Sample records for drug induced parkinsonism

  1. Manganese-induced Parkinsonism among ephedrone users and drug policy in Poland.

    PubMed

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

    2013-01-01

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

  2. Intraneuronal generation of a pyridinium metabolite may cause drug-induced parkinsonism.

    PubMed

    Markey, S P; Johannessen, J N; Chiueh, C C; Burns, R S; Herkenham, M A

    The compound 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induces an irreversible neurological syndrome in man and monkey which is similar to idiopathic Parkinson's disease in its clinical, pathological, neurochemical and pharmacological response properties. MPTP is selectively neurotoxic to the dopaminergic regions of the brain, destroying neurones in the substantia nigra (A8 and A9 cells, nigrostriatal system) but not the ventral tegmental area (A10 cells, mesolimbic system). Selective dopamine depletion and nigral cell loss after MPTP treatment has also been reported recently in the mouse. The mechanism by which a peripherally administered, low-molecular weight compound exerts permanent but selective toxic effects on dopamine systems in the brain may be relevant to parkinsonian syndromes induced by other toxins and to the disease process in idiopathic Parkinson's disease. We report here that MPTP is oxidized in the brain to a pyridinium species (a compound with potent herbicidal activity) and, in the monkey, is trapped intraneuronally. Furthermore, we demonstrate that this enzymatic oxidation is blocked in vivo in the mouse by a monoamine oxidase inhibitor, a condition which also blocks the neurotoxicity, indicating that the oxidative metabolism of MPTP is required for its neurotoxic effect. PMID:6332988

  3. Pharmacogenetics of drug response in Parkinson's disease.

    PubMed

    Džolji?, Eleonora; Novakovi?, Ivana; Krajinovic, Maja; Grbatini?, Ivan; Kosti?, Vladimir

    2014-10-15

    Parkinson's disease (PD) is a debilitating, demoralizing and financially devastating condition affecting 1% of population at the age of 60 years. Thus, very important issue to address is individual therapy optimization. Recent results have shown evidence that variable efficacy of treatment and risk of motor and mental complications could have genetic origin. Significant roles in that process play (pharmaco)genomic/genetic studies of PD. Variability in genes coding for drug-metabolizing enzymes, drug receptors and proteins involved in drug pathway signaling is an important factor determining inter-individual variability in drug responses. Interpersonal differences in drug responses are clearly documented although individualized treatment of PD is not widely known. Treatment with antiparkinsonian drugs is associated with the development of complications, such as L-DOPA-induced dyskinesia (LID), hallucinations and excessive daytime sleepiness. Carriers of specific genetic polymorphisms are particularly susceptible to development of some of these drug adverse effects. Pharmacogenomics aims to understand the relationship between genetic factors and inter-individual variations in drug responses, and to translate this information in therapy tailored to individual patient genetics. Relatively few efforts have been made to investigate the role of pharmacogenetics in the individual response to anti-PD drugs. Thus, many genetic variations and polymorphisms in myriad of different proteins can influence individual response to anti-PD drugs. PMID:25226559

  4. Drug therapy in patients with Parkinson’s 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

  5. Drug treatments for Parkinson's disease compared.

    PubMed

    2015-01-01

    Three classes of drug, levodopa, dopamine agonists and monoamine-oxidase-B inhibitors (MAOBI), are used in the initial treatment of Parkinson's disease. Levodopa is better at controlling motor symptoms but abnormal involuntary movements known as dyskinesias develop after long-term use or high-dose treatment. As a result levodopa is used as the initial treatment most often in patients over the age of 70 in whom long-term complications are judged less important. PMID:25633702

  6. Manganese induced parkinsonism: a case report.

    PubMed

    Kim, J W; Kim, Y; Cheong, H K; Ito, K

    1998-08-01

    Manganese (Mn) intoxication is known to induce parkinsonism. Mn-induced parkinsonism preferentially affect the globus pallidus in contrast to idiopathic parkinsonism where degeneration predominantly involves the nigral pars compacta. We describe a 51-year-old man who had been occupationally exposed to Mn. He had parkinsonian features including masked face, resting tremor, and bradykinesia. He also had a cock walk and a particular propensity to fall in a backward gait. There was no sustained therapeutic response to levodopa. A fluorodopa PET scan was normal. This case indicates that Mn-induced parkinsonism can be differentiated from idiopathic parkinsonism in that the former has unique clinical features and a normal fluorodopa PET scan. PMID:9741552

  7. Intracranial Meningioma-induced Parkinsonism

    PubMed Central

    Kim, Ji-In; Choi, Jin Kyo; Lee, Jin-Woo; Hong, Jin Yong

    2014-01-01

    An intracranial tumor is a rare cause of secondary parkinsonism. Our patient presented to our clinic for recently-developed asymmetric parkinsonism without pyramidal signs. However, a meningioma located in the sphenoidal ridge was identified upon imaging studies. This case suggests that additional causes should be considered when approaching patients with parkinsonism and that imaging studies can provide useful information to make accurate diagnoses.

  8. Drug discovery in Parkinson’s disease—Update and developments in the use of cellular models

    PubMed Central

    Skibinski, Gaia; Finkbeiner, Steven

    2013-01-01

    Parkinson’s disease (PD) is the second most common neurodegenerative disorder and is characterized by the degeneration of dopaminergic (DA) neurons within the substantia nigra. Dopamine replacement drugs remain the most effective PD treatment but only provide temporary symptomatic relief. New therapies are urgently needed, but the search for a disease-modifying treatment and a definitive understanding of the underlying mechanisms of PD has been limited by the lack of physiologically relevant models that recapitulate the disease phenotype. The use of immortalized cell lines as in vitro model systems for drug discovery has met with limited success, since efficacy and safety too often fail to translate successfully in human clinical trials. Drug discoverers are shifting their focus to more physiologically relevant cellular models, including primary neurons and stem cells. The recent discovery of induced pluripotent stem (iPS) cell technology presents an exciting opportunity to derive human DA neurons from patients with sporadic and familial forms of PD. We anticipate that these human DA models will recapitulate key features of the PD phenotype. In parallel, high-content screening platforms, which extract information on multiple cellular features within individual neurons, provide a network-based approach that can resolve temporal and spatial relationships underlying mechanisms of neurodegeneration and drug perturbations. These emerging technologies have the potential to establish highly predictive cellular models that could bring about a desperately needed revolution in PD drug discovery. PMID:23505333

  9. 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

  10. Eye movements in ephedrone-induced parkinsonism.

    PubMed

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

    2014-01-01

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

  11. Eye Movements in Ephedrone-Induced Parkinsonism

    PubMed Central

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

    2014-01-01

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

  12. Piracetam and vinpocetine ameliorate rotenone-induced Parkinsonism in rats

    PubMed Central

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

    2012-01-01

    Objective: To evaluate the neuroprotective effect of the nootropic drugs, piracetam (PIR) and vinpocetine (VIN), in rotenone-induced Parkinsonism in rats. Materials and Methods: Sixty male rats were divided into 6 groups of 10 rats each. The groups were administered vehicle, control (rotenone, 1.5 mg/kg/48 h/6 doses, s.c.), PIR (100 and 200 mg/kg/day, p.o.) and VIN (3 and 6 mg/kg/day, p.o.). The motor performance of the rats was evaluated by the open field and pole test. Striatal dopamine level, malondialdehyde (MDA), reduced glutathione (GSH) and tumor necrosis factor-? (TNF-?) were assayed. Histopathological study of the substantia nigra was also done. Results: Results showed that rotenone-treated rats exhibited bradykinesia and motor impairment in the open-field test. In addition, GSH level was decreased whereas MDA and TNF-? increased in striata of rotenone-treated rats as compared to vehicle-treated rats. Marked degeneration of the substantia nigra pars compacta (SNpc) neurons and depletion of striatal dopamine was also observed in the rotenone-treated rats. Treatment with PIR or VIN significantly reversed the locomotor deficits and increased striatal dopamine level. Treatment with VIN significantly (P < 0.05) reduced the striatal level of MDA and GSH in comparison to rotenone group whereas TNF-? production was found to be significantly decreased in PIR group (P < 0.05). Conclusion: VIN and PIR exhibit neuroprotective activity in rotenone-induced Parkinsonism. Hence, these nootropic agents may be considered as possible candidates in the treatment of Parkinson's disease. PMID:23248410

  13. 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

    2015-01-01

    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

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

    Microsoft Academic Search

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

    2007-01-01

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

  15. Neuropathy in Parkinson’s Disease Patients with Intestinal Levodopa Infusion versus Oral Drugs

    PubMed Central

    Jugel, Constanze; Ehlen, Felicitas; Taskin, Birol; Marzinzik, Frank; Müller, Thomas; Klostermann, Fabian

    2013-01-01

    Background Severe polyneuropathy has been observed in a number of patients treated for Parkinson’s disease with Levodopa/Carbidopa intestinal gel infusion. This may reflect a rare individual complication or a systematic side effect. Objective To investigate whether peripheral nerve function differed between patients with oral treatment versus Levodopa/Carbidopa intestinal gel infusion. Methods In an observational design, data from median, tibial, and peroneal neurography were prospectively assessed and compared between patients with conventional drug treatment (n?=?15) and with Levodopa/Carbidopa intestinal gel infusion (n?=?15). The groups were matched for age and disease duration. In view of the medical risk profile for polyneuropathy, comorbidity and basic serological parameters were assessed. Results Axonal neuropathy was common in both patient groups. However, although group differences in risk factors for polyneuropathy were not evident, neurographic abnormalities were more severe in the patients treated with Levodopa/Carbidopa intestinal gel infusion than in the orally treated patients. In the group with Levodopa/Carbidopa intestinal gel infusion, the degree of neuropathic change correlated with weight lost since therapy initiation and with the drug dose. In contrast to the axonal abnormalities, conduction velocity was found normal in both groups. Conclusion The results are compatible with the promotion of axonal neuropathy by Levodopa/Carbidopa intestinal gel infusion. This could be due to the intrinsically high levodopa doses associated with the therapy and/or malnutritional effects from intestinal drug application. The results should be corroborated by a larger longitudinal and controlled trial. PMID:23818953

  16. Thrombocytopenia - drug induced

    MedlinePLUS

    ... and a seizure medication called valproic acid may lead to this problem. Other medicines that cause drug-induced thrombocytopenia include: Furosemide Gold, used to treat arthritis Nonsteroidal anti-inflammatory drugs ( ...

  17. Anchanling reduces pathology in a lactacystin- induced Parkinson's disease model?

    PubMed Central

    Li, Yinghong; Wu, Zhengzhi; Gao, Xiaowei; Zhu, Qingwei; Jin, Yu; Wu, Anmin; Huang, Andrew C. J.

    2012-01-01

    A rat model of Parkinson's disease was induced by injecting lactacystin stereotaxically into the left mesencephalic ventral tegmental area and substantia nigra pars compacta. After rats were intragastrically perfused with Anchanling, a Chinese medicine, mainly composed of magnolol, for 5 weeks, when compared with Parkinson's disease model rats, tyrosine hydroxylase expression was increased, ?-synuclein and ubiquitin expression was decreased, substantia nigra cell apoptosis was reduced, and apomorphine-induced rotational behavior was improved. Results suggested that Anchanling can ameliorate Parkinson's disease pathology possibly by enhancing degradation activity of the ubiquitin-proteasome system. PMID:25767493

  18. Drug-induced phospholipidosis.

    PubMed

    Anderson, Nora; Borlak, Jürgen

    2006-10-01

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

  19. Drug-induced phospholipidosis

    Microsoft Academic Search

    Nora Anderson; Jürgen Borlak

    2006-01-01

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

  20. MPTP and other Parkinson-inducing agents.

    PubMed

    Schapira, A H

    1992-06-01

    The ability of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to produce parkinsonism has focused attention on potential endogenous or exogenous toxins that may follow similar uptake and conversion pathways to selectively target mitochondrial function in dopaminergic neurones. Exposure to such agents, together with a genetically determined susceptibility, is an attractive working hypothesis for the cause of Parkinson's disease. New insights into the mechanism of action of MPTP and its analogues are presented together with evidence supporting the potential role of endogenously produced toxins in the death of dopaminergic neurones in Parkinson's disease. PMID:1623269

  1. Drug-induced panniculitides.

    PubMed

    Borroni, G; Torti, S; D'Ospina, R M; Pezzini, C

    2014-04-01

    A substantial number of all panniculitides fails to recognize a specific etiology, and that is true also for a relatively frequent type of panniculitis, such as erythema nodosum (EN). Between the recognized causative factors of panniculitides, infectious, physical agents, autoimmune mechanisms and neoplastic disorders are well known. On the contrary, the role of drugs as inducers of panniculitides is marginally considered, and their report limited to anecdotal observations, often without due histopathological support. Since the clinical and histopathological features of drug-induced panniculitides are indistinguishable from those caused by other agents, the causative relationship may be demonstrated by the history of previous drug intake and by clinical improvement after drug discontinuation. We reviewed the currently reported descriptions of drug-induced panniculitis, including a few exemplificative original observations. EN results as the most frequently reported drug-induced panniculitis. Among the causative drugs of EN a variety of medications, with disparate, or even opposite, mechanisms of action are reported, thus limiting the understanding of the pathogenesis. Common causative drugs include oral contraceptives, nonsteroidal anti-inflammatory drugs, antiobiotics and leukotriene-modifying agents. Unfortunately, in several cases, the diagnosis of drug-induced EN is done on clinical findings alone. In those cases, the lack of histopathological support does not allow to define a precise clinicopathological correlation on etiologic grounds. Drug-induced lobular and mixed panniculitides, including eosinophilic panniculitis, are even more rarely described. Reported causative agents are glatiramer acetate, interferon beta and heparin (at sites of injections), and systemic steroids, tyrosine kinase inhibitors and BRAF with subcutaneous fat involvement at distance. In view of the recent introduction of new classes of drugs, attention should be paid to disclose their possible etiologic role in inducing among other side effects, also panniculitides. PMID:24819647

  2. Drug-induced phospholipidosis

    Microsoft Academic Search

    K.-U. Seiler; O. Wassermann

    1975-01-01

    In three species chronic treatment with the anorectic drug chlorphentermine causes a profound alteration of the phospholipid\\/lipid metabolism in the organism, resulting in an increase of the fractions of phospholipids and lipids, e.g. in lungs, livers and adrenals. The results are interpreted as drug-induced generalized phospholipidosis, which is caused by amphiphilic drugs, like chlorphentermine and others. Its extent depends on

  3. 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 ...

  4. DRUG INDUCED CHOLESTASIS

    PubMed Central

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

    2011-01-01

    Recent progress in understanding the molecular mechanisms of bile formation and cholestasis have led to new insights into the pathogenesis of drug induced cholestasis. This review summarizes their variable clinical presentations, examines the, role of transport proteins in hepatic drug clearance and toxicity and addresses the increasing importance of genetic determinants, as well as practical aspects of diagnosis and management. PMID:21480339

  5. 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

  6. Drug-induced esophagitis.

    PubMed

    Zografos, G N; Georgiadou, D; Thomas, D; Kaltsas, G; Digalakis, M

    2009-01-01

    Drug-induced esophagitis is being recognized increasingly in the past few years. Since 1970 more than 650 cases have been reported worldwide caused by 30 or more medications. We have reviewed these cases with a view to classifying this disease based on underlying pathological mechanism. Drug-induced esophageal injury tends to occur at the anatomical site of narrowing, with the middle third behind the left atrium predominating (75.6%). The disease is broadly classified into two groups. The first group being transient and self-limiting as exemplified by the tetracycline group induced injury (65.8%). The second is the persistent esophagitis group, often with stricture, with two distinct entities: (i) patients on nonsteroidal anti-inflammatory agents whose injury is aggravated by gastroesophageal reflux (21.8%) (reflux aggravated); and (ii) patients with potasium chloride and quinidine sulphate induced injury (12.4%) (persistent drug injury). Severe esophageal injury has been reported in some women taking biphosphonates as treatment for postmenopausal osteoporosis. Endoscopic findings in such patients with esophageal injury generally suggested a chemical esophagitis, with erosions or ulcerations and exudative inflammation accompanied by thickening of the esophageal wall. Most cases of medication-induced esophageal injury heal without intervention within a few days. Thus, the most important aspect of therapy is to make the correct diagnosis and then to avoid reinjury with the drug. When possible, potentially caustic oral medications should be discontinued. PMID:19392845

  7. 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

  8. OXIDANTS INDUCE ALTERNATIVE SPLICING OF ?-SYNUCLEIN: IMPLICATIONS FOR PARKINSON’S DISEASE

    PubMed Central

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

    2015-01-01

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

  9. PET imaging of dopamine receptors in MPTP-induced parkinsonism

    SciTech Connect

    Larson, S.M.; DiChiro, G.; Burns, R.S.; Dannals, R.F.; Kopin, I.J.; Brooks, R.A.; Kessler, R.M.; Wagner, R.F.; Eckelman, W.C.; Margolin, R.A.

    1984-01-01

    MPTP(N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) induces parkinsonism in animals and man by selectively destroying dopaminergic neurons in the pars compacta of the substantia nigra. The postsynaptic neurons (and presumably the dopamine receptors) are intact. The authors have imaged dopamine receptors in a patient with MPTP induced parkinsonism, using /sup 11/CMS (3-N(/sup 11/C) methylspiperone. Seven and 9 mCi's, respectively, were injected at one week intervals while the patient was first off, and then on, L-dopa. As measured by NeuroPET (NIH), putamen to cerebellum concentration ratios rose progressively to 5.5:1, by 90 min. after injection. At this time the concentration of /sup 11/CMS was 10 picomole/cc (off L-dopa), and 14 picomole/cc (on L-dopa). The Duvoisin scale was used to assess the severity of the patient's parkinsonism immediately prior and at the end of PET imaging. On both occasions, despite the small mass amount of /sup 11/CMS injected, (1.1 g/kg), a transient worsening of symptoms was seen. The effect of L-Dopa was almost completely reversed by the /sup 11/CMS. In contrast, off L-Dopa the patients severe basal state was worsened only slightly. The PET scans suggested that dopamine receptors are not reduced in MPTP-induced parkinsonism. The findings were consistent with the hypotheses that PET may identify patients who will benefit from L-Dopa, and that expression of parkinsonian symptoms reflects desaturation of dopamine receptors in striatum.

  10. Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients

    PubMed Central

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

    2014-01-01

    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

  11. Protective Effects of Curcumin Against Rotenone and Salsolinol Induced Toxicity: Implications for Parkinson’s Disease

    PubMed Central

    Qualls, Zakiya; Brown, Dwayne; Ramlochansingh, Carlana; Hurley, Laura L.; Tizabi, Yousef

    2013-01-01

    Parkinson’s disease (PD) is a debilitating neurodegenerative disorder that results from the loss of or damage to dopaminergic cells in the substantia nigra. Exposure to either the pesticide rotenone or the endogenous neurotoxin salsolinol has been shown to mimic this dopaminergic cell loss. In this study we first sought to determine whether combination of rotenone and salsolinol would result in an additive or synergistic toxicity. For this purpose we utilized SH-SY5Y cells, a human neuroblastoma cell line that is commonly used to model dopaminergic neurodegeneration. We then tested whether curcumin, a natural plant compound with known health benefits including potential neuroprotective properties, could also protect against rotenone and/or salsolinol induced toxicity. Moreover, since apoptotic mechanism has been implicated in toxicity of these compounds the anti-apoptotic effect of curcumin was also evaluated. Our results indicate a synergistic toxicity of low concentrations of rotenone (1 and 5 uM) and salsolinol (25 and 50 mM) that was associated with apoptosis as determined by cell flow cytometry. There was also an increase in caspase-3 levels. Pretreatment with curcumin (1-10 uM) dose-dependently attenuated rotenone and/or salsolinol induced toxicity and the associated apoptosis. These results suggest that exposure to a combination of rotenone and salsolinol may contribute to the pathology of PD, and that curcumin has a therapeutic potential in this disease. PMID:24122264

  12. Drug-Induced Lung Toxicity

    Microsoft Academic Search

    Mannfred A. Hollinger

    1993-01-01

    The number of blood-borne chemotherapeutic agents implicated in drug-induced lung toxicity continues to increase, although problems in detection remain. The initiation of drug-induced lung injury can have an immunologic or nonimmunologic basis. If endothelial cells are injured, interstitial pulmonary edema may result. Regardless of the source of injury, the progression of drug-induced lung toxicity is often quite similar, involving (1)

  13. Verbal Memory in Drug-Naive, Newly Diagnosed Parkinson's Disease. The Retrieval Deficit Hypothesis Revisited

    Microsoft Academic Search

    Kolbjørn Brønnick; Guido Alves; Dag Aarsland; Ole-Bjørn Tysnes; Jan Petter Larsen

    2011-01-01

    Objective: The retrieval deficit hypothesis on memory impairment in patients with Parkinson's disease (PD) implies a selective impairment in recall of learned material with normal encoding, retention, and recognition. This hypothesis has been challenged by new data. We have therefore investigated verbal memory and learning in a large sample of newly diagnosed, drug naïve, non-demented patients with PD. Method: From

  14. Oleoylethanolamide reduces L-DOPA-induced dyskinesia via TRPV1 receptor in a mouse model of Parkinson´s disease.

    PubMed

    González-Aparicio, Ramiro; Moratalla, Rosario

    2014-02-01

    The long-term use of levodopa (L-DOPA) in Parkinson's disease (PD) results in the development of abnormal involuntary movements called L-DOPA-induced dyskinesias. Increasing evidences suggest that the endocannabinoid system may play a role in the modulation of dyskinesias. In this work, we assessed the antidyskinetic effect of the endocannabinoid analog oleoylethanolamide (OEA), an agonist of PPAR? and antagonist of TRPV1 receptors. We used a hemiparkinsonian model of PD in mice with 6-OHDA striatal lesion. The chronic L-DOPA treatment developed intense axial, forelimb and orolingual dyskinetic symptoms, as well as contralateral rotations. Treatment with OEA reduced all these symptoms without reducing motor activity or the therapeutic motor effects of L-DOPA. Moreover, the OEA-induced reduction in dyskinetic behavior correlated with a reduction in molecular correlates of dyskinesia. OEA reduced FosB striatal overexpression and phosphoacetylation of histone 3, both molecular markers of L-DOPA-induced dyskinesias. We found that OEA antidyskinetic properties were mediated by TRPV1 receptor, as pretreatment with capsaicin, a TRPV1 agonist, blocked OEA antidyskinetic actions, as well as the reduction in FosB- and pAcH3-overexpression induced by L-DOPA. This study supports the hypothesis that the endocannabinoid system plays an important role in the development and expression of dyskinesias and might be an effective target for the treatment of L-DOPA-induced dyskinesias. Importantly, there was no development of tolerance to OEA in any of the parameters we examined, which has important implications for the therapeutic potential of drugs targeting the endocannabinoid system. PMID:24140894

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

    PubMed Central

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

    2012-01-01

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

  16. Serotonergic markers in Parkinson's disease and levodopa-induced dyskinesias.

    PubMed

    Cheshire, Perdita; Ayton, Scott; Bertram, Kelly L; Ling, Helen; Li, Abi; McLean, Catriona; Halliday, Glenda M; O'Sullivan, Sean S; Revesz, Tamas; Finkelstein, David I; Storey, Elsdon; Williams, David R

    2015-05-01

    Preclinical animal models implicate serotonin neurons in the pathophysiology of levodopa (l-dopa)-induced dyskinesias in Parkinson's disease (PD), but effective treatment remains elusive. We examined the relationship between serotonin and l-dopa-induced dyskinesias in a pathologically confirmed cohort of PD patients. We obtained brain tissue from 44 PD cases and 17 age-matched controls and assessed monoamine levels and the serotonin and dopamine transporters in the striatum, and the extent of dopaminergic and serotonergic cell preservation in the substantia nigra (SN) and the dorsal raphe nuclei (DRN), respectively. As expected, PD patients demonstrated a severe loss of all dopaminergic markers, including dopamine (P?induced dyskinesias suggests that an intact and functioning serotonergic system is not a risk factor for developing dyskinesias in PD. © 2015 International Parkinson and Movement Disorder Society. PMID:25649148

  17. Drug-induced tremor

    MedlinePLUS

    ... Certain high blood pressure drugs Epinephrine and norepinephrine Weight loss medication (tiratricol) Too much thryoid medication (levothyroxine) Tetrabenazine, a medicine to treat excessive movement disorder

  18. [Drug-induced lung diseases].

    PubMed

    Medici, T C; Fontana, A

    1977-02-12

    Adverse drug reactions involving different organs, including the lung, are numerous; much more numerous, however, are the offending drugs. According to the results of the Boston Collaborative Drug Surveillance Program, adverse reactions occur in about 6% of all drug exposures and 28% of all patients. Drug-induced lung diseases may present as bronchial reactions (e.g. bronchial asthma), diseases of the parenchyma (e.g. pulmonary infiltrates with eosinophilia, diffuse fibrosing alveolitis), of the pulmonary vasculature (vasculitis) and of the pleura (e.g. pleurisy or pleural fibrosis). Pathogenetically the two most pertinent types of reaction are hypersensitivity or toxic reactions, and less often biologic reactions such as opportunistic infections after cytotoxic and immunosuppressive therapy. Many drug-induced respiratory diseases are reversible upon withdrawal of the offending agent; others may be irreversibly or even progress. PMID:13491

  19. Drug-induced lupus erythematosus

    Microsoft Academic Search

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

    2009-01-01

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

  20. Drug-induced lupus erythematosus

    MedlinePLUS

    Drug-induced lupus erythematosus is an autoimmune disorder that is brought on by a reaction to a medicine. ... to systemic lupus erythematosus (SLE). It is an autoimmune disorder. This means your body attacks healthy tissue by ...

  1. 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. ...

  2. Drug-induced hepatic steatosis.

    PubMed

    Amacher, David E; Chalasani, Naga

    2014-05-01

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

  3. 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

  4. Antiviral drug-induced nephrotoxicity.

    PubMed

    Izzedine, Hassane; Launay-Vacher, Vincent; Deray, Gilbert

    2005-05-01

    Drug-induced kidney injury is a major side effect in clinical practice, frequently leading to acute renal failure (ARF). It accounts for more than 2% to 15% of cases of ARF in patients admitted to the hospital or in the intensive care unit, respectively. The exact frequency of nephrotoxicity induced by antiviral drugs is difficult to determine. Antiviral drugs cause renal failure through a variety of mechanisms. Direct renal tubular toxicity has been described with a number of new medications with unique effects on epithelial cells of the kidney. These include cidofovir, adefovir dipivoxil, and tenofovir, as well as acyclovir. Additionally, crystal deposition in the kidney may promote the development of renal failure. Several different drugs have been described to induce crystal nephropathy, including acyclovir and the protease inhibitor indinavir. Renal injury associated with antiviral drugs involves diverse processes having effects on the renal transporters, as well as on tubule cells. In this article, we review the pathogenesis of antiviral drug-induced kidney injury, common nephrotoxic renal syndromes, and strategies for preventing kidney injury. PMID:15861345

  5. Gastrodia elata Blume alleviates L-DOPA-induced dyskinesia by normalizing FosB and ERK activation in a 6-OHDA-lesioned Parkinson’s disease mouse model

    PubMed Central

    2014-01-01

    Background Gastrodia elata Blume (GEB), commonly used medicinal herb, has been reported as a promising candidate for neurodegenerative diseases such as Parkinson’s disease. The dopamine precursor, L-3,4-dihydroxyphenylalanine (L-DOPA), is the gold-standard drug for Parkinson’s disease, but long-term treatment results in the L-dopa-induced dyskinesia (LID). This study was undertaken to examine the beneficial effects of GEB on L-DOPA induced dyskinesia in 6-hydroxydopamine (6-OHDA)-induced experimental Parkinsonism. Methods We tested the effects of GEB on LID in 6-hydroxydopamine hydrochloride-hemiparkinsonian mice. To analyze the dyskinetic anomalies, we measured abnormal involuntary movement (AIM). Immunohistological analyses of pERK and FosB expressions in the striatum are performed to explore the mechanism of GEB on LID. Results The finding of this study demonstrated that GEB (200, 400 and 800 mg/kg) alleviated L-dopa induced AIMs in a dose-dependent manner. In each integrative AIM subtype analysis, we also found that the GEB (400 and 800 mg/kg) treatment decreased L-DOPA-induced axial, limb, orolingual, and locomotive AIMs compared to the LID group. In addition, GEB normalized the abnormal LID-induced increase of pERK1/2 and FosB, the immediate early genes of LID in the striatum. Conclusions In conclusion, our results provide a novel insight into the pharmacological actions of GEB that could have a benefit for PD patients through the reduction of LID. PMID:24650244

  6. Drug-induced Liver Injury

    PubMed Central

    David, Stefan; Hamilton, James P

    2011-01-01

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

  7. Dieldrin-Induced Neurotoxicity: Relevance to Parkinson's Disease Pathogenesis

    Microsoft Academic Search

    Anumantha G. Kanthasamy; Masashi Kitazawa; Arthi Kanthasamy; Vellareddy Anantharam

    2005-01-01

    Parkinson's disease (PD) is increasingly recognized as a neurodegenerative disorder strongly associated with environmental chemical exposures. Recent epidemiological data demonstrate that environmental risk factors may play a dominant role as compared to genetic factors in the etiopathogenesis of idiopathic Parkinson's disease. Identification of key genetic defects such as alpha-synuclein and parkin mutations in PD also underscores the important role of

  8. [Drug treatment of early-stage (de novo and "honeymoon") Parkinson disease].

    PubMed

    Cesaro, P; Defebvre, L

    2014-04-01

    In this article, we discuss the management of motor symptoms during the early phases of Parkinson's disease, excluding that of any other clinical manifestation. We relied primarily upon recently published data and do not describe older publications relating to anticholinergic drugs or amantadine. The initial pharmacological treatment of idiopathic Parkinson's disease (IPD) is symptomatic and remains based upon dopaminergic drugs. However, the development of new drugs has broadened the range of strategic options and improved overall patient management. Announcing the diagnosis is a critical moment, as pointed out by patients' associations. Patients should be advised to maintain personal, professional, social and physical activities as long as possible. The potential benefit of early pharmacological treatment should be explained, focusing on the possible disease-modifying effect of drugs such as rasagiline. According to current guidelines, L-Dopa is preferred in patients above 65years of age, while those below 65 should be treated with dopamine agonists. Like monoamine oxidase inhibitors B (MAOI-B), synthetic dopamine agonists exhibit several advantages: easy-to-use treatment with a once-daily administration, delayed L-Dopa initiation, significant efficacy on motor symptoms (although lower than that of L-Dopa). MOAI can be prescribed in association with L-Dopa or dopamine agonists. Rasagiline also delays L-Dopa initiation, and consequently motor complications. PMID:24673985

  9. 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 ...

  10. Drug Induced Interstitial Lung Disease

    PubMed Central

    Schwaiblmair, Martin; Behr, Werner; Haeckel, Thomas; Märkl, 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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

    Zeng, Hui; 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. Database URL: http://www.cuilab.cn/drugpath

  13. Compound Formula Rehmannia alleviates levodopa-induced dyskinesia in Parkinson's disease

    PubMed Central

    Teng, Long; Hong, Fang; Zhang, Chenguang; He, Jiancheng; Wang, Haiying

    2014-01-01

    Compound Formula Rehmannia has been shown to be clinically effective in treating Parkinson's disease and levodopa-induced dyskinesia; however, the mechanisms remain unclear. In this study, we established a model of Parkinson's disease dyskinesia in rats, and treated these animals with Compound Formula Rehmannia. Compound Formula Rehmannia inhibited the increase in mRNA expression of N-methyl-D-aspartate receptor subunits 1 and 2 and excitatory amino acid neurotransmitter genes, and it inhibited the reduction in expression of ?-aminobutyric acid receptor B1, an inhibitory amino acid neurotransmitter gene, in the corpus striatum. In addition, Compound Formula Rehmannia alleviated dyskinesia symptoms in the Parkinson's disease rats. These experimental findings indicate that Compound Formula Rehmannia alleviates levodopa-induced dyskinesia in Parkinson's disease by modulating neurotransmitter signaling in the corpus striatum. PMID:25206828

  14. 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

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

    E-print Network

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

    2005-01-01

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

  16. Accelerometric assessment of levodopa-induced dyskinesias in Parkinson's disease.

    PubMed

    Hoff, J I; van den Plas, A A; Wagemans, E A; van Hilten, J J

    2001-01-01

    Our objective was to develop parameters for objective ambulatory measurements of levodopa-induced dyskinesias (LID) in patients with Parkinson's disease (PD). Twenty-three PD patients with mild to severe LID were submitted to a standardized protocol of 1-minute recordings during rest, talking, stress, and four activities of daily life (ADL). Patients were simultaneously monitored with portable multi-channel accelerometry (four pairs of bi-axial sensors mounted onto the most affected arm, leg, and at the trunk) and recorded by video. LID severity was assessed with a modified Abnormal Involuntary Movement Scale (m-AIMS). The signals were analyzed, and every 1/8-second interval the amplitude was obtained of the dominant frequency within 1-4 Hz and 4-8 Hz frequency bands (Amp1-4 and Amp4-8). For both measures, convergent validity, reproducibility, and responsiveness were determined. In absence of voluntary movements, a significant relation was found between Amp1-4 and Amp4-8 and m-AIMS. Repeated measurements during rest showed a high reproducibility (intraclass correlation coefficient = 0.90 [Amp1-4] and 0.86 [Amp4-8]). The extent to which LID increased with talking and stress correlated significantly (p = 0.02) between the objective and clinical measures (intraclass correlation for differences = 0.67). During ADL, LID occurred in a similar frequency band as voluntary movements and only Amp1-4 and Amp4-8 of the trunk and leg sensor remained highly correlated with m-AIMS. Although objective measures of LID are reliable and responsive, they fail to distinguish LID from voluntary movements. These measures are of value only when obtained during rest (all sensor sites) or during ADL when derived from those body segments that are normally not involved in these ADL tasks (trunk and leg). PMID:11215593

  17. Mechanism of neuroprotective action of the anti-Parkinson drug rasagiline and its derivatives.

    PubMed

    Mandel, Silvia; Weinreb, Orly; Amit, Tamar; Youdim, Moussa B H

    2005-04-01

    The mitochondria are directly involved in cell survival and death. Drugs that protect mitochondria viability and prevent apoptotic cascade mechanisms involved in mitochondrial permeability transition pore (MPTp) will be cytoprotective. Rasagiline (N-propargyl-1R-aminoindan) is a novel, highly potent irreversible monoamine oxidase (MAO) B inhibitor, anti-Parkinson drug. Unlike selegiline, rasagiline is not derived from amphetamine, is not metabolized to neurotoxic l-methamphetamine derivative, nor does it have sympathomimetic activity. Rasagiline is effective as monotherapy or adjunct to L-dopa for patients with early and late Parkinson's disease (PD), and adverse events do not occur with greater frequency in subjects receiving rasagiline than those on placebo. Controlled studies indicate that it might have a disease-modifying effect in PD that may be related to neuroprotection. Its S-isomer, TVP1022, is a relatively inactive MAO inhibitor. However, both drugs have similar neuroprotective activities in neuronal cell cultures in response to various neurotoxins and in vivo (global ischemia, neurotrauma, head injury, anoxia, etc.), indicating that MAO inhibition is not a pre-requisite for neuroprotection. Structure activity studies have shown that the neuroprotective activity is associated with the propargyl moiety of rasagiline which protects mitochondrial viability and MPTp by activating Bcl-2 and protein kinase C (PKC), and down regulating pro-apoptotic FAS and Bax. Rasagiline and its derivatives also process amyloid precursor protein (APP) to the neuroprotective-neurotrophic soluble APP alpha (sAPPalpha) by PKC and MAP kinase-dependent activation of alpha-secretase. The neuroprotective activity of propargylamine has led us to develop novel bifunctional neuroprotective iron-chelating MAO-inhibiting drugs possessing propargyl moiety for the treatment of other neurodegenerative diseases. PMID:15850677

  18. Drug-induced esophageal strictures.

    PubMed Central

    Bonavina, L; DeMeester, T R; McChesney, L; Schwizer, W; Albertucci, M; Bailey, R T

    1987-01-01

    A retrospective study of 55 patients with a benign esophageal stricture showed that in 11 patients (20%) the cause was a drug-induced lesion due to potassium chloride (3), tetracyclines (3), aspirin (2), vitamin C (1), phenytoin (1), and quinidine (1). Five of the 11 patients would have been diagnosed as having a reflux etiology of their stricture if 24-hour esophageal pH monitoring was not performed. Six patients responded to dilatation and five patients required resection or bypass. A prospective study of 18 asymptomatic volunteers showed a high incidence of esophageal lodgment of a radiolabeled medicinal capsule, with subsequent dissolution and release of the isotope. This occurred most frequently in elderly subjects and was reduced by increasing the volume of water chaser. The sites of lodgment correspond to the location of the observed strictures in the patient population. An in vitro study showed that, when the causative drugs were mixed with saliva, dissolution occurred within 60 minutes and was associated with significant changes in pH. These investigations show that drug-induced esophageal strictures are more common than previously appreciated, and can be confused with a reflux etiology. Diagnosis is suggested by a history of drug ingestion, location of the stricture, and a normal esophageal acid exposure on 24-hour pH monitoring. The severity of the esophageal injury is variable and requires dilatation to resection for therapy. Images Fig. 1. Fig. 2. Fig. 3. Fig. 4. Fig. 5. Fig. 6. PMID:3606243

  19. Drug-Induced Liver Injury.

    PubMed

    Fisher, Kurt; Vuppalanchi, Raj; Saxena, Romil

    2015-07-01

    Context .- Drug-induced liver injury (DILI) represents a diverse set of responses following exposure to any manufactured or naturally occurring chemical compound. Drug-induced liver injury is of major concern owing to the ever increasing number of compounds introduced into the market for treatment of various diseases as well as the increasing popularity of herbals, which lend themselves to self-medication but are not rigorously regulated. Objective .- To provide an overview of the prevalence, classification, and diagnosis of DILI with emphasis on pathogenesis and the role of a liver biopsy. To focus on the most common, emerging, and herbal agents that cause DILI with emphasis on the histologic pattern of injury observed. Data Sources .- A review of the literature was drawn from the PubMed (US National Library of Medicine) repository, textbooks, and online databases. All figures were taken from cases seen at our tertiary referral center, which is 1 of 12 participating sites in the National Institutes of Health-funded Drug-Induced Liver Injury Network. Conclusions .- Drug-induced liver injury due to prescription, over-the-counter, and herbal products is a major cause of liver disease in the United States and around the world. Diagnosis of DILI is challenging because there is no single clinical, laboratory, or histologic feature specific to DILI. Accurate diagnosis requires establishing a causal relationship with the suspected agent and excluding competing causes of liver injury. The liver biopsy is an essential component in the management of DILI by offering clues to the underlying pathogenesis, providing prognostic information, and guiding therapy. PMID:26125428

  20. [The clinical picture and diagnosis of manganese-induced parkinsonism].

