasing factor (CRF), noradrenaline, dopamine, glutamate, kappa/dynorphin, and several other peptide and neurotransmitter systems in stress-induced reinstatement. Neuropharmacology and circuitry studies indicate the involvement of CRF and noradrenaline transmission in bed nucleus of stria terminalis and central amygdala, and dopamine, CRF, kappa/dynorphin, and glutamate transmission in other components of the mesocorticolimbic dopamine system (ventral tegmental area, medial prefrontal cortex, orbitofrontal cortex, and nucleus accumbens). (3) Translational human laboratory studies and a recent clinical trial study show the efficacy of alpha-2 adrenoceptor agonists in decreasing stress-induced drug craving and stress-induced initial heroin lapse. PMID:25976297

  5. [Drug-induced QT interval prolongation: do we know the risks?].

    PubMed

    VillamaŮŠn, Elena; Armada, Eduardo; Ruano, Margarita

    2015-03-15

    Sudden cardiac death is an important cause of mortality in developed countries, most of them being consequence of acute ventricular arrhythmias. These arrhythmias, in some cases, owe to QT interval prolongation. A major risk factor for this condition is the use of drugs that prolong the QT interval. In fact, in recent years, one of the most common reasons for drug withdrawal or usage restrictions has been drug induced QT interval prolongation that involves both cardiovascular and non-cardiovascular drugs. Taking into account the severity that the occurrence of such an event may have, it is important for clinicians to know the risks of these drugs in certain patients. In this review we analyze the drugs that prolong the QT interval, the risk factors that can enhance QT prolongation and the drug interactions that can increase these risks. PMID:24656122

  6. Pesticides and parkinsonism: is there an etiological link?

    PubMed

    Lockwood, A H

    2000-12-01

    Two hundred years ago, Parkinson's disease was rare. Now, it is the second most common neurodegenerative disorder. A recent twin study showed clearly that genetic factors play a minor role in determining whether an individual develops this disease, rekindling an interest in the etiological significance of environmental factors. Earlier studies had shown that a MPTP, a contaminant found in some illegal drugs, caused Parkinson's disease. This provided the original impetus for the pesticide hypothesis. Similarities between MPTP and pesticides coupled with epidemiological and animal studies have strengthened the possible link between pesticide exposure and the subsequent development of Parkinson's disease. PMID:11148671

  7. 21 CFR 341.80 - Labeling of nasal decongestant drug products.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... drugs for depression, psychiatric, or emotional conditions, or Parkinson's disease), or for 2 weeks... emotional conditions, or Parkinson's disease), or for 2 weeks after stopping the MAOI drug. If you do...

  8. 21 CFR 341.80 - Labeling of nasal decongestant drug products.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... drugs for depression, psychiatric, or emotional conditions, or Parkinson's disease), or for 2 weeks... emotional conditions, or Parkinson's disease), or for 2 weeks after stopping the MAOI drug. If you do...

  9. 21 CFR 341.80 - Labeling of nasal decongestant drug products.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... drugs for depression, psychiatric, or emotional conditions, or Parkinson's disease), or for 2 weeks... emotional conditions, or Parkinson's disease), or for 2 weeks after stopping the MAOI drug. If you do...

  10. 21 CFR 341.80 - Labeling of nasal decongestant drug products.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... drugs for depression, psychiatric, or emotional conditions, or Parkinson's disease), or for 2 weeks... emotional conditions, or Parkinson's disease), or for 2 weeks afte