    PubMed

    Petkova, V; Karadzhov, K

    1991-01-01

    As a result of 5-year-long electromyographic observation of 144 persons engaged in ferroalloy production, the parkinsonism syndrome was diagnosed in 4 persons. The disease development was slow, gradual, with the muscular tension growth against the asthenovegetative symptoms. This particularity did not correspond to the traditional view of the three-stage development of chronic manganese intoxication prior to the acute phase of manganese parkinsonism. The contributors hold that the stretch reflex proved to be the most early-stage oriented, prognostically and diagnostically reliable among the other electromyographic techniques. PMID:1879747

  1. 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

  2. Neuroprotective Effects of Protocatechuic Aldehyde against Neurotoxin-Induced Cellular and Animal Models of Parkinson’s Disease

    PubMed Central

    Zhao, Xin; Zhai, Shenyu; An, Ming-Sheng; Wang, Yue-Hua; Yang, Ying-Fan; Ge, Hui-Qi; Liu, Jin-Hao; Pu, Xiao-Ping

    2013-01-01

    Protocatechuic aldehyde (PAL) has been reported to bind to DJ-1, a key protein involved in Parkinson’s disease (PD), and exerts potential neuroprotective effects via DJ-1 in SH-SY5Y cells. In this study, we investigated the neuroprotective pharmacological effects of PAL against neurotoxin-induced cell and animal models of PD. In cellular models of PD, PAL markedly increased cell viability rates, mitochondrial oxidation-reduction activity and mitochondrial membrane potential, and reduced intracellular ROS levels to prevent neurotoxicity in PC12 cells. In animal models of PD, PAL reduced the apomorphine injection, caused turning in 6-OHDA treated rats, and increased the motor coordination and stride decreases in MPTP treated mice. Meanwhile, in an MPTP mouse model, PAL prevented a decrease of the contents of dopamine (DA) and its metabolites in the striatum and TH-positive dopaminergic neuron loss in the substantia nigra (SN). In addition, PAL increased the protein expression of DJ-1 and reduced the level of ?-synuclein in the SN of MPTP lesioned mice. PAL also increased the spine density in hippocampal CA1 neurons. The current study demonstrates that PAL can efficiently protect dopaminergic neurons against neurotoxin injury in vitro and in vivo, and that the potential mechanisms may be related to its effects in increasing DJ-1, decreasing ?-synuclein and its growth-promoting effect on spine density. PMID:24205164

  3. Neurological morphofunctional differentiation induced by REAC technology in PC12. A neuro protective model for Parkinson’s 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, 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. Possible pharmacokinetic and pharmacodynamic factors affecting parkinsonism inducement by cinnarizine and flunarizine.

    PubMed

    Kariya, S; Isozaki, S; Masubuchi, Y; Suzuki, T; Narimatsu, S

    1995-11-01

    Potentialities of cinnarizine [1-(diphenylmethyl)-4-(3-phenyl-2-propenyl)piperazine, CZ] and its fluorine derivative flunarizine [1-[bis(4-fluorophenyl)-methyl]-4-(3-phenyl-2-propenyl)piperazine, FZ] to induce parkinsonism as an adverse effect were evaluated pharmacokinetically and pharmacodynamically in rats. In multiple-dose experiments, CZ or FZ was given to rats at a daily dose of 20 mumol/kg for 1, 5, 10, 15, and 30 days, and CZ, FZ, and the ring-hydroxylated metabolites of their cinnamyl moiety [1-(diphenylmethyl)-4-[3-(4'-hydroxyphenyl)-2-propenyl]piperazine, C-2 and 1-[bis(4-fluorophenyl)methyl]-4-[3-(4'- hydroxyphenyl)propenyl]piperazine, F-2] in the plasma and striatum were determined 24 hr after the final dose. Plasma and striatum concentrations of the above compounds except for FZ reached steady state after 10 doses, but their concentrations of FZ continued to increase throughout the experiments. The concentrations obtained after the 30 doses were in the order of FZ > F-2 > CZ > C-2 for the plasma and of F-2 > FZ > CZ > C-2 for the striatum. The ratios of striatum to plasma concentrations of C-2 and F-2 were 2.4 and 3 times higher than those of the parent drugs. Binding affinities of CZ, FZ, and their 10 metabolites for rat striatal dopamine D-2 receptors (D2-R) were assessed by competitive radioligand-binding studies using [3H]-N-[(2RS,3RS)-1-benzyl-2-methyl-3-pyrrolidinyl]-5-chloro-2-met hoxy- 4-methylamino-benzamide ([3H]-YM-09151-2). The IC50s calculated from their Ki values were in the order of F-2 < C-2 < FZ < CZ < C-4 < F-1, indicating that C-2 and F-2 exhibit higher affinities for D2-R than the parent drugs, whereas affinities of other metabolites were 1 to 2 orders of magnitude less than those of C-2 and F-2. These results suggest some important roles of C-2 and F-2 in the development of parkinsonism as active metabolites during chronic medication with CZ and FZ, respectively. PMID:7503767

  5. Gender differences in non-motor symptoms in early, drug naïve 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-naïve PD patients. This study is to assess gender differences in the prevalence of NMS in a large sample of early, drug-naïve PD patients compared with age and sex-matched healthy controls. Two hundred early, drug-naïve 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-naïve 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

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

    NASA Astrophysics Data System (ADS)

    Jaramillo Raquejo, Daniela

    2013-05-01

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

  7. Functional connectome assessed using graph theory in drug-naive Parkinson's disease.

    PubMed

    Luo, Chun Yan; Guo, Xiao Yan; Song, Wei; Chen, Qin; Cao, Bei; Yang, Jing; Gong, Qi Yong; Shang, Hui-Fang

    2015-06-01

    The purpose of this study is to investigate whether the topological organization of whole-brain functional network is disrupted in patients with Parkinson's disease (PD). We employed resting-state functional MRI (R-fMRI) and graph theory to investigate the topological organization of the functional connectome in 47 early-stage drug-naïve PD patients and 47 healthy control subjects. Correlations between network properties and clinical variables were tested. Both the PD and control groups showed small-world architecture in brain functional networks. However, the PD patients had lower clustering coefficient and local efficiency relative to control subjects, indicating disrupted topologic organization and a shift toward randomization in their functional brain network. At node and connection level, reduced node centralities and connectivity strength were found mainly in temporal-occipital regions and also in sensorimotor regions of PD patients. In PD patients, altered global network properties correlated with cognitive function, while motor impairment was correlated with local connection changes. This study demonstrates a disruption of whole-brain topological organization of the functional brain networks in early-stage drug-naïve PD patients and this disruption might contribute to preclinical changes in cognitive process in these patients. PMID:25929663

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

    PubMed

    Hölscher, Christian

    2014-10-25

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

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

    PubMed Central

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

    2014-01-01

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

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

    SciTech Connect

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

    2010-02-15

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

  11. Increased reflection impulsivity in patients with ephedrone induced Parkinsonism

    PubMed Central

    Djamshidian, Atbin; Sanotsky, Yanosh; Matviyenko, Yuriy; O’Sullivan, 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 ‘beads task’, 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

  12. Nicotine prevents experimental parkinsonism in rodents and induces striatal increase of neurotrophic factors.

    PubMed

    Maggio, R; Riva, M; Vaglini, F; Fornai, F; Molteni, R; Armogida, M; Racagni, G; Corsini, G U

    1998-12-01

    The repeated finding of an apparent protective effect of cigarette smoking on the risk of Parkinson's disease is one of the few consistent results in the epidemiology of this disorder. Among the numerous substances that originate from tobacco smoke, nicotine is by far the most widely studied. Nicotine is a natural alkaloid that has considerable stimulatory effects on the CNS. Its effects on the CNS are mediated by the activation of neuronal heteromeric acetylcholine-gated ion channel receptors (nAChRs, also termed nicotinic acetylcholine receptors). In the present study, we describe the neuroprotective effects of (-)-nicotine in two animal models of parkinsonism: diethyldithiocarbamate-induced enhancement of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in mice and methamphetamine-induced neurotoxicity in rats and mice. The neuroprotective effect of (-)-nicotine was very similar to that of the noncompetitive NMDA receptor antagonist (+)-MK-801. In parallel experiments, we found that (-)-nicotine induces the basic fibroblast growth factor-2 (FGF-2) and the brain-derived neurotrophic factor in rat striatum. The effect of (-)-nicotine on the induction of FGF-2 was prevented by the nAChR antagonist mecamylamine. We also found that (+)-MK-801 was able to induce FGF-2 in the striatum. As trophic factors have been reported to be neuroprotective for dopaminergic cells, our data suggest that the increase in neurotrophic factors is a possible mechanism by which (-)-nicotine protects from experimental parkinsonisms. PMID:9832142

  13. New drug treatments show neuroprotective effects in Alzheimer's and Parkinson's diseases

    PubMed Central

    Hölscher, Christian

    2014-01-01

    Type 2 diabetes is a risk factor for Alzheimer's disease and Parkinson's disease. Insulin signaling in the brains of people with Alzheimer's disease or Parkinson's disease is impaired. Preclinical studies of growth factors showed impressive neuroprotective effects. In animal models of Alzheimer's disease and Parkinson's disease, insulin, glia-derived neurotrophic factor, or analogues of the incretin glucagon-like peptide-1 prevented neurodegenerative processes and improved neuronal and synaptic functionality in Alzheimer's disease and Parkinson's disease. On the basis of these promising findings, several clinical trials are ongoing with the first encouraging clinical results published. This gives hope for developing effective treatments for Alzheimer's disease and Parkinson's disease that are currently unavailable. PMID:25558231

  14. Loss of mitochondrial complex I activity potentiates dopamine neuron death induced by microtubule dysfunction in a Parkinson’s disease model

    PubMed Central

    Choi, Won-Seok; Palmiter, Richard D.

    2011-01-01

    Mitochondrial complex I dysfunction is regarded as underlying dopamine neuron death in Parkinson’s disease models. However, inactivation of the Ndufs4 gene, which compromises complex I activity, does not affect the survival of dopamine neurons in culture or in the substantia nigra pars compacta of 5-wk-old mice. Treatment with piericidin A, a complex I inhibitor, does not induce selective dopamine neuron death in either Ndufs4+/+ or Ndufs4?/? mesencephalic cultures. In contrast, rotenone, another complex I inhibitor, causes selective toxicity to dopamine neurons, and Ndufs4 inactivation potentiates this toxicity. We identify microtubule depolymerization and the accumulation of cytosolic dopamine and reactive oxygen species as alternative mechanisms underlying rotenone-induced dopamine neuron death. Enhanced rotenone toxicity to dopamine neurons from Ndufs4 knockout mice may involve enhanced dopamine synthesis caused by the accumulation of nicotinamide adenine dinucleotide reduced. Our results suggest that the combination of disrupting microtubule dynamics and inhibiting complex I, either by mutations or exposure to toxicants, may be a risk factor for Parkinson’s disease. PMID:21383081

  15. 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

  16. 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.

  17. Non-steroidal drug-induced glaucoma

    PubMed Central

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

    2011-01-01

    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

  18. Manganese-Induced Parkinsonism due to Ephedrone Abuse.

    PubMed

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

  19. Clinically available iron chelators induce neuroprotection in the 6-OHDA model of Parkinson’s disease after peripheral administration

    Microsoft Academic Search

    David T. Dexter; Sarah A. Statton; Charlotte Whitmore; Wolfhardt Freinbichler; Peter Weinberger; Keith F. Tipton; Laura Della Corte; Roberta J. Ward; Robert R. Crichton

    2011-01-01

    The iron content of the substantia nigra pars compacta increases in the brains of Parkinson’s disease patients. Hence, its\\u000a removal by iron chelators may retard the progression of the disease. However, information on the ability of clinically available\\u000a iron chelators to cross the blood brain barrier and be neuroprotective is limited. In this present study three iron chelators,\\u000a which are

  20. Acute dystonia induced by neuroleptic drugs

    Microsoft Academic Search

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

    1986-01-01

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

  1. Mechanisms of Drug-Induced Nephrotoxicity

    Microsoft Academic Search

    Thomas D. Nolin; Jonathan Himmelfarb

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

  2. Parkinsonism following neuroleptic exposure: A double-hit hypothesis?

    PubMed

    Erro, Roberto; Bhatia, Kailash P; Tinazzi, Michele

    2015-05-01

    Drug-induced parkinsonism is caused by an offending drug and should resolve after the causative agent has been withdrawn. However, in a number of patients, symptoms persist or may even worsen over time, suggesting the development of concomitant Parkinson's disease. The prevalence estimates of Parkinson's disease after neuroleptic exposure are unexpectedly high, suggesting a causal relationship. We critically review available literature in this regard, and some pathophysiological hypotheses that might explain such a relationship are suggested. Some patients may have an undetermined genetic susceptibility to parkinsonism. We speculate that the possible neurotoxic effect of neuroleptics exerted on a susceptible dopaminergic system would lead over the long-term to a self-fostering, progressive process. Knowledge gaps and future perspectives are discussed. © 2015 International Parkinson and Movement Disorder Society. PMID:25801826

  3. Static Magnetic Field Exposure Reproduces Cellular Effects of the Parkinson's Disease Drug Candidate ZM241385

    PubMed Central

    Wang, Zhiyun; Che, Pao-Lin; Du, Jian; Ha, Barbara; Yarema, Kevin J.

    2010-01-01

    Background This study was inspired by coalescing evidence that magnetic therapy may be a viable treatment option for certain diseases. This premise is based on the ability of moderate strength fields (i.e., 0.1 to 1 Tesla) to alter the biophysical properties of lipid bilayers and in turn modulate cellular signaling pathways. In particular, previous results from our laboratory (Wang et al., BMC Genomics, 10, 356 (2009)) established that moderate strength static magnetic field (SMF) exposure altered cellular endpoints associated with neuronal function and differentiation. Building on this background, the current paper investigated SMF by focusing on the adenosine A2A receptor (A2AR) in the PC12 rat adrenal pheochromocytoma cell line that displays metabolic features of Parkinson's disease (PD). Methodology and Principal Findings SMF reproduced several responses elicited by ZM241385, a selective A2AR antagonist, in PC12 cells including altered calcium flux, increased ATP levels, reduced cAMP levels, reduced nitric oxide production, reduced p44/42 MAPK phosphorylation, inhibited proliferation, and reduced iron uptake. SMF also counteracted several PD-relevant endpoints exacerbated by A2AR agonist CGS21680 in a manner similar to ZM241385; these include reduction of increased expression of A2AR, reversal of altered calcium efflux, dampening of increased adenosine production, reduction of enhanced proliferation and associated p44/42 MAPK phosphorylation, and inhibition of neurite outgrowth. Conclusions and Significance When measured against multiple endpoints, SMF elicited qualitatively similar responses as ZM241385, a PD drug candidate. Provided that the in vitro results presented in this paper apply in vivo, SMF holds promise as an intriguing non-invasive approach to treat PD and potentially other neurological disorders. PMID:21079735

  4. Neuroprotective effect of lycopene against MPTP induced experimental Parkinson's disease in mice.

    PubMed

    Prema, Asokan; Janakiraman, Udaiyappan; Manivasagam, Thamilarasan; Arokiasamy, Justin Thenmozhi

    2015-07-10

    Parkinson's disease (PD) is the second most common neurodegenerative disorder that mainly affects the movement of the aged populations. Lycopene is a carotenoid with unique pharmacological properties and its efficacy on experimental Hunginton's disease and brain ischemia has shown intense neuroprotective effects. The present study was aimed to explore the neuroprotective effect of lycopene against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced PD mice. Administration of lycopene (5, 10 and 20mg/kg/day orally) protected MPTP induced depletion of striatal dopamine (DA) and its metabolites in a dose dependent manner. It also attenuated MPTP-induced oxidative stress and motor abnormalities seen in PD mice. Our western blot studies showed that treatment with lycopene reversed MPTP induced apoptosis may be due to its antioxidant and antiapoptotic properties. As to conclude, lycopene reverses neurochemical deficts, oxidative stress, apoptosis and physiological abnormalities in PD mice and offer promise strategy in the treatment of this neurodegenerative disease. PMID:25980996

  5. 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

  6. Neuroprotective effects of madecassoside in early stage of Parkinson's disease induced by MPTP in rats.

    PubMed

    Xu, Chang-Liang; Qu, Rong; Zhang, Jin; Li, Lu-Fan; Ma, Shi-Ping

    2013-10-01

    In this study, we investigated the neuroprotective effects of madecassoside, isolated from the Chinese medicinal herb Centella asiatica, in the rat model of early phase of parkinsonism. During intragastric administrations of madecassoside for 7 days, the rats were injected with MPTP on the 7th day. And for the following 14 days, madecassoside were also administered. On the 14th day, the behavioral tests were assessed after 1h of administration. And then, the rats were sacrificed, substantia nigra and striatum were dissected. The content of DA, MDA, GSH, and Bcl-2/Bax gene expression levels and BDNF protein level was determined. Treatment with madecassoside was found to improve locomotor dysfunction and to protect dopaminergic neuron by antagonizing MPTP induced neurotoxicity. Madecassoside significantly attenuated the MPTP-induced reduction of dopamine in the striatum. The MDA contents were significantly decreased while the GSH levels, Bcl-2/Bax ratio and protein expression of BDNF were significantly increased in madecassoside treated groups. These results indicated that madecassoside was effective in recovering MPTP-induced early signs of parkinsonism via its neuroprotective effects including reversing the depletion of DA, antioxidant activity, increasing ratio of Bcl-2/Bax, increasing protein expression of BDNF. PMID:23876367

  7. Drug-induced arrhythmia: pharmacogenomic prescribing?

    PubMed Central

    Behr, Elijah R.; Roden, Dan

    2013-01-01

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

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

    PubMed

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

    2014-02-01

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

  9. 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

  10. Drug-induced Sweet's syndrome by aceclofenac.

    PubMed

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

    2011-12-01

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

  11. Pharmacogenetics of antiepileptic drug-induced hypersensitivity.

    PubMed

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

    2014-04-01

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

  12. Antithyroid drug-induced fetal goitrous hypothyroidism

    Microsoft Academic Search

    Sofie Bliddal; Åse Krogh Rasmussen; Karin Sundberg; Vibeke Brocks; Ulla Feldt-Rasmussen

    2011-01-01

    Maternal overtreatment with antithyroid drugs can induce fetal goitrous hypothyroidism. This condition can have a critical effect on pregnancy outcome, as well as on fetal growth and neurological development. The purpose of this Review is to clarify if and how fetal goitrous hypothyroidism can be prevented, and how to react when prevention has failed. Understanding the importance of pregnancy-related changes

  13. Median nerve somatosensory evoked potentials. Apomorphine-induced transient potentiation of frontal components Clin. Parkinson's disease and in parkinsonism

    Microsoft Academic Search

    Paolo M. Rossini; M. Antonietta Bassetti; Patrizio Pasqualetti

    1995-01-01

    Somatosensory evoked potentials (SEPs) to median nerve stimulation have been recorded from parietal and frontal districts Clin. 43 parkinsonians, 17 patients with parkinsonism and 35 healthy controls matched for age and sex. Latency\\/ amplitude characteristics of the parietal P14-N20-P25 and of the frontal P20-N30-P40 wave complexes before and after (10, 20, 30 and 60 min) subcutaneous administration of apomorphine chloride

  14. Dopaminergic Neurotoxicant 6-OHDA Induces Oxidative Damage through Proteolytic Activation of PKC? in Cell Culture and Animal Models of Parkinson’s Disease

    PubMed Central

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

    2011-01-01

    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 ?M) for 24h 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 ?M) significantly attenuated 6-OHDA-induced caspase activities. Interestingly, 6-OHDA induced proteolytic cleavage and activation of protein kinase C delta (PKC?) was completely suppressed by treatment with a caspase-3-specific inhibitor, Z-DEVD-FMK (50 ?M). Furthermore, expression of caspase-3 cleavage site-resistant mutant PKC?D327A and kinase dead PKC?K376R or siRNA-mediated knockdown of PKC? protected against 6-OHDA-induced neuronal cell death, suggesting that caspase-3-dependent PKC? promotes oxidative stress-induced dopaminergic degeneration. Suppression of PKC? expression by siRNA also effectively protected N27 cells from 6-OHDA-induced apoptotic cell death. PKC? 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?D327A protein protected against 6-OHDA-induced PKC? activation in mouse substantia nigra. Collectively, these results strongly suggest that proteolytic activation of PKC? is a key downstream event in dopaminergic degeneration, and these results may have important translational value for development of novel treatment strategies for PD. PMID:21846476

  15. A single-center, cross-sectional prevalence study of impulse control disorders in Parkinson disease: association with dopaminergic drugs.

    PubMed

    Poletti, Michele; Logi, Chiara; Lucetti, Claudio; Del Dotto, Paolo; Baldacci, Filippo; Vergallo, Andrea; Ulivi, Martina; Del Sarto, Simone; Rossi, Giuseppe; Ceravolo, Roberto; Bonuccelli, Ubaldo

    2013-10-01

    The current study aimed at establishing the prevalence of impulse control disorders (ICDs) in patients with Parkinson disease (PD) and their association with demographic, drug-related, and disease-related characteristics. We performed a single-center cross-sectional study of 805 PD patients. Impulse control disorders were investigated with the Questionnaire for Impulsive Compulsive Disorders in Parkinson's Disease; also comorbid neuropsychiatric complications (dementia, delusions, visual hallucinations) were investigated with clinical interviews and ad hoc instruments (Parkinson Psychosis Questionnaire and Neuropsychiatry Inventory). Impulse control disorders were identified in 65 patients (prevalence, 8.1%), with pathological gambling and hypersexuality the most frequent. Impulse control disorders were present in 57 of 593 cognitively preserved patients (prevalence, 9.6%) and in 8 of 212 demented patients (prevalence, 3.8%). Impulse control disorders were significantly associated with dopamine agonists (odds ratio [OR], 5.50; 95% confidence interval [CI], 2.60-12.46; P < 0.0001) and levodopa (OR, 2.43; 95% CI, 1.06-6.35; P = 0.034). Impulse control disorders frequency was similar for pramipexole and ropinirole (16.6% vs 12.5%; OR, 1.45; 95% CI, 0.79-2.74; P = 0.227). Additional variables associated with ICDs were male sex and younger age. These findings suggested that dopaminergic treatments in PD are associated with increased odds of having an ICD, but also other demographic and clinical variables are associated with ICDs, suggesting the multifactorial nature of the ICD phenomenon in PD. PMID:23857310

  16. Dopamine mediated iron release from ferritin is enhanced at higher temperatures: Possible implications for fever-induced Parkinson's disease

    NASA Astrophysics Data System (ADS)

    Babincová, Melánia; Babinec, Peter

    2005-05-01

    A new molecular mechanism is proposed to explain the pathogenesis of fever-induced Parkinson's disease. This proposal is based on dopamine and 6-hydroxydopamine-mediated free iron release from ferritin magnetic nanoparticles, which is enhanced at higher temperatures, and which may lead to substantial peroxidation and injury of lipid biomembranes of the substantia nigra in the brain.

  17. Methods to characterize spontaneous and startle-induced locomotion in a rotenone-induced Parkinson's disease model of Drosophila.

    PubMed

    Liao, Jennifer; Morin, Laura W; Ahmad, S Tariq

    2014-01-01

    Parkinson's disease is a neurodegenerative disorder that results from the degeneration of dopaminergic neurons in the central nervous system, primarily in the substantia nigra. The disease causes motor deficiencies, which present as rigidity, tremors and dementia in humans. Rotenone is an insecticide that causes oxidative damage by inhibiting the function of the electron transport chain in mitochondria. It is also used to model Parkinson's disease in the Drosophila. Flies have an inherent negative geotactic response, which compels them to climb upwards upon being startled. It has been established that rotenone causes early mortality and locomotion defects that disrupt the flies' ability to climb after they have been tapped downwards. However, the effect of rotenone on spontaneous movement is not well documented. This study outlines two sensitive, reproducible, and high throughput assays to characterize rotenone-induced deficiencies in short-term startle-induced locomotion and long-term spontaneous locomotion in Drosophila. These assays can be conveniently adapted to characterize other Drosophila models of locomotion defects and efficacy of therapeutic agents. PMID:25178101

  18. [Dermal application of lisuride on parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the common marmoset and on cases with Parkinson's disease].

    PubMed

    Nomoto, M; Iwata, S; Irifune, M; Kaseda, S; Osame, M; Fukuda, T

    1998-06-01

    Dermal administration is a nonoral drug delivery system that can keep the concentration of a drug in the body at a proper level for a long time. This is suitable especially in patients in the advanced stages of Parkinson's disease with a wearing-off phenomenon (short duration of effects on antiparkinsonian drugs), or in postoperative patients who cannot be treated with oral administration. We studied the effects of lisuride, a dopamine receptor agonist, in the dermal application on MPTP-treated common marmosets and on 5 patients with Parkinson's disease. Lisuride was applied to 4 x 5 cm of skin of the abdomen of monkeys. In patients with Parkinson's disease, lisuride was applied to the skin of the chest. The agent reversed akinesia of MPTP-treated animals within 30 min following the application and relieved the animal of parkinsonism for 5 days at a dose of 2 mg/kg. In patients, the dermal application of lisuride increased the duration of the ON period at doses of 1 to 2 mg/kg. These results suggest that the dermal application of lisuride is a useful treatment in parkinsonism. PMID:9800199

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

    Microsoft Academic Search

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

    2004-01-01

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

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

    PubMed Central

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

    2013-01-01

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

  1. [Metabolic activation of azaheterocyclics induced dopaminergic toxicity: possible candidate neurotoxins underlying idiopathic Parkinson's disease].

    PubMed

    Matsubara, K

    1998-10-01

    In 1983, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a contaminant of "synthetic heroin", has been reported to induce parkinsonian symptoms in humans, who were responsive to L-DOPA therapy, as a result of the degeneration of nigrostriatal neurons. The "MPTP story" hypothesizes that Parkinson's disease may be initiated or percipitated by environmental and/or endogenous toxins by a mechanism similar to that of MPTP in genetically-predisposed individuals. Several classes of heterocyclic molecules structurally related to MPTP have been advanced as possible neurotoxicant precursors underlying the nigrostriatal degeneration in Parkinson's disease. Indoleamine-related beta-carbolines (beta Cs), a class of heterocyclics which are basically plant alkaloids, are proposed as the most promising natural MPTP-like toxicants or protoxicants. In this article, beta Cs and N-methylated beta C cations are reviewed with regards to their formation, bioactivation, toxicity and presence in the human central nervous system. The enzymes in mammalian brain particulate fractions methylate beta Cs, sequentially forming 2-mono-[N]-methylated (2-Me beta C+s) and neurotoxic 2,9-di-[N, N']-methylated (2,9-Me2 beta C+s) beta-carbolinium cations. These beta C+s are structural analogs of 1-methyl-4-phenylpyridinium ion (MPP+), an active metabolite of MPTP, with a nitrogen bridge. The beta C+s not only inhibit DA reuptake and tyrosine hydroxylase, but also function as NADH-linked respiratory inhibitors in isolated mitochondria. The quarternization of beta C strikingly increased the affinity for dopamine transporter with 2-10 times greater Km and 10 times smaller Vmax values than MPP+. Furthermore, we have found higher concentrations of beta C+s localized in the nigra than in the cortex, and observed the S-adenosyl-L-methionine-dependent methylation of 2[beta]- and 9[indole]-nitrogens of beta Cs in non-parkinsonian human brains. Moreover, the cerebrospinal fluid levels of these beta C+s are higher in parkinsonian than non-parkinsonian patients. Simple beta-carboline induced parkinsonian-like symptoms in mice via N-methylation. These results indicated that beta C is a selective dopaminergic toxin precursor, that is sequentially methylated to form 2,9-Me2 beta C+ that could be an underlying factor in idiopathic Parkinson's disease. PMID:10077975

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

    PubMed Central

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

    2014-01-01

    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

  3. 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

  4. 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

  5. HIV transactivator of transcription enhances methamphetamine-induced Parkinson's-like behavior in the rats.

    PubMed

    Liu, Zengxun; Shi, Zhenchun; Liu, Jintong; Wang, Yang

    2014-06-01

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

  6. Salvianolic Acid B Attenuates Toxin-Induced Neuronal Damage via Nrf2-Dependent Glial Cells-Mediated Protective Activity in Parkinson’s 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 Parkinson’s 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

  7. GRK3 suppresses L-DOPA-induced dyskinesia in the rat model of Parkinson’s 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 Parkinson’s 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

  8. Targeting ?-arrestin2 in the treatment of l-DOPA-induced dyskinesia in Parkinson's disease.

    PubMed

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

    2015-05-12

    Parkinson's 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-DOPA-induced 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 Parkinson's 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-hydroxydopamine-treated mice or rats and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated 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

  9. Headache in Drug-Induced Aseptic Meningitis.

    PubMed

    Holle, Dagny; Obermann, Mark

    2015-07-01

    Drug-associated headache is a quite common phenomenon, e.g. as a side effect of distinct substances such as nitric oxide or as a result of medication overuse of analgesic drugs. A different drug-associated headache entity is headache in drug-induced aseptic meningitis (DIAM). This is a rare disorder and only described in few case reports or smaller case series. One of the main clinical features of DIAM despite fever is headache. Based on the literature, no typical or even pathognomonical clinical presentation of this headache entity can be described. Sometimes, migrainous features might be present, and treatment response to triptans was reported in single case reports. Headache in DIAM seems to be emerging from sterile meningeal inflammation, which is suggested to represent the underlying pathology in DIAM. Headache in DIAM usually ceases when treated sufficiently, mainly through termination or withdrawal of the causing agent. Migraine as a predisposing factor of DIAM has been discussed previously but remains unproven. PMID:26049774

  10. Drug-Induced Glomerular Disease: Attention Required!

    PubMed

    Radhakrishnan, Jai; Perazella, Mark A

    2015-07-01

    Drugs and toxins frequently are associated with the development of various types of acute kidney disease and CKD. Although medications are a widely known cause of tubulointerstitial damage, drug-related glomerular injury is not well appreciated but nonetheless, important. Glomerular damage that occurs after exposure to medications can be caused by direct cellular injury involving the mesangial, endothelial, or visceral epithelial cells (podocytes). Examples include nodular glomerulosclerosis associated with smoking and endothelial injury with thrombotic microangiopathy from a number of medications. Podocyte injury with the development of a minimal change or FSGS lesion has also been described with various medications. Glomerulopathies may also be associated with drug-induced immune-mediated processes. Through various pathways, drugs may promote the formation of a number of antibodies, which may, ultimately, affect the glomerulus. Examples include lupus-like renal lesions and ANCA-related pauci-immune vasculitis. It is critical to recognize these conditions early, because in many patients, there is improvement in renal parameters on stopping the offending medication. PMID:25876771

  11. Current approaches to the treatment of Parkinson’s disease

    PubMed Central

    Jankovic, Joseph; Aguilar, L Giselle

    2008-01-01

    Enormous progress has been made in the treatment of Parkinson’s disease (PD). As a result of advances in experimental therapeutics, many promising therapies for PD are emerging. Levodopa remains the most potent drug for controlling PD symptoms, yet is associated with significant complications such as the “wearing off” effect, levodopa-induced dyskinesias and other motor complications. Catechol-o-methyl-transferase inhibitors, dopamine agonists and nondopaminergic therapy are alternative modalities in the management of PD and may be used concomitantly with levodopa or one another. The neurosurgical treatment, focusing on deep brain stimulation, is reviewed briefly. Although this review has attempted to highlight the most recent advances in the treatment of PD, it is important to note that new treatments are not necessarily better than the established conventional therapy and that the treatment options must be individualized and tailored to the needs of each individual patient. PMID:19043519

  12. Antithyroid drug-induced fetal goitrous hypothyroidism.

    PubMed

    Bliddal, Sofie; Rasmussen, Ase Krogh; Sundberg, Karin; Brocks, Vibeke; Feldt-Rasmussen, Ulla

    2011-07-01

    Maternal overtreatment with antithyroid drugs can induce fetal goitrous hypothyroidism. This condition can have a critical effect on pregnancy outcome, as well as on fetal growth and neurological development. The purpose of this Review is to clarify if and how fetal goitrous hypothyroidism can be prevented, and how to react when prevention has failed. Understanding the importance of pregnancy-related changes in maternal thyroid status when treating a pregnant woman is crucial to preventing fetal goitrous hypothyroidism. Maternal levels of free T(4) are the most consistent indication of maternal and fetal thyroid status. In patients with fetal goitrous hypothyroidism, intra-amniotic levothyroxine injections improve fetal outcome. The best way to avoid maternal overtreatment with antithyroid drugs is to monitor closely the maternal thyroid status, especially estimates of free T(4) levels. PMID:21403664

  13. Neural correlates of STN DBS-induced cognitive variability in Parkinson disease

    PubMed Central

    Campbell, M.C.; Karimi, M.; Weaver, P.M.; Wu, J.; Perantie, D.C.; Golchin, N.A.; Tabbal, S.D.; Perlmutter, J. S.; Hershey, T.

    2008-01-01

    Background Although deep brain stimulation of the subthalamic nucleus (STN DBS) in Parkinson disease (PD) improves motor function, it has variable effects on working memory (WM) and response inhibition (RI) performance. The purpose of this study was to determine the neural correlates of STN DBS-induced variability in cognitive performance. Methods We measured bilateral STN DBS-induced blood flow changes (PET and [15O]-water on one day) in the supplementary motor area (SMA), dorsolateral prefrontal cortex (DLPFC), anterior cingulate cortex (ACC), and right inferior frontal cortex (rIFC) as well as in exploratory ROIs defined by published meta-analyses. STN DBS-induced WM and RI changes (Spatial Delayed Response and Go-No-Go on the next day) were measured in 24 PD participants. On both days, participants withheld PD medications overnight and conditions (OFF v. ON) were administered in a counterbalanced, double-blind manner. Results As predicted, STN DBS-induced DLPFC blood flow change correlated with change in WM, but not RI performance. Furthermore, ACC blood flow change correlated with change in RI but not WM performance. For both relationships, increased blood flow related to decreased cognitive performance in response to STN DBS. Of the exploratory regions, only blood flow changes in DLPFC and ACC were correlated with performance. Conclusions These results demonstrate that variability in the effects of STN DBS on cognitive performance relates to STN DBS-induced cortical blood flow changes in DLPFC and ACC. This relationship highlights the need to further understand the factors that mediate the variability in neural and cognitive response to STN DBS. PMID:18682259

  14. Symptomatic Models of Parkinson's Disease and L-DOPA-Induced Dyskinesia in Non-human Primates.

    PubMed

    Johnston, Tom M; Fox, Susan H

    2015-01-01

    Models of Parkinson's disease (PD) can be produced in several non-human primate (NHP) species by applying neurotoxic lesions to the nigrostriatal dopamine pathway. The most commonly used neurotoxin is MPTP, a compound accidentally discovered as a contaminant of street drugs. Compared to other neurotoxins, MPTP has the advantage of crossing the blood-brain barrier and can thus be administered systemically. MPTP-lesioned NHPs exhibit the main core clinical features of PD. When treated with L-DOPA, these NHP models develop involuntary movements resembling the phenomenology of human dyskinesias. In old-world NHP species (macaques, baboons), choreic and dystonic dyskinesias can be readily distinguished and quantified with specific rating scales. More recently, certain non-motor symptoms relevant to human PD have been described in L-DOPA-treated MPTP-NHPs, including a range of neuropsychiatric abnormalities and sleep disturbances. The main shortcomings of MPTP-NHP models consist in a lack of progression of the underlying neurodegenerative lesion, along with an inability to model the intracellular protein-inclusion pathology typical of PD. The strength of MPTP-NHP models lies in their face and predictive validity for symptomatic treatments of parkinsonian motor features. Indeed, these models have been instrumental to the development of several medical and surgical approaches that are currently applied to treat PD. PMID:25158623

  15. 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

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

    PubMed

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

    2014-01-01

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

  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(3)/D(2)/D(1) 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 (C max), 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(3)/D(2)/D(1) dopamine receptor agonist in the treatment of PD and RLS. PMID:25795100

  18. Drug-induced regeneration in adult mice.

    PubMed

    Zhang, Yong; Strehin, Iossif; Bedelbaeva, Khamilia; Gourevitch, Dmitri; Clark, Lise; Leferovich, John; Messersmith, Phillip B; Heber-Katz, Ellen

    2015-06-01

    Whereas amphibians regenerate lost appendages spontaneously, mammals generally form scars over the injury site through the process of wound repair. The MRL mouse strain is an exception among mammals because it shows a spontaneous regenerative healing trait and so can be used to investigate proregenerative interventions in mammals. We report that hypoxia-inducible factor 1? (HIF-1?) is a central molecule in the process of regeneration in adult MRL mice. The degradation of HIF-1? protein, which occurs under normoxic conditions, is mediated by prolyl hydroxylases (PHDs). We used the drug 1,4-dihydrophenonthrolin-4-one-3-carboxylic acid (1,4-DPCA), a PHD inhibitor, to stabilize constitutive expression of HIF-1? protein. A locally injectable hydrogel containing 1,4-DPCA was designed to achieve controlled delivery of the drug over 4 to 10 days. Subcutaneous injection of the 1,4-DPCA/hydrogel into Swiss Webster mice that do not show a regenerative phenotype increased stable expression of HIF-1? protein over 5 days, providing a functional measure of drug release in vivo. Multiple peripheral subcutaneous injections of the 1,4-DPCA/hydrogel over a 10-day period led to regenerative wound healing in Swiss Webster mice after ear hole punch injury. Increased expression of the HIF-1? protein may provide a starting point for future studies on regeneration in mammals. PMID:26041709

  19. 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 (Tpeak–Tend, Tp–Te) as an index of SDR and transmural dispersion of repolarization, in particular. PMID:18651395

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

    PubMed

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

    2013-12-01

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

  1. NMR Fingerprints of the Drug-like Natural-Product Space Identify Iotrochotazine A: A Chemical Probe to Study Parkinson’s Disease**

    PubMed Central

    Grkovic, Tanja; Pouwer, Rebecca H; Vial, Marie-Laure; Gambini, Luca; Noël, 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 Parkinson’s 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

  2. 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 10meter walking test (10MWT), Timed Up and Go test (TUG) and 360° 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, 10MWT, 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

  3. PINK1-associated Parkinson's disease is caused by neuronal vulnerability to calcium-induced cell death.

    PubMed

    Gandhi, Sonia; Wood-Kaczmar, Alison; Yao, Zhi; Plun-Favreau, Helene; Deas, Emma; Klupsch, Kristina; Downward, Julian; Latchman, David S; Tabrizi, Sarah J; Wood, Nicholas W; Duchen, Michael R; Abramov, Andrey Y

    2009-03-13

    Mutations in PINK1 cause autosomal recessive Parkinson's disease. PINK1 is a mitochondrial kinase of unknown function. We investigated calcium homeostasis and mitochondrial function in PINK1-deficient mammalian neurons. We demonstrate physiologically that PINK1 regulates calcium efflux from the mitochondria via the mitochondrial Na(+)/Ca(2+) exchanger. PINK1 deficiency causes mitochondrial accumulation of calcium, resulting in mitochondrial calcium overload. We show that calcium overload stimulates reactive oxygen species (ROS) production via NADPH oxidase. ROS production inhibits the glucose transporter, reducing substrate delivery and causing impaired respiration. We demonstrate that impaired respiration may be restored by provision of mitochondrial complex I and II substrates. Taken together, reduced mitochondrial calcium capacity and increased ROS lower the threshold of opening of the mitochondrial permeability transition pore (mPTP) such that physiological calcium stimuli become sufficient to induce mPTP opening in PINK1-deficient cells. Our findings propose a mechanism by which PINK1 dysfunction renders neurons vulnerable to cell death. PMID:19285945

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

    PubMed

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

    2013-05-01

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

  5. [Synchrotron radiation-based FTIR microspectroscopy study of 6-hydroxydopamine induced Parkinson's disease cell model].

    PubMed

    Zhu, Hong-Yan; Pei, Xiao; Wu, Ling-Yan; Qi, Ze-Ming; Wang, Yu-Yin; Liu, Bo; Zhou, Hou-Guang

    2013-03-01

    SH-SY5Y cell line treated with 6-hydroxydopamine (6-OHDA) is a classical Parkinson's disease (PD). In the present study, synchrotron-based Fourier transform infrared (FTIR) microspectroscopy was used to analyze the biochemical composition of SH-SY5Y cell line treated with 6-OHDA. The detailed spectral analyses show the significant changes in cellular compositions such as lipids, proteins and nucleic acids in SH-SY5Y cells treated with 6-OHDA compared to control SH-SY5Y cells. As a result, the unsaturation levels of phospholipids decrease in SH-SY5Y cells treated with 6-OHDA compared to control cells, the analysis of protein secondary structure shows the significantly higher ratio of beta-sheet in PD cells compared to that of control cells, and the content of nuclear acid is highly decreased compared to that of control cells, suggesting that 6-OHDA induces the serious oxidative damage in SH-SY5Y cells. These findings suggest that SR-FTIR is an effective and precise technical tool to probe the biochemical changes of cells and then evaluate the pathological damage in cells. PMID:23705433

  6. 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 ...

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

    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.

    2014-01-01

    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

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

    Microsoft Academic Search

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

    2003-01-01

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

  10. An update on drug induced liver injury.

    PubMed

    Rangnekar, A S; Fontana, R J

    2011-06-01

    Drug induced liver injury (DILI) is an uncommon cause of acute and chronic liver injury of increasing importance to patients, clinicians, and regulators. The incidence of DILI due to an individual agent is not well defined but population-based studies suggest that the overall incidence of DILI may be as high as 10 to 15 cases per 100000 patient years. Bona fide risk factors for DILI are also not well established, but ongoing multicenter registry studies such as the Drug Induced Liver Injury Network are attempting to identify the role of genetic, environmental, and immunological factors in DILI pathogenesis and outcomes. Acute hepatocellular injury (~50%) is more common than mixed or cholestatic liver injury but jaundiced DILI subjects with either type of liver injury have a ~10% risk of short-term mortality. Antibiotics are the most commonly implicated agents associated with DILI, but there are emerging reports of liver injury associated with the use of a multitude of herbal and dietary supplements. Despite their widespread use, the HMG-CoA reductase inhibitors or statins are an uncommon cause of idiosyncratic DILI. Furthermore, recent studies have shown that statins are actually safe and efficacious to use in hyperlipidemic patients with chronic liver disease. Acetaminophen hepatotoxicity remains a leading cause of severe acute liver injury. Limiting the amount of acetaminophen in prescription narcotic products may help reduce the incidence of future non-intentional overdoses but educating patients and providers of the multitude of over the counter products that contain acetaminophen is also recommended. PMID:21587150

  11. The role of calcium channel blockers and resveratrol in the prevention of paraquat-induced parkinsonism in Drosophila melanogaster: a locomotor analysis.

    PubMed

    Bagatini, Pamela Brambilla; Saur, Lisiani; Rodrigues, Mariana Freitas; Bernardino, Guilherme Cardoso; Paim, Mariana Fontoura; Coelho, Guilherme Peres; Silva, Daniele Vieira da; de Oliveira, Raquel Mattos; Schirmer, Helena; Souto, André Arigony; Vianna, Mônica Ryff Moreira Roca; Xavier, Léder Leal

    2011-06-01

    Studies have suggested that neuronal loss in Parkinson's disease (PD) could be related to the pacemaker activity of the substantia nigra pars compacta generated by L-type Ca(v) 1.3 calcium channels, which progressively substitute voltage-dependent sodium channels in this region during aging. Besides this mechanism, which leads to increases in intracellular calcium, other factors are also known to play a role in dopaminergic cell death due to overproduction of reactive oxygen species. Thus, dihydropyridines, a class of calcium channel blockers, and resveratrol, a polyphenol that presents antioxidant properties, may represent therapeutic alternatives for the prevention of PD. In the present study, we tested the effects of the dihydropyridines, isradipine, nifedipine, and nimodipine and of resveratrol upon locomotor behavior in Drosophila melanogaster. As previously described, paraquat induced parkinsonian-like motor deficits. Moreover, none of the drugs tested were able to prevent the motor deficits produced by paraquat. Additionally, isradipine, nifedipine, resveratrol, and ethanol (vehicle), when used in isolation, induced motor deficits in flies. This study is the first demonstration that dyhidropyridines and resveratrol are unable to reverse the locomotor impairments induced by paraquat in Drosophila melanogaster. PMID:21523449

  12. Lipid-lowering drugs in the MPTP mouse model of Parkinson's disease: Fenofibrate has a neuroprotective effect, whereas bezafibrate and HMG-CoA reductase inhibitors do not

    Microsoft Academic Search

    Alexandre Kreisler; Patrick Gelé; Jean-François Wiart; Michel Lhermitte; Alain Destée; Régis Bordet

    2007-01-01

    We tested the ability of simvastatin, atorvastatin, fenofibrate and bezafibrate (two synthetic peroxisome proliferator-activated receptor-alpha (PPAR-alpha) agonists) to prevent dopaminergic cell death in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease. Tyrosine hydroxylase (TH) immunochemistry was performed 8 days after acute MPTP intoxication. When orally administered for the week prior to intoxication and a week thereafter, fenofibrate prevented the MPTP-induced dopaminergic

  13. Drug-Induced Glomerular Disease: Immune-Mediated Injury.

    PubMed

    Hogan, Jonathan J; Markowitz, Glen S; Radhakrishnan, Jai

    2015-07-01

    Drug-induced autoimmune disease was initially described decades ago, with reports of vasculitis and a lupus-like syndrome in patients taking hydralazine, procainamide, and sulfadiazine. Over the years, multiple other agents have been linked to immune-mediated glomerular disease, often with associated autoantibody formation. Certain clinical and laboratory features may distinguish these entities from their idiopathic counterparts, and making this distinction is important in the diagnosis and management of these patients. Here, drug-induced, ANCA-associated vasculitis, drug-induced lupus, and drug-associated membranous nephropathy are reviewed. PMID:26092827

  14. Ameliorative effect of Sida cordifolia in rotenone induced oxidative stress model of Parkinson's disease.

    PubMed

    Khurana, Navneet; Gajbhiye, Asmita

    2013-12-01

    Present study focused on the evaluation of aqueous extract of Sida cordifolia (AESC), and its different fractions; hexane (HFSC), chloroform (CFSC) and aqueous (AFSC), against rotenone induced biochemical, neurochemical, histopathological and behavioral alterations in a rat model of Parkinson's disease (PD). An estimation of the level of thiobarbituric acid reactive substances (TBARS), glutathione (GSH) and catalase (CAT) along with superoxide anion generation (SAG) in different brain regions (cortex, midbrain and cerebellum) was carried out to assess biochemical changes. Behavioral evaluation tests (catalepsy, rearing behavior and posture instability) and neurochemical estimations (norepinephrine, dopamine and serotonin level) along with histopathological evaluations of different brain regions were also performed. The varying doses (50, 100, 250mg/kg; p.o.) of different test treatments (AESC, HFSC, CFSC and AFSC) were co-administered along with rotenone (2mg/kg; s.c.), for a period of 35 days to rats of various groups and compared with rotenone per se (negative control) and l-deprenyl (positive control; 10mg/kg; p.o.) treated groups for the above mentioned parameters. The increase in catalepsy and posture instability along with decrease in rearing behavior observed due to rotenone treatment was significantly attenuated by co-treatment with varying doses of AESC and AFSC. Results of the histopathological studies of different brain regions of rats showed eosinophilic lesions in the mid brain region due to rotenone treatment. The eosinophilic lesions were significantly attenuated in co-treated groups of AESC-100mg/kg and AFSC-100mg/kg. Rotenone induced oxidative damage, revealed by increased level of TBARS, SAG and decreased level of GSH and CAT in mid brain region of rats, was attenuated by the co-treatment of AESC and AFSC. The rotenone induced decrease of dopamine level in the midbrain region of rats was also attenuated by co-treatment of AESC-100mg/kg and AFSC-100mg/kg. The maximum effect in all the above activities was observed in AFSC (100mg/kg) treated group, which was comparable to l-deprenyl treated group. The HFSC and CFSC co-treatment failed to show significant attenuation of rotenone induced damage. These results indicate the possible therapeutic potential of most polar fraction of AESC i.e. AFSC in PD by virtue of its antioxidative actions. PMID:23994302

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

    Microsoft Academic Search

    Adrian Carter; Polly Ambermoon; Wayne D. Hall

    2011-01-01

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

  16. Signal Transduction Pathways Involved in Drug-Induced Liver Injury

    Microsoft Academic Search

    Derick Han; Mie Shinohara; Maria D. Ybanez; Behnam Saberi; Neil Kaplowitz

    Hepatocyte death following drug intake is the critical event in the clinical manifestation of drug-induced liver injury (DILI).\\u000a Traditionally, hepatocyte death caused by drugs had been attributed to overwhelming oxidative stress and mitochondria dysfunction\\u000a caused by reactive metabolites formed during drug metabolism. However, recent studies have also shown that signal transduction\\u000a pathways activated\\/inhibited during oxidative stress play a key role

  17. Interstitial Lung Disease Induced by Drugs and Radiation

    Microsoft Academic Search

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

    2004-01-01

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

  18. The rotenone-induced rat model of Parkinson's disease: behavioral and electrophysiological findings.

    PubMed

    von Wrangel, Christof; Schwabe, Kerstin; John, Nadine; Krauss, Joachim K; Alam, Mesbah

    2015-02-15

    Exposure to rotenone leads to parkinsonian features, such as loss of dopaminergic neurons in the substantia nigra and motor impairment, however, the validity of this model has recently been questioned. In rodent and monkey models of Parkinson's disease (PD) abnormal neuronal activity in the basal ganglia motor loop has been described, with hyperactivity of the subthalamic nucleus (STN) similar to that found in PD. The present study aims at providing new and more specific evidence for the validity of the rotenone rat model of PD by examining whether neuronal activity in the STN is altered. Male Sprague Dawley rats were treated with rotenone injections (2.5mg/kg bodyweight intraperitoneally) for 60 days. Behavioral analysis showed an impairment in the rotarod and hanging wire test in the rotenone group (p<0.05), accompanied by a decline in tyrosine hydroxylase immunoreactive neurons in the nigro-striatal region (p<0.001). Thereafter, single unit (SU) activities and local field potentials were recorded in the STN in urethane anesthetized rats. The SU analysis revealed a higher neuronal discharge rate (p<0.001), more bursts per minute (p=0.006) and a higher oscillatory activity (p=0.008) in the STN of rotenone treated rats. Spectral analysis showed an increase of relative beta power in the STN as well as in the motor cortex. We found electrophysiological key features of PD pathology and pathophysiology in the STN of rotenone treated rats. Therefore, the rotenone-induced rat model of PD deserves further attention since it covers more aspects than dopamine depletion and implies the reproducibility of PD specific features. PMID:25446762

  19. From manganism to manganese-induced parkinsonism: a conceptual model based on the evolution of exposure.

    PubMed

    Lucchini, Roberto G; Martin, Christopher J; Doney, Brent C

    2009-01-01

    Manganism is a distinct medical condition from Parkinson's disease. Manganese exposure scenarios in the last century generally have changed from the acute, high-level exposure conditions responsible for the occurrence of manganism to chronic exposure to much lower levels. Such chronic exposures may progressively extend the site of manganese deposition and toxicity from the globus pallidus to the entire area of the basal ganglia, including the substantia nigra pars compacta involved in Parkinson's disease. The mechanisms of manganese neurotoxicity from chronic exposure to very low levels are not well understood, but promising information is based on the concept of susceptibility that may place individuals exposed to manganese at a higher risk for developing Parkinsonian disturbances. These conditions include mutations of genes which play important pathogenetic roles in both Parkinsonism and in the regulation of manganese transport and metabolism. Liver function is also important in manganese-related neurotoxicity and sub-clinical impairment may increase the risk of Parkinsonism. The purpose and scope of this report are to explore the literature concerning manganese exposure and potential subclinical effects and biological pathways, impairment, and development of diseases such as Parkinsonism and manganism. Inhalation and ingestion of manganese will be the focus of this report. PMID:20012385

  20. Drug-induced chronic pigmented purpura.

    PubMed

    Nishioka, K; Katayama, I; Masuzawa, M; Yokozeki, H; Nishiyama, S

    1989-06-01

    A close correlation between purpuric reaction and drugs was observed in seven cases of chronic pigmented purpura. The patients developed purpuric lesions after taking certain drugs for more than 3 years, were thiamine propyldisulfide in 2 cases, and chlordiazepoxide in 1 case. The purpuric lesions stopped recurring after removal of the drugs in the rest of the cases. It is suggested that drugs are among the etiological factors in chronic pigmented purpura. PMID:2507607

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

    PubMed

    Shi, Huifen; Song, Jie; Yang, Xuming

    2014-05-01

    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

  2. Identification of drugs inducing phospholipidosis by novel in vitro data.

    PubMed

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

    2012-11-01

    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 blood-brain barrier, and compounds that violate Lipinski's rule of five. Furthermore, we were able to show that PLD-inducing compounds applied in combination additively induce PLD. PMID:22945602

  3. 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

  4. Hallucinations and sleep disturbances in Parkinson's disease.

    PubMed

    Kulisevsky, Jaime; Roldan, Eliana

    2004-10-26

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

  5. Effect of Different Doses of Estrogen on the Nigrostriatal Dopaminergic System in Two 6-Hydroxydopamine-Induced Lesion Models of Parkinson’s Disease

    Microsoft Academic Search

    Marcela Ferreira Cordellini; Giovana Piazzetta; Karin Cristine Pinto; Ana Márcia Delattre; Francesca Matheussi; Ruither O. G. Carolino; Raphael Escorsim Szawka; Janete A. Anselmo-Franci; Anete Curte Ferraz

    2011-01-01

    Parkinson’s disease results from a degeneration of dopaminergic neurons of the substantia nigra pars compacta (SNpc) and it\\u000a is more prevalent in men than in women. Estrogen has neuroprotective action of the nigrostriatal dopaminergic (NSDA) neurons.\\u000a It was investigated whether differences in plasma 17?-estradiol (E2) levels alter the degree of neuroprotection in NSDA neurons.\\u000a Ovariectomized rats, implanted with subcutaneous capsules

  6. Parkinson's Disease

    MedlinePLUS

    ... is responsible for the core features, other affected locations contribute to the complicated picture of Parkinson's. Parkinson's disease is both chronic, meaning it lasts for a long time, and progressive, ...

  7. Drug-induced liver injury: mechanisms, types and biomarkers.

    PubMed

    Vinken, M; Maes, M; Vanhaecke, T; Rogiers, V

    2013-01-01

    Drug-induced liver injury is a ubiquitous issue in clinical settings and pharmaceutical industry. Hepatotoxicity elicited by drugs may be intrinsic or idiosyncratic, both which are driven by different molecular mechanisms. Recently, a unifying mechanistic model of drug-induced liver injury has been introduced. According to this model, drug-induced hepatotoxicity relies on 3 consecutive steps, namely an initial cellular insult that leads to the occurrence of mitochondrial permeability transition, which in turn ultimately burgeons into the onset of cell death. Clinically, drug-induced liver injury can be manifested in a number of acute and chronic conditions, including hepatitis, cholestasis, steatosis and fibrosis. These pathologies can be diagnosed and monitored by addressing well-established physical, clinical chemistry and histopathological biomarkers. In the last few years, several novel read-outs of drug-induced liver injury have been proposed, involving genetic, epigenetic, transcriptomic, proteomic and metabolomic parameters. These new concepts and recent developments in the field of drug-induced liver injury are revised in the current paper. PMID:23746274

  8. Fixed drug eruption - a sexually inducible reaction?

    PubMed

    Zawar, Vijay; Kirloskar, Milind; Chuh, Antonio

    2004-08-01

    We present three cases of diagnosed fixed drug eruption (FDE) in male patients with known drug sensitivity. In each case, the patient has refrained strictly from intake of the offending agent over many years. FDE developed after history of sexual contact with their spouses who were found to be receiving the same medication to which their partners were hypersensitive. We hypothesized that sexual transfer of the drug antigen occurs through the vaginal fluid on the sensitized area of the male genitalia. PMID:15307969

  9. Drug-Induced Glomerular Disease: Direct Cellular Injury.

    PubMed

    Markowitz, Glen S; Bomback, Andrew S; Perazella, Mark A

    2015-07-01

    The potential of medications to cause kidney injury is well known. Although nephrotoxicity is most commonly associated with injury in the tubulointerstitial compartment as either acute tubular necrosis or acute interstitial nephritis, a growing body of literature has also highlighted the potential for drug-induced glomerular lesions. This review surveys the three primary patterns of drug-induced glomerular diseases stratified by the cell type at which the glomerular lesion is focused: visceral epithelial cell (or podoctye) injury, endothelial cell injury, and mesangial cell injury. A number of commonly prescribed medications, including IFNs, bisphosphonates, nonsteroidal anti-inflammatory drugs, antiplatelet agents, and antiangiogenesis drugs, that are both prescribed and available over the counter, have been implicated in these iatrogenic forms of glomerular disease. Recognition of these drug-induced etiologies of glomerular disease and rapid discontinuation of the offending agent are critical to maximizing the likelihood of renal function recovery. PMID:25862776

  10. Drug induced `softening' in phospholipid monolayers

    NASA Astrophysics Data System (ADS)

    Basak, Uttam Kumar; Datta, Alokmay; Bhattacharya, Dhananjay

    2015-06-01

    Compressibility measurements on Langmuir monolayers of the phospholipid Dimystoryl Phospatidylcholine (DMPC) in pristine form and in the presence of the Non-steroidal Anti-inflammatory Drug (NSAID) Piroxicam at 0.025 drug/lipid (D/L) molecular ratio at different temperatures, show that the monolayer exhibits large increase (and subsequent decrease) in compressibility due to the drug in the vicinity of the Liquid Expanded - Liquid Condensed (LE-LC) phase transition. Molecular dynamics simulations of the lipid monolayer in presence of drug molecules show a disordering of the tail tilt, which is consistent with the above result.

  11. Acute Hepatocellular Drug Induced Liver Injury Probably by Alfuzosin

    PubMed Central

    Cicek, Tufan; Gokturk, Huseyin Savas; Unler, Gulhan Kanat

    2015-01-01

    Alpha blockers are the drugs that exert their effects by binding to alpha receptors and relaxing smooth muscles and are currently used for treatment of benign prostate hyperplasia (BPH). These drugs are often tolerated well by the patients. However, they also possess some common side effects. Hepatotoxicity, on the other hand, is quite rare. We report herein a case with the rare complication of acute hepatocellular drug induced liver injury (DILI) by administration of Alfuzosin. PMID:25793140

  12. Parkinson’s disease - resources

    MedlinePLUS

    Resources - Parkinson's disease ... The following organizations are good resources for information on Parkinson's disease : The Michael J. Fox Foundation - www.michaeljfox.org National Institute of Neurological Disorders and Stroke - www. ...

  13. 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

  14. Drug-induced myoclonus: a French pharmacovigilance database study

    Microsoft Academic Search

    C. Brefel-Courbon; V. Gardette; F. Ory; J. L. Montastruc

    2006-01-01

    Various drugs have been reported to induce myoclonus. However, this adverse event is not well known because of the difficult diagnosis and the lack of pharmaco-epidemiological or controlled studies. As far as we know, there are only case reports. In the literature, antiparkinsonian medications, antipsychotics, antidepressants, anesthetics, opiates and anti-infectious drugs have been reported in the occurrence of myoclonus. In

  15. Drug-induced apoptosis in yeast

    Microsoft Academic Search

    B. Almeida; A. Silva; A. Mesquita; B. Sampaio-Marques; F. Rodrigues; P. Ludovico

    2008-01-01

    In order to alter the impact of diseases on human society, drug development has been one of the most invested research fields. Nowadays, cancer and infectious diseases are leading targets for the design of effective drugs, in which the primary mechanism of action relies on the modulation of programmed cell death (PCD). Due to the high degree of conservation of

  16. In silico modeling to predict drug-induced phospholipidosis

    SciTech Connect

    Choi, Sydney S.; Kim, Jae S.; Valerio, Luis G., E-mail: luis.valerio@fda.hhs.gov; 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–activity relationship (QSAR) modeling using machine learning approaches has shown promise with a large dataset of drugs but included unconfirmed data as well. In this study, we report the construction and validation of a battery of complementary in silico QSAR models using the FDA's updated database on phospholipidosis, new algorithms and predictive technologies, and in particular, we address high performance with a high-confidence dataset. The results of our modeling for DIPL include rigorous external validation tests showing 80–81% concordance. Furthermore, the predictive performance characteristics include models with high sensitivity and specificity, in most cases above ? 80% leading to desired high negative and positive predictivity. These models are intended to be utilized for regulatory toxicology applied science needs in screening new drugs for DIPL. - Highlights: • New in silico models for predicting drug-induced phospholipidosis (DIPL) are described. • The training set data in the models is derived from the FDA's phospholipidosis database. • We find excellent predictivity values of the models based on external validation. • The models can support drug screening and regulatory decision-making on DIPL.

  17. 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

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

    PubMed

    Jalalat, Sheila Z; Cohen, Philip R

    2013-10-01

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

  19. Parkinson’s Disease

    PubMed Central

    Boyd, James T.; Hamill, Robert W.; Maguire-Zeiss, Kathleen A.

    2015-01-01

    Parkinson’s disease (PD) is the most common age-related motoric neurodegenerative disease initially described in the 1800’s by James Parkinson as the ‘Shaking Palsy’. Loss of the neurotransmitter dopamine was recognized as underlying the pathophysiology of the motor dysfunction; subsequently discovery of dopamine replacement therapies brought substantial symptomatic benefit to PD patients. However, these therapies do not fully treat the clinical syndrome nor do they alter the natural history of this disorder motivating clinicians and researchers to further investigate the clinical phenotype, pathophysiology/pathobiology and etiology of this devastating disease. Although the exact cause of sporadic PD remains enigmatic studies of familial and rare toxicant forms of this disorder have laid the foundation for genome wide explorations and environmental studies. The combination of methodical clinical evaluation, systematic pathological studies and detailed genetic analyses have revealed that PD is a multifaceted disorder with a wide-range of clinical symptoms and pathology that include regions outside the dopamine system. One common thread in PD is the presence of intracytoplasmic inclusions that contain the protein, ?-synuclein. The presence of toxic aggregated forms of ?-synuclein (e.g., amyloid structures) are purported to be a harbinger of subsequent pathology. In fact, PD is both a cerebral amyloid disease and the most common synucleinopathy, that is, diseases that display accumulations of ?-synuclein. Here we present our current understanding of PD etiology, pathology, clinical symptoms and therapeutic approaches with an emphasis on misfolded ?-synuclein. PMID:23225012

  20. Bromocriptine in Parkinsonism

    Microsoft Academic Search

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

    1974-01-01

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

  1. The hidden side of drug action: Brain temperature changes induced by neuroactive drugs

    PubMed Central

    Kiyatkin, Eugene A.

    2013-01-01

    Rationale Most neuroactive drugs affect brain metabolism as well as systemic and cerebral blood flow, thus altering brain temperature. Although this aspect of drug action usually remains in the shadows, drug-induced alterations in brain temperature reflect their metabolic neural effects and affect neural activity and neural functions. Objectives Here, I review brain temperature changes induced by neuroactive drugs, which are used therapeutically (general anesthetics), as a research tool (dopamine agonists and antagonists), and self-administered to induce desired psychic effects (cocaine, methamphetamine, ecstasy). I consider the mechanisms underlying these temperature fluctuations and their influence on neural, physiological, and behavioral effects of these drugs. Results By interacting with neural mechanisms regulating metabolic activity and heat exchange between the brain and the rest of the body, neuroactive drugs either increase or decrease brain temperatures both within (35-39°C) and exceeding the range of physiological fluctuations. These temperature effects differ drastically depending upon the environmental conditions and activity state during drug administration. This state-dependence is especially important for drugs of abuse that are usually taken by humans during psycho-physiological activation and in environments that prevent proper heat dissipation from the brain. Under these conditions, amphetamine-like stimulants induce pathological brain hyperthermia (>40°C) associated with leakage of the blood-brain barrier and structural abnormalities of brain cells. Conclusions The knowledge on brain temperature fluctuations induced by neuroactive drugs provides new information to understand how they influence metabolic neural activity, why their effects depend upon the behavioral context of administration, and the mechanisms underlying adverse drug effects including neurotoxicity PMID:23274506

  2. Neuroprotective effects of Withania somnifera on 6-hydroxydopamine induced Parkinsonism in rats

    Microsoft Academic Search

    Muzamil Ahmad; Sofiyan Saleem; Abdullah Shafique Ahmad; Mubeen Ahmad Ansari; Seema Yousuf; Fakhrul Islam

    2005-01-01

    6-Hydroxydopamine (6-OHDA) is one of the most widely used rat models for Parkinson's disease. There is ample evidence in the literature that 6-OHDA elicits its toxic manifestations through oxidant stress. In the present study, we evaluated the anti-parkinsonian effects of Withania somnifera extract, which has been reported to have potent anti-oxidant, anti-peroxidative and free radical quenching properties in various diseased

  3. Hypersexuality and paraphilia induced by selegiline in Parkinson's disease: report of 2 cases.

    PubMed

    Shapiro, Michael A; Chang, Yu Ling; Munson, Sarah K; Okun, Michael S; Fernandez, Hubert H

    2006-09-01

    While hypersexuality and paraphilia are known side effects of anti-Parkinson medications, it is seldom reported. Furthermore, selegiline is rarely implicated in such behaviors. We report two cases of early onset PD who experienced paraphilia and hypersexuality when selegiline was initiated, and later developing obsessive-compulsive and punding behavior with the addition of dopamine agonists. Social repercussions may prohibit patients and/or their families from volunteering such information. PMID:16730214

  4. Hypersexuality and paraphilia induced by selegiline in Parkinson's disease: Report of 2 cases

    Microsoft Academic Search

    Michael A. Shapiro; Yu Ling Chang; Sarah K. Munson; Michael S. Okun; Hubert H. Fernandez

    2006-01-01

    While hypersexuality and paraphilia are known side effects of anti-Parkinson medications, it is seldom reported. Furthermore, selegiline is rarely implicated in such behaviors. We report two cases of early onset PD who experienced paraphilia and hypersexuality when selegiline was initiated, and later developing obsessive–compulsive and punding behavior with the addition of dopamine agonists. Social repercussions may prohibit patients and\\/or their

  5. Computational approaches to predicting drug induced toxicity

    E-print Network

    Marchese Robinson, Richard Liam

    2013-01-08

    .3.17 Prior to this, however, a variety of experimental toxicology assays are carried out during drug discovery. Early stage in vitro assays may be divided into "prospective" and "retrospective" assays. "Retrospective" assays, e.g. for phospholipidosis...

  6. Uncomplicated drug-induced disseminated exanthemas.

    PubMed

    Bircher, Andreas J

    2012-01-01

    Exanthematous reactions with various morphological and localization patterns are the most frequently encountered adverse drug reactions involving the skin. The time course of benign exanthemas typically encompasses a few days to some weeks. They are not complicated by severe systemic symptoms or internal organ involvement. They manifest themselves in a polymorphous manner with primary efflorescences including macules, papules, and more rarely limited pustules, vesicles or bullae, followed by secondary lesions such as scales, and more rarely erosions and hemorrhage. Due to the limited inflammatory reaction pattern of the skin, these exanthemas may mimic other discrete skin disorders and infectious exanthemas. Rarely, typical skin disorders such as lichen planus or psoriasis are imitated or inflammatory reaction patterns such as Sweet's syndrome and erythema nodosum are observed. The most common groups of eliciting drugs include antibiotics, antiinfectious drugs, tuberculostatic drugs, anticonvulsant and antihypertensive agents. On the other hand, there are some drugs that have been very rarely associated with an adverse cutaneous reaction. Immunological effector mechanisms often include T cells and various chemokines and cytokines. Diagnosis is based on a detailed history, an exact morphological diagnosis and an accurate evaluation of the chronology. Histology may support the clinical diagnosis. After complete healing and within an interval of 6 weeks to 6 months, diagnostic skin and some in vitro tests are recommended. The treatment includes early withdrawal of the suspected culprit drugs, application of topical corticosteroids, systemic antihistamines and, if necessary, systemic corticosteroids. PMID:22613855

  7. 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

  8. Neuroprotective and antidepressant-like effects of melatonin in a rotenone-induced Parkinson's disease model in rats.

    PubMed

    Bassani, Taysa B; Gradowski, Raisa W; Zaminelli, Tiago; Barbiero, Janaína K; Santiago, Ronise M; Boschen, Suelen L; da Cunha, Claudio; Lima, Marcelo M S; Andreatini, Roberto; Vital, Maria A B F

    2014-12-17

    Parkinson?s disease (PD) is a neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Systemic and intranigral exposure to rotenone in rodents reproduces many of the pathological and behavioral features of PD in humans and thus has been used as an animal model of the disease. Melatonin is a neurohormone secreted by the pineal gland, which has several important physiological functions. It has been reported to be neuroprotective in some animal models of PD. The present study investigated the effects of prolonged melatonin treatment in rats previously exposed to rotenone. The animals were intraperitoneally treated for 10 days with rotenone (2.5mg/kg) or its vehicle. 24h later, they were intraperitoneally treated with melatonin (10mg/kg) or its vehicle for 28 days. One day after the last rotenone exposure, the animals exhibited hypolocomotion in the open field test, which spontaneously reversed at the last motor evaluation. We verified that prolonged melatonin treatment after dopaminergic lesion did not alter motor function but produced antidepressant-like effects in the forced swim test, prevented the rotenone-induced reduction of striatal dopamine, and partially prevented tyrosine hydroxylase immunoreactivity loss in the SNpc. Our results indicate that melatonin exerts neuroprotective and antidepressant-like effects in the rotenone model of PD. PMID:25301688

  9. 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

  10. 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

  11. Chronic thalamic stimulation improves tremor and levodopa induced dyskinesias in Parkinson's disease.

    PubMed Central

    Caparros-Lefebvre, D; Blond, S; Vermersch, P; Pécheux, N; Guieu, J D; Petit, H

    1993-01-01

    Chronic thalamic stimulation was performed in 10 Parkinsonian patients with disabling tremor and poor response to drug therapy. During the stereotactic procedure, an electrode was introduced in the ventralis intermediate nucleus of the thalamus. Test stimulation was performed during the intra-operative procedure and a few days after surgery using an external stimulator. When tremor was obviously reduced by thalamic stimulation, an internal stimulator was implanted under the clavicle. Tremor was initially suppressed in all cases and reappeared whenever stimulation was stopped. Patients were followed for 22 to 34 months. Tremor was controlled in eight cases but reappeared after three months in two cases. Levodopa induced dyskinesias were observed before electrode implantation in 5 cases. They consisted of peak-dose choreic or ballistic dyskinesias in 4 cases and biphasic dystonic dyskinesias in 3 cases. Peak-dose dyskinesias were greatly improved or suppressed in all cases. Biphasic dyskinesias were improved in 2 cases. Thalamic stimulation was well tolerated. Mild dystonic hand posture related to the deep brain stimulation was observed in one case. No neuropsychological side-effects were noted. Thalamic stimulation could prove to be an adequate treatment for resistant tremor and levodopa induced dyskinesias. PMID:8459243

  12. Nicotine-encapsulated poly(lactic-co-glycolic) acid nanoparticles improve neuroprotective efficacy against MPTP-induced parkinsonism.

    PubMed

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

    2013-12-01

    For some instances of Parkinson disease (PD), current evidence in the literature is consistent with reactive oxygen species being involved in the etiology of the disease. The management of PD is still challenging owing to its ambiguous etiology and lack of permanent cure. Because nicotine offers neuroprotection against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism, the neuroprotective efficacy of nicotine-encapsulated poly(lactic-co-glycolic) acid (PLGA) nanoparticles and the underlying mechanism of improved efficacy, if any, over bulk nicotine were assessed in this study. The selected indicators of oxidative stress, dopaminergic neurodegeneration and apoptosis, were measured in both in vitro and rodent models of parkinsonism in the presence or absence of "nanotized" or bulk nicotine. The levels of dopamine and its metabolites were measured in the striatum, nicotine and its metabolite in the nigrostriatal tissues while the immunoreactivities of tyrosine hydroxylase (TH), metallothionein-III (MT-III), inducible nitric oxide synthase (iNOS) and microglial activation were checked in the substantia nigra of controls and treated mice. GSTA4-4, heme oxygenase (HO)-1, tumor suppressor protein 53 (p53), caspase-3, lipid peroxidation (LPO), and nitrite levels were measured in the nigrostriatal tissues. Nicotine-encapsulated PLGA nanoparticles improved the endurance of TH-immunoreactive neurons and the number of fiber outgrowths and increased the mRNA expression of TH, neuronal cell adhesion molecule, and growth-associated protein-43 over bulk against 1-methyl-4-phenyl pyridinium ion-induced degeneration in the in vitro model. MPTP reduced TH immunoreactivity and levels of dopamine and its metabolites and increased microglial activation, expression of GSTA4-4, iNOS, MT-III, HO-1, p53, and caspase-3, and levels of nitrite and LPO. Whereas both bulk nicotine and nicotine-encapsulated PLGA nanoparticles modulated the changes toward controls, the modulation was more pronounced in nicotine-encapsulated PLGA nanoparticle-treated parkinsonian mice. The levels of nicotine and cotinine were elevated in nicotine-encapsulated PLGA nanoparticle-treated PD mouse brain compared with bulk. The results obtained from this study demonstrate that nanotization of nicotine improves neuroprotective efficacy by enhancing its bioavailability and subsequent modulation in the indicators of oxidative stress and apoptosis. PMID:23933227

  13. Drug-induced skin reactions: a 2-year study

    PubMed Central

    Farshchian, Mahmood; Ansar, Akram; Zamanian, Abbas; Rahmatpour-Rokni, Ghasem; Kimyai-Asadi, Arash; Farshchian, Mehdi

    2015-01-01

    Background The aim of this study was to analyze the clinical characteristics of patients with adverse cutaneous drug reactions, which occur when a medicinal product results in cutaneous morbidity. Methods The study included 308 patients who were diagnosed as having an adverse cutaneous drug reaction during the study period (2007–2009). In 84 cases, histopathologic examination of skin biopsies were also performed. Results Patients with drug reactions were found to be more commonly female (63%) than male (37%). Beta-lactam antibiotics were found to be the most frequent cause of adverse cutaneous drug reactions (42.7%), followed by non-steroidal anti-inflammatory drugs (16.5%). Acute urticaria was the most common clinical presentation (59.2%) followed by fixed drug eruptions (18.5%), and maculopapular eruptions (14.9%). Conclusion Adverse cutaneous drug reactions in our study population were mainly induced by beta-lactam antibiotics and non-steroidal anti-inflammatory drugs. The most common forms of cutaneous adverse drug reactions were found to be acute urticaria, fixed drug eruptions, and maculopapular rashes. PMID:25709487

  14. Differential Involvement of D1 and D2 Dopamine Receptors in L-DOPA-Induced Angiogenic Activity in a Rat Model of Parkinson's Disease

    Microsoft Academic Search

    Hanna S Lindgren; K Elisabet Ohlin; M Angela Cenci

    2009-01-01

    Angiogenesis occurs in the brains of Parkinson's disease patients, but the effects of dopamine replacement therapy on this process have not been examined. Using rats with 6-hydroxydopamine lesions, we have compared angiogenic responses induced in the basal ganglia by chronic treatment with either L-DOPA, or bromocriptine, or a selective D1 receptor agonist (SKF38393). Moreover, we have asked whether L-DOPA-induced angiogenesis

  15. Light induced drug delivery into cancer cells.

    PubMed

    Shamay, Yosi; Adar, Lily; Ashkenasy, Gonen; David, Ayelet

    2011-02-01

    Cell-penetrating peptides (CPPs) can be used for intracellular delivery of a broad variety of cargoes, including various nanoparticulate pharmaceutical carriers. However, the cationic nature of all CPP sequences, and thus lack of cell specificity, limits their in vivo use for drug delivery applications. Here, we have devised and tested a strategy for site-specific delivery of dyes and drugs into cancer cells by using polymers bearing a light activated caged CPP (cCPP). The positive charge of Lys residues on the minimum sequence of the CPP penetratin ((52)RRMKWKK(58)) was masked with photo-cleavable groups to minimize non-specific adsorption and cellular uptake. Once illuminated by UV light, these protecting groups were cleaved, the positively charged CPP regained its activity and facilitated rapid intracellular delivery of the polymer-dye or polymer-drug conjugates into cancer cells. We have found that a 10-min light illumination time was sufficient to enhance the penetration of the polymer-CPP conjugates bearing the proapoptotic peptide, (D)(KLAKLAK)(2), into 80% of the target cells, and to promote a 'switch' like cytotoxic activity resulting a shift from 100% to 10% in cell viability after 2 h. This report provides an example for tumor targeting by means of light activation of cell-penetrating peptides for intracellular drug delivery. PMID:21074848

  16. 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 Parkinson’s 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

  17. 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

  18. Idiosyncratic drug-induced liver injury: a clinical update.

    PubMed

    Maddur, Haripriya; Chalasani, Naga

    2011-02-01

    Drug-induced liver injury (DILI) is a rare but potentially devastating adverse drug reaction. Its presentation can range from asymptomatic elevation in liver biochemistries to fulminant liver failure. Over the past decade, clinical and research interest in the field of idiosyncratic DILI has been intense, and several new findings have been reported. In this article, we provide an update on implicated agents, clinical features, outcomes, and the results of recently reported genetic studies. PMID:21049293

  19. 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 60–70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the “Rule of Three” was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity. PMID:22194678

  20. A case highlighting antituberculosis drug induced hepatotoxicity

    Microsoft Academic Search

    L Paskin; A Gerrard

    2011-01-01

    Objective\\/BackgroundA reasonable incidence of tuberculosis (TB) still occurs in the United Kingdom with around 9000 cases reported each year. In 2008 415 of these cases occurred in the 15–19 year age category.1 The British Thoracic Society and National Institute for Health and Clinical Excellence recommend management of active TB in children with a four drug regime of isoniazid, rifampicin, pyrazinamide

  1. Role of dermatology in pharmacogenomics: drug-induced skin injury.

    PubMed

    Borroni, Riccardo G

    2015-01-01

    Different individuals may respond diversely to the same drug, in terms of efficacy and toxicity. Adverse drug reactions cause about 6% of all hospital admissions and account for up to 9% of hospitalization costs. Drug-induced skin injury (DISI) is the most common presentation of adverse drug reactions, ranging from maculopapular eruptions to severe adverse cutaneous drug reactions (SCARs) with mortality of up to 40%. Specific genetic polymorphisms confer susceptibility to different types of DISI. Identifying patients genetically at risk for SCARs is one of the goals of pharmacogenomics. In this article, the aspects of clinical dermatology relevant to the pharmacogenetics of DISI are reviewed. Many SCARs are now preventable, with consequent reduction of morbidity, mortality and healthcare costs. PMID:25823788

  2. A strategy for risk management of drug-induced phospholipidosis.

    PubMed

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

    2009-12-01

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

  3. Levodopa in the treatment of Parkinson’s disease

    Microsoft Academic Search

    S. Fahn

    Levodopa is the most efficacious drug to treat the symptoms of Parkinson’s disease (PD) and is widely considered the “gold\\u000a standard” by which to compare other therapies, including surgical therapy. Response to levodopa is one of the criteria for\\u000a the clinical diagnosis of PD. A major limiting factor in levodopa therapy is the development of motor complications, namely\\u000a dyskinesias and

  4. In silico modeling to predict drug-induced phospholipidosis.

    PubMed

    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-activity relationship (QSAR) modeling using machine learning approaches has shown promise with a large dataset of drugs but included unconfirmed data as well. In this study, we report the construction and validation of a battery of complementary in silico QSAR models using the FDA's updated database on phospholipidosis, new algorithms and predictive technologies, and in particular, we address high performance with a high-confidence dataset. The results of our modeling for DIPL include rigorous external validation tests showing 80-81% concordance. Furthermore, the predictive performance characteristics include models with high sensitivity and specificity, in most cases above ?80% leading to desired high negative and positive predictivity. These models are intended to be utilized for regulatory toxicology applied science needs in screening new drugs for DIPL. PMID:23541745

  5. Periodic paralysis: An unusual presentation of drug-induced hyperkalemia

    PubMed Central

    Agrawal, Poonam; Chopra, Deepti; Patra, Surajeet K.; Madaan, Himanshu

    2014-01-01

    Hyperkalemia is a life-threatening electrolyte abnormality. The most common cause of hyperkalemia includes renal disease and ingestion of medications. Drug-induced hyperkalemia may develop in patients with underlying renal impairment, disturbed cellular uptake of potassium load, excessive ingestion or infusion of potassium-containing substances. We report a case of “drug-induced severe hyperkalemia” presenting as periodic paralysis. A 67-year-old diabetic and hypertensive woman presented to emergency department with the complaint of intermittent episode of inability to walk for the past 5 days. Each episode lasted for 15-20 minutes and was associated with breathlessness and restlessness. There was no family history of periodic paralysis and drug history revealed that the patient was onolmesartan 20 mg per day (for past 2 years), perindopril 4 mg per day (for past 16 months), and torsemide 10 mg/day. On examination patient was found to be conscious, alert, and afebrile. Vitals were normal. Examination of cardiovascular and respiratory system did not reveal any significant finding. Blood report of the patient showed serum K+ level 8.6 mmol/l. All other investigations were within normal limits. A diagnosis of drug-induced hyperkalemia was made. Patient responded well to the symptomatic treatment. To the best of the author's knowledge, this is the first case report of drug-induced hyperkalemia presenting as periodic paralysis. PMID:24554915

  6. Low Dosage of Rasagiline and Epigallocatechin Gallate Synergistically Restored the Nigrostriatal Axis in MPTP-Induced Parkinsonism

    Microsoft Academic Search

    Lydia Reznichenko; Limor Kalfon; Tamar Amit; Moussa B. H. Youdim; Silvia A. Mandel

    2010-01-01

    Background: The anti-Parkinson monoamine oxidase B inhibitor rasagiline appears to be the first neuroprotective disease-modifying therapy in early-stage Parkinson’s disease (PD). Objective: Using a polypharmacy paradigm, we tested whether the distinct neuroprotective pharmacological profile of rasagiline would complement that of (–)-epigallocatechin-3-gallate (EGCG), the main antioxidant\\/iron chelator polyphenol constituent of green tea, and restore the neuronal loss and molecular targets damaged

  7. PEP-1-ribosomal protein S3 protects dopaminergic neurons in an MPTP-induced Parkinson's disease mouse model.

    PubMed

    Ahn, Eun Hee; Kim, Dae Won; Shin, Min Jea; Kim, Young Nam; Kim, Hye Ri; Woo, Su Jung; Kim, So Mi; Kim, Duk-Soo; Kim, Joon; Park, Jinseu; Eum, Won Sik; Hwang, Hyun Sook; Choi, Soo Young

    2013-02-01

    Parkinson's disease (PD) is a neurodegenerative disease characterized by a gradual loss of dopaminergic (DA) neurons in the substantia nigra (SN) of the brain. Ribosomal protein S3 (rpS3) has multiple functions related to protein synthesis, antioxidative activity, and UV endonuclease III activity. We have previously shown that PEP-1-rpS3 inhibits skin inflammation and provides neuroprotection against experimental cerebral ischemic damage. In this study, we examined whether PEP-1-rpS3 can protect DA neurons against oxidative stress in SH-SY5Y neuroblastoma cells and in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model. PEP-1-rpS3 was efficiently delivered to SH-SY5Y cells and the SN of the brain as confirmed by Western blot and immunohistochemical analysis. PEP-1-rpS3 significantly inhibited reactive oxygen species generation and DNA fragmentation induced by 1-methyl-4-phenylpyridinium, consequently leading to the survival of SH-SY5Y cells. The neuroprotection was related to the antiapoptotic activity of PEP-1-rpS3 that affected the levels of proapoptotic and antiapoptotic mediators. In addition, immunohistochemical data collected using a tyrosine hydroxylase antibody and cresyl violet staining demonstrated that PEP-1-rpS3 markedly protected DA cells in the SN against MPTP-induced oxidative stress. Therefore, our results suggest that PEP-1-rpS3 may be a potential therapy for PD. PMID:23178948

  8. Long-Term Systemic Exposure to Rotenone Induces Central and Peripheral Pathology of Parkinson's Disease in Mice.

    PubMed

    Murakami, Shinki; Miyazaki, Ikuko; Miyoshi, Ko; Asanuma, Masato

    2015-06-01

    Parkinson's disease (PD) is a progressive neurodegenerative disease with motor and non-motor symptoms that precede the onset of motor symptoms. Rotenone is often used to induce PD-like pathology in the central nervous system (CNS) and enteric nervous system (ENS). However, there is little or no information on the temporal changes in other neural tissues and the spread of pathology throughout the entire body organs. Here, we recorded the serial immunohistochemical changes in neurons and glial cells of the striatum, substantia nigra (SN), olfactory bulb (OB), thoracic cord (ThC) and ascending colon (AC) induced by 1-, 3- and 6-week administration of rotenone (50 mg/kg/day) infused subcutaneously in C57BL mice using an osmotic pump. Rotenone exposure for 3 or 6 weeks caused neurodegeneration in the striatum, whereas neuronal damage was seen in the SN and OB only after 6 weeks. Moreover, rotenone induced neurodegeneration in the myenteric plexus of AC but not in ThC. Rotenone also activated glial cells before any apparent neurodegeneration in the CNS but not in the ENS. Our results demonstrated that subcutaneous administration of rotenone can cause progressive neurodegeneration in the OB and AC, in addition to the nigrostriatal pathway, and temporal differential glial activation, and that these changes do not spread retrogradely from OB or ENS to nigrostriatal pathway. The results suggested that the different vulnerability of neurons to the neurotoxic effects of rotenone administrated subcutaneously are due to glial activation in these neural tissues. PMID:25894684

  9. 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.

  10. Biomarkers to monitor drug-induced phospholipidosis

    SciTech Connect

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

  11. Improving Response Inhibition in Parkinson’s 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 Parkinson’s 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 Parkinson’s 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 Parkinson’s disease. These results point the way to new stratified clinical trials of atomoxetine to treat impulsivity in selected patients with Parkinson’s disease. PMID:24655598

  12. 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

  13. Drug-induced acne and rose pearl: similarities*

    PubMed Central

    Pontello Junior, Rubens; Kondo, Rogerio Nabor

    2013-01-01

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

  14. As a rare cause of drug-induced cough: topiramate.

    PubMed

    Tosun, Emine; Topalo?lu, Oya; Akkalyoncu, Behiye

    2012-06-01

    The most common causes of chronic cough in nonsmokers are postnasal drip syndrome, asthma, and gastroesophageal reflux disease. Drugs are also important in the etiology of resistant cough. Most common drugs inducing cough are the ACE inhibitors. Many drugs other than ACE inhibitors can also cause dry cough and one among them is topiramate. It is a new generation, efficacy-proved antiepileptic drug that is used widely for migraine prophylaxis in many countries. Most common adverse events of topiramate are paresthesia, cognitive symptoms, fatigue, insomnia, nausea, loss of apetite, anxiety, and dizziness. There is only one case report about topiramate associated cough in the literature. The present report refers to a patient, presenting with cough who is on topiramate treatment for migraine prophylaxis. PMID:22426660

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

    PubMed

    Thakur, Poonam; Nehru, Bimla

    2014-09-01

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

  16. Isogenic human iPSC Parkinson's model shows nitrosative stress-induced dysfunction in MEF2-PGC1? transcription.

    PubMed

    Ryan, Scott D; Dolatabadi, Nima; Chan, Shing Fai; Zhang, Xiaofei; Akhtar, Mohd Waseem; Parker, James; Soldner, Frank; Sunico, Carmen R; Nagar, Saumya; Talantova, Maria; Lee, Brian; Lopez, Kevin; Nutter, Anthony; Shan, Bing; Molokanova, Elena; Zhang, Yaoyang; Han, Xuemei; Nakamura, Tomohiro; Masliah, Eliezer; Yates, John R; Nakanishi, Nobuki; Andreyev, Aleksander Y; Okamoto, Shu-ichi; Jaenisch, Rudolf; Ambasudhan, Rajesh; Lipton, Stuart A

    2013-12-01

    Parkinson's disease (PD) is characterized by loss of A9 dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc). An association has been reported between PD and exposure to mitochondrial toxins, including environmental pesticides paraquat, maneb, and rotenone. Here, using a robust, patient-derived stem cell model of PD allowing comparison of A53T ?-synuclein (?-syn) mutant cells and isogenic mutation-corrected controls, we identify mitochondrial toxin-induced perturbations in A53T ?-syn A9 DA neurons (hNs). We report a pathway whereby basal and toxin-induced nitrosative/oxidative stress results in S-nitrosylation of transcription factor MEF2C in A53T hNs compared to corrected controls. This redox reaction inhibits the MEF2C-PGC1? transcriptional network, contributing to mitochondrial dysfunction and apoptotic cell death. Our data provide mechanistic insight into gene-environmental interaction (GxE) in the pathogenesis of PD. Furthermore, using small-molecule high-throughput screening, we identify the MEF2C-PGC1? pathway as a therapeutic target to combat PD. PMID:24290359

  17. Glutamatergic mechanisms in the dyskinesias induced by pharmacological dopamine replacement and deep brain stimulation for the treatment of Parkinson's disease.

    PubMed

    Sgambato-Faure, Véronique; Cenci, Maria Angela

    2012-01-01

    Dyskinesias represent a major complication of dopamine replacement therapy in Parkinson's disease (PD) and have prompted a search for alternative treatments. The most radical advances in this field have been provided by surgical manipulations of the deep basal ganglia nuclei, and particularly by deep brain stimulation (DBS) of the subthalamic nucleus (STN). Although being very effective, high-frequency stimulation (HFS) of the STN is a poorly understood treatment. Besides its anti-akinetic activity, it can be pro-dyskinetic above a certain stimulation intensity. Accumulating evidence indicates that dyskinesias induced by STN-HFS and dopamine replacement therapy are linked to dysregulation of glutamate transmission in the basal ganglia. In rat models of PD, both types of dyskinesia are associated with increased concentrations of extracellular glutamate and altered expression of glutamate transporters in the substantia nigra pars reticulata and the striatum. Furthermore, a vast and ever growing literature has revealed changes in the expression, phosphorylation state, and/or subcellular distribution of specific subtypes of glutamate receptors in these dyskinetic conditions. Both types of dyskinesias are linked to an increased phosphorylation of NR2B-containing NMDA receptors in critical basal ganglia circuits. We conclude that disruption of glutamate homeostasis and activation of perisynaptic and extra-synaptic glutamate receptors are an important pathophysiological component of these treatment-induced dyskinesias in PD. These findings lay the ground for therapeutic development initiatives targeting dysfunctional components of glutamate transmission in the basal ganglia. PMID:22075179

  18. Drug-induced liver injury: Interactions between drug properties and host factors.

    PubMed

    Chen, Minjun; Suzuki, Ayako; Borlak, Jürgen; Andrade, Raúl J; Lucena, M Isabel

    2015-08-01

    Idiosyncratic drug-induced liver injury (DILI) is a common cause for drug withdrawal from the market and although infrequent, DILI can result in serious clinical outcomes including acute liver failure and the need for liver transplantation. Eliminating the iatrogenic "harm" caused by a therapeutic intent is a priority in patient care. However, identifying culprit drugs and individuals at risk for DILI remains challenging. Apart from genetic factors predisposing individuals at risk, the role of the drugs' physicochemical and toxicological properties and their interactions with host and environmental factors need to be considered. The influence of these factors on mechanisms involved in DILI is multi-layered. In this review, we summarize current knowledge on 1) drug properties associated with hepatotoxicity, 2) host factors considered to modify an individuals' risk for DILI and clinical phenotypes, and 3) drug-host interactions. We aim at clarifying knowledge gaps needed to be filled in as to improve risk stratification in patient care. We therefore broadly discuss relevant areas of future research. Emerging insight will stimulate new investigational approaches to facilitate the discovery of clinical DILI risk modifiers in the context of disease complexity and associated interactions with drug properties, and hence will be able to move towards safety personalized medicine. PMID:25912521

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

    PubMed Central

    Maria, V; Victorino, R

    1997-01-01

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

  20. The Brain Lesion Responsible for Parkinsonism After Carbon Monoxide Poisoning

    Microsoft Academic Search

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

    2000-01-01

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

  1. 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 Guével, Xavier; Yliperttula, Marjo; Murtomäki, 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

  2. 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 ±4.3 and 110.6 ±5.3) and ATP levels (10.6 ±1.1 and 15.5 ±1.14) compared to MPTP (60.1 ±3.9 pmol/g and 3.6 ±0.09 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 ±3.01 and 107.8 ±8.6) 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 ±5.2) compared to both MPTP (37.6 ±3.1) and levodopa groups (41.6 ±3.5). 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

  3. In vitro validation of drug-induced phospholipidosis.

    PubMed

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

    2012-01-01

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

  4. D-512 and D-440 as Novel Multifunctional Dopamine Agonists: Characterization of Neuroprotection Properties and Evaluation of In Vivo Efficacy in a Parkinson’s Disease Animal Model

    PubMed Central

    2013-01-01

    In this Article, we have demonstrated the in vivo efficacy of D-512 and D-440 in a 6-OHDA-induced unilaterally lesioned rat model experiment, a Parkinson’s disease animal model. D-512 is a novel highly potent D2/D3 agonist, and D-440 is a novel highly selective D3 agonist. We evaluated the neuroprotective properties of D-512 and D-440 in the dopaminergic MN9D cells. Cotreatment of these two drugs with 6-OHDA and MPP+ significantly attenuated and reversed 6-OHDA- and MPP+-induced toxicity in a dose-dependent manner in the dopaminergic MN9D cells. The inhibition of caspase 3/7 and lipid peroxidation activities along with the restoration of tyrosine hydroxylase levels by D-512 in 6-OHDA-treated cells may partially explain the mechanism of its neuroprotective property. Furthermore, studies were carried out to elucidate the time-dependent changes in the pERK1/2 and pAkt, two kinases implicated in cell survival and apoptosis, levels upon treatment with 6-OHDA in presence of D-512. The neuroprotective property exhibited by these drugs was independent of their dopamine-agonist activity, which is consistent with our multifunctional drug-development approach that is focused on the generation of disease-modifying symptomatic-treatment agents for Parkinson’s disease. PMID:23906010

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

    PubMed

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

    2012-09-01

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

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

    PubMed Central

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

    2012-01-01

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

  7. Young-Onset Parkinson's

    MedlinePLUS

    ... Disease > Young-Onset Parkinson's Text Size Young-Onset Parkinson's The diagnosis of Young-Onset Parkinson’s disease is the same ... as thing as Juvenile Parkinsonism? In rare instances, Parkinson’s-like symptoms can appear in children and teenagers. This form ...

  8. Retrospective evaluation of adverse drug reactions induced by antihypertensive treatment

    PubMed Central

    Rende, Pierandrea; Paletta, Laura; Gallelli, Giuseppe; Raffaele, Gianluca; Natale, Vincenzo; Brissa, Nazareno; Costa, Cinzia; Gratteri, Santo; Giofrè, Chiara; Gallelli, Luca

    2013-01-01

    The use of cardiovascular drugs is related to the development of adverse drug reactions (ADRs) in about 24% of the patients in the Cardiovascular Care Unit. Here, we evaluated the ADRs in patients treated with antihypertensive drugs. The study was conducted in two phases: In the first phase, we performed a retrospective study on clinical records of Clinical Divisions (i.e., Internal Medicine Operative Unit and Geriatric Operative Unit) from January 1, 2012 to December 31, 2012. Moreover from January 1, 2013 to March 30, 2013 we performed a prospective study on the outpatients attending the Emergency Department (ED) of the Pugliese-Ciaccio Hospital of Catanzaro, by conducting patient interviews after their informed consent was obtained. The association between a drug and ADR was evaluated using the Naranjo scale. We recorded 72 ADRs in the Clinical Divisions and six in the ED, and these were more frequent in women. Using the Naranjo score, we showed a probable association in 92% of these reactions and a possible association in 8%. The most vulnerable age group involved in ADRs was that of the elderly patients. In conclusion, our results indicate that antihypertensive drugs may be able to induce the development of ADRs, particularly in elderly women receiving multiple drug treatment. Therefore, it is important to motivate the healthcare providers to understand their role and responsibility in the detection, management, documentation, and reporting of ADRs, as also all the essential activities for optimizing patient safety. PMID:24347982

  9. Retrospective evaluation of adverse drug reactions induced by antihypertensive treatment.

    PubMed

    Rende, Pierandrea; Paletta, Laura; Gallelli, Giuseppe; Raffaele, Gianluca; Natale, Vincenzo; Brissa, Nazareno; Costa, Cinzia; Gratteri, Santo; Giofrè, Chiara; Gallelli, Luca

    2013-12-01

    The use of cardiovascular drugs is related to the development of adverse drug reactions (ADRs) in about 24% of the patients in the Cardiovascular Care Unit. Here, we evaluated the ADRs in patients treated with antihypertensive drugs. The study was conducted in two phases: In the first phase, we performed a retrospective study on clinical records of Clinical Divisions (i.e., Internal Medicine Operative Unit and Geriatric Operative Unit) from January 1, 2012 to December 31, 2012. Moreover from January 1, 2013 to March 30, 2013 we performed a prospective study on the outpatients attending the Emergency Department (ED) of the Pugliese-Ciaccio Hospital of Catanzaro, by conducting patient interviews after their informed consent was obtained. The association between a drug and ADR was evaluated using the Naranjo scale. We recorded 72 ADRs in the Clinical Divisions and six in the ED, and these were more frequent in women. Using the Naranjo score, we showed a probable association in 92% of these reactions and a possible association in 8%. The most vulnerable age group involved in ADRs was that of the elderly patients. In conclusion, our results indicate that antihypertensive drugs may be able to induce the development of ADRs, particularly in elderly women receiving multiple drug treatment. Therefore, it is important to motivate the healthcare providers to understand their role and responsibility in the detection, management, documentation, and reporting of ADRs, as also all the essential activities for optimizing patient safety. PMID:24347982

  10. 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

  11. Effect of serotonin transporter blockade on L-DOPA-induced dyskinesia in animal models of Parkinson's disease.

    PubMed

    Fidalgo, C; Ko, W K D; Tronci, E; Li, Q; Stancampiano, R; Chuan, Q; Bezard, E; Carta, M

    2015-07-01

    Serotonin transporter blockade with selective serotonin reuptake inhibitors (SSRIs) was recently shown to counteract L-DOPA-induced dyskinesia in 6-hydroxydopamine (6-OHDA)-lesioned rats. However, this effect has never been described in Parkinson's disease (PD) patients, despite that they often receive SSRIs for the treatment of depression. In the present study, we investigated the efficacy of the SSRI citalopram against dyskinesia in two experimental models of PD, the 6-OHDA-lesioned rat and 1-methyl-4-phenyl 1,2,3,6-tetrahydropyridine (MPTP)-treated macaque. First, we studied the acute and chronic effect of citalopram, given at different time points before L-DOPA, in L-DOPA-primed parkinsonian rats. Moreover, the acute effect of citalopram was also evaluated in dyskinetic MPTP-treated macaques. In L-DOPA-primed rats, a significant and long-lasting reduction of L-DOPA-induced dyskinesia (LID) was observed only when citalopram was given 30min before L-DOPA, suggesting that the time of injection relative to L-DOPA is a key factor for the efficacy of the treatment. Interestingly, an acute challenge with the 5-HT1A/1B receptor agonist eltoprazine, given at the end of the chronic study, was equally effective in reducing LID in rats previously chronically treated with L-DOPA or L-DOPA plus citalopram, suggesting that no auto-receptor desensitization was induced by chronic citalopram treatment. In MPTP-treated macaques, citalopram produced a striking suppression of LID but at the expense of L-DOPA therapeutic efficacy, which represents a concern for possible clinical application. PMID:25907446

  12. Ceftriaxone prevents and reverses behavioral and neuronal deficits in an MPTP-induced animal model of Parkinson's disease dementia.

    PubMed

    Hsu, Chao-Yu; Hung, Ching-Sui; Chang, Hung-Ming; Liao, Wen-Chieh; Ho, Shih-Chun; Ho, Ying-Jui

    2015-04-01

    Glutamatergic hyperactivity plays an important role in the pathophysiology of Parkinson's disease (PD). Ceftriaxone increases expression of glutamate transporter 1 (GLT-1) and affords neuroprotection. This study was aimed at clarifying whether ceftriaxone prevented, or reversed, behavioral and neuronal deficits in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. Male Wistar rats were injected daily with either ceftriaxone starting 5 days before or 3 days after MPTP lesioning (day 0) or saline and underwent a bar-test on days 1-7, a T-maze test on days 9-11, and an object recognition test on days 12-14, then the brains were taken for histological evaluation on day 15. Dopaminergic degeneration in the substantia nigra pars compacta and striatum was observed on days 3 and 15. Motor dysfunction in the bar test was observed on day 1, but disappeared by day 7. In addition, lesioning resulted in deficits in working memory in the T-maze test and in object recognition in the object recognition task, but these were not observed in rats treated pre- or post-lesioning with ceftriaxone. Lesioning also caused neurodegeneration in the hippocampal CA1 area and induced glutamatergic hyperactivity in the subthalamic nucleus, and both changes were suppressed by ceftriaxone. Increased GLT-1 expression and its co-localization with astrocytes were observed in the striatum and hippocampus in the ceftriaxone-treated animals. To our knowledge, this is the first study showing a relationship between ceftriaxone-induced GLT-1 expression, neuroprotection, and improved cognition in a PD rat model. Ceftriaxone may have clinical potential for the prevention and treatment of dementia associated with PD. PMID:25499022

  13. 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

  14. Neuroprotective Effects of ?-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

    2014-11-18

    ?-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 ?-asarone on behavioral tests, neurotransmitters, tyrosine hydroxylase (TH), and ?-synuclein (?-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 ?-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 ?-asarone, the TH level was elevated but the ?-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 ?-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 ?-asarone may be explored as a potential therapeutic agent in PD therapy. PMID:25404088

  15. 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

  16. In vitro assays and biomarkers for drug-induced phospholipidosis.

    PubMed

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

    2006-10-01

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

  17. Enhanced de novo neurogenesis and dopaminergic neurogenesis in the substantia nigra of MPTP-induced Parkinson’s disease-like mice

    PubMed Central

    Shan, Xiaoyang; Chi, Liying; Bishop, Michael; Luo, Chun; Lien, Lindsey; Zhang, Zheng; Liu, Rugao

    2007-01-01

    Research reports on de novo neurogenesis, particularly dopaminergic (DA) neurogenesis in the adult mammalian substantia nigra (SN) remain very controversial. For this reason, we utilized the nestin second-intron enhancer controlled LacZ reporter (pNes-LacZ) transgenic mouse model coupled with MPTP lesion system to investigate whether there are neurogenesis and DA neurogenesis in the SN of the adult normal and Parkinson’s disease (PD)–like mice. First, we demonstrated the presence of neural progenitor cells (NPCs), basal levels of neurogenesis, and DA neurogenesis in the normal adult mouse SN. Second, we showed there is not only a significant increase in the number of NPCs, but also a dramatic increase of neurogenesis from the NPCs in the SN and the midline region adjacent to the SN of the PD-like mice, compared with that of normal controls. More importantly, we also demonstrated there is an increase of DA neurogenesis in the SN of the MPTP lesioned mice. Third, we showed that the increased DA neurogenesis in the MPTP lesioned mice was derived from the NPCs and BrdU positive cells, suggesting multiple stem cell lineages may contribute to the enhanced neurogenesis in the adult SN. Taken together, these results establish that there are basal levels, albeit low, and increased levels of de novo neurogenesis and DA neurogenesis in the SN of the adult normal and PD-like mice respectively. The increased NPCs in the MPTP lesioned mice further suggest that experimental approaches to promote de novo neurogenesis may provide an effective therapy for PD by functional replacement of degenerated DAs. PMID:16424396

  18. Drug-Induced Liver Injury After Soy Protein Supplement Use

    PubMed Central

    Thapar, Manish

    2015-01-01

    Drug-induced liver injury (DILI) is an important and often elusive cause of iatrogenic hepatic injury which complicates its recognition and treatment. We describe a rare case of severe liver injury in a previously healthy individual associated with a commonly used and reportedly safe soy protein powder supplement. Discontinuation of the supplements and initiation of ursodeoxycholic acid provided symptomatic relief, decreased pruritus, and resulted in a resolution of hepatic panel labs.

  19. EXPLORING THE RELATIONSHIP BETWEEN DRUG-INDUCED PARKINSONISM AND TARDIVE DYSKINESIAS

    E-print Network

    Lichtarge, Olivier

    and definitions. J Clin Psychopharmacol. 2006;26:560-5 3. Kenney C et al. Metoclopramide, an Increasingly: thioridazine,loxapine, amoxapine, fluoxetine,trifluoperazine, estrogen receptor antagonist 34 patients returned

  20. Novel action of metformin in the prevention of haloperidol-induced catalepsy in mice: Potential in the treatment of Parkinson's disease?

    PubMed

    Adeyemi, Olufunmilayo O; Ishola, Ismail O; Adedeji, Halimah A

    2013-10-24

    Metformin is widely used to treat type II diabetes and other metabolic syndromes. In addition, it has been shown to increase neurogenesis, spatial memory formation and reduce the risk of Parkinson's disease. On this basis, the aim of the present study was the investigation of the protective potential of metformin in the haloperidol-induced catalepsy model of Parkinson's disease in mice. The effect of metformin (20 - 100mg/kg, p.o) on motor coordination was assessed using rotarod and forced swimming tests (FST), while the effect on memory function was evaluated using the Y-maze test. The neuroprotective activity was investigated in acute/chronic (21days) haloperidol-induced catalepsy in mice. On the 21st day, biochemical estimation of nitrosative and oxidative stress parameters was carried out. Metformin (50 or 100mg/kg, p.o.) did not affect motor coordination in rotarod test and FST but significantly reversed haloperidol-induced memory deficit (+35.50%) at 100mg/kg. Importantly, metformin significantly reduced the duration of catalepsy score during acute and chronic catalepsy tests as compared to trihexylphenidyl (reference standard). Intraperitoneal chronic injection of haloperidol (1mg/kg) significantly increased malondialdehyde and nitrite levels, while it significantly attenuated the activity of reduced glutathione, catalase and superoxide dismutase. Moreover, oral chronic administration of metformin significantly attenuated the haloperidol-induced increase of malondialdehyde and nitrite, as well as the deficit of glutathione and catalase. These findings suggest that metformin protects against haloperidol-induced catalepsy through inhibition of oxidative/nitrosative stress and has the potential for adjuvant action in the management of Parkinson's disease. PMID:24513020

  1. Carpal Tunnel Syndrome in Patients with Tremor Dominant Parkinson’s Disease

    PubMed Central

    Han, Sang Won; Cheon, Kyeong Yeol; Kim, Jeong Yeon; Baik, Jong Sam

    2015-01-01

    Background Unilateral hand tremor is one of the cardinal symptoms of Parkinson’s disease. Additionally, mechanical traumatic hand movement is one of the risk factors for carpal tunnel syndrome. Our objective in this study was to examine whether repetitive mechanical movement may be related to the development of carpal tunnel syndrome in Parkinson’s disease with unilateral hand tremor using neurophysiological methods. Methods The study participants included 33 de novo Parkinson’s disease patients with unilateral hand tremor, and we compared the tremor hand and non-tremor hand within the same patients. Results Seven (21.2%) of the 33 patients had carpal tunnel syndrome. All of carpal tunnel syndrome patients showed neurophysiological abnormalities in both the hand without tremor and the hand with tremor. In addition, in patients without carpal tunnel syndrome, the sensory nerve action potential was lower in the hand without tremor than in the hand with tremor, although there were no significant differences. Conclusions We concluded that hand tremor in de novo Parkinson’s disease patients was not directly related to the development of carpal tunnel syndrome. In contrast, more frequent use of hand without tremor may induce mechanical loading and may be associated with CTS in the hand without tremor. Early diagnosis of Parkinson’s disease and proper education in hand use may be essential for preventing carpal tunnel syndrome in Parkinson’s disease tremor patients. PMID:26091110

  2. Altered Brain Activation in Early Drug-Naive Parkinson's Disease during Heat Pain Stimuli: An fMRI Study

    PubMed Central

    Tan, Ying; Tan, Juan; Cui, Wenjuan; He, Hui; Bin, Yi; Deng, Jiayan; Tan, Rui; Tan, Wenrong; Liu, Tao; Zeng, Nanlin; Xiao, Ruhui; Yao, Dezhong; Wang, Xiaoming

    2015-01-01

    Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by motor and nonmotor signs and symptoms. To date, many studies of PD have focused on its cardinal motor symptoms. To study the nonmotor signs of early PD, we investigated the reactions solicited by heat pain stimuli in early untreated PD patients without pain using fMRI. The activation patterns of contact heat stimuli (51°C) were assessed in 14 patients and 17 age- and sex-matched healthy controls. Patients with PD showed significant decreases in activation of the superior temporal gyrus (STG) and insula compared with controls. In addition, a significant relationship between activation of the insula and STG and the pain scores was observed in healthy controls but not in PD. This study provided further support that the insula and STG are important parts of the somatosensory circuitry recruited during the period of pain. The hypoactivity of the STG and insula in PD implied that functions including affective, cognitive, and sensory-discriminative processes, which are associated with the insula and STG, were disturbed. This finding supports the view that leaving early PD untreated could be tied directly to central nervous system dysfunction. PMID:25628915

  3. 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

  4. Identifying the Basal Ganglia network model markers for medication-induced impulsivity in Parkinson's disease patients.

    PubMed

    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

  5. 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

  6. The nonsteroidal antiinflammatory drug piroxicam reverses the onset of depressive-like behavior in 6-OHDA animal model of Parkinson's disease.

    PubMed

    Santiago, R M; Tonin, F S; Barbiero, J; Zaminelli, T; Boschen, S L; Andreatini, R; Da Cunha, C; Lima, M M S; Vital, M A B F

    2015-08-01

    Depression is one of the most common psychiatric symptoms in patients with Parkinson's disease (PD). Some authors have reported that depression is characterized by activation of the inflammatory response. Animal models of PD also present with depressive-like behavior, such as increased immobility time in the modified forced swim test and anhedonia-like behavior in the sucrose preference test. Considering the potential neuroprotective effect of nonsteroidal antiinflammatory drugs in neurodegenerative diseases, the objective of the present study was to investigate the effects of piroxicam on depressive-like behavior in male Wistar rats lesioned with 6-hydroxydopamine (6-OHDA) in the substantia nigra (SN). Antidepressant-like effects were observed after prolonged administration of piroxicam for 21days. In the forced swim test, the 6-OHDA+saline group exhibited significant reductions in swimming time and increased immobility time compared with the sham+saline. In the sucrose preference test, the 6-OHDA+piroxicam group exhibited no reduction of sucrose preference compared with the sham+saline, with significant effects of treatment and time and a significant treatment×time interaction. 5-Hydroxytryptamine (5-HT) levels significantly decreased in the hippocampus in the 6-OHDA+saline group and not changed in the 6-OHDA+piroxicam group when compared with the sham+saline on day 21. In conclusion, 21-day treatment with piroxicam reversed the onset of depressive-like behavior and prevented the reduction of hippocampal 5-HT levels. PMID:25999296

  7. Comparison of spontaneous, UV-induced, and nitrosoguanidine-induced mutability to drug resistance in myxobacteria.

    PubMed Central

    Grimm, K

    1978-01-01

    The UV survival curves of different strains of myxobacteria exhibited shoulders; in the case of Polyangium luteum, an unusual double shoulder appeared. Repair inhibitors like acriflavine, caffeine, and coumarin reduced the survival of UV-irradiated cells if the drugs were incorporated in the post-irradiation plating medium. The shoulders were reduced, but the final inactivation slopes were not affected by the repair inhibitors. Those strains that were resistant to UV were also more resistant to being killed by nitrosoguanidine. A variety of drug-resistant mutants occurred. The spontaneous mutation frequencies to drug resistance varied with the drug and the strain used. Drug-resistant mutants were inducible by UV irradiation and nitrosoguanidine. The UV mutability of Myxococcus xanthus was high compared to Cystobacter sp. However, the nitrosoguanidine mutability of M. xanthus was low compared to the other strains. PMID:99434

  8. 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

  9. Combined exposure to agriculture pesticides, paraquat and maneb, induces alterations in the N/OFQ-NOPr and PDYN/KOPr systems in rats: Relevance to sporadic Parkinson's disease.

    PubMed

    Bastías-Candia, Sussy; Di Benedetto, Manuela; D'Addario, Claudio; Candeletti, Sanzio; Romualdi, Patrizia

    2015-05-01

    Despite several years of research, the aetiology of Parkinson's disease (PD) is quite far from being solved. In PD, as well as in other neurodegenerative disorders, it has been proposed that the combination of multiple factors might contribute to the onset of the disease. Indeed, several authors have suggested that environmental factors, such as pollutants and chemicals, might be associated with the onset of several neurodegenerative disorders. On the other hand, several studies have described that the nociceptin/orphanin-NOP and prodynorphin-KOP opioid systems are implicated in the pathology of Parkinson's disease. Considering the nonrestricted commercial availability and common use of several pesticides, such as paraquat and maneb, in agriculture of less developed countries, the aim of our study was to investigate the involvement of nociceptin/orphanin-NOP and prodynorphin-KOP systems in a chronic paraquat and maneb animal model of Parkinson's disease. Our results showed that after paraquat/maneb (5/15 mg kg(-1) ) treatment, a significant reduction in tyrosine hydroxylase (TH) levels, the rate-limiting enzyme for dopamine synthesis, was observed. Also, the association of paraquat and maneb (5/15 mg kg(-1) ) induced an increase in nociceptin/orphanin and a decrease of prodynorphin gene expression levels in the substantia nigra with a down-regulation of NOP and KOP receptors after both treatments in the substantia nigra and caudate putamen. These data further confirm that paraquat and maneb toxicity can modulate gene expression of the nociceptin/orphanin-NOP receptor and prodynorphin-KOP receptor systems in the substantia nigra and caudate putamen, offering further support to the hypothesis that chronic exposure to these agrochemicals might be implicated in the mechanisms underlying sporadic Parkinson's disease. © 2013 Wiley Periodicals, Inc. Environ Toxicol 30: 656-663, 2015. PMID:24376148

  10. Transgenic supplementation of SIRT1 fails to alleviate acute loss of nigrostriatal dopamine neurons and gliosis in a mouse model of MPTP-induced parkinsonism

    PubMed Central

    Kitao, Yasuko; Ageta-Ishihara, Natsumi; Takahashi, Ryosuke; Kinoshita, Makoto; Hori, Osamu

    2015-01-01

    Background Dopamine (DA) neuron-selective uptake and toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes parkinsonism in humans. Loss of DA neurons via mitochondrial damage and oxidative stress is reproduced by systemic injection of MPTP in animals, which serves as models of parkinsonism and Parkinson’s disease (PD). This study aimed to test whether pan-neural supplementation of the longevity-related, pleiotropic deacetylase SIRT1, which confers partial tolerance to at least three models of stroke and neurodegeneration, could also alleviate MPTP-induced acute pathological changes in nigrostriatal DA neurons and neighboring glia. Results We employed a line of prion promoter-driven Sirt1-transgenic (Sirt1Tg) mice that chronically overexpress murine SIRT1 in the brain and spinal cord. Sirt1Tg and wild-type (WT) male littermates (3?4 months old) were subjected to intraperitoneal injection of MPTP. Acute histopathological changes in the midbrain and striatum (caudoputamen) were assessed with serial coronal sections triply labeled for tyrosine hydroxylase (TH), glial fibrillary acidic protein (GFAP), and nuclear DNA. In the substantia nigra pars compacta (SNpc) of the midbrain, the number of TH-positive neurons and the reactive gliosis were comparable between the Sirt1Tg and WT littermates. In the striatum, the relative fluorescence intensity of TH-positive nerve terminals and the level of gliosis did not differ by the genotypes. Conclusions Sirt1Tg and WT littermate mice exhibited comparable acute histopathological reactions to the systemic injection of MPTP, loss of TH-positive neurons and reactive gliosis. Thus, the genetic supplementation of SIRT1 does not confer histologically recognizable protection on nigrostriatal DA neurons against acute toxicity of MPTP.

  11. 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 Araújo, Dayane Pessoa; De Sousa, Caren Nádia Soares; Araújo, Paulo Victor Pontes; Menezes, Carlos Eduardo de Souza; Sousa Rodrigues, Francisca Taciana; Escudeiro, Sarah Souza; Lima, Nicole Brito Cortez; Patrocínio, Manoel Claúdio Azevedo; Aguiar, Lissiana Magna Vasconcelos; Viana, Glauce Socorro de Barros; Vasconcelos, Silvânia Maria Mendes

    2013-01-01

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

  12. Bupropion-induced convulsions: preclinical evaluation of antiepileptic drugs.

    PubMed

    Tutka, Piotr; Mróz, Tomasz; Klucha, Katarzyna; Piekarczyk, Ma?gorzata; Wielosz, Marian

    2005-01-01

    Bupropion, a unique, non-nicotine smoking cessation aid and an effective antidepressant, is well known to produce seizures following overdosing in humans. However, the experimental background for the usefulness of antiepileptic drugs in the protection against bupropion-induced convulsions has not been established yet. Therefore, we tested if the antiepileptic drugs were able to protect mice against clonic convulsions induced by intraperitoneally (i.p.) administered bupropion in the CD97 dose (139.5 mg/kg). Among 13 tested drugs, clonazepam showed the greatest potency (dose-dependent full protection; ED50 = 0.06 mg/kg, i.p.). No signs of locomotor impairment were observed in the rotarod test after anticonvulsive doses of clonazepam, resulting in a broad therapeutic window and favorable protective index (PI) (33.3). Gabapentin produced dose-dependent protection against convulsions at nontoxic doses (up to 1000 mg/kg), having PI>29. Diazepam in a very high dose showed full protection but its PI (1.7) was much less favorable than that of clonazepam. The PI values for ethosuximide, phenobarbital and valproate were slightly higher than unity and lower than 2, and for topiramate and felbamate were lower than unity. Phenytoin, carbamazepine, and lamotrigine as well as tiagabine failed to block the convulsant effects of bupropion even at doses that caused severe motor impairment. Our results encourage clinical testing of clonazepam against seizures developing after bupropion overdose. PMID:15866510

  13. Treatment with icatibant in the management of drug induced angioedema.

    PubMed

    Bertazzoni, G; Bresciani, E; Cipollone, L; Fante, E; Galandrini, R

    2015-01-01

    Acute, drug-induced angioedema may not respond to standard therapies, because the pathogenetic mechanism that induces the pathology is not always mediated by histamine but, in certain instances, by bradykinin. A case of angioedema is reported here, in which allergic etiology was excluded by the non-response to antihistamines. Considering the clinical history (repeated use of drugs) and the ineffectiveness of standard therapy, it was decided to administer a beta2 receptor antagonist, icatibant. After 20 minutes, the patient reported a subjective improvement. The only form of angioedema for which this type of medication is licensed is the hereditary deficiency of C1 inhibitor. The use of icatibant for the treatment of other types of angioedema (which can also be life-saving if the airway is involved) is off label. The off-label use of a drug is allowed in the absence of a viable alternative therapy, if there is scientific evidence in the literature and if the prescriber takes responsibility. The case here reported draws attention to this therapeutic problem and underlines the fact that a life-threatening emergency can justify the use of icatibant. PMID:25635988

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

    Microsoft Academic Search

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

    2009-01-01

    SUMMARY Induced pluripotent stem cells (iPSCs) derived from somatic cells of patients represent a powerful tool for biomedical research and may provide a source for replacement therapies. However, the use of viruses encoding the reprogramming factors repre- sents a major limitation of the current technology since even low vector expression may alter the differ- entiation potential of the iPSCs or

  15. Bromocriptine treatment in Parkinson's disease

    Microsoft Academic Search

    J D Parkes; C D Marsden; I Donaldson; A Galea-Debono; J Walters; G Kennedy; P Asselman

    1976-01-01

    Thirty-one patients with Parkinson's disease were treated with the ergot alkaloid bromocriptine, a drug which stimulates dopamine receptors. Bromocriptine had a slight therapeutic effect in patients on no other treatment and an additional effect in patients on levodopa. The mean optimum dosage of bromocriptine, established over a 12 week period, was 26 mg daily. In 20 patients bromocriptine was compared

  16. Drug-induced solar urticaria due to repirinast.

    PubMed

    Kurumaji, Y; Shono, M

    1994-01-01

    We describe the first case of drug-induced solar urticaria due to repirinast, an antiallergic drug developed and introduced into the market in Japan in 1987. The patient was a 72-year-old woman who had been on repirinast for 1 year and 8 months. She developed urticaria immediately after an irradiation with 1.5 J/cm2 of UVA, and the provocation test confirmed that repirinast was responsible for the urticarial reaction. The action spectrum of the urticarial reaction was deduced to be 320-350 nm. Passive and reverse passive transfer test results were both negative. However, intradermal injection of patient serum, obtained while she was on repirinast and irradiated in vitro with UVA, demonstrated positive reactions both in the patient and in a normal volunteer. Our findings suggest that nonallergic mechanisms are involved in the reaction. However, the rarity of the phenomenon also suggests an association with some allergic mechanisms. PMID:8136537

  17. Genetic predisposition to drug-induced liver disease.

    PubMed

    Fontana, R J; Watkins, P B

    1995-12-01

    Rarely do otherwise safe drugs administered at recommended doses produce liver damage that may progress to liver failure and death. Because we are generally unable to identify the patients most susceptible to this "idiosyncratic" form of toxicity, many potentially useful medications are not made available to patients. The most promising developments in identifying susceptible patients have stemmed from recent advances in characterization of bioactivation and detoxification enzyme systems, and the discovery of marked variation in the activities of these enzymes among patients. Tests capable of quantitating the activities of specific relevant enzymes have been recently developed and are now being applied in clinical trials to assess risk factors for drug-induced liver disease. These tests hold promise of identifying subsets of patients who may need close monitoring or who may be best served with an alternate treatment. PMID:8749900

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

    PubMed

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

    2014-11-01

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

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

    PubMed

    Donato, M Teresa; Gómez-Lechón, M José

    2012-10-01

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

  20. Two-step grafting significantly enhances the survival of foetal dopaminergic transplants and induces graft-derived vascularisation in a 6-OHDA model of Parkinson's disease.

    PubMed

    Büchele, Fabian; Döbrössy, Máté; Hackl, Christina; Jiang, Wei; Papazoglou, Anna; Nikkhah, Guido

    2014-08-01

    Following transplantation of foetal primary dopamine (DA)-rich tissue for neurorestaurative treatment of Parkinson's disease (PD), only 5-10% of the functionally relevant DAergic cells survive both in experimental models and in clinical studies. The current work tested how a two-step grafting protocol could have a positive impact on graft survival. DAergic tissue is divided in two portions and grafted in two separate sessions into the same target area within a defined time interval. We hypothesized that the first graft creates a "DAergic" microenvironment or "nest" similar to the perinatal substantia nigra that stimulates and protects the second graft. 6-OHDA-lesioned rats were sequentially transplanted with wild-type (GFP-, first graft) and transgenic (GFP+, second graft) DAergic cells in time interims of 2, 5 or 9days. Each group was further divided into two sub-groups receiving either 200k (low cell number groups: 2dL, 5dL, 9dL) or 400k cells (high cell number groups: 2dH, 5dH, 9dH) as first graft. During the second transplantation, all groups received the same amount of 200k GFP+ cells. Controls received either low or high cell numbers in one single session (standard protocol). Drug-induced rotations, at 2 and 6weeks after grafting, showed significant improvement compared to the baseline lesion levels without significant differences between the groups. Rats were sacrificed 8weeks after transplantation for post-mortem histological assessment. Both two-step groups with the time interval of 2days (2dL and 2dH) showed a significantly higher survival of DAergic cells compared to their respective standard control group (2dL, +137%; 2dH, +47%). Interposing longer intervals of 5 or 9days resulted in the loss of statistical significance, neutralising the beneficial two-step grafting effect. Furthermore, the transplants in the 2dL and 2dH groups had higher graft volume and DA-fibre-density values compared to all other two-step groups. They also showed intense growth of GFP+ vessels - completely absent in control grafts - in regions where the two grafts overlap, indicating second-graft derived angiogenesis. In summary, the study shows that two-step grafting with a 2days time interval significantly increases DAergic cell survival compared to the standard protocol. Furthermore, our results demonstrate, for the first time, a donor-derived neoangiogenesis, leading to a new understanding of graft survival and development in the field of cell-replacement therapies for neurodegenerative diseases. PMID:24780496

  1. Approaches to the study of drug-induced liver injury.

    PubMed

    Fontana, R J

    2010-09-01

    Retrospective studies of administrative databases have led to highly variable estimates of the incidence and natural history of drug-induced liver injury (DILI) and the agents implicated. In contrast, prospective multicenter registry studies allow for more accurate phenotyping of individual patients with DILI, as well as for collection of biological samples for mechanistic studies. In addition to improved diagnostic and prognostic biomarkers, standardized causality assessment tools are needed, as well as population-based studies that represent the full spectrum of disease severity. This would facilitate further research into the pathogenesis of DILI, leading ultimately to the prevention of this condition. PMID:20664536

  2. Clinical manifestations and treatment of drug-induced hepatotoxicity.

    PubMed

    Giordano, Christin M; Zervos, Xaralambos B

    2013-11-01

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

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

    PubMed

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

    2008-09-01

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

  4. Reduced anti-oxidative stress activities of DJ1 mutants found in Parkinson’s disease patients

    Microsoft Academic Search

    Kazuko Takahashi-Niki; Takeshi Niki; Takahiro Taira; Sanae M. M Iguchi-Ariga; Hiroyoshi Ariga

    2004-01-01

    DJ-1 is a multi-functional protein that plays roles in transcriptional regulation and anti-oxidative stress, and loss of its function is thought to result in onset of Parkinson’s disease. We have previously reported that L166P, a mutant DJ-1 found in Parkinson’s disease patients, had no activity to prevent hydrogen peroxide (H2O2)-induced cell death. In this study, we analyzed other mutants of

  5. Parkinson's Empowering the

    E-print Network

    Parkinson's Disease: Empowering the Community a free symposium Saturday, May 17, 2014 92037 Parkinson's Disease: Empowering the Community a free symposium Faculty Irene Litvan, MD Director Parkinson's disease symposium for patients, their families and caregivers. Each speaker in this year

  6. Normal lipase drug-induced pancreatitis: a novel finding.

    PubMed

    Shafqet, Muhammad A; Brown, Teresa V; Sharma, Ranita

    2015-03-01

    Acute pancreatitis (AP) in the setting of a normal serum amylase has been previously reported in the literature. Serum lipase on the other hand has a negative predictive value approaching 100% and therefore is an excellent test to rule out AP in the emergency department. The occurrence of AP with a normal lipase is extremely rare and has never been reported in the setting of drug-induced pancreatitis. Thiazide diuretics have been implicated as a cause of pancreatic injury via a number of proposed mechanisms. However, all such cases have been in the setting of elevated serum amylase or lipase. We report the first case of radiographically proven hydrochlorothiazide-induced pancreatitis with a normal lipase. PMID:25227976

  7. AC-186, a Selective Nonsteroidal Estrogen Receptor ? Agonist, Shows Gender Specific Neuroprotection in a Parkinson’s 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 Parkinson’s 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

  8. 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

  9. 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

  10. Osteoporosis and Parkinson’s disease

    PubMed Central

    Raglione, Laura Maria; Sorbi, Sandro; Nacmias, Benedetta

    2011-01-01

    Summary Parkinson’s disease (PD) and osteoporosis are two conditions with a quite high prevalence in older people. From the literature we learn that in parkinsonian people there a is e major reduction of Bone Mass Density (BMD) compared to age-matched controls. A low BMD is one of the factors related to fracture’s frequency in PD patients besides an increased risk of falls. From the standpoint pathophysiology, various factors are involved in osteoporosis: immobilization, endocrine factors like hypovitaminosis D, nutritional and iatrogenic factors. Considering morbidity and mortality related to fractures in old people and in particular in PD patients it is reasonable that these patients would undergo to vitamin and BMD measuring, to fall risk assessment and that all preventive measure are implemented to reduce the risk of fractures. Possible interventions are essentially based on fall prevention and treatment of osteoporosis. Randomized clinical studies in the literature, in which it was studied the effect of anti-osteoporotic drugs in patients with MP showed a significant reduction in the number of fractures and increase BMD. PMID:22461823

  11. Risk factors for complications of drug-induced seizures.

    PubMed

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

    2011-03-01

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

  12. 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 these…

  13. PEP1–SOD fusion protein efficiently protects against paraquat-induced dopaminergic neuron damage in a Parkinson disease mouse model

    Microsoft Academic Search

    Hee Soon Choi; Jae Jin An; So Young Kim; Sun Hwa Lee; Dae Won Kim; Ki-Yeon Yoo; Moo Ho Won; Tae-Cheon Kang; Hyung Joo Kwon; Jung Hoon Kang; Sung-Woo Cho; Oh-Shin Kwon; Won Sik Eum; Soo Young Choi

    2006-01-01

    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

  14. Contact dependent reproducible hypomania induced by deep brain stimulation in Parkinson's disease: clinical, anatomical and functional imaging study

    Microsoft Academic Search

    Miguel Ulla; Stéphane Thobois; Pierre-Michel Llorca; Philippe Derost; Jean-Jacques Lemaire; Isabelle Chereau-Boudet; Ingrid de Chazeron; Audrey Schmitt; Bénédicte Ballanger; Emmanuel Broussolle; Franck Durif

    2010-01-01

    Hypomanic symptoms depending on anatomical location of contacts are reported in patients with Parkinson's disease (PD) treated by deep brain stimulation (DBS) of the subthalamic nucleus (STN). However, the underlying cortical and subcortical dysfunction is debated. In this study, five PD patients implanted with DBS–STN who presented with reversible and reproducible hypomanic symptoms after stimulation of specific ‘manic’ contacts were

  15. 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

  16. Neurokinin B, neurotensin, and cannabinoid receptor antagonists and Parkinson disease.

    PubMed

    Mesnage, V; Houeto, J L; Bonnet, A M; Clavier, I; Arnulf, I; Cattelin, F; Le Fur, G; Damier, P; Welter, M L; Agid, Y

    2004-01-01

    The neuropeptides neurokinin B, neurotensin, and anandamide, the endogenous ligands of NK3, NT1, and CB1 receptors respectively, are known to interact with brain dopaminergic transmission. This study evaluated the effects of these three antagonists of the NK3 (SR 142801), neurotensin (SR 48692), and cannabinoid (SR 141716) receptors on the severity of motor symptoms and levodopa-induced dyskinesias after administration of a single dose of levodopa in 24 patients with Parkinson disease. In this exploratory randomized, double-blind, placebo-controlled study, at the dose used, the drugs tested were well tolerated and could not improve parkinsonian motor disability. PMID:15190231

  17. Affective disorders in Parkinson’s disease

    PubMed Central

    Aminian, Kelly S.G.; Strafella, Antonio P.

    2014-01-01

    Purpose of review This review explores recent literature pertaining to affective disorders associated with Parkinson’s disease. Recent findings Nonmotor symptoms including affective disorders are becoming more widely recognized as complications of Parkinson’s disease. As awareness of these symptoms increases, and new neuroimaging tools are developed and become more accessible, more studies are being conducted pertaining to behavioral complications in Parkinson’s disease. The functional connectivity of the basal ganglia can predispose people with Parkinson’s to develop affective disorders. Furthermore, dopaminergic treatments may exacerbate or trigger behavioral symptoms. It is now understood that changes associated with Parkinson’s disease are widespread, affecting striatal and extrastriatal regions and resulting in alterations in gray matter, white matter, blood flow, metabolism, and dopaminergic and serotonergic function. Summary Neuroimaging is advancing our knowledge of the mechanisms involved in Parkinson’s disease, and their role in the development of behavioral disorders. An increased understanding of these disorders may lead to the discovery of new therapeutic targets, or the identification of risk factors for the development of these disorders. If preventive therapies become available, identification of risk factors will be important for the identification and treatment of susceptible individuals. PMID:23757262

  18. 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

  19. Antidiabetic Drug Metformin Suppresses Endotoxin-Induced Uveitis in Rats

    PubMed Central

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

    2012-01-01

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

  20. 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

  1. 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

  2. Drug induced phospholipidosis: an acquired lysosomal storage disorder.

    PubMed

    Shayman, James A; Abe, Akira

    2013-03-01

    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. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism. PMID:22960355

  3. Livedo racemosa, secondary to drug-induced systemic lupus erythematosus.

    PubMed

    Defelice, Taylor; Lu, Phoebe; Loyd, Aaron; Patel, Rishi; Franks, Andrew G

    2010-01-01

    We present a 40-year-old man with erythematous-to-violaceous, broken, reticulated patches on the upper chest, back, and extremities, which is consistent with livedo racemosa. The cutaneous findings appeared after an increase in dilantin dose and subsequently improved after a reduction in dilantin dose. Furthermore, antinuclear antibodies and antihistone antibodies were detected. We therefore believe that the livedo racemosa is a cutaneous manifestation of a drug-induced systemic lupus erythematosus. We review the distinctive features of livedo racemosa as well as its associations with several disorders. Although there are no effective treatments for livedo racemosa, patients often are placed on low-dose aspirin and counseled to avoid smoking in an effort to protect against their increased risk of stroke and arterial thrombosis. PMID:21163175

  4. Drug-induced phospholipidosis: issues and future directions.

    PubMed

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

    2006-07-01

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

  5. Drug-induced long QT syndrome in women.

    PubMed

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

    2013-09-01

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

  6. 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.

  7. Epidemiology of Idiosyncratic Drug-Induced Liver Injury

    PubMed Central

    Bell, Lauren N.; Chalasani, Naga

    2010-01-01

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

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

    Microsoft Academic Search

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

    2010-01-01

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

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

    Microsoft Academic Search

    Clare L. Parish; Ernest Arenas

    2007-01-01

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

  10. 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

  11. Round window membrane intracochlear drug delivery enhanced by induced advection.

    PubMed

    Borkholder, David A; Zhu, Xiaoxia; Frisina, Robert D

    2014-01-28

    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 1week, 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 1week 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

  12. Redox Imbalance in Parkinson’s Disease

    PubMed Central

    Chinta, Shankar J.; Andersen, Julie K.

    2008-01-01

    Parkinson’s 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

  13. Novel monohydroxamate drugs attenuate myocardial reperfusion-induced arrhythmias.

    PubMed

    Collis, C S; Rice-Evans, C; Davies, M J

    1996-04-01

    The novel monohydroxamates N-methyl hexanoylhydroxamic acid, N-methyl acetohydroxamic acid, and N-methyl butyrohydroxamic acid have antioxidant and iron chelating properties. They attenuated reperfusion-induced contractile dysfunction following long periods of ischaemia (50 min) in the isolated rat heart. Here we compare their effects and that of the trihydroxamate desferrioxamine on reperfusion-induced arrhythmias following short duration ischaemia (10 min). Isolated rat hearts were perfused by the Langendorff method, subjected to regional ischaemia and reperfusion. Arrhythmias induced during the first 5 min of reperfusion were quantified. Drugs (all at 150 microM) were introduced during the last 2 min of ischaemia and remained throughout reperfusion. Although the monohydroxamate- and desferrioxamine-treated hearts showed a reduction in the incidence of ventricular tachycardia and fibrillation, only the reduction in the incidence of sustained fibrillation ( > 3 min duration) in N-methyl acetohydroxamic acid--(27%), N-methyl hexanoylhydroxamic acid--(27%) and desferrioxamine-treated hearts (20%) was statistically significant (p < 0.05 vs control 73%; n = 15). There was a reduction in the severity of the arrhythmias, manifest as a significant increase in the duration of sinus rhythm in all the monohydroxamate-treated hearts, and a significant reduction (vs control 218 +/- 29 s; mean +/- SEM) in the duration of ventricular fibrillation in hearts treated with N-methyl acetohydroxamic acid (101 +/- 31 s) and desferrioxamine (112 +/- 30 s). This improvement was offset by an increase in the duration of ventricular tachycardia, in hearts treated with N-methyl acetohydroxamic acid, N-methyl butyrohydroxamic acid and desferrioxamine. These results suggest that these novel monohydroxamates, particularly N-methyl acetohydroxamic acid, attenuate reperfusion-induced arrhythmias in this model when introduced during the ischaemic period. PMID:9026351

  14. Detection of preclinical Parkinson's disease with PET

    SciTech Connect

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

    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.

  15. 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

  16. A role for lysosomal phospholipase A2 in drug induced phospholipidosis.

    PubMed

    Abe, Akira; Hiraoka, Miki; Shayman, James A

    2007-01-01

    Many therapeutic drugs currently in use are cationic amphiphiles. These cationic amphiphilic drugs (CADs) induce phospholipidosis in humans and experimental animals. The recent study shows that CAD-induced cellular phospholipidosis is linked to the impairment of phospholipid catabolism by inhibition of lysosomal phospholipase A2 activity. PMID:19356018

  17. 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 °C) and released a majority of the cargo only when exposed to an external AMF. Our designed magnetic drug delivery platform is the first example of an AMF-inducible system that does not depend on the inclusion of thermosensitive materials. Finally, we have developed a bioanalytical application of the highly chemosele

  18. THE ETIOLOGY, EEPIDEMIOLOGY AND MANAGEMENT OF IDIOSYNCRATIC DRUG-INDUCED AGRANULOCYTOSIS

    Microsoft Academic Search

    EMMANUEL ANDRÈS; STÉPHANE AFFENBERGER; MARTINE ALT; GEORGES KALTENBACH; FRÉDÉRIC MALOISEL

    OBJECTIVE: To review the literature concerning idiosyn- cratic drug-induced agranulocytosis, a rare but life-threatening potential ad- verse event of most drugs. DATA SOURCES: Articles were identified through searches of MEDLINE (January 1966 to March 2005). Unpublished data from our cohort of drug-induced agranulocytosis in the University Hospital of Strasbourg, France were also considered. DATA EXTRACTION AND SYNTH- ESIS: All of

  19. The effects of cardioactive drugs on cardiomyocytes derived from human induced pluripotent stem cells

    Microsoft Academic Search

    Noritaka Yokoo; Shiro Baba; Shinji Kaichi; Akira Niwa; Takahiro Mima; Hiraku Doi; Shinya Yamanaka; Tatsutoshi Nakahata; Toshio Heike

    2009-01-01

    Developing effective drug therapies for arrhythmic diseases is hampered by the fact that the same drug can work well in some individuals but not in others. Human induced pluripotent stem (iPS) cells have been vetted as useful tools for drug screening. However, cardioactive drugs have not been shown to have the same effects on iPS cell-derived human cardiomyocytes as on

  20. Discovery of the neuroprotective effects of alvespimycin by computational prioritization of potential anti-Parkinson agents.

    PubMed

    Gao, Li; Zhao, Gang; Fang, Jian-Song; Yuan, Tian-Yi; Liu, Ai-Lin; Du, Guan-Hua

    2014-02-01

    Based on public gene expression data, we propose a computational approach to optimize gene expression signatures for the use with Connectivity Map (CMap) to reposition drugs or discover lead compounds for Parkinson's disease. This approach integrates genetic information from the Gene Expression Omnibus (GEO) database, the Parkinson's disease gene expression database (ParkDB), the Online Mendelian Inheritance in Man (OMIM) database and the Comparative Toxicogenomics Database (CTD), with the aim of identifying a set of interesting genes for use in computational drug screening via CMap. The results showed that CMap, using the top 20 differentially expressed genes identified by our approach as a gene expression signature, outperformed the same method using all differentially expressed genes (n = 535) as a signature. Utilizing this approach, the candidate compound alvespimycin (17-DMAG) was selected for experimental evaluation in a model of rotenone-induced toxicity in human SH-SY5Y neuroblastoma cells and isolated rat brain mitochondria. The results showed that 17-DMAG significantly attenuated rotenone-induced toxicity, as reflected by the increase of cell viability, the reduction of intracellular reactive oxygen species generation and a reduction in mitochondrial respiratory dysfunction. In conclusion, this computational method provides an effective systematic approach for drug repositioning or lead compound discovery for Parkinson's disease, and the discovery of the neuroprotective effects of 17-DMAG supports the practicability of this method. PMID:24304935

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

    PubMed

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

    2012-08-01

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

  2. Depression Impairs Learning Whereas Anticholinergics Impair Transfer Generalization in Parkinson Patients

    E-print Network

    Gluck, Mark

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

  3. 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

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

    PubMed

    Fitzgerald, Patrick T; Ackerman, Michael J

    2005-11-01

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

  5. Novel pharmacological targets for the treatment of Parkinson's disease

    Microsoft Academic Search

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

    2006-01-01

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

  6. Differential involvement of D1 and D2 dopamine receptors in L-DOPA-induced angiogenic activity in a rat model of Parkinson's disease.

    PubMed

    Lindgren, Hanna S; Ohlin, K Elisabet; Cenci, M Angela

    2009-11-01

    Angiogenesis occurs in the brains of Parkinson's disease patients, but the effects of dopamine replacement therapy on this process have not been examined. Using rats with 6-hydroxydopamine lesions, we have compared angiogenic responses induced in the basal ganglia by chronic treatment with either L-DOPA, or bromocriptine, or a selective D1 receptor agonist (SKF38393). Moreover, we have asked whether L-DOPA-induced angiogenesis can be blocked by co-treatment with either a D1- or a D2 receptor antagonist (SCH23390 and eticlopride, respectively), or by an inhibitor of extracellular signal-regulated kinases 1 and 2 (ERK1/2) (SL327). L-DOPA, but not bromocriptine, induced dyskinesia, which was associated with endothelial proliferation, upregulation of immature endothelial markers (nestin) and downregulation of endothelial barrier antigen in the striatum and its output structures. At a dose inducing dyskinesia (1.5 mg/kg/day), SKF38393 elicited angiogenic changes similar to L-DOPA. Antagonism of D1- but not D2 class receptors completely suppressed both the development of dyskinesia and the upregulation of angiogenesis markers. In fact, L-DOPA-induced endothelial proliferation was markedly exacerbated by low-dose D2 antagonism (0.01 mg/kg eticlopride). Inhibition of ERK1/2 by SL327 attenuated L-DOPA-induced dyskinesia and completely inhibited all markers of angiogenesis. These results highlight the specific link between treatment-induced dyskinesias and microvascular remodeling in the dopamine-denervated brain. L-DOPA-induced angiogenesis requires stimulation of D1 receptors and activation of ERK1/2, whereas the stimulation of D2 receptors seems to oppose this response. PMID:19606087

  7. Evaluation of the association between blood homocysteine concentration and the degree of behavioral symptoms in the 6-hydroxydopamine-induced Parkinsonism in rat.

    PubMed

    Haghdoost-Yazdi, Hashem; Sarookhani, Mohammad; Faraj, Ayda; Fraidouni, Negin; Dargahi, Tahereh; Yaghoubidoust, Mohammad Hosein; Azhdari-Zarmehri, Hassan

    2014-09-01

    Growing evidence indicates that homocysteine (Hcy) may be involved in the pathophysiology of several neurological disorders including Parkinson's disease. In the present study, the association between blood Hcy concentration and the degree of behavioral symptoms in the 6-hydroxydopamine (6-OHDA)-induced Parkinsonism in rat was evaluated. Total serum Hcy (tHcy) was measured before and 6 weeks after the intracerebral injection of 6-OHDA. Apomorphine-induced rotational test was performed at second, third and sixth weeks after 6-OHDA injection. Subsequently, cell replacement therapy was performed on rats with good rotation score. No correlation between tHcy in before 6-OHDA injection and severity of the rotations after 6-OHDA injection was observed. On the other hand, 6-OHDA treatment significantly decreased tHcy level. However, this reduction was only observed in animals with low degree of rotations and in rats with high number of rotations; tHcy did not change significantly. Furthermore, 10 weeks after cell transplantation, tHcy was significantly lower than that found before therapy if the rats showed good improvement in the degree of rotations. We also examined the effect of different supplements of B vitamins on tHcy before and after 6-OHDA injection. In healthy rats, all kinds of B vitamins and also supplement B6 or B12 alone reduced tHcy. Following 6-OHDA injection, B vitamin supplementation failed to cause remarkable effect. Considering the direct correlation between the severity of rotational behavior and the degree of lesion in the substantia nigra (SN), our data indicate that higher tHcy values can predict higher SN dopaminergic neurodegeneration. PMID:24992727

  8. Quercetin glycosides induced neuroprotection by changes in the gene expression in a cellular model of Parkinson's disease.

    PubMed

    Magalingam, Kasthuri Bai; Radhakrishnan, Ammu; Ramdas, Premdass; Haleagrahara, Nagaraja

    2015-03-01

    Quercetin glycosides, rutin and isoquercitrin, are potent antioxidants that have been found to possess neuroprotective effect in diseases like Parkinson's and Alzheimer's disease. In the present study, we have examined the gene expression changes with rutin and isoquercitrin pretreatment on 6-hydroxydopamine (6-OHDA)-treated toxicity in rat pheochromocytoma (PC12) cells. PC12 cells were pretreated with rutin or isoquercitrin and subsequently exposed to 6-OHDA. Rutin-pretreated PC12 attenuated the Park2, Park5, Park7, Casp3, and Casp7 genes which were expressed significantly in the 6-OHDA-treated PC12 cells. Rutin upregulated the TH gene which is important in dopamine biosynthesis, but isoquercitrin pretreatment did not affect the expression of this gene. Both rutin and isoquercitrin pretreatments upregulated the ion transport and antiapoptotic genes (NSF and Opa1). The qPCR array data were further validated by qRT-PCR using four primers, Park5, Park7, Casp3, and TH. This finding suggests that changes in the expression levels of transcripts encoded by genes that participate in ubiquitin pathway and dopamine biosynthesis may be involved in Parkinson's disease. PMID:25129099

  9. DIGRE: Drug-Induced Genomic Residual Effect Model for Successful Prediction of Multidrug Effects

    PubMed Central

    Yang, J; Tang, H; Li, Y; Zhong, R; Wang, T; Wong, STC; Xiao, G; Xie, Y

    2015-01-01

    Multidrug regimens are a promising strategy for improving therapeutic efficacy and reducing side effects, especially for complex disorders such as cancer. However, the use of multidrug therapies is very challenging, due to a lack of understanding of the mechanisms of drug interactions. We herein present a novel computational approach—Drug-Induced Genomic Residual Effect (DIGRE) Computational Model—to predict drug combination effects by explicitly modeling drug response curves and gene expression changes after drug treatments. The prediction performance of DIGRE was evaluated using two datasets: (i) OCI-LY3 B-lymphoma cells treated with 14 different drugs and (ii) MCF breast cancer cells treated with combinations of gefitinib and docetaxel at different doses. In both datasets, the predicted drug combination effects significantly correlated with the experimental results. The results indicated the model was useful in predicting drug combination effects, which may greatly facilitate the discovery of new, effective multidrug therapies.

  10. Glutathione Metabolism and Parkinson’s Disease

    PubMed Central

    Smeyne, Michelle

    2013-01-01

    It has been established that oxidative stress, defined as the condition when the sum of free radicals in a cell exceeds the antioxidant capacity of the cell, contributes to the pathogenesis of Parkinson’s disease. Glutathione is a ubiquitous thiol tripeptide that acts alone, or in concert with enzymes within cells to reduce superoxide radicals, hydroxyl radicals and peroxynitrites. In this review, we examine the synthesis, metabolism and functional interactions of glutathione, and discuss how this relates to protection of dopaminergic neurons from oxidative damage and its therapeutic potential in Parkinson’s disease. PMID:23665395

  11. 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 “The role of neuropeptides in stress and addiction”, we review results from studies on the role of corticotropin-releasing factor (CRF) and several other peptides in stress-induced reinstatement of drug seeking in laboratory animals. The results of the studies reviewed indicate that extrahypothalamic CRF plays a critical role in stress-induced reinstatement of drug seeking; this role is largely independent of drug class, experimental procedure, and type of stressor. There is also limited evidence for the role of dynorphins, hypocretins (orexins), nociceptin (orphanin FQ), and leptin in stress-induced reinstatement of drug seeking. PMID:19631614

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

    SciTech Connect

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

    2006-07-21

    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.

  13. 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

  14. 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

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

    Microsoft Academic Search

    Krystyna Honczarenko; Jan Stankiewicz; Zbigniew Sych

    2003-01-01

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

  16. The selective mu-opioid receptor antagonist ADL5510 reduces levodopa-induced dyskinesia without affecting antiparkinsonian action in MPTP-lesioned macaque model of Parkinson's disease.

    PubMed

    Koprich, James B; Fox, Susan H; Johnston, Tom H; Goodman, Allan; Le Bourdonnec, Bertrand; Dolle, Roland E; DeHaven, Robert N; DeHaven-Hudkins, Diane L; Little, Patrick J; Brotchie, Jonathan M

    2011-06-01

    In Parkinson's disease (PD), dyskinesia develops following long-term treatment with 3,4-dihydroxyphenylalanine (L-dopa). Given the prominent role of the opioid system in basal ganglia function, nonselective opioid receptor antagonists have been tested for antidyskinetic efficacy in the clinic (naltrexone and naloxone), although without success. In the current study, ADL5510, a novel, orally active opioid antagonist with mu opioid receptor selectivity, was examined in L-dopa-treated 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) macaques. Antidyskinetic effects were compared with those of naltrexone. Parkinsonian monkeys with established L-dopa-induced dyskinesia (LID) received acute challenges with L-dopa (subcutaneously) in combination with either vehicle, ADL5510 (0.1, 1, 3 or 10 mg/kg by mouth), or naltrexone (1, 3, or 10 mg/kg subcutaneously). Following treatments, behavior was monitored for 6 hours. Parameters assessed were total activity, parkinsonism, and dyskinesia. ADL5510 (1, 3, and 10 mg/kg) reduced activity and LID (chorea and dystonia) without affecting the antiparkinsonian benefits of L-dopa. The antidyskinetic effect of ADL5510 showed a U-shaped dose-response. It was inactive at 0.1 mg/kg, efficacious at 1 and 3 mg/kg (72% and 40% reductions, respectively), and then less effective at 10 mg/kg. The quality of ON time produced by L-dopa was improved, as indicated by a reduction in the percentage of ON time spent experiencing disabling dyskinesia (70% and 61% reductions with 1 and 3 mg/kg, respectively, compared with L-dopa). Naltrexone, in contrast, did not alleviate LID or affect the antiparkinsonian actions of L-dopa. Mu-selective opioid antagonists have the potential to form the basis of novel antidyskinetic therapies for PD. PMID:21465551

  17. Drug-induced autoimmunity: experience of the French Pharmacovigilance system

    Microsoft Academic Search

    Thierry Vial; Brigitte Nicolas; Jacques Descotes

    1997-01-01

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

  18. 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

  19. Steroidal and nonsteroidal drugs in endotoxin-induced uveitis.

    PubMed

    Kulkarni, P S

    1994-01-01

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

  20. Pharmacotherapy in Parkinson’s disease: case studies

    PubMed Central

    Mestre, Tiago; Ferreira, Joaquim J.

    2010-01-01

    Parkinson’s disease is a common neurodegenerative disorder with the particular feature of having various available treatments with proven efficacy. However, no treatment is curative. Recent trial results provided data for the discussion about the potential disease-modifying effect of new drugs as well as of other therapeutic strategies. The changing clinical phenotype following the progression of the disease multiplies the number of treatment targets and makes the application of recommendations from guidelines or other treatment algorithms to the individual patient a complex task. In the present manuscript, we discuss the treatment management of three case studies illustrating different stages of disease with distinct phenomenology. The proposed therapeutic alternatives are discussed based on the best data available; that is, treatment guidelines, clinical trial results or observational data. PMID:21179604

  1. 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

  2. ?-Synuclein-induced mitochondrial dysfunction in isolated preparation and intact cells: implications in the pathogenesis of Parkinson's disease.

    PubMed

    Bir, Aritri; Sen, Oishimaya; Anand, Shruti; Khemka, Vineet Kumar; Banerjee, Priyanjalee; Cappai, Roberto; Sahoo, Arghyadip; Chakrabarti, Sasanka

    2014-12-01

    This study has shown that purified recombinant human ?-synuclein (20 ?M) causes membrane depolarization and loss of phosphorylation capacity of isolated purified rat brain mitochondria by activating permeability transition pore complex. In intact SHSY5Y (human neuroblastoma cell line) cells, lactacystin (5 ?M), a proteasomal inhibitor, causes an accumulation of ?-synuclein with concomitant mitochondrial dysfunction and cell death. The effects of lactacystin on intact SHSY5Y cells are, however, prevented by knocking down ?-synuclein expression by specific siRNA. Furthermore, in wild-type (non-transfected) SHSY5Y cells, the effects of lactacystin on mitochondrial function and cell viability are also prevented by cyclosporin A (1 ?M) which blocks the activity of the mitochondrial permeability transition pore. Likewise, in wild-type SHSY5Y cells, typical mitochondrial poison like antimycin A (50 nM) produces loss of cell viability comparable to that of lactacystin (5 ?M). These data, in combination with those from isolated brain mitochondria, strongly suggest that intracellularly accumulated ?-synuclein can interact with mitochondria in intact SHSY5Y cells causing dysfunction of the organelle which drives the cell death under our experimental conditions. The results have clear implications in the pathogenesis of sporadic Parkinson's disease. ?-Synuclein is shown to cause mitochondrial impairment through interaction with permeability transition pore complex in isolated preparations. Intracellular accumulation of ?-synuclein in SHSY5Y cells following proteasomal inhibition leads to mitochondrial impairment and cell death which could be prevented by knocking down ?-synuclein gene. The results link mitochondrial dysfunction and ?-synuclein accumulation, two key pathogenic mechanisms of Parkinson's disease, in a common damage pathway. PMID:25319443

  3. Cancer stem cells and escape from drug-induced premature senescence in human lung tumor cells: implications for drug resistance and in vitro drug screening models.

    PubMed

    Sabisz, Michal; Skladanowski, Andrzej

    2009-10-01

    In this study, using an in vitro human tumor model, we show that non-small lung adenocarcinoma A549 cells after treatment with DNA damaging antitumor drugs become permanently growth-arrested as a result of so-called drug-induced premature senescence (pseudo-senescence). However, a small fraction of drug-treated cells escapes pseudo-senescence that leads to re-growth of tumor cell population after drug treatment. We show that this re-growth is associated with the presence of cancer stem cells (CSCs) in lung tumor cell population. We also document that re-growth of CSCs can be greatly delayed if lung tumor cells are treated with drug/caffeine combination that leads to the inhibition of the ATM/ATR pathway and decreased phosphorylation of PKB/Akt at Ser473. We show that in non-treated A549 cells caffeine by itself induces a reversible growth arrest that is associated with increased fraction of so-called side population cells, containing CSCs. These results point to the existence of an unknown, caffeine-sensitive mechanism that controls the number of CSCs in lung tumor cell population. Full characterization of this mechanism may lead to the development of innovative cancer therapies, which are based on small molecular weight inhibitors of CSC differentiation and self-renewal, which mimic caffeine action. Our results have also important implications for drug screening tumor models in vitro. PMID:19738435

  4. 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...

  5. Intense pseudotransport of a cationic drug mediated by vacuolar ATPase: Procainamide-induced autophagic cell vacuolization

    Microsoft Academic Search

    Guillaume Morissette; Robert Lodge; François Marceau

    2008-01-01

    Cationic drugs frequently exhibit large apparent volumes of distribution, consistent with various forms of cellular sequestration. The contributions of organelles and metabolic processes that may mimic drug transport were defined in human vascular smooth muscle cells. We hypothesized that procainamide-induced vacuolar cytopathology is driven by intense pseudotransport mediated by the vacuolar (V)-ATPase and pursued the characterization of vesicular trafficking alterations

  6. Research Paper A Novel in Vitro and Numerical Analysis of Shear-Induced Drug Release

    E-print Network

    Brasseur, James G.

    Research Paper A Novel in Vitro and Numerical Analysis of Shear-Induced Drug Release from Extended apparatus; extended release; stomach. INTRODUCTION In vitro drug dissolution testing is a key tool viscosity of test media and rotation rate of the beaker. Results. Mass erosion rate and surface shear were

  7. (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

  8. 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.

  9. Drug-Induced Bronchospasm: Analysis of 187 Spontaneously Reported Cases

    Microsoft Academic Search

    Jörg D. Leuppi; Pia Schnyder; Katharina Hartmann; Walter H. Reinhart; Max Kuhn

    2001-01-01

    Background: The Swiss Drug Monitoring Center (SANZ) uses a systematic approach to the collection of spontaneously reported individual cases on suspected adverse drug reactions (ADRs). Spontaneous reporting schemes are designed to detect new, rare and unexpected ADRs and to act as an early warning system but there is a tendency to overreport severe reactions. Objectives: The aim of the study

  10. Pathologic gambling in patients with Parkinson's disease.

    PubMed

    Gschwandtner, U; Aston, J; Renaud, S; Fuhr, P

    2001-01-01

    Patients with Parkinson's disease frequently have depression, anxiety, and obsessive-compulsive disorder. We observed two patients who had episodes of pathologic gambling. At the same time, their Parkinson's disease deteriorated and they initiated self-medication with dopaminergic drugs. In both patients, signs were present of an addiction to dopaminergic medication. Pathologic gambling ceased in these patients after a few months. The significance of an insufficient dopaminergic reward system in patients with stereotypical addictive-like behavior (e.g., pathologic gambling) is discussed in this report. The most likely explanation for this newly recognized behavioral disorder in patients with Parkinson's disease is enhanced novelty seeking as a consequence of overstimulation of mesolimbic dopamine receptors resulting from addiction to dopaminergic drugs. PMID:11391129

  11. Parkinson's disease.

    PubMed

    Benninger, David H

    2013-01-01

    In advanced Parkinson's disease (PD), the emergence of symptoms refractory to conventional therapy poses therapeutic challenges. The success of deep brain stimulation (DBS) and advances in the understanding of the pathophysiology of PD have raised interest in noninvasive brain stimulation as an alternative therapeutic tool. The rationale for its use draws from the concept that reversing abnormalities in brain activity and physiology thought to cause the clinical deficits may restore normal functioning. Currently the best evidence in support of this concept comes from DBS, which improves motor deficits, and modulates brain activity and motor cortex physiology, although whether a causal interaction exists remains largely undetermined. Most trials of noninvasive brain stimulation in PD have applied repetitive transcranial magnetic stimulation (rTMS), targeting the motor cortex. Current studies suggest a possible therapeutic potential for rTMS and transcranial direct current stimulation (tDCS), but clinical effects so far have been small and negligible with regard to functional independence and quality of life. Approaches to potentiate the efficacy of rTMS include increasing stimulation intensity and novel stimulation parameters that derive their rationale from studies on brain physiology. These novel parameters are intended to simulate normal firing patterns or to act on the hypothesized role of oscillatory activity in the motor cortex and basal ganglia with regard to motor control and its contribution to the pathogenesis of motor disorders. Noninvasive brain stimulation studies will enhance our understanding of PD pathophysiology and might provide further evidence for potential therapeutic applications. PMID:24112916

  12. Glomerular tip lesion associated with nonsteroidal anti-inflammatory drug-induced nephrotic syndrome.

    PubMed

    Sekhon, Inderpreet; Munjal, Sandeep; Croker, Byron; Johnson, Richard J; Ejaz, A Ahsan

    2005-10-01

    Glomerular tip lesion and its relation to different glomerular diseases is a subject of controversy. The therapeutic and prognostic clinical implications of glomerular tip lesions are ambiguous. We present a case of glomerular tip lesion associated with nonsteroidal anti-inflammatory drug-induced nephrotic syndrome that further complicates this issue. To our knowledge, this is the first case report of glomerular tip lesion associated with nonsteroidal anti-inflammatory drug-induced nephrotic syndrome. PMID:16183408

  13. Opiate-Androgen Interactions in Drug-Induced Yawning and Penile Erections in the Rat

    Microsoft Academic Search

    Hemmie H. G. Berendsen; Alma J. Gower

    1986-01-01

    The effects of pretreatment with drugs on drug-induced yawning and penile erection in intact and chronically castrated rats were investigated. Naloxone partially blocked yawning in intact rats and in castrated rats pretreated with dihydro-testosterone propionate (DHTP) but not in control castrates. In contrast, naloxone potentiated apomorphine-induced penile erections in intact rats. Morphine, haloperidol and atropine blocked yawning and penile erections.

  14. 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 silicon’s 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 dissolution–drug release phase. PMID:25678746

  15. 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

  16. Rasagiline promotes regeneration of substantia nigra dopaminergic neurons in post-MPTP-induced Parkinsonism via activation of tyrosine kinase receptor signaling pathway.

    PubMed

    Mandel, Silvia A; Sagi, Yotam; Amit, Tamar

    2007-10-01

    The anti-Parkinson drug rasagiline (Azilect), an irreversible and selective monoamine oxidase (MAO)-B inhibitor, was shown to possess neuroprotective activities, involving multiple survival pathways among them the up-regulation of protein kinase C (PKC)alpha, PKCepsilon, the anti-apoptotic Bcl-2, Bcl-xL, and Bcl-w and the induction of brain-derived- and glial cell line-derived neurotrophic factors (BDNF, GDNF). More recently, employing conventional neurochemical techniques, as well as transcriptomic and proteomic screening tools, combined with a biology-based clustering method, it was shown that rasagiline also possesses neurorescue/neurogenesis activity in mice midbrain dopaminergic neurons when given chronically, post-MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). This action was attributed to the activation of cell signaling mediators associated with neurotrophic factors responsive-tyrosine kinase receptor (Trk) pathway, including ShcC, SOS, AF6, Rin1, and Ras and the increase in the Trk-downstream effecter phosphatidylinositol 3 kinase (PI3K) protein and its substrate, Akt/PKB. It is interesting to determine whether a similar effect is seen in Parkinsonian patients after long-term treatment with rasagiline, which may have implications as a possible disease modifying agent. PMID:17701352

  17. Drug Induced Liver Injury Caused by Intravenously Administered Medications: The Drug Induced Liver Injury Network (DILIN) Experience

    PubMed Central

    Ghabril, Marwan; Fontana, Robert; Rockey, Don; Jiezhun, Gu; Chalasani, Naga

    2012-01-01

    Background and Aims Idiosyncratic drug induced liver injury (DILI) can be caused by intravenous (IV) medications, but the characteristics of DILI caused by these agents are not known. The aim of this study is to characterize the clinical features of subjects with suspected DILI associated with IV agents enrolled into the DILIN Prospective Study. Methods Subjects with suspected DILI due to IV medications with probable, highly likely, or definite causality scores were eligible. Results Between 2004 and October 2010, 542 cases of DILI were adjudicated for causality, of which 32 were eligible for inclusion in this study. DILI was ascribed to a single IV agent in 27 and to multiple IV agents in 5 subjects. Antimicrobial agents (62%), anti-neoplastic agents (16%), and phenytoin (9%) were most commonly implicated. The pattern of liver injury was hepatocellular in 30%, mixed in 33%, and cholestatic in 37%. The peak ALT, AlkP, and total bilirubin were 686 ± 915 U/L, 623 ± 563 U/L, and 8.7 ± 10.3 mg/dL, respectively. The duration for ? 50% improvement from peak ALT, AlkP, and total bilirubin were 25 ± 37, 59 ± 69, and 20 ± 28 days respectively. DILI severity was mild in 37%, moderate in 47%, and severe in 13% and fatal in 3%, with no liver transplantation. Their causality was adjudicated as definite in 5, very likely in 17, and probable in 10 subjects. The frequency of chronic DILI was 13%. Conclusion Antimicrobial agents and anti-neoplastic are the most common IV agents to cause DILI. DILI ascribed to IV agents is relatively infrequent, but its outcomes are similar to those of the overall DILIN cohort. PMID:23388845

  18. Dietary Supplementation of Walnut Partially Reverses 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Induced Neurodegeneration in a Mouse Model of Parkinson's Disease.

    PubMed

    Essa, Musthafa Mohamed; Subash, Selvaraju; Dhanalakshmi, Chinnasamy; Manivasagam, Thamilarasan; Al-Adawi, Samir; Guillemin, Gilles J; Justin Thenmozhi, Arokiasamy

    2015-06-01

    Numerous studies indicating that natural plant sources and their active phytochemicals offer protection to the pathological processes related to the development of neurogenerative diseases including Parkinson's disease (PD). In the present study, the neuro protective efficacy of dietary supplementation of walnut (6 %) for 28 days was examined in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (i.p., 20 mg/kg body weight/day) for last four consecutive days. MPTP injection diminished the levels of GSH, dopamine and metabolites along with decreased activities of GPx and mitochondrial complex I. Further, the levels of TBARS and enzymatic antioxidants such as SOD and catalase, MAO-B activities were enhanced by MPTP treatment. Behavioral deficits and lowered TH expression are also proved MPTP induced neurotoxicity. Dietary supplementation of walnut attenuated MPTP-induced impairment in PD mice might be by its MAO-B inhibitory, antioxidant and mitochondrial protective actions. To find out the exact mechanism of action walnut on PD mice warrants further extensive studies. PMID:25944473

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

    E-print Network

    ://www.parkinsons.org.uk/ A list of grant schemes can be found on the Parkinson's UK website under the Research tab (or you can use the following link http://www.parkinsons.org.uk/research/for_researchers/research_grants.aspx) 2. You to the Parkinson's UK grant application system A Quick Guide for applicants applying for funding from Parkinson

  20. Drug-induced sensorineural deafness caused by antithyroid drugs: a rare side effect.

    PubMed

    Raja, U Y; Kumar, A; Possamai, V; Warner, D; Barton, D

    2010-09-01

    Acute ototoxicity is a rare but important complication of antithyroid drugs. Although previous cases have been reported in the medical literature, these cases occurred in younger patients with serological evidence of lupus-like syndrome with positive antidouble-stranded deoxyribonucleic acid and antineutrophil cytoplasmic antibodies. We describe the case of a 68-year-old Caucasian male who developed deafness and tinnitus one week after being prescribed carbimazole. The management options include stopping the culprit drug, treatment with immunosuppressive drugs and referring the patient for urgent thyroidectomy. Healthcare professionals who prescribe antithyroid drugs should be aware of this rare but potentially serious complication, so that early drug withdrawal and referral for surgery can be considered. PMID:21127764

  1. Pathologic Role of Stressed-Induced Glucocorticoids in Drug-Induced Liver Injury in Mice

    PubMed Central

    Masson, Mary Jane; Collins, Lindsay A.; Carpenter, Leah D.; Graf, Mary L.; Ryan, Pauline M.; Bourdi, Mohammed; Pohl, Lance R.

    2010-01-01

    We previously reported that acetaminophen (APAP)-induced liver injury (AILI) in mice is associated with a rise in serum levels of the glucocorticoid (GC), corticosterone. In the current study, we provide evidence that endogenous GC play a pathologic role in AILI. Specifically, pretreatment of mice with the GC receptor (GCR) inhibitor, RU486 (mifepristrone), protected normal but not adrenalectomized mice from AILI, while pretreatment with dexamethasone, a synthetic GC, exacerbated AILI. RU486 did not affect the depletion of whole liver reduced GSH or the formation of APAP-protein adducts. It also had no effects on the formation of reactive oxygen species or the depletion of mitochondrial GSH or ATP. While RU486 pretreatment also protected against halothane-induced liver injury, it exacerbated concanavalin A (ConA)- and carbon tetrachloride (CCl4)-induced liver injury, demonstrating the complexity of GC effects in different types of liver injury. Conclusion: These results suggest that under certain conditions, elevated levels of GC might represent a previously unappreciated risk factor for liver injury caused by APAP and other drugs through the diverse biological processes regulated by GCR. PMID:20510877

  2. Hepatocyte-based in vitro model for assessment of drug-induced cholestasis

    SciTech Connect

    Chatterjee, Sagnik, E-mail: Sagnik.Chatterjee@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium); Richert, Lysiane, E-mail: l.richert@kaly-cell.com [KaLy-Cell, 20A rue du Général Leclerc, 67115 Plobsheim (France); Augustijns, Patrick, E-mail: Patrick.Augustijns@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium); Annaert, Pieter, E-mail: Pieter.Annaert@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium)

    2014-01-01

    Early detection of drug-induced cholestasis remains a challenge during drug development. We have developed and validated a biorelevant sandwich-cultured hepatocytes- (SCH) based model that can identify compounds causing cholestasis by altering bile acid disposition. Human and rat SCH were exposed (24–48 h) to known cholestatic and/or hepatotoxic compounds, in the presence or in the absence of a concentrated mixture of bile acids (BAs). Urea assay was used to assess (compromised) hepatocyte functionality at the end of the incubations. The cholestatic potential of the compounds was expressed by calculating a drug-induced cholestasis index (DICI), reflecting the relative residual urea formation by hepatocytes co-incubated with BAs and test compound as compared to hepatocytes treated with test compound alone. Compounds with clinical reports of cholestasis, including cyclosporin A, troglitazone, chlorpromazine, bosentan, ticlopidine, ritonavir, and midecamycin showed enhanced toxicity in the presence of BAs (DICI ? 0.8) for at least one of the tested concentrations. In contrast, the in vitro toxicity of compounds causing hepatotoxicity by other mechanisms (including diclofenac, valproic acid, amiodarone and acetaminophen), remained unchanged in the presence of BAs. A safety margin (SM) for drug-induced cholestasis was calculated as the ratio of lowest in vitro concentration for which was DICI ? 0.8, to the reported mean peak therapeutic plasma concentration. SM values obtained in human SCH correlated well with reported % incidence of clinical drug-induced cholestasis, while no correlation was observed in rat SCH. This in vitro model enables early identification of drug candidates causing cholestasis by disturbed BA handling. - Highlights: • Novel in vitro assay to detect drug-induced cholestasis • Rat and human sandwich-cultured hepatocytes (SCH) as in vitro models • Cholestatic compounds sensitize SCH to toxic effects of accumulating bile acids • Drug-induced cholestasis index (DICI) as measure of a drug's cholestatic signature • In vitro findings correlate well with clinical reports on cholestasis.

  3. Management of psychotic aspects of Parkinson's disease.

    PubMed

    Juncos, J L

    1999-01-01

    Psychotic symptoms have become increasingly common in patients with idiopathic Parkinson's disease and other parkinsonian syndromes. This increased prevalence of psychoses is in part a reflection of the greater longevity of people with Parkinson's disease and, to a certain extent, is a consequence of our success in treating the motor symptoms of these syndromes. The psychotic symptoms associated with Parkinson's disease can be as varied as the motor symptoms. They stem from interactions between the underlying neuropathologies of the syndromes and the adverse effects associated with chronic antiparkinsonian drug administration. In patients with advanced Parkinson's disease, there is also a high prevalence of affective comorbidity. This increase in affective symptoms and the relatively high incidence of cognitive and affective side effects of the antiparkinsonian medications contribute to the increase in psychoses observed in these older patients. The most significant risk factors for developing psychosis in Parkinson's disease are (1) coexistence of dementia, (2) protracted sleep disturbances, and (3) nighttime use of long-acting dopaminomimetics. This article reviews the phenomenology, pathophysiology, and treatment of psychosis associated with parkinsonism and discusses how atypical antipsychotic medications have revolutionized the management of the symptoms and improved the quality of life of those affected. PMID:10335670

  4. Posteroventral Pallidotomy in Parkinson's Disease

    Microsoft Academic Search

    E. J. Herrera; J. C. Viano; M. Cáceres; G. Costello; M. Suárez; J. C. Suárez

    2000-01-01

    Summary  ??Objective. We analyse the clinical aspects, results and reliability of posteroventral pallidotomy (PVP) carried out as treatment for\\u000a the principal symptoms and treatment induced complications in patients with Parkinson's disease (PD).\\u000a \\u000a ?Patients and Methods. Between August 1995–January 1998, 17 patients with PD were treated surgically, 13 patients with PVP. A pre- and post-surgical\\u000a clinical evaluation was carried out. Riechert's Stereotactic

  5. 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

  6. Acetaldehyde and parkinsonism: role of CYP450 2E1.

    PubMed

    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

  7. The neuropsychiatry of Parkinson's disease.

    PubMed

    Lauterbach, E C

    2005-06-01

    The neuropsychiatry of Parkinson's disease (PD) and its correlates are reviewed. Dementia occurs in up to 30% and can be treated with cholinesterase inhibitors. Cognitive impairments involve executive, visuospatial, attentional, and memory dysfunctions. Apathy may respond to dopamine agonists or cholines-terase inhibitors. Cognitive impairment, psychosis, and depression predict quality of life. Visual hallucinations and paranoia are common, and respond to low dose clozapine. Depression is common and predicts caregiver burden and depression. The best data suggest the efficacy of nortriptyline and the safety of SSRIs. Anxiety disorders occur in 40% of patients, especially off-period panic attacks and specific phobias. Bromazepam has proven useful for anxiety in PD, but buspirone has only diminished drug-induced dyskinesias to date. Sleep disorders occur in up to 94% of patients. Insomnia is common and is treated by dopaminergic agent dose reduction, nocturnal dosing, treatment of depression, or use of short half-lived hypnotics, depending on etiology. Parasomnias include REM behavior disorder and vivid dreams and nightmares. Excessive daytime somnolence occurs in at least 15% of patients. Sleep attacks are common and patients should be warned about driving when taking dopamine agonists. Sexual disorders occur in most patients. Paraphilias are associated with dopamine agonists, and clozapine may be useful in their treatment. Surgical therapies are associated with a wide variety of neuropsychiatric features, and vigilance for suicide attempts with subthalamic nucleus stimulation seems warranted. Neuropsychiatric disorders are important determinants of quality of life and caregiver burden in PD. More clinical research is needed to establish effective treatments. PMID:16175159

  8. 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.

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

    Microsoft Academic Search

    Alain Dagher; Trevor W. Robbins

    2009-01-01

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

  10. 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 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

  11. 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, Jörg; 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

  12. 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, E-mail: arthik@iastate.edu

    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.

  13. The Role of Bile Salt Export Pump Gene Repression in Drug-Induced Cholestatic Liver Toxicity

    PubMed Central

    Garzel, Brandy; Yang, Hui; Zhang, Lei; Huang, Shiew-Mei; Polli, James E.

    2014-01-01

    The bile salt export pump (BSEP, ABCB11) is predominantly responsible for the efflux of bile salts, and disruption of BSEP function is often associated with altered hepatic homeostasis of bile acids and cholestatic liver injury. Accumulating evidence suggests that many drugs can cause cholestasis through interaction with hepatic transporters. To date, a relatively strong association between drug-induced cholestasis and attenuated BSEP activity has been proposed. However, whether repression of BSEP transcription would contribute to drug-induced cholestasis is largely unknown. In this study, we selected 30 drugs previously reported as BSEP inhibitors to evaluate their effects on BSEP expression, farnesoid X receptor (FXR) activation, and correlations to clinically reported liver toxicity. Our results indicate that of the 30 BSEP inhibitors, five exhibited potent repression of BSEP expression (?60% repression), ten were moderate repressors (20–60% repression), whereas others had negligible effects (?20% repression). Of importance, two drugs (troglitazone and benzbromarone), previously withdrawn from the market because of liver injury, are among the potent repressors. Further investigation of the five potent repressors revealed that transcriptional repression of BSEP by lopinavir and troglitazone may occur through their interaction with FXR, whereas others are via FXR-independent yet unidentified pathways. Our data suggest that in addition to functional inhibition, repression of BSEP expression may play an important role in drug-induced cholestatic liver toxicity. Thus, a combination of the two would reveal a more accurate prediction of drug-induced cholestasis than does either repression or inhibition alone. PMID:24335466

  14. High-content screening technology for studying drug-induced hepatotoxicity in cell models.

    PubMed

    Tolosa, Laia; Gómez-Lechón, M José; Donato, M Teresa

    2015-07-01

    High-content screening is the application of automated microscopy and image analysis to both cell biology and drug discovery. Over the last decade, this technique has emerged as a useful technology that allows the simultaneous measurement of different parameters at a single-cell level. Hepatotoxicity is a compelling reason for drug nonapprovals and withdrawals. It is recognized that the safety of a compound cannot be based on a single in vitro assay, and existing methods are not predictive of drug-induced toxicity. However, different HCS assays have been recently demonstrated as being powerful for identifying different mechanisms implicated in drug-induced toxicity with high sensitivity and specificity. These assays integrate the data obtained from different cell function indicators and can be easily incorporated into basic screening processes for the safety evaluation and selection of drug candidates; thus, they contribute greatly to lessen the likelihood of drug failure. Exploring the use of cellular imaging technology in drug-induced liver injury by reviewing the different tests proposed provides evidence that this technology has a strong impact on drug discovery. PMID:25787152

  15. Dermatomyositis and Paclitaxel-Induced Cutaneous Drug Eruption Associated with Metastatic Breast Cancer

    PubMed Central

    Kim, Youngji; Jung, Woojin

    2015-01-01

    Dermatomyositis (DM) is an idiopathic autoimmune connective disease characterized by muscles and skin inflammation of and a well-recognized association with several human malignancies, especially breast cancer. Paclitaxel is a taxane antineoplastic agent with therapeutic effects against a wide range of cancers including breast cancer. This drug is well known for neurotoxicity and hypersensitivity reactions. However, cutaneous drug eruptions, especially those of grade III or higher, are not frequent. Here, we describe the case of a 55-year-old woman with metastatic breast cancer who developed paraneoplastic DM and a paclitaxel-induced exanthematous drug eruption. This case report emphasizes the importance of evaluating internal malignancies, such as advanced breast cancer, in newly developed DM patients. In addition, it presents a rare case of paclitaxel-induced exanthematous drug eruption. The purpose of this case report highlights the immunological pathogenic mechanism of DM and drug eruption in underlying advanced breast cancer.

  16. Adenosine A2A Receptor Antagonists and Parkinson’s Disease

    PubMed Central

    2011-01-01

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

  17. Effects of Antihypertensive Drugs on Alcohol-Induced Functional Responses of Cultured Human Endothelial Cells

    Microsoft Academic Search

    Giorgio Soardo; Debora Donnini; Massimo Moretti; Carla Milocco; Cristiana Catena; Leonardo A. SECHI

    2008-01-01

    Alcohol-induced endothelial changes might contribute to an increase in blood pressure in regular alcohol consumers. Some antihypertensive drugs affect oxidative stress and endothelial function and might counteract the effects of alcohol at the cellular level. The aim of this study was to investigate in vitro the effects of three different types of antihypertensive agents on alcohol-induced endothelial responses and oxidative

  18. In Vitro Detection of Drug-Induced Phospholipidosis Using Gene Expression and Fluorescent Phospholipid Based Methodologies

    Microsoft Academic Search

    Paul Nioi; Brad K. Perry; Er-Jia Wang; Yi-Zhong Gu; Ronald D. Snyder

    2007-01-01

    Phospholipidosis (PLD) is characterized by the excessive intracellular accumulation of phospholipids. It is well established that a large number of cationic amphiphilic drugs have the potential to induce PLD. In the present study, we describe two facile in vitro methods to determine the PLD-inducing potential of a molecule. The first approach is based on a recent study by (Sawada et

  19. Drug resistance and apoptosis in ENU-induced rat brain tumors treated with anti-cancer drugs

    Microsoft Academic Search

    Toru Yabuno; Noboru Konishi; Mitsutoshi Nakamura; Toshihide Tsuzuki; Shigeru Tsunoda; Toshisuke Sakaki; Yoshio Hiasa

    1998-01-01

    To cast light on the mechanisms of drug-resistance, experimental brain tumors were immunohistochemically evaluated for expression of glutathione S-transferase (GST)-a, µ, p, p-glycoprotein and apoptosis-related factors, such as bcl-2 and p53, as well as by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labelling (TUNEL) method. Rat brain tumors induced by means of prenatal exposure to ethylnitrosourea (ENU) were treated with

  20. Modified Bulgarian belladonna treatment of Parkinsonism

    Microsoft Academic Search

    Leon Reznikoff

    1941-01-01

    Summary and Conclusions 1.Symptomatic treatment of postencephalitic Parkinsonism with Bulgarian belladonna root extract is superior to all other medications tried in the past.3.Treatment must be individualized; better results are obceive it; when administration of the drug is discontinued symptoms return.3.Treatment must be individualized; better results are obtained when “bellabulgara” is combined with other drugs: For example, patients who are hyperkynetic

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

    PubMed Central

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

    2013-01-01

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

  2. Patterned, but not tonic, optogenetic stimulation in motor thalamus improves reaching in acute drug-induced Parkinsonian rats.

    PubMed

    Seeger-Armbruster, Sonja; Bosch-Bouju, Clémentine; Little, Shane T C; Smither, Roseanna A; Hughes, Stephanie M; Hyland, Brian I; Parr-Brownlie, Louise C

    2015-01-21

    High-frequency deep brain stimulation (DBS) in motor thalamus (Mthal) ameliorates tremor but not akinesia in Parkinson's disease. The aim of this study was to investigate whether there are effective methods of Mthal stimulation to treat akinesia. Glutamatergic Mthal neurons, transduced with channelrhodopsin-2 by injection of lentiviral vector (Lenti.CaMKII.hChR2(H134R).mCherry), were selectively stimulated with blue light (473 nm) via a chronically implanted fiber-optic probe. Rats performed a reach-to-grasp task in either acute drug-induced parkinsonian akinesia (0.03-0.07 mg/kg haloperidol, s.c.) or control (vehicle injection) conditions, and the number of reaches was recorded for 5 min before, during, and after stimulation. We compared the effect of DBS using complex physiological patterns previously recorded in the Mthal of a control rat during reaching or exploring behavior, with tonic DBS delivering the same number of stimuli per second (rate-control 6.2 or 1.8 Hz, respectively) and with stimulation patterns commonly used in other brain regions to treat neurological conditions (tonic 130 Hz, theta burst (TBS), and tonic 15 Hz rate-control for TBS). Control rats typically executed >150 reaches per 5 min, which was unaffected by any of the stimulation patterns. Acute parkinsonian rats executed <20 reaches, displaying marked akinesia, which was significantly improved by stimulating with the physiological reaching pattern or TBS (both p < 0.05), whereas the exploring and all tonic patterns failed to improve reaching. Data indicate that the Mthal may be an effective site to treat akinesia, but the pattern of stimulation is critical for improving reaching in parkinsonian rats. PMID:25609635

  3. Patient Knowledge of Antithyroid Drug-Induced Agranulocytosis

    PubMed Central

    Robinson, Jonah; Richardson, Max; Hickey, Janis; James, Andy; Pearce, Simon H.; Ball, Steve G.; Quinton, Richard; Morris, Margaret; Miller, Margaret; Perros, Petros

    2014-01-01

    Background Agranulocytosis is a serious side effect of antithyroid drugs. Objective To ascertain the knowledge of patients and review the quality of information available on the internet. Methods A questionnaire survey was performed for patients receiving antithyroid drugs. Patients attending endocrine clinics who were receiving antithyroid drug treatment (group A, n = 33) were interviewed. A further national cohort of patients (group B, n = 100) treated with antithyroid drugs, participated in an online survey. Results 60.9% of responders were not aware of the common symptoms of agranulocytosis. 18.6% had never received any information about side effects. Of the 108 patients who recalled receiving information, 30% rated the quality as ‘poor’ or ‘not good at all’. Structured interviews of group A patients revealed that almost half (45.5%, 15/33) had experienced symptoms that could be indicative of agranulocytosis, but only 53.3% (8/15) had a blood count checked. A review of 20 selected patient information internet sites revealed a significant variation in advice given to patients. Conclusions Inadequate knowledge about agranulocytosis among patients receiving antithyroid drug treatment is common. The available information on the internet is variable and inconsistent. PMID:25759801

  4. Dimethyl fumarate attenuates 6-OHDA-induced neurotoxicity in SH-SY5Y cells and in animal model of Parkinson's disease by enhancing Nrf2 activity.

    PubMed

    Jing, X; Shi, H; Zhang, C; Ren, M; Han, M; Wei, X; Zhang, X; Lou, H

    2015-02-12

    Oxidative stress is central to the pathology of several neurodegenerative diseases, including Parkinson's disease (PD), and therapeutics designed to enhance antioxidant potential could have clinical value. In this study, we investigated whether dimethyl fumarate (DMF) has therapeutic effects in cellular and animal model of PD, and explore the role of nuclear transcription factor related to NF-E2 (Nrf2) in this process. Treatment of animals and dopaminergic SH-SY5Y cells with DMF resulted in increased nuclear levels of active Nrf2, with subsequent upregulation of antioxidant target genes. The cytotoxicity of 6-hydroxydopamine (6-OHDA) was reduced by pre-treatment with DMF in SH-SY5Y cells. The increase in the reactive oxygen species caused by 6-OHDA treatment was also attenuated by DMF in SH-SY5Y cells. The neuroprotective effects of DMF against 6-OHDA neurotoxicity were dependent on Nrf2, since treatment with Nrf2 siRNA failed to block against 6-OHDA neurotoxicity and induce Nrf2-dependent cytoprotective genes in SH-SY5Y cells. In vivo, DMF oral administration was shown to upregulate mRNA and protein levels of Nrf2 and Nrf2-regulated cytoprotective genes, attenuate 6-OHDA induced striatal oxidative stress and inflammation in C57BL/6 mice. Moreover, DMF ameliorated dopaminergic neurotoxicity in 6-OHDA-induced PD animal models as evidenced by amelioration of locomotor dysfunction, loss in striatal dopamine, and reductions in dopaminergic neurons in the substantia nigra and striatum. Taken together, these data strongly suggest that DMF may be beneficial for the treatment of neurodegenerative diseases like PD. PMID:25449120

  5. Effect of bilateral subthalamic electrical stimulation in Parkinson’s disease

    Microsoft Academic Search

    Giovanni Broggi; Angelo Franzini; Paolo Ferroli; Domenico Servello; Ludovico D’Incerti; Silvia Genitrini; Paola Soliveri; Floriano Girotti; Tommaso Caraceni

    2001-01-01

    BACKGROUNDBilateral high frequency subthalamic stimulation has been reported to be effective in the treatment of Parkinson’s disease and levodopa-induced dyskinesias. To analyze the results of this surgical procedure we critically reviewed 17 parkinsonian patients with advanced disease complicated by motor fluctuations and dyskinesias.METHODSBetween January 1998 and June 1999 these 17 consecutive patients (age 48–68 years; illness duration 8–27 years) underwent

  6. Risk factors in development of motor complications in Chinese patients with idiopathic Parkinson’s disease

    Microsoft Academic Search

    Wan Fung Kum; Jing Gao; Siva Sundara Kumar Durairajan; Sui Cheung Man; Li Xia Xie; Jia Hong Lu; Wai Leuk Fong; Min Li

    2009-01-01

    Motor complications induced by levodopa (L-dopa) treatment in Parkinson’s disease (PD) are not well documented in patients of Chinese ethnicity. We performed a cross-sectional study to investigate the prevalence of dyskinesias and motor fluctuations, and the factors determining their development, in a population of Chinese patients with PD. Among 137 patients with PD, 98 (71.5%) had received a L-dopa preparation.

  7. Late acute myopia syndrome induced by combination of sulfonamide drugs.

    PubMed

    Kozner, Pavel; Simonova, Katarina; Brozek, Bretislav; Singh, Kuldev

    2014-02-01

    We present a case of late acute myopia syndrome following discontinuation of treatment with a combination of sulphonamide drugs. To the best of our knowledge, this is the first reported case with such a presentation, and suggests that the pathophysiological basis for the acute myopia syndrome is a rapid decrease in serum carbonic anhydrase inhibitors levels which may lead to a rebound increase in the production of aqueous humor and accumulation of suprachoroidal fluid. It is further postulated that there may be a cumulative effect of sulphonamide drug use on carbonic anhydrase activity in the ciliary body epithelium of susceptible individuals. PMID:23661047

  8. Inhibition of 2-Aminoethoxydiphenyl Borate-induced Rat Atrial Ectopic Activity by Antiarrhythmic Drugs

    Microsoft Academic Search

    Rong Huo; Zhe Li; Cui-Cui Lu; Yan Xie; Bin Wang; Yu-Jie Tu; Jun-Tao Hu; Chang-Qing Xu; Bao-Feng Yang; De-Li Dong

    2010-01-01

    Background\\/Aims: 2-aminoethoxydiphenyl borate (2-APB) provokes spontaneous mechanical activity in isolated rat left atria. The present study is to characterize 2-APB-induced ectopic activity in rat atria and to investigate the inhibition of 2-APB-induced ectopic activity by anti-arrhythmic drugs. Methods: 2-APB-induced ectopic activity was measured through an isometric force transducer connected to a multichannel acquisition and analysis system. Intracellular [Ca2+]i was measured

  9. 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

  10. 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

  11. Activation of tyrosine kinase receptor signaling pathway by rasagiline facilitates neurorescue and restoration of nigrostriatal dopamine neurons in post-MPTP-induced parkinsonism.

    PubMed

    Sagi, Yotam; Mandel, Silvia; Amit, Tamar; Youdim, Moussa B H

    2007-01-01

    The anti-Parkinson monoamine oxidase (MAO)-B inhibitor rasagiline (Azilect) was shown to possess neuroprotective activities, involving the induction of brain-derived- and glial cell line-derived neurotrophic factors (BDNF, GDNF). Employing conventional neurochemical techniques, transcriptomics and proteomic screening tools combined with a biology-based clustering method, we show that rasagiline, given chronically post-MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine), exerts neurorescue/neurotrophic activity in mice midbrain dopamine neurons. Rasagiline induced the activation of cell signaling mediators associated with neurotrophic factors responsive-tyrosine kinase receptor (Trk) pathway including ShcC, SOS, AF6, Rin1 and Ras and the increase in the Trk-downstream effector phosphatidylinositol 3 kinase (PI3K) protein. Confirmatory Western and immunohistochemical analyses indicated activation of the substrate of PI3K, Akt and phosphorylative inactivation of glycogen synthase kinase-3beta and Raf1. Thus, the activation of Ras-PI3K-Akt survival pathway may contribute to rasagiline-mediated neurorescue effect. It is interesting to determine whether a similar effect is seen in parkinsonian patients after long-term treatment with rasagiline. PMID:17055733

  12. 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

  13. Imaging stress- and cue-induced drug and alcohol craving: association with relapse and clinical implications.

    PubMed

    Sinha, Rajita; Li, C S R

    2007-01-01

    Stress- and drug-related cues are major factors contributing to high rates of relapse in addictive disorders. Brain imaging studies have begun to identify neural correlates of stress and drug cue-induced craving states. Findings indicate considerable overlap in neural circuits involved in processing stress and drug cues with activity in the corticostriatal limbic circuitry underlying both affective and reward processing. More recent efforts have begun to identify the relationships between neural activity during stress and drug cue exposure and drug relapse outcomes. Findings suggest medial prefrontal, anterior and posterior cingulate, striatal and posterior insula regions to be associated with relapse outcomes. Altered function in these brain regions is associated with stress-induced and drug cue-induced craving states and an increased susceptibility to relapse. Such alterations can serve as markers to identify relapse propensity and a more severe course of addiction. Efficacy of pharmacological and behavioral treatments that specifically target stress and cue-induced craving and arousal responses may also be assessed via alterations in these brain correlates. PMID:17364833

  14. The clinically approved drugs dasatinib and bosutinib induce anti-inflammatory macrophages by inhibiting the salt-inducible kinases

    PubMed Central

    Ozanne, James; Prescott, Alan R.; Clark, Kristopher

    2014-01-01

    Macrophages switch to an anti-inflammatory, ‘regulatory’-like phenotype characterized by the production of high levels of interleukin (IL)-10 and low levels of pro-inflammatory cytokines to promote the resolution of inflammation. A potential therapeutic strategy for the treatment of chronic inflammatory diseases would be to administer drugs that could induce the formation of ‘regulatory’-like macrophages at sites of inflammation. In the present study, we demonstrate that the clinically approved cancer drugs bosutinib and dasatinib induce several hallmark features of ‘regulatory’-like macrophages. Treatment of macrophages with bosutinib or dasatinib elevates the production of IL-10 while suppressing the production of IL-6, IL-12p40 and tumour necrosis factor ? (TNF?) in response to Toll-like receptor (TLR) stimulation. Moreover, macrophages treated with bosutinib or dasatinib express higher levels of markers of ‘regulatory’-like macrophages including LIGHT, SPHK1 and arginase 1. Bosutinib and dasatinib were originally developed as inhibitors of the protein tyrosine kinases Bcr-Abl and Src but we show that, surprisingly, the effects of bosutinib and dasatinib on macrophage polarization are the result of the inhibition of the salt-inducible kinases. Consistent with the present finding, bosutinib and dasatinib induce the dephosphorylation of CREB-regulated transcription co-activator 3 (CRTC3) and its nuclear translocation where it induces a cAMP-response-element-binding protein (CREB)-dependent gene transcription programme including that of IL-10. Importantly, these effects of bosutinib and dasatinib on IL-10 gene expression are lost in macrophages expressing a drug-resistant mutant of salt-inducible kinase 2 (SIK2). In conclusion, our study identifies the salt-inducible kinases as major targets of bosutinib and dasatinib that mediate the effects of these drugs on the innate immune system and provides novel mechanistic insights into the anti-inflammatory properties of these drugs. PMID:25351958

  15. The clinically approved drugs dasatinib and bosutinib induce anti-inflammatory macrophages by inhibiting the salt-inducible kinases.

    PubMed

    Ozanne, James; Prescott, Alan R; Clark, Kristopher

    2015-01-15

    Macrophages switch to an anti-inflammatory, 'regulatory'-like phenotype characterized by the production of high levels of interleukin (IL)-10 and low levels of pro-inflammatory cytokines to promote the resolution of inflammation. A potential therapeutic strategy for the treatment of chronic inflammatory diseases would be to administer drugs that could induce the formation of 'regulatory'-like macrophages at sites of inflammation. In the present study, we demonstrate that the clinically approved cancer drugs bosutinib and dasatinib induce several hallmark features of 'regulatory'-like macrophages. Treatment of macrophages with bosutinib or dasatinib elevates the production of IL-10 while suppressing the production of IL-6, IL-12p40 and tumour necrosis factor ? (TNF?) in response to Toll-like receptor (TLR) stimulation. Moreover, macrophages treated with bosutinib or dasatinib express higher levels of markers of 'regulatory'-like macrophages including LIGHT, SPHK1 and arginase 1. Bosutinib and dasatinib were originally developed as inhibitors of the protein tyrosine kinases Bcr-Abl and Src but we show that, surprisingly, the effects of bosutinib and dasatinib on macrophage polarization are the result of the inhibition of the salt-inducible kinases. Consistent with the present finding, bosutinib and dasatinib induce the dephosphorylation of CREB-regulated transcription co-activator 3 (CRTC3) and its nuclear translocation where it induces a cAMP-response-element-binding protein (CREB)-dependent gene transcription programme including that of IL-10. Importantly, these effects of bosutinib and dasatinib on IL-10 gene expression are lost in macrophages expressing a drug-resistant mutant of salt-inducible kinase 2 (SIK2). In conclusion, our study identifies the salt-inducible kinases as major targets of bosutinib and dasatinib that mediate the effects of these drugs on the innate immune system and provides novel mechanistic insights into the anti-inflammatory properties of these drugs. PMID:25351958

  16. Association of Cerebrospinal Fluid ?-Amyloid 1-42, T-tau, P-tau181, and ?-Synuclein Levels With Clinical Features of Drug-Naive Patients With Early Parkinson Disease

    PubMed Central

    Kang, Ju-Hee; Irwin, David J.; Chen-Plotkin, Alice S.; Siderowf, Andrew; Caspell, Chelsea; Coffey, Christopher S.; Waligórska, Teresa; Taylor, Peggy; Pan, Sarah; Frasier, Mark; Marek, Kenneth; Kieburtz, Karl; Jennings, Danna; Simuni, Tanya; Tanner, Caroline M.; Singleton, Andrew; Toga, Arthur W.; Chowdhury, Sohini; Mollenhauer, Brit; Trojanowski, John Q.; Shaw, Leslie M.

    2014-01-01

    Importance We observed a significant correlation between cerebrospinal fluid (CSF) levels of tau proteins and ?-synuclein, but not ?-amyloid 1–42 (A?1–42), and lower concentration of CSF biomarkers, as compared with healthy controls, in a cohort of entirely untreated patients with Parkinson disease (PD) at the earliest stage of the disease studied so far. Objective To evaluate the baseline characteristics and relationship to clinical features of CSF biomarkers (A?1–42, total tau [T-tau], tau phosphorylated at threonine 181 [P-tau181], and ?-synuclein) in drug-naive patients with early PD and demographically matched healthy controls enrolled in the Parkinson’s Progression Markers Initiative (PPMI) study. Design, Setting, and Participants Cross-sectional study of the initial 102 research volunteers (63 patients with PD and 39 healthy controls) of the PPMI cohort. Main Outcomes and Measures The CSF biomarkers were measured by INNO-BIA AlzBio3 immunoassay (A?1–42, T-tau, and P-tau181; Innogenetics Inc) or by enzyme-linked immunosorbent assay (?-synuclein). Clinical features including diagnosis, demographic characteristics, motor, neuropsychiatric, and cognitive assessments, and DaTscan were systematically assessed according to the PPMI study protocol. Results Slightly, but significantly, lower levels of A?1–42, T-tau, P-tau181, ?-synuclein, and T-tau/A?1–42 were seen in subjects with PD compared with healthy controls but with a marked overlap between groups. Using multivariate regression analysis, we found that lower A?1–42 and P-tau181 levels were associated with PD diagnosis and that decreased CSF T-tau and ?-synuclein were associated with increased motor severity. Notably, when we classified patients with PD by their motor phenotypes, lower CSF A?1–42 and P-tau181 concentrations were associated with the postural instability–gait disturbance–dominant phenotype but not with the tremor-dominant or intermediate phenotype. Finally, we found a significant correlation of the levels of ?-synuclein with the levels of T-tau and P-tau181. Conclusions and Relevance In this first report of CSF biomarkers in PPMI study subjects, we found that measures of CSF A?1–42, T-tau, P-tau181, and ?-synuclein have prognostic and diagnostic potential in early-stage PD. Further investigations using the entire PPMI cohort will test the predictive performance of CSF biomarkers for PD progression. PMID:23979011

  17. [Impulse control disorders in Parkinson's disease].

    PubMed

    Joutsa, Juho; Kaasinen, Valtteri

    2013-01-01

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

  18. Drug-Induced Gambling: Valid Excuse of True Addiction?

    Microsoft Academic Search

    Lareina Maskell

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

  19. Review: Drug-Induced Neutropenia - Pathophysiology, Clinical Features, and Management

    Microsoft Academic Search

    Varsha Bhatt; Abdus Saleem

    Drug therapy plays a significant role in causing neutropenia. The neutropenia may be immune mediated or due to direct inhibition of the bone marrow precursors. Recently, due to wide use of chemotherapy, febrile neutropenia has become a common and devastating problem. Neutropenia predisposes to many bacterial and fungal infections with organisms including Gram negative bacilli such as E. coli, Klebsiella,

  20. Drug-induced long-QT syndrome: a case report

    PubMed Central

    Vorel-Havelkova, E.; Vorel, S.; Brombacher, P.J.

    2005-01-01

    An elderly psychiatric female patient with a long-lasting severe resistant depression was referred for medical examination because of gastrointestinal complaints. The ECG revealed a strongly extended QT interval. No other cardiological abnormalities were observed. The patient's symptoms as well as the QT interval and biochemical abnormalities could be reduced by changing psychiatric drug treatment and reduction of concomitant medication. PMID:25696462

  1. Treatment of Early Parkinson’s Disease

    Microsoft Academic Search

    Tanya Simuni; Kelly E. Lyons; Rajesh Pahwa; Robert A. Hauser; Cynthia Comella; Lawrence Elmer; Daniel Weintraub

    2009-01-01

    The management of early Parkinson’s disease (PD) involves the treatment of motor symptoms, and, increasingly, non-motor symptoms. Given the fast pace of clinical research in PD, clinicians are faced with the challenge of integrating the latest findings into the ongoing care of individual PD patients. Part 1 of this 2-part article reviews efficacy and safety data for the newest PD

  2. Physical inactivity in Parkinson’s disease

    Microsoft Academic Search

    Marlies van Nimwegen; Arlène D. Speelman; Esther J. M. Hofman-van Rossum; Sebastiaan Overeem; Dorly J. H. Deeg; George F. Borm; Marleen H. L. van der Horst; Bastiaan R. Bloem; Marten Munneke

    2011-01-01

    Patients with Parkinson’s disease (PD) are likely to become physically inactive, because of their motor, mental, and emotional\\u000a symptoms. However, specific studies on physical activity in PD are scarce, and results are conflicting. Here, we quantified\\u000a daily physical activities in a large cohort of PD patients and another large cohort of matched controls. Moreover, we investigated\\u000a the influence of disease-related

  3. Exome Sequencing in Parkinson’s disease

    PubMed Central

    Bras, Jose M; Singleton, Andrew B

    2011-01-01

    Exome Sequencing is rapidly becoming a fundamental tool for genetics and functional genomics laboratories. This methodology has enabled the discovery of novel pathogenic mutations causing mendelian diseases that had, until now, remained elusive. In this review we discuss not only how we envisage exome sequencing being applied to a complex disease, such as Parkinson’s disease, but also what are the known caveats of this approach. PMID:21651510

  4. Thyroid-Induced Worsening of Parkinsonian Tremor Resistant to Drugs and Subthalamic Nucleus Deep Brain Stimulation

    PubMed Central

    Minár, Michal; Valkovi?, Peter

    2014-01-01

    Introduction. Symptoms of both hypothyroidism and thyrotoxicosis can be easily overlooked in patients with Parkinson's disease (PD). We report on a patient whose parkinsonian tremor worsened and proved refractory not only to common treatment, but also to deep brain stimulation (DBS). Case Presentation. A 61-year-old woman with advanced PD underwent bilateral subthalamic DBS, with an excellent outcome. Twenty-one months after the surgery, however, patient's resting/postural tremor markedly worsened. There was a slight improvement for 1 month after repeated adjustments of DBS parameters, but then the tremor worsened again. Since even a minimal increase of the dose of dopaminergic drugs caused extremely severe dyskinesias, an anticholinergic drug biperiden and benzodiazepine clonazepam were introduced, what helped for another month. With the onset of severe diarrhoea, a laboratory workup was performed. Thyrotoxicosis was detected. During treatment with the antithyroid agent carbimazole, the parkinsonian tremor clearly improved within two weeks. Conclusion. A hyperthyroid state can markedly exaggerate all forms of tremor, as well as other types of movement disorders. This condition can be overlooked or masked by other symptoms. Therefore, if the tremor in a patient with PD gradually worsens and proves resistant to the usual treatment, examine the thyroid gland. PMID:25628904

  5. Depression in Parkinson's disease.

    PubMed

    Rihmer, Zoltán; Gonda, Xénia; Döme, Péter

    2014-07-30

    The prevalence of major and minor depression in Parkinson's disease is around 30-40% but, unfortunately, depression remains frequently underrecognized and often undertreated. However, recognition and appropriate treatment of depression in patients with Parkinson's disease is essential for improving the cross-sectional picture and longitudinal course. This review focuses on the epidemiology, pathophysiology and different treatment modalities of depression in Parkinson's disease. PMID:25509363

  6. NMR fingerprints of the drug-like natural-product space identify iotrochotazine A: a chemical probe to study Parkinson's disease.

    PubMed

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

    2014-06-10

    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 Parkinson's 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

  7. L-DOPA-induced behavioral sensitization of motor activity in the MPTP-treated common marmoset as a Parkinson's disease model.

    PubMed

    Ando, Kiyoshi; Inoue, Takashi; Itoh, Toshio

    2014-12-01

    l-DOPA is the gold standard for treatment of Parkinson's disease (PD). However, the drug produces some serious side effects, including dyskinesia, which is characterized by repetitive involuntary movements-including chorea. In the present preclinical study using a nonhuman primate model, dyskinesia caused by repeated l-DOPA administration was investigated in the context of behavioral sensitization by objectively quantifying motor activity in the common marmoset of PD model (the Parkinsonian marmoset). Twelve male Parkinsonian marmosets previously treated with MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and six intact male marmosets were used. The motor activity of each marmoset was measured using infrared sensors attached to each individual living cage. Parkinsonian marmosets (n=6) exhibited behavioral sensitization (enhanced motor activity) in 10weeks upon oral administration of l-DOPA (10mg/kg per day on 3days/week). These animals also exhibited dyskinesia characterized by repetitive rapid movements including chorea in 6-10weeks. Neither behavioral sensitization nor dyskinesia was observed in Parkinsonian marmosets given vehicle and in intact marmosets given l-DOPA at the same dose (both n=6 each). Behavioral sensitization was detected sensitively and objectively on motor activity only in Parkinsonian marmosets given repeated l-DOPA at a similar dose used in PD patients. The behavioral feature of the marmosets was dyskinesia similar to that of PD patients but appeared earlier than would be manifested in humans. In spite of statistically significant behavioral sensitization, some marmosets did not exhibit dyskinesia in the present limited l-DOPA administration period. Although both commonalities and differences may exist between behavioral sensitization and dyskinesia, behavioral sensitization is considered to be an objective, quantitative, sensitive and predictive measure of behavioral mechanism underlying dyskinesia in preclinical studies in evaluating compounds. PMID:25449794

  8. 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 ?-glutamate-cysteine ligase catalytic subunit, ?-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

  9. Novel Treatments for Drug-Induced Toxic Epidermal Necrolysis (Lyell’s Syndrome)

    Microsoft Academic Search

    Philippe Paquet; Gérald E. Piérard; Pascale Quatresooz

    2005-01-01

    Drug-induced toxic epidermal necrolysis (TEN) is a life-threatening disease characterized by extensive destruction of the epidermis. It apparently results from the formation of specific toxic drug metabolites by the keratinocytes. The mortality rate which averages 25–30% is mainly due to secondary septicemia, and to ionic and metabolic disturbances following loss of epidermal integrity. Apoptosis is the likely mechanism leading to

  10. Induced pluripotent stem cells — opportunities for disease modelling and drug discovery

    Microsoft Academic Search

    Marica Grskovic; Ashkan Javaherian; Berta Strulovici; George Q. Daley

    2011-01-01

    The ability to generate induced pluripotent stem cells (iPSCs) from patients, and an increasingly refined capacity to differentiate these iPSCs into disease-relevant cell types, promises a new paradigm in drug development — one that positions human disease pathophysiology at the core of preclinical drug discovery. Disease models derived from iPSCs that manifest cellular disease phenotypes have been established for several

  11. Canagliflozin-induced pancreatitis: a rare side effect of a new drug

    PubMed Central

    Chowdhary, Mudit; Kabbani, Ahmad A; Chhabra, Akansha

    2015-01-01

    Acute pancreatitis is most commonly attributed to gallstones, alcohol abuse, and metabolic disorders such as hyperlipidemia and hypercalcemia. Medications are an infrequent yet commonly overlooked etiology of pancreatitis. Although several drugs have been implicated, antidiabetic agents are a rare cause for drug-induced pancreatitis. Canagliflozin is a new drug in the class of SGLT-2 inhibitors used for the treatment of type 2 diabetes mellitus. Serious reported side effects include renal impairment, hyperkalemia, and hypotension. Pancreatitis as a result of canagliflozin, however, is exceedingly rare. Here we describe a case of a 33-year old female who presented with severe acute pancreatitis in the setting of recent initiation of canagliflozin. Given the timing of her presentation and after excluding all other possible etiologies, it was determined that canagliflozin was the likely source of her illness. This case highlights the importance of identifying drug-induced pancreatitis, especially in novel drugs, as it is commonly neglected in patients with multiple medical comorbidities and those taking numerous medications. Prompt identification of drug-induced pancreatitis can improve management as well as decrease morbidity and mortality in these individuals. PMID:26170677

  12. Neural Correlates of Stress-Induced and Cue-Induced Drug Craving: Influences of Sex and Cocaine Dependence

    PubMed Central

    Potenza, Marc N.; Hong, Kwang-ik Adam; Lacadie, Cheryl M.; Fulbright, Robert K.; Tuit, Keri L.; Sinha, Rajita

    2013-01-01

    Objective Although stress and drug cue exposure each increase drug craving and contribute to relapse in cocaine dependence, no previous research has directly examined the neural correlates of stress-induced and drug cue-induced craving in cocaine-dependent women and men relative to comparison subjects. Method Functional MRI was used to assess responses to individualized scripts for stress, drug/alcohol cue and neutral-relaxing-imagery conditions in 30 abstinent cocaine-dependent individuals (16 women, 14 men) and 36 healthy recreational-drinking comparison subjects (18 women, 18 men). Results Significant three-way interactions between diagnostic group, sex, and script condition were observed in multiple brain regions including the striatum, insula, and anterior and posterior cingulate. Within women, group-by-condition interactions were observed involving these regions and were attributable to relatively increased regional activations in cocaine-dependent women during the stress and, to a lesser extent, neutral-relaxing conditions. Within men, group main effects were observed involving these same regions, with cocaine-dependent men demonstrating relatively increased activation across conditions, with the main contributions from the drug and neutral-relaxing conditions. In men and women, subjective drug-induced craving measures correlated positively with corticostriatal-limbic activations. Conclusions In cocaine dependence, corticostriatal-limbic hyperactivity appears to be linked to stress cues in women, drug cues in men, and neutral-relaxing conditions in both. These findings suggest that sex should be taken into account in the selection of therapies in the treatment of addiction, particularly those targeting stress reduction. PMID:22294257

  13. Induced disorder in protein-ligand complexes as a drug-design strategy.

    PubMed

    Crespo, Alejandro; Fernández, Ariel

    2008-01-01

    Protein associations are poorly understood from a chemical perspective. If the contrary were true, drug inhibitors would be routinely designed based on target structure. While enthalpy/entropy balance is critical for affinity optimization, most drug-design strategies focus solely on promoting favorable intermolecular interactions. However, protein-drug associations often entail an entropic penalty, mostly arising from induced fits, which compromises affinity. Rather than restricting the conformational freedom of the protein, this work reports on an alternative design strategy to enhance affinity by inducing conformational disorder. This approach is adopted to target kinases by boosting their conformational entropy, taking advantage of their structural plasticity. As proof of concept we redesigned the anticancer drug imatinib to inhibit the imatinib-resistant D816V mutant of the C-Kit kinase, one of imatinib's primary targets. The prototype is engineered to promote an entropic boost on the activation loop that restores affinity. We also show that induced disorder is actually operational in kinase inhibitory action: a comparison of the binding of imatinib and PD173955 to Bcr-Abl kinase reveals that imatinib forms stronger intermolecular nonbonded interactions than PD173955, yet the latter binds with higher affinity by boosting the complex entropy. Induced disorder thus becomes a promising concept for drug design. PMID:18278867

  14. NEK2 induces drug resistance mainly through activation of efflux drug pumps and is associated with poor prognosis in myeloma and other cancers.

    PubMed

    Zhou, Wen; Yang, Ye; Xia, Jiliang; Wang, He; Salama, Mohamed E; Xiong, Wei; Xu, Hongwei; Shetty, Shashirekha; Chen, Tiehua; Zeng, Zhaoyang; Shi, Lei; Zangari, Maurizio; Miles, Rodney; Bearss, David; Tricot, Guido; Zhan, Fenghuang

    2013-01-14

    Using sequential gene expression profiling (GEP) samples, we defined a major functional group related to drug resistance that contains chromosomal instability (CIN) genes. One CIN gene in particular, NEK2, was highly correlated with drug resistance, rapid relapse, and poor outcome in multiple cancers. Overexpressing NEK2 in cancer cells resulted in enhanced CIN, cell proliferation and drug resistance, while targeting NEK2 by NEK2 shRNA overcame cancer cell drug resistance and induced apoptosis in vitro and in a xenograft myeloma mouse model. High expression of NEK2 induced drug resistance mainly through activation of the efflux pumps. Thus, NEK2 represents a strong predictor for drug resistance and poor prognosis in cancer and could be an important target for cancer therapy. PMID:23328480

  15. NEK2 Induces Drug-resistance Mainly through Activation of Efflux Drug Pumps and Is Associated with Poor Prognosis in Myeloma and Other Cancers

    PubMed Central

    Zhou, Wen; Yang, Ye; Xia, Jiliang; Wang, He; Salama, Mohamed E; Xiong, Wei; Xu, Hongwei; Shetty, Shashirekha; Chen, Tiehua; Zeng, Zhaoyang; Shi, Lei; Zangari, Maurizio; Miles, Rodney; Bearss, David; Tricot, Guido; Zhan, Fenghuang

    2014-01-01

    SUMMARY Using sequential gene expression profiling (GEP) samples, we defined a major functional group related to drug resistance that contains chromosomal instability (CIN) genes. One CIN gene in particular, NEK2, was highly correlated with drug resistance, rapid relapse, and poor outcome in multiple cancers. Over-expressing NEK2 in cancer cells resulted in enhanced CIN, cell proliferation and drug resistance, while targeting NEK2 by NEK2 shRNA overcame cancer cell drug resistance and induced apoptosis in vitro and in a xenograft myeloma mouse model. High expression of NEK2 induced drug resistance mainly through activation of the efflux pumps. Thus, NEK2 represents a strong predictor for drug resistance and poor prognosis in cancer and could be an important target for cancer therapy. PMID:23328480

  16. Sleepiness in Parkinson's disease.

    PubMed

    Arnulf, Isabelle; Leu-Semenescu, Smaranda

    2009-12-01

    Excessive daytime sleepiness is a disabling and vital problem in patients with PD. It affects around 33% patients and culminates in sleep attacks (without prodroma) in 1 to 4% of the patients. When monitored, short, narcolepsy-like naps with abnormal intrusion of REM sleep during daytime (and hypnagogic hallucinations as wakeful dreams) are observed in 33-41% patients, while other patients display naps with non REM sleep. Although insomnia, sleep apnea and periodic leg movements are common in these patients, there is no clear link between the night events and the level of sleepiness. Patients treated with dopamine agonists are two to three fold more exposed to sleep attacks than those on levodopa, with large variability between patients. Sleepiness may exist, to a lesser degree, before the onset of parkinsonism and before the use of dopamine agents, suggesting that other, disease-dependant factors contribute to the sleepiness. Most arousal systems are indeed damaged in PD brains, including the locus coeruleus (noradrenalin), the pedunculo-pontine nucleus and the basal forebrain (acetylcholine), the median raphe (serotonin), and the lateral hypothalamus (orexin), while histamine dopamine arousal system are normal. Treating patients with stimulants such as modafinil is only partially efficacious, while trials of anti-H3 drugs and sodium oxybate seem more active. Eventually, the recent stimulation of the pedunculopontine nucleus has stimulant or sedative effects in patients, depending on the frequency of stimulation. These results provide new insights into the mechanisms of arousal in PD. PMID:20082966

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

    PubMed

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

    2014-04-27

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

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

    PubMed Central

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

    2014-01-01

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

  19. Smoking and Parkinson's disease

    Microsoft Academic Search

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

    1982-01-01

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

  20. Characterization of carbon-containing aerosolized drugs using laser-induced breakdown spectroscopy.

    PubMed

    Mukherjee, Dibyendu; Cheng, Meng-Dawn

    2008-05-01

    Aerosolized drug delivery methods have increasingly become popular for pharmaceutical applications. This is mainly due to their ease of application and the more recent advancements incorporating nano-sized generation of particles that find deeper penetration routes and more efficient administration of the drug to specific target organs. Their effectiveness heavily relies on the uniformity of the chemical composition of these aerosolized drugs. Thus, it calls for a real-time on-line analytical tool that can accurately characterize the chemical constituents of the drug powder particles generated to ensure a stringent quality control. We present laser-induced breakdown spectroscopy (LIBS) for the first time as an efficient analytical tool to carry out on-line quantitative chemical characterization of aerosolized drugs. We used three different carbon based aerosolized drugs, namely L-ascorbic acid 2-phosphate sesquimagnesium salt hydrate (C(6)H(9)Mg(1.5)O(9)P.xH(2)O), Iron(II) L-ascorbate (C(12)H(14)FeO(12)), and DL-pantothenic acid hemicalcium salt (C(9)H(16)NO(5)0.5Ca) for our quantitative LIBS studies here. Our results show that LIBS can effectively estimate the quantitative ratios of carbon to various trace elements for each of these drugs, thereby enabling on-line unique characterization of individual aerosolized drugs. The quantitative LIBS technique predicted the [C]/[Mg], [C]/[Fe], and [C]/[Ca] ratios as 4.02+/-0.76, 12.42+/-2.36, and 18.47+/-4.39 for each of the above aerosolized drugs, respectively. Within error limits, we find these ratios in good agreement with the respective stoichiometric values of 4, 12, and 18 corresponding to the drugs above. Thus, the work demonstrated the utility and validity of LIBS in accurate on-line identification of drug powders during real-time manufacturing processes. PMID:18498697

  1. Endoplasmic reticulum stress response is involved in nonsteroidal anti-inflammatory drug-induced apoptosis.

    PubMed

    Tsutsumi, S; Gotoh, T; Tomisato, W; Mima, S; Hoshino, T; Hwang, H-J; Takenaka, H; Tsuchiya, T; Mori, M; Mizushima, T

    2004-09-01

    Apoptosis induced by nonsteroidal anti-inflammatory drugs (NSAIDs) is involved not only in the production of NSAID-induced gastric lesions but also in the antitumor activity of these drugs. The endoplasmic reticulum (ER) stress response is a cellular mechanism that aids in protecting the ER against ER stressors and is involved in ER stressor-induced apoptosis. Here, we examine the relationship between this response and NSAID-induced apoptosis in cultured guinea-pig gastric mucosal cells. Exposure of cells to indomethacin, a commonly used NSAID, induced GRP78 as well as CHOP, a transcription factor involved in apoptosis. Three factors that positively regulate CHOP expression (ATF6, ATF4 and XBP-1) were activated and/or induced by indomethacin. NSAIDs other than indomethacin (diclofenac, ibuprofen and celecoxib) also induced CHOP. Monitoring of the transcriptional activities of ATF6 and CHOP by luciferase assay revealed that both were stimulated in the presence of indomethacin. Furthermore, indomethacin-induced apoptosis was suppressed in cultured guinea-pig gastric mucosal cells by expression of the dominant-negative form of CHOP, or in peritoneal macrophages from CHOP-deficient mice. These results suggest that ER stress response-related proteins, particularly CHOP, are involved in NSAID-induced apoptosis. PMID:15131590

  2. 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

  3. Involvement of 5HT 1C -receptors in drug-induced penile erections in rats

    Microsoft Academic Search

    Hemmie H. G. Berendsen; François Jenck; Chris L. E. Broekkamp

    1990-01-01

    Drug-induced penile erections (PE) were initially suggested to be 5-HT1B receptor mediated. However, since the discovery of the 5-HT1C receptor a number of compounds, considered to be 5-HT1B selective, appear to bind more strongly to the 5-HT1C receptor and this prompted a re-evaluation of the receptor subtype involved in PE induction. PE could be induced by the 5-HT agonists mCPP

  4. Parkinson's disease, pesticides and mitochondrial dysfunction

    Microsoft Academic Search

    Peter Jenner

    2001-01-01

    Selective nigral degeneration with inclusion formation provoked by systemic administration of the herbicide rotenone, through inhibition of complex I, raises the question of pesticide exposure and environmental factors in general, as a cause of Parkinson's disease (PD). Toxin-induced complex I inhibition probably represents one of many potential causes of PD, but it alerts us to the dangers of such substances

  5. Regulation of drug-induced liver injury by signal transduction pathways: critical role of mitochondria.

    PubMed

    Han, Derick; Dara, Lily; Win, Sanda; Than, Tin Aung; Yuan, Liyun; Abbasi, Sadeea Q; Liu, Zhang-Xu; Kaplowitz, Neil

    2013-04-01

    Drugs that cause liver injury often 'stress' mitochondria and activate signal transduction pathways important in determining cell survival or death. In most cases, hepatocytes adapt to the drug-induced stress by activating adaptive signaling pathways, such as mitochondrial adaptive responses and nuclear factor erythroid 2-related factor 2 (Nrf-2), a transcription factor that upregulates antioxidant defenses. Owing to adaptation, drugs alone rarely cause liver injury, with acetaminophen (APAP) being the notable exception. Drug-induced liver injury (DILI) usually involves other extrinsic factors, such as the adaptive immune system, that cause 'stressed' hepatocytes to become injured, leading to idiosyncratic DILI, the rare and unpredictable adverse drug reaction in the liver. Hepatocyte injury, due to drug and extrinsic insult, causes a second wave of signaling changes associated with adaptation, cell death, and repair. If the stress and injury reach a critical threshold, then death signaling pathways such as c-Jun N-terminal kinase (JNK) become dominant and hepatocytes enter a failsafe mode to undergo self-destruction. DILI can be seen as an active process involving recruitment of death signaling pathways that mediate cell death rather than a passive process due to overwhelming biochemical injury. In this review, we highlight the role of signal transduction pathways, which frequently involve mitochondria, in the development of DILI. PMID:23453390

  6. Drug-induced liver injury: an overview over the most critical compounds.

    PubMed

    Björnsson, Einar S

    2015-03-01

    There has been a substantial interest in drug-induced liver injury (DILI) recently. National Institutes of Health has sponsored a multicenter study in the USA for the last 10 years, which has collected valuable information in this context. Idiosyncratic DILI is like other adverse effects of drugs underestimated and underreported in most epidemiological studies. A recent prospective population-based study from Iceland found a crude incidence of approximately 19 cases per 100,000 and year. Antibiotic is the class of drugs most commonly implicated in patients with DILI. Amoxicillin-clavulanate continues to be the most commonly implicated agent occurring in approximately 1 out of 2,300 users. Drugs with the highest risk of DILI in the Icelandic study were azathioprine and infliximab. Although rare, statin-induced hepatotoxicity has been well documented. Liver injury associated with the use of herbal medicines and dietary supplements seems to be increasing. Information on the documented hepatotoxicity of drugs has recently been made easier by a website available in the public domain: LiverTox ( http://livertox.nlm.nih.gov ). Unfortunately, at the current time, pre-therapy risk assessment for DILI in the individual patient is difficult but previous well-documented hepatotoxicity is usually a contraindication for a subsequent treatment with the same drug. PMID:25618544

  7. The Concept of Continuous Dopaminergic Stimulation: What We Should Consider when Starting Parkinson’s Disease Treatment

    Microsoft Academic Search

    Fabrizio Stocchi

    2010-01-01

    Treatment of early Parkinson’s disease (PD) should pursue objectives like possible disease-modifying effect, more physiological dopaminergic stimulation, and avoidance of motor fluctuations. The recent published ADAGIO trial showed that rasagiline (1 mg\\/day), used in early PD, has a disease-modifying effect. Dopaminergic drugs administered to provide more continuous dopaminergic stimulation prevent or minimize motor fluctuations in experimental animals. Dopamine (DA) agonists

  8. Both methods made the cells sensitive to drug-induced apoptosis (Fig. 1b, c). Con-

    E-print Network

    Chapman, Clark R.

    Both methods made the cells sensitive to drug-induced apoptosis (Fig. 1b, c). Con- versely a partial reversion to normal glandular structures, which then were resistant to apoptosis (Fig. 1a, b with abnormal anchorage to the basement membrane did not protect against apoptosis. Interestingly, however

  9. Antituberculosis drug-induced hepatotoxicity: concise up-to-date review

    Microsoft Academic Search

    Alma Tostmann; Martin J Boeree; Rob E Aarnoutse; Wiel C M de Lange; Andre J A M van der Ven; Richard Dekhuijzen

    2008-01-01

    The cornerstone of tuberculosis management is a 6-month course of isoniazid, rifampicin, pyrazinamide and ethambutol. Compliance is crucial for curing tuberculosis. Adverse effects often negatively affect the compliance, because they frequently require a change of treatment, which may have negative consequences for treatment outcome. In this paper we review the incidence, pathology and clinical features of antituberculosis drug-induced hepatotoxicity, discuss

  10. Effecting Drug Attitude Change in College Students via Induced Cognitive Dissonance.

    ERIC Educational Resources Information Center

    Horan, John J.; Swisher, John D.

    In this study, the authors deliberately set out to modify the attitudes of new students toward drugs in a conservative direction by inducing cognitive dissonance. The method used was a pretest-posttest design in which the experimental group of students were to fill out a value-preference inventory that yielded a score, sorting the students into 2…

  11. Facilitation of enkephalins catabolism inhibitor-induced antinociception by drugs classically used in pain management

    Microsoft Academic Search

    Magdalena Mas Nieto; Jodie Wilson; Judith Walker; Jesus Benavides; Marie-Claude Fournié-Zaluski; Bernard P Roques; Florence Noble

    2001-01-01

    The aim of this study was to investigate the facilitatory effects of subanalgesic or low doses of different drugs (acetylsalicylic acid, ibuprofen and morphine) on the antinociceptive responses induced by the endogenous opioid peptides, enkephalins, protected from their catabolism by the dual enkephalin-degrading enzymes inhibitor RB101. According to the analgesic profile of the three studied compounds different antinociceptive assays were

  12. Sex, drugs, and mating role: testosterone-induced phenotype-switching

    E-print Network

    Plummer, Michael V.

    Sex, drugs, and mating role: testosterone-induced phenotype-switching in Galapagos marine iguanas each mating season whether to adopt sneaker, satellite, or territorial mating tactics. How do males territories (64 6 8 ng/ml) or sneaker males that behaved like females within territories (43 6 11ng

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

    PubMed

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

    2011-06-01

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

  14. [Importance of drug-induced ulceration in endoscopic lesions of the esophagus].

    PubMed

    Baeriswyl, G; Bengoa, J; de Peyer, R; Loizeau, E

    1985-01-01

    Drug-induced ulcers of the oesophagus represent a rare but probably under-recorded complication. In a series of 5900 endoscopies performed in 32 months, oesophageal ulcers were seen in 4 cases following the intake of doxycycline, and in one case after ingestion of pinaverium bromide and a bulk laxative respectively. Oesophageal ulcers were seen mainly in young patients without underlying oesophageal disease, presenting with chest pain and odynophagia. The most common site of involvement was at the aortic notch in the middle third of the oesophagus. The course was quickly favorable within 5-10 days after the drug was discontinued, but transient complete abstention from oral intake was required in some cases. Ulceration is thought to be secondary to drug stasis and local cytotoxic effects. Oesophageal ulcers can be prevented simply by recommending intake of the drug with sufficient water in the upright position at least two hours before retiring. PMID:3864236

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

    PubMed

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

    2014-10-01

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

  16. The anti-hypertensive drug reserpine induces neuronal cell death through inhibition of autophagic flux.

    PubMed

    Lee, Kang Il; Kim, Min Ju; Koh, Hyongjong; Lee, Jin I; Namkoong, Sim; Oh, Won Keun; Park, Junsoo

    2015-07-10

    Reserpine is a well-known medicine for the treatment of hypertension and schizophrenia, but its administration can induce Parkinson's disease (PD)-like symptoms in humans and animals. Reserpine inhibits the vesicular transporter of monoamines and depletes the brain of monoamines such as dopamine. However, the cellular function of reserpine is not fully understood. In this report, we present one possible mechanism by which reserpine may contribute to PD-like symptoms. Reserpine treatment induced the formation of enlarged autophagosomes by inhibiting the autophagic flux and led to accumulation of p62, an autophagy adapter molecule. In particular, reserpine treatment increased the level of ?-synuclein protein and led to accumulation of ?-synuclein in autophagosomes. Treatment with rapamycin enhanced the effect of reserpine by further increasing the level of ?-synuclein and neuronal cell death. Drosophila raised on media containing reserpine showed loss of dopaminergic neurons. Furthermore, cotreatment with reserpine and rapamycin aggravated the loss of dopaminergic neurons. Our results suggest that reserpine contributes to the loss of dopaminergic neurons by interfering with autophagic flux. PMID:25976674

  17. Mechanisms of the hepatoprotective effects of tamoxifen against drug-induced and chemical-induced acute liver injuries

    SciTech Connect

    Yoshikawa, Yukitaka; Miyashita, Taishi; Higuchi, Satonori [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920?1192 (Japan)] [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920?1192 (Japan); Tsuneyama, Koichi [Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Sugitani, Toyama 930?0194 (Japan)] [Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Sugitani, Toyama 930?0194 (Japan); Endo, Shinya [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920?1192 (Japan)] [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920?1192 (Japan); Tsukui, Tohru [Research Center for Genomic Medicine, Saitama Medical University, Yamane, Hidaka 350?1241 (Japan)] [Research Center for Genomic Medicine, Saitama Medical University, Yamane, Hidaka 350?1241 (Japan); Toyoda, Yasuyuki; Fukami, Tatsuki; Nakajima, Miki [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920?1192 (Japan)] [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920?1192 (Japan); Yokoi, Tsuyoshi, E-mail: tyokoi@p.kanazawa-u.ac.jp [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920?1192 (Japan)] [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920?1192 (Japan)

    2012-10-01

    Although estrogen receptor (ER)? agonists, such as estradiol and ethinylestradiol (EE2), cause cholestasis in mice, they also reduce the degree of liver injury caused by hepatotoxicants as well as ischemia–reperfusion. The functional mechanisms of ER? have yet to be elucidated in drug-induced or chemical-induced liver injury. The present study investigated the effects of an ER? agonist, selective ER modulators (SERMs) and an ER antagonist on drug-induced and chemical-induced liver injuries caused by acetaminophen, bromobenzene, diclofenac, and thioacetamide (TA). We observed hepatoprotective effects of EE2, tamoxifen (TAM) and raloxifene pretreatment in female mice that were exposed to a variety of hepatotoxic compounds. In contrast, the ER antagonist did not show any hepatoprotective effects. DNA microarray analyses suggested that monocyte to macrophage differentiation-associated 2 (Mmd2) protein, which has an unknown function, is commonly increased by TAM and RAL pretreatment, but not by pretreatment with the ER antagonist. In ER?-knockout mice, the hepatoprotective effects of TAM and the increased expression of Mmd2 mRNA were not observed in TA-induced liver injury. To investigate the function of Mmd2, the expression level of Mmd2 mRNA was significantly knocked down to approximately 30% in mice by injection of siRNA for Mmd2 (siMmd2). Mmd2 knockdown resulted in a reduction of the protective effects of TAM on TA-induced liver injury in mice. This is the first report of the involvement of ER? in drug-induced or chemical-induced liver injury. Upregulation of Mmd2 protein in the liver was suggested as the mechanism of the hepatoprotective effects of EE2 and SERMs. -- Highlights: ? Liver injury induced by drugs or chemicals was investigated in mice. ? Liver injury was suppressed by pretreatment with tamoxifen in female mice. ? Mmd2, whose function was unknown, could be a candidate gene for liver protection. ? Tamoxifen up-regulated Mmd2 mRNA expression via ER?.

  18. Translating Drug-Induced Hibernation to Therapeutic Hypothermia.

    PubMed

    Jinka, Tulasi R; Combs, Velva M; Drew, Kelly L

    2015-06-17

    Therapeutic hypothermia (TH) improves prognosis after cardiac arrest; however, thermoregulatory responses such as shivering complicate cooling. Hibernators exhibit a profound and safe reversible hypothermia without any cardiovascular side effects by lowering the shivering threshold at low ambient temperatures (Ta). Activation of adenosine A1 receptors (A1ARs) in the central nervous system (CNS) induces hibernation in hibernating species and a hibernation-like state in rats, principally by attenuating thermogenesis. Thus, we tested the hypothesis that targeted activation of the central A1AR combined with a lower Ta would provide a means of managing core body temperature (Tb) below 37 °C for therapeutic purposes. We targeted the A1AR within the CNS by combining systemic delivery of the A1AR agonist (6)N-cyclohexyladenosine (CHA) with 8-(p-sulfophenyl)theophylline (8-SPT), a nonspecific adenosine receptor antagonist that does not readily cross the blood-brain barrier. Results show that CHA (1 mg/kg) and 8-SPT (25 mg/kg), administered intraperitoneally every 4 h for 20 h at a Ta of 16 °C, induce and maintain the Tb between 29 and 31 °C for 24 h in both naïve rats and rats subjected to asphyxial cardiac arrest for 8 min. Faster and more stable hypothermia was achieved by continuous infusion of CHA delivered subcutaneously via minipumps. Animals subjected to cardiac arrest and cooled by CHA survived better and showed less neuronal cell death than normothermic control animals. Central A1AR activation in combination with a thermal gradient shows promise as a novel and effective pharmacological adjunct for inducing safe and reversible targeted temperature management. PMID:25812681

  19. Gender-specific brain regional variation of neurons, endogenous estrogen, neuroinflammation and glial cells during rotenone-induced mouse model of Parkinson's disease.

    PubMed

    Mitra, S; Chakrabarti, N; Dutta, S S; Ray, S; Bhattacharya, P; Sinha, P; Bhattacharyya, A

    2015-04-30

    Rotenone (RT) produces reactive oxygen species (ROS) by inhibiting the mitochondrial electron transport chain; causing dopaminergic (DA) cell death in the substantia nigra (SN) and simulates other models of induced Parkinson's disease (PD). There is a sincere dearth of knowledge regarding the status of glial cells, neuroprotective estrogen and the status of neuroinflammatory TNF-? in the different brain regions in either sex during healthy, as well as during PD conditions. In the present study of RT-induced mouse model of PD, we have selected the frontal cortex (FC), hippocampus (HC) and SN from either sex of Swiss albino mice as these are the major regions involved during PD pathogenesis. During non pathogenic conditions, the ROS-scavenging enzyme activity varied among the brain regions and also in between genders. The number of DOPA decarboxylase-positive cells, astrocytes and microglia was similar in the respective regions of the brain in both the sexes. The level of proinflammatory cytokine TNF-? was same in the respective FC and HC in either sex except that of SN. The expression level of estrogen and its receptors varied among the three brain regions. During RT treatment, ROS-scavenging enzyme activities increased, DOPA decarboxylase-positive neurons and fibers in DA as well as in norepinephrinergic (NE) systems become degenerated, number of astrocytes decreased and microglial cells increased in those specific brain regions in either of the sexes except in the SN region of males where astrocyte number remained unaltered and microglial cell percentage decreased. TNF-? increased in the FC and SN but remained unaltered in the HC of both sexes. Estradiol level decreased in the HC and SN but the level unevenly varied in the FC. Similarly, the estrogen bound and nuclear-cytosolic receptor ? and ? also varied differentially among the brain regions of the two sexes. Therefore our present study depicts that there exists a clear variation of neuronal and astroglial cell population, estrogen and its receptor levels in different brain regions of both the sexes during control and RT-treated pathogenic condition and these variations have major implication in PD pathogenesis and progression. PMID:25592425

  20. Increased antiparkinson efficacy of the combined administration of VEGF- and GDNF-loaded nanospheres in a partial lesion model of Parkinson’s disease

    PubMed Central

    Herrán, Enara; Requejo, Catalina; Ruiz-Ortega, Jose Angel; Aristieta, Asier; Igartua, Manoli; Bengoetxea, Harkaitz; Ugedo, Luisa; Pedraz, Jose Luis; Lafuente, Jose Vicente; Hernández, Rosa Maria

    2014-01-01

    Current research efforts are focused on the application of growth factors, such as glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF), as neuroregenerative approaches that will prevent the neurodegenerative process in Parkinson’s disease. Continuing a previous work published by our research group, and with the aim to overcome different limitations related to growth factor administration, VEGF and GDNF were encapsulated in poly(lactic-co-glycolic acid) nanospheres (NS). This strategy facilitates the combined administration of the VEGF and GDNF into the brain of 6-hydroxydopamine (6-OHDA) partially lesioned rats, resulting in a continuous and simultaneous drug release. The NS particle size was about 200 nm and the simultaneous addition of VEGF NS and GDNF NS resulted in significant protection of the PC-12 cell line against 6-OHDA in vitro. Once the poly(lactic-co-glycolic acid) NS were implanted into the striatum of 6-OHDA partially lesioned rats, the amphetamine rotation behavior test was carried out over 10 weeks, in order to check for in vivo efficacy. The results showed that VEGF NS and GDNF NS significantly decreased the number of amphetamine-induced rotations at the end of the study. In addition, tyrosine hydroxylase immunohistochemical analysis in the striatum and the external substantia nigra confirmed a significant enhancement of neurons in the VEGF NS and GDNF NS treatment group. The synergistic effect of VEGF NS and GDNF NS allows for a reduction of the dose by half, and may be a valuable neurogenerative/neuroreparative approach for treating Parkinson’s disease. PMID:24920904

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

    PubMed Central

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

    2015-01-01

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

  2. Drug-induced hypersensitivity reactions and pharmacogenomics: past, present and future.

    PubMed

    Alfirevic, Ana; Pirmohamed, Munir

    2010-04-01

    Drug-induced hypersensitivity reactions represent a major concern for clinicians, patients, regulators and drug developers. Severe hypersensitivity is associated with high morbidity and mortality, it cannot be predicted from the known pharmacology of the drug and it is usually detected post-marketing when a large number of patients have been exposed to a particular drug. Recent success in developing clinically useful genetic tests that have allowed us to predict the risk of abacavir-induced hypersensitivity has helped to pave the path for a pharmacogenetic approach. However, the loop from identifying a genetic association to improving clinical outcome is still lacking for many drugs. In this commentary, we discuss the progress of hypersensitivity pharmacogenomics over the last decade and point out what remains to be done in the future. The current efforts of the international community are focused on the development of consortia, which aim to standardize disease phenotypes, but also to collect larger numbers of well-phenotyped patients and to pool biological samples through these collaborations. In addition, it is necessary to advance our knowledge of hypersensitivity mechanisms through functional studies, which will lead to the development of predictive and diagnostic tests. PMID:20350129

  3. Pharmacogenetic Aspects of Antipsychotic Drug-induced Weight Gain - A Critical Review

    PubMed Central

    2012-01-01

    Treatment with several antipsychotic drugs can result in weight gain, which may lead to further morbidity such as type 2 diabetes and cardiovascular disease via the development of metabolic syndrome. These important and problematic metabolic consequences of antipsychotic drug treatment probably reflect a pharmacological disruption of the mechanisms involved in control of food intake and body weight. The extent of weight gain following antipsychotic drug treatment shows substantial variability between individuals, due in part to genetic factors. Common functional polymorphisms in many candidate genes implicated in the control of body weight and various aspects of energy and lipid metabolism have been investigated for association with weight gain in subjects receiving antipsychotic drug treatment, and with metabolic pathology in chronic schizophrenia. Perhaps the strongest and most replicated findings are the associations with promoter polymorphisms in the 5-HT2C receptor and leptin genes, although many other possible genetic risk factors, including polymorphisms in the fat mass and obesity associated (FTO) gene and genes for the alpha2A adrenoceptor and melanocortin4 receptor, have been reported. Genome-wide association studies (GWAS) have also addressed antipsychotic-induced weight gain and other indicators of metabolic disturbances. However there is as yet little consistency between these studies or between GWAS and classical candidate gene approaches. Identifying common genetic factors associated with drug-induced weight gain and its metabolic consequences may provide opportunities for personalized medicine in the predictive assessment of metabolic risk as well as indicating underlying physiological mechanisms. PMID:23431082

  4. Translation strategy for the qualification of drug-induced vascular injury biomarkers.

    PubMed

    Bendjama, Kaïdre; Guionaud, Silvia; Aras, Gulfidan; Arber, Nadir; Badimon, Lina; Bamberger, Uwe; Bratfalean, Dorina; Brott, David; David, Maayan; Doessegger, Lucette; Firat, Hüseyin; Gallas, Jean-François; Gautier, Jean-Charles; Hoffmann, Peter; Kraus, Sarah; Padro, Teresa; Saadoun, David; Szczesny, Piotr; Thomann, Peter; Vilahur, Gemma; Lawton, Michael; Cacoub, Patrice

    2014-06-01

    Drug-induced vascular injury (DIVI) is a common preclinical toxicity usually characterized by hemorrhage, vascular endothelial and smooth muscle damage, and inflammation. DIVI findings can cause delays or termination of drug candidates due to low safety margins. The situation is complicated by the absence of sensitive, noninvasive biomarkers for monitoring vascular injury and the uncertain relevance to humans. The Safer And Faster Evidence-based Translation (SAFE-T) consortium is a public-private partnership funded within the European Commission's Innovative Medicines Initiative (IMI) aiming to accelerate drug development by qualifying biomarkers for drug-induced organ injuries, including DIVI. The group is using patients with vascular diseases that have key histomorphologic features (endothelial damage, smooth muscle damage, and inflammation) in common with those observed in DIVI, and has selected candidate biomarkers associated with these features. Studied populations include healthy volunteers, patients with spontaneous vasculitides and other vascular disorders. Initial results from studies with healthy volunteers and patients with vasculitides show that a panel of biomarkers can successfully discriminate the population groups. The SAFE-T group plans to seek endorsement from health authorities (European Medicines Agency and Food and Drug Administration) to qualify the biomarkers for use in regulatory decision-making processes. PMID:24771082

  5. Assessment of temperature-induced hERG channel blockade variation by drugs.

    PubMed

    Kauthale, Rahul R; Dadarkar, Shruta S; Husain, Raghib; Karande, Vikas V; Gatne, Madhumanjiri M

    2015-07-01

    Drug-induced QT prolongation has been reported in humans and animals. This potentially lethal effect can be induced by drugs interacting with a cardiac potassium channel, namely hERG (human ether-a go-go-related gene) leading to arrhythmia or torsade de pointes (TdP). Hence, in vitro evaluation of therapeutics for their effects on the rapid delayed rectifier current (IKr ) mediated by the K(+) ion channel encoded by hERG is a valuable tool for identifying potential arrhythmic side effects during drug safety testing. Our objective was to evaluate the temperature-induced hERG channel blockade variation by human and veterinary drugs using the IonFlux 16 system. A panel of eight drugs was tested for IKr inhibition at both ambient (23?°C) and physiological (37?°C) temperatures at various concentrations using IonFlux 16, an automated patch clamp system. Our results established that both amiodarone (IC50 ?=?0.56??M at 23?°C and 0.30??M at 37?°C) and ?-estradiol (IC50 ?=?24.72??M at 23?°C and 8.17??M at 37?°C) showed a dose-dependent IKr blockade with a higher blockade at 37?°C. Whereas, blockade of IKr by both ivermectin (IC50 ?=?12.52??M at 23?°C and 24.41??M at 37?°C) and frusemide (IC50 ?=?12.58??M at 23?°C and 25.55??M at 37?°C) showed a dose-dependent IKr blockade with a lower blockade at 37?°C. Gentamicin, enrofloxacin, xylazine and albendazole did not block IKr at both the assessed temperatures. Collectively, these results demonstrate that the effect of temperature variation should be taken into consideration during the evaluation of test drugs for their hERG channel blockade potential. Copyright © 2014 John Wiley & Sons, Ltd. PMID:25348819

  6. Drug-induced anaphylactic reactions in Indian population: A systematic review

    PubMed Central

    Patel, Tejas K.; Patel, Parvati B.; Barvaliya, Manish J.; Tripathi, C. B.

    2014-01-01

    Background: Epidemiological data on drug-induced anaphylactic reactions are limited in India and are largely depending on studies from developed countries. Aim: The aim was to analyze the published studies of drug-induced anaphylaxis reported from India in relation with causative drugs and other clinical characteristics. Materials and Methods: The electronic databases were searched for Indian publications from 1998 to 2013 describing anaphylactic reactions. The information was collected for demographics, set up in which anaphylaxis occurred, causative drugs, incubation period, clinical features, associated allergic conditions, past reactions, co-morbid conditions, skin testing, IgE assays, therapeutic intervention and mortality. Reactions were analyzed for severity, causality, and preventability. Data were extracted and summarized by absolute numbers, mean (95% confidence interval [CI]), percentages and odds ratio (OR) (95% CI). Results: From 3839 retrieved references, 52 references describing 54 reactions were included. The mean age was 35.31 (95% CI: 30.52–40.10) years. Total female patients were 61.11%. Majority reactions were developed in perioperative conditions (53.70%), ward (20.37%) and home (11.11%). The major incriminated groups were antimicrobials (18.52%), nonsteroidal antiinflammatory drugs-(NSAIDs) (12.96%) and neuromuscular blockers (12.96%). Common causative drugs were diclofenac (11.11%), atracurium (7.41%) and ?-lactams (5.96%). Cardiovascular (98.15%) and respiratory (81.48%) symptoms dominated the presentation. Skin tests and IgE assays were performed in 37.03% and 18.52% cases, respectively. The fatal cases were associated with complications (OR =5.04; 95% CI: 1.41–17.92), cerebral hypoxic damage (OR =6.80; 95% CI: 2.14–21.58) and preventable reactions (OR =14.33; 95% CI: 2.33–87.97). Conclusion: Antimicrobials, NSAIDs, and neuromuscular blockers are common causative groups. The most fatal cases can be prevented by avoiding allergen drugs. PMID:25538414

  7. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury.

    PubMed

    Chalasani, Naga P; Hayashi, Paul H; Bonkovsky, Herbert L; Navarro, Victor J; Lee, William M; Fontana, Robert J

    2014-07-01

    Idiosyncratic drug-induced liver injury (DILI) is a rare adverse drug reaction and it can lead to jaundice, liver failure, or even death. Antimicrobials and herbal and dietary supplements are among the most common therapeutic classes to cause DILI in the Western world. DILI is a diagnosis of exclusion and thus careful history taking and thorough work-up for competing etiologies are essential for its timely diagnosis. In this ACG Clinical Guideline, the authors present an evidence-based approach to diagnosis and management of DILI with special emphasis on DILI due to herbal and dietary supplements and DILI occurring in individuals with underlying liver disease. PMID:24935270

  8. Serum drug level-related sodium valproate-induced hair loss

    PubMed Central

    Ramakrishnappa, Suresh K.; Belhekar, Mahesh N.

    2013-01-01

    Sodium valproate is a well-established treatment in epilepsy and mood disorders. Its utility is compromised by its adverse effects such as tremor, weight gain, hair loss, and liver dysfunction. Hair loss may occur when drug is used in higher dose. Drug-induced hair loss is diffused and non-scarring, which is reversible upon withdrawal. But there are no case reports showing relation between serum levels of valproate and occurrence of hair loss. So we took interest in reporting this case report. PMID:23716898

  9. Measurement of caspase-2 activation during different anti-tumor drugs induced apoptosis by FRET technique

    NASA Astrophysics Data System (ADS)

    Lin, Juqiang; Zeng, Shaoqun; Luo, Qingming; Rong, Chen; Zhang, Zhihong

    2007-11-01

    Caspase-2 is important for the engagement of the mitochondrial apoptotic pathway, in the presence of DNA-damaging agents, such as cisplatin; however, the mechanism by which caspase-2 executes apoptosis remains obscure. In this study, we carried out the measurements of the dynamics of caspase-2 activation in a single living cell by a FRET (fluorescence resonance energy transfer) probe. A FRET probe was constructed that encoded a CRS (caspase-2 recognition site) fused with a cyan fluorescent protein (CFP) and a red fluorescent protein (DsRed) (CFP-CRS-DsRed). Using this probe, we found that during TRAIL-induced apoptosis, caspase-2 was not activated, and caspase-2 activation occurred in etoposide and cisplatin treated cells. However, during cisplatin-induced apoptosis caspase-2 activation was initiated much earlier than that of etoposide. Cisplatin and etoposide is one of the most broadly used drugs in the Clinical applications of cancer chemotherapy, and TRAIL, which belongs to the TNF family proteins, can selectively induce apoptosis in many transformed cells but not in normal cells. Most of anticancer drugs can induce apoptosis mediated by the activation of caspase pathway. Thus, the perfect synergistic effect group of multi-drug can be selected by using our FRET probe.

  10. Drug-Induced Apoptosis: Mechanism by which Alcohol and Many Other Drugs can Disrupt Brain Development

    PubMed Central

    Creeley, Catherine E.; Olney, John W.

    2013-01-01

    Maternal ingestion of alcohol during pregnancy can cause a disability syndrome termed Fetal Alcohol Spectrum Disorder (FASD), which may include craniofacial malformations, structural pathology in the brain, and a variety of long-term neuropsychiatric disturbances. There is compelling evidence that exposure to alcohol during early embryogenesis (4th week of gestation) can cause excessive death of cell populations that are essential for normal development of the face and brain. While this can explain craniofacial malformations and certain structural brain anomalies that sometimes accompany FASD, in many cases these features are absent, and the FASD syndrome manifests primarily as neurobehavioral disorders. It is not clear from the literature how alcohol causes these latter manifestations. In this review we will describe a growing body of evidence documenting that alcohol triggers widespread apoptotic death of neurons and oligodendroglia (OLs) in the developing brain when administered to animals, including non-human primates, during a period equivalent to the human third trimester of gestation. This cell death reaction is associated with brain changes, including overall or regional reductions in brain mass, and long-term neurobehavioral disturbances. We will also review evidence that many drugs used in pediatric and obstetric medicine, including general anesthetics (GAs) and anti-epileptics (AEDs), mimic alcohol in triggering widespread apoptotic death of neurons and OLs in the third trimester-equivalent animal brain, and that human children exposed to GAs during early infancy, or to AEDs during the third trimester of gestation, have a significantly increased incidence of FASD-like neurobehavioral disturbances. These findings provide evidence that exposure of the developing human brain to GAs in early infancy, or to alcohol or AEDs in late gestation, can cause FASD-like neurodevelopmental disability syndromes. We propose that the mechanism by which alcohol, GAs and AEDs produce neurobehavioral deficit syndromes is by triggering apoptotic death and deletion of neurons and OLs (or their precursors) from the developing brain. Therefore, there is a need for research aimed at deciphering mechanisms by which these agents trip the apoptosis trigger, the ultimate goal being to learn how to prevent these agents from causing neurodevelopmental disabilities. PMID:24587895

  11. Use of complementary therapies and non-prescribed medication in patients with Parkinson's disease.

    PubMed

    Ferry, P; Johnson, M; Wallis, P

    2002-10-01

    Patients with Parkinson's disease resort to complementary therapy and non-prescribed medication in the hope of improving their quality of life. In the US 40% of patients with Parkinson's disease reported the use of at least one form of complementary therapy for Parkinson's disease. Data for the UK are limited. A structured questionnaire was administered to consecutive patients attending a Parkinson's disease clinic. Patients were excluded if they were cognitively impaired, if they were living in an institution, or if they declined to take part. The participants were asked about current and previous use of complementary therapy in general and Parkinson's disease in particular and were presented with an extensive list of complementary therapies and non-prescribed medications. The response rate was 90% and 80 patients met the inclusion criteria. Fifty four per cent (n=44) reported the use of at least one form of complementary therapy or non-prescribed medication either for Parkinson's disease or for some other indication, of whom 31 (38.7% of the total sample) used it solely for the treatment of Parkinson's disease. The most commonly used complementary therapies for Parkinson's disease were massage (n=9) and aromatherapy (n=8). Non-prescribed medication was mainly used for indications other than Parkinson's disease and the commonest drugs used were simple analgesics (n=7), cod liver oil (n=5), and multivitamins (n=4). The use of complementary therapy for Parkinson's disease correlated significantly (Pearson's r=0.44, p=0.01) with a younger age at diagnosis of Parkinson's disease. Comorbidity correlated significantly with complementary therapy use for indications other than Parkinson's disease (Pearson's r=0.29, p= 0.01). The use of complementary therapy for Parkinson's disease in this UK based clinic closely mimics that in the US. Non-pharmacological complementary therapy is mainly used for Parkinson's disease, while non-prescribed medication is more commonly used for other indications. PMID:12415085

  12. Use of complementary therapies and non-prescribed medication in patients with Parkinson's disease

    PubMed Central

    Ferry, P; Johnson, M; Wallis, P

    2002-01-01

    Patients with Parkinson's disease resort to complementary therapy and non-prescribed medication in the hope of improving their quality of life. In the US 40% of patients with Parkinson's disease reported the use of at least one form of complementary therapy for Parkinson's disease. Data for the UK are limited. A structured questionnaire was administered to consecutive patients attending a Parkinson's disease clinic. Patients were excluded if they were cognitively impaired, if they were living in an institution, or if they declined to take part. The participants were asked about current and previous use of complementary therapy in general and Parkinson's disease in particular and were presented with an extensive list of complementary therapies and non-prescribed medications. The response rate was 90% and 80 patients met the inclusion criteria. Fifty four per cent (n=44) reported the use of at least one form of complementary therapy or non-prescribed medication either for Parkinson's disease or for some other indication, of whom 31 (38.7% of the total sample) used it solely for the treatment of Parkinson's disease. The most commonly used complementary therapies for Parkinson's disease were massage (n=9) and aromatherapy (n=8). Non-prescribed medication was mainly used for indications other than Parkinson's disease and the commonest drugs used were simple analgesics (n=7), cod liver oil (n=5), and multivitamins (n=4). The use of complementary therapy for Parkinson's disease correlated significantly (Pearson's r=0.44, p=0.01) with a younger age at diagnosis of Parkinson's disease. Comorbidity correlated significantly with complementary therapy use for indications other than Parkinson's disease (Pearson's r=0.29, p= 0.01). The use of complementary therapy for Parkinson's disease in this UK based clinic closely mimics that in the US. Non-pharmacological complementary therapy is mainly used for Parkinson's disease, while non-prescribed medication is more commonly used for other indications. PMID:12415085

  13. [The Parkinson puzzle].

    PubMed

    Guseo, András

    2012-12-30

    Parkinson's disease is one of the most frequent progressive degenerative disorders with unknown origin of the nervous system. The commutation of the disease on Guam led to the discovery of a neurotoxin which was also found in other continents. This neurotoxin was identified in the common cyanobacteria (blue-green algae). Early clinical observations suggested some loose correlations with gastric and duodenal ulcer and Parkinson's disease, while recent studies revealed a toxin, almost identical to that found in cyanobacteria in one strain of Helicobacter pylori, which proved to cause Parkinson like symptoms in animals. Therefore, it cannot be ruled out that there is a slowly progressive poisoning in Parkinson's disease. The disease specific alpha-sinuclein inclusions can be found in nerve cells of the intestinal mucosa far before the appearance of clinical symptoms indicating that the disease may start in the intestines. These results are strengthened by the results of Borody's fecal transplants, after which in Parkinson patients showed a symptomatic improvement. Based on these observations the Parkinson puzzle is getting complete. Although these observations are not evidence based, they may indicate a new way for basic clinical research, as well as a new way of thinking for clinicians. These new observations in psycho-neuro-immunology strengthen the fact that immunological factors may also play a critical factor facilitating local cell necrosis which may be influenced easily. PMID:23261994

  14. [Severe drug-induced skin reactions. Stevens-Johnson syndrome and toxic epidermal necrolysis].

    PubMed

    Mockenhaupt, M

    2014-05-01

    Stevens-Johnson syndrome (SJS) and Toxic epidermal necrolysis (TEN) are characterized by extensive blistering of the skin and mucosa; they are considered as one disease entity with varying severity. They are rare but potentially life-threatening and accompanied by high mortality. A clear clinical diagnosis is needed to direct specific therapy, but supportive therapy remains most important. In order to identify and withdraw the inducing drug, a very detailed and thorough medication history has to be obtained. Among the highly suspected (strongly associated) agents are allopurinol, antibacterial sulfonamides, non-steroidal anti-inflammatory drugs of the oxicam type, various anti-epileptics and nevaripine. Together they account for more than half of the cases of SJS/TEN. Although a drug is not always the cause, it is considered very like in approximately 75% of cases. Infections have also to be considered as etiologic factors. PMID:24820799

  15. Quality of life in Parkinson`s Disease

    PubMed Central

    Opara, JA; Brola, W; Leonardi, M; B?aszczyk, B

    2012-01-01

    In this review report, current possibilities of evaluation of quality of life in Parkinson’s disease have been critically presented. Health Related Quality of Life (-HRQoL) comprises a wide spectrum of consequences of the disease. Measurement of quality of life has become increasingly relevant as an outcome parameter, especially in long-term trials. Most of the available QoL instruments depend on patient self-reports. The data can be collected by written questionnaires. There are universal questionnaires of QoL – for many diseases and the specific ones – specially created for one disease. Among universal questionnaires, the Sickness Impact Profile (SIP) and the Short-Form Health Status Survey (SF-36) are the most popular in Parkinson’s disease. As for specific questionnaires: the Parkinson`s Disease Questionnaire (PDQ-39) and the Parkinson`s Disease Quality of Life Questionnaire (PDQL) have been described. PMID:23346238

  16. Potential candidate genomic biomarkers of drug induced vascular injury in the rat

    SciTech Connect

    Dalmas, Deidre A., E-mail: Deidre.A.Dalmas@gsk.com [Department of Safety Assessment, King of Prussia, PA 19406 (United States); Scicchitano, Marshall S., E-mail: Marshall.S.Scicchitano@gsk.com [Department of Safety Assessment, King of Prussia, PA 19406 (United States); Mullins, David, E-mail: David.R.Mullins@gsk.com [Department of Safety Assessment, King of Prussia, PA 19406 (United States)] [Department of Safety Assessment, King of Prussia, PA 19406 (United States); Hughes-Earle, Angela, E-mail: Angela.R.Hughes-Earle@gsk.com [Department of Safety Assessment, King of Prussia, PA 19406 (United States)] [Department of Safety Assessment, King of Prussia, PA 19406 (United States); Tatsuoka, Kay, E-mail: Kay.S.Tatsuoka@gsk.com [Department of Quantitative Sciences GlaxoSmithKline, King of Prussia, PA 19406 (United States)] [Department of Quantitative Sciences GlaxoSmithKline, King of Prussia, PA 19406 (United States); Magid-Slav, Michal, E-mail: Michal.M.Magid-Slav@gsk.com [Department of Quantitative Sciences GlaxoSmithKline, King of Prussia, PA 19406 (United States)] [Department of Quantitative Sciences GlaxoSmithKline, King of Prussia, PA 19406 (United States); Frazier, Kendall S., E-mail: Kendall.S.Frazier@gsk.com [Department of Safety Assessment, King of Prussia, PA 19406 (United States); Thomas, Heath C., E-mail: Heath.C.Thomas@gsk.com [Department of Safety Assessment, King of Prussia, PA 19406 (United States)

    2011-12-15

    Drug-induced vascular injury is frequently observed in rats but the relevance and translation to humans present a hurdle for drug development. Numerous structurally diverse pharmacologic agents have been shown to induce mesenteric arterial medial necrosis in rats, but no consistent biomarkers have been identified. To address this need, a novel strategy was developed in rats to identify genes associated with the development of drug-induced mesenteric arterial medial necrosis. Separate groups (n = 6/group) of male rats were given 28 different toxicants (30 different treatments) for 1 or 4 days with each toxicant given at 3 different doses (low, mid and high) plus corresponding vehicle (912 total rats). Mesentery was collected, frozen and endothelial and vascular smooth muscle cells were microdissected from each artery. RNA was isolated, amplified and Affymetrix GeneChip Registered-Sign analysis was performed on selectively enriched samples and a novel panel of genes representing those which showed a dose responsive pattern for all treatments in which mesenteric arterial medial necrosis was histologically observed, was developed and verified in individual endothelial cell- and vascular smooth muscle cell-enriched samples. Data were confirmed in samples containing mesentery using quantitative real-time RT-PCR (TaqMan Trade-Mark-Sign ) gene expression profiling. In addition, the performance of the panel was also confirmed using similarly collected samples obtained from a timecourse study in rats given a well established vascular toxicant (Fenoldopam). Although further validation is still required, a novel gene panel has been developed that represents a strategic opportunity that can potentially be used to help predict the occurrence of drug-induced mesenteric arterial medial necrosis in rats at an early stage in drug development. -- Highlights: Black-Right-Pointing-Pointer A gene panel was developed to help predict rat drug-induced mesenteric MAN. Black-Right-Pointing-Pointer A gene panel was identified following treatment of rats with 28 different toxicants. Black-Right-Pointing-Pointer There was a strong correlation of genes and histologic evidence of mesenteric MAN. Black-Right-Pointing-Pointer Many genes were also regulated prior to histologic evidence of arterial effects.

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

    PubMed Central

    Lee, Jee-Young; Jeon, Beom Seok

    2014-01-01

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

  18. Chemical screen identifies FDA-approved drugs and target pathways that induce precocious pancreatic endocrine differentiation

    PubMed Central

    Rovira, Meritxell; Huang, Wei; Yusuff, Shamila; Shim, Joong Sup; Ferrante, Anthony A.; Liu, Jun O.; Parsons, Michael J.

    2011-01-01

    Pancreatic ?-cells are an essential source of insulin and their destruction because of autoimmunity causes type I diabetes. We conducted a chemical screen to identify compounds that would induce the differentiation of insulin-producing ?-cells in vivo. To do this screen, we brought together the use of transgenic zebrafish as a model of ?-cell differentiation, a unique multiwell plate that allows easy visualization of lateral views of swimming larval fish and a library of clinical drugs. We identified six hits that can induce precocious differentiation of secondary islets in larval zebrafish. Three of these six hits were known drugs with a considerable background of published data on mechanism of action. Using pharmacological approaches, we have identified and characterized two unique pathways in ?-cell differentiation in the zebrafish, including down-regulation of GTP production and retinoic acid biosynthesis. PMID:22084084

  19. Student Preferences Regarding Teaching Methods in a Drug-Induced Diseases and Clinical Toxicology Course

    PubMed Central

    Gim, Suzanna

    2013-01-01

    Objectives. To determine which teaching method in a drug-induced diseases and clinical toxicology course was preferred by students and whether their preference correlated with their learning of drug-induced diseases. Design. Three teaching methods incorporating active-learning exercises were implemented. A survey instrument was developed to analyze students’ perceptions of the active-learning methods used and how they compared to the traditional teaching method (lecture). Examination performance was then correlated to students’ perceptions of various teaching methods. Assessment. The majority of the 107 students who responded to the survey found traditional lecture significantly more helpful than active-learning methods (p=0.01 for all comparisons). None of the 3 active-learning methods were preferred over the others. No significant correlations were found between students’ survey responses and examination performance. Conclusions. Students preferred traditional lecture to other instructional methods. Learning was not influenced by the teaching method or by preference for a teaching method. PMID:23966726

  20. Drug-induced hypothermia in stroke models: does it always protect?

    PubMed Central

    Zhang, Meijuan; Wang, Haiying; Zhao, Jinbing; Chen, Cong; Leak, Rehana K.; Xu, Yun; Vosler, Peter; Gao, Yanqin; Zhang, Feng

    2014-01-01

    Ischemic stroke is a common neurological disorder lacking a cure. Recent studies show that therapeutic hypothermia is a promising neuroprotective strategy against ischemic brain injury. Several methods to induce therapeutic hypothermia have been established; however, most of them are not clinically feasible for stroke patients. Therefore, pharmacological cooling is drawing increasing attention as a neuroprotective alternative worthy of further clinical development. We begin this review with a brief introduction to the commonly used methods for inducing hypothermia; we then focus on the hypothermic effects of eight classes of hypothermia-inducing drugs: the cannabinoids, opioid receptor activators, transient receptor potential vanilloid, neurotensins, thyroxine derivatives, dopamine receptor activators, hypothermia-inducing gases, adenosine, and adenine nucleotides. Their neuroprotective effects as well as the complications associated with their use are both considered. This article provides guidance for future clinical trials and animal studies on pharmacological cooling in the setting of acute stroke. PMID:23469851

  1. Twenty-Four Hour Non-Invasive Ambulatory Blood Pressure and Heart Rate Monitoring in Parkinson’s Disease

    PubMed Central

    Stuebner, Eva; Vichayanrat, Ekawat; Low, David A.; Mathias, Christopher J.; Isenmann, Stefan; Haensch, Carl-Albrecht

    2013-01-01

    Non-motor symptoms are now commonly recognized in Parkinson’s disease (PD) and can include dysautonomia. Impairment of cardiovascular autonomic function can occur at any stage of PD but is typically prevalent in advanced stages or related to (anti-Parkinsonian) drugs and can result in atypical blood pressure (BP) readings and related symptoms such as orthostatic hypotension (OH) and supine hypertension. OH is usually diagnosed with a head-up-tilt test (HUT) or an (active) standing test (also known as Schellong test) in the laboratory, but 24?h ambulatory blood pressure monitoring (ABPM) in a home setting may have several advantages, such as providing an overview of symptoms in daily life alongside pathophysiology as well as assessment of treatment interventions. This, however, is only possible if ABPM is administrated correctly and an autonomic protocol (including a diary) is followed which will be discussed in this review. A 24-h ABPM does not only allow the detection of OH, if it is present, but also the assessment of cardiovascular autonomic dysfunction during and after various daily stimuli, such as postprandial and alcohol dependent hypotension, as well as exercise and drug induced hypotension. Furthermore, information about the circadian rhythm of BP and heart rate (HR) can be obtained and establish whether or not a patient has a fall of BP at night (i.e., “dipper” vs. non-“dipper”). The information about nocturnal BP may also allow the investigation or detection of disorders such as sleep dysfunction, nocturnal movement disorders, and obstructive sleep apnea, which are common in PD. Additionally, a 24-h ABPM should be conducted to examine the effectiveness of OH therapy. This review will outline the methodology of 24?h ABPM in PD, summarize findings of such studies in PD, and briefly consider common daily stimuli that might affect 24?h ABPM. PMID:23720648

  2. Locomotor response to levodopa in fluctuating Parkinson’s disease

    Microsoft Academic Search

    Steven T. Moore; Hamish G. MacDougall; Jean-Michel Gracies; William G. Ondo

    2008-01-01

    The aim of this study was to quantify the dynamic response of locomotion to the first oral levodopa administration of the\\u000a day in patients with fluctuating Parkinson’s disease (PD). Stride length, walking speed, cadence and gait variability were\\u000a measured with an ambulatory gait monitor in 13 PD patients (8 males) with a clinical history of motor fluctuations. The Unified\\u000a Parkinson’s

  3. Sleep disorders and daytime sleepiness in Parkinson’s disease

    Microsoft Academic Search

    Renee Monderer; Michael Thorpy

    2009-01-01

    Patients with Parkinson’s disease commonly have sleep disturbances that significantly alter quality of life but are often\\u000a underrecognized. Awareness of the importance of these sleep disorders has been growing, and more research is being conducted.\\u000a Patients with Parkinson’s disease have difficulties that not only include falling asleep and staying asleep but also include\\u000a excessive daytime sleepiness and abnormal events during

  4. Radiation Retinopathy Caused by Low Dose Irradiation and Antithyroid Drug-Induced Systemic Vasculitis

    Microsoft Academic Search

    Koh-Hei Sonoda; Masahiro Yamamoto; Tatsuro Ishibashi

    2005-01-01

    Background: We report on a patient with Graves’ disease with radiation retinopathy caused by lowdose irradiation and antithyroid drug-induced antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis. Case: A 38-year-old woman with Graves’ disease presented with bilateral blurred vision, microaneurysms, telangiectasia, and macular edema. The patient was examined by ophthalmoscopy and fluorescein angiography, and radiation retinopathy was diagnosed. Observations: The patient had been

  5. Drug-Induced Hypersensitivity Syndrome due to Mexiletine Hydrochloride Associated with Reactivation of Human Herpesvirus 7

    Microsoft Academic Search

    Akiko Yagami; Tetsushi Yoshikawa; Yoshizo Asano; Shin Koie; Tetsuo Shiohara; Kayoko Matsunaga

    2006-01-01

    It has been suggested that reactivation of human herpesvirus 6 (HHV-6) infection may be involved in the pathogenesis of drug-induced hypersensitivity syndrome. We report a 45-year-old Japanese man who developed a generalized papuloerythematous rash, fever, hepatitis, lymphadenopathy and lymphocytosis with an increased number of atypical lymphocytes. He was diagnosed with DIHS due to mexiletine hydrochloride based on laboratory data, results

  6. Anticonvulsant drug-induced osteomalacia: Alterations in mineral metabolism and response to vitamin D 3 administration

    Microsoft Academic Search

    Theodore J. Hahn; Linda R. Halstead

    1979-01-01

    Summary  Parameters of mineral metabolism were examined in 6 patients with moderately severe anticonvulsant drug-induced osteomalacia.\\u000a Compared to 15 matched controls, the patients exhibited significantly reduced serum calcium, inorganic phosphate, and 25-hydroxyvitamin\\u000a D concentration, elevated serum alkaline phosphatase and immunoreactive parathyroid hormone (iPTH) concentration, reduced\\u000a intestinal47Ca absorption, reduced urinary calcium and increased urinary hydroxyproline excretion, and reduced forearm bone mass. Intestinal

  7. In vitro detection of drug-induced phospholipidosis using gene expression and fluorescent phospholipid based methodologies.

    PubMed

    Nioi, Paul; Perry, Brad K; Wang, Er-Jia; Gu, Yi-Zhong; Snyder, Ronald D

    2007-09-01

    Phospholipidosis (PLD) is characterized by the excessive intracellular accumulation of phospholipids. It is well established that a large number of cationic amphiphilic drugs have the potential to induce PLD. In the present study, we describe two facile in vitro methods to determine the PLD-inducing potential of a molecule. The first approach is based on a recent study by (Sawada et al., 2005, Toxicol. Sci. 83, 282-292) in which 17 genes were identified as potential biomarkers of PLD in HepG2 cells. To confirm the utility of this gene panel, we treated HepG2 cells with PLD-positive and -negative compounds and then analyzed gene expression using real-time PCR. Our initial analysis, which used a single dose of each drug, correctly identified five of eight positive compounds and four of four negative compounds. We then increased the doses of the three false negatives (amiodarone, tamoxifen, and loratadine) and found that the changes in gene expression became large enough to correctly identify them as PLD-inducing drugs. Our results suggest that a range of concentrations should be used to increase the accuracy of prediction in this assay. Our second approach utilized a fluorescently labeled phospholipid (LipidTox) which was added to the media of growing HepG2 cells along with compounds positive and negative for PLD. Phospholipid accumulation was determined using confocal microscopy and, more quantitatively, using a 96-well plate assay and a fluorescent plate reader. Using an expanded set of compounds, we show that this assay correctly identified 100% of PLD-positive and -negative compounds. Dose-dependent increases in intracellular fluorescent phospholipid accumulation were observed. We found that this assay was less time consuming, more sensitive, and higher throughput than gene expression analysis. To our knowledge, this study represents the first validation of the use of LipidTox in identifying drugs that can induce PLD. PMID:17567588

  8. Drug-induced Sweet's syndrome secondary to hepatitis C antiviral therapy.

    PubMed

    Gheorghe, Liana; Cotruta, Bogdan; Trifu, Viorel; Cotruta, Cristina; Becheanu, Gabriel; Gheorghe, Cristian

    2008-09-01

    Pegylated interferon-alpha in combination with ribavirin currently represents the therapeutic standard for the hepatitis C virus infection. Interferon based therapy may be responsible for many cutaneous side effects. We report a case of drug-induced Sweet's syndrome secondary to hepatitis C antiviral therapy. To our knowledge, this is the first reported case of Sweet's syndrome in association with pegylated interferon-alpha therapy. PMID:18937663

  9. The effect of various drugs on experimentally induced ulcers in immobilized rats

    NASA Technical Reports Server (NTRS)

    Schramm, H.

    1978-01-01

    Experiments related to the importance of functional disorders in the central nervous system in connection with stomach diseases were performed on Wistar rats. Assuming that severe mental strains may be triggering factors for such disorders, testing of the effects of different drugs on experimentally induced ulcers in these rats was done. The immobilization method described by Bonfils was used. Particular importance was placed on the sex related difference which appeared.

  10. Alveolar macrophage mediated pulmonary clearance suppressed by drug-induced phospholipidosis

    Microsoft Academic Search

    J. Ferin

    1982-01-01

    Drug-induced phopholipidosis in rats treated with chlorphentermine (CP) for 4-7 days suppressed totally alveolar pulmonary clearance in the first days after a TiOâ aerosol exposure. Reversing phospholipidosis by treatment interruption led to a recovery of particle clearance. Morphological observations indicated that ''foam cells'' contained less TiOâ particles than alveolar macrophages (AM) of control rats. Clearance of ZnO particles which seems

  11. Drug-induced hepatitis and the risk factors for liver injury in pulmonary tuberculosis patients

    PubMed Central

    Gaude, Gajanan S.; Chaudhury, Alisha; Hattiholi, Jyothi

    2015-01-01

    Introduction: Short-course chemotherapy containing rifampicin and isoniazid in combination has proved to be highly effective in the treatment of tuberculosis, but one of its adverse effects is hepatotoxicity. Various risk factors have been found to be associated with drug-induced liver injury (DILI) in general population. The study aimed to determine the prevalence of drug-induced hepatitis and the risk factors associated with the DILI among the patients of pulmonary tuberculosis in Indian patients. Setting and Design: Prospective nested case control study. Materials and Methods: Out of the cohort of 3900 tuberculosis patients who were initiated on anti-tubercular therapy, 150 patients who developed drug-induced liver injury due to short-course chemotherapy under RNTCP were included in the analysis. Thirty cases were being followed up in our hospital and other 120 were referred to us for the management of drug-induced hepatitis from the primary health centers. The diagnostic criteria's for DILI were made according to the American Thoracic Society criteria. Analyses of various risk factors were done for the development of DILI. Results: The prevalence of DILI in the present study was 3.8%. It was observed that DILI patients were older and their serum albumin levels were lower, and they had multiple co-morbid conditions. Regular alcohol intake, more extensive disease associated with radiological and female gender were observed to be independent risk factors for the development of DILI. Conclusions: Of the various risk factors analyzed, advanced age, hypoalbuminemia, regular alcohol intake and advanced nature of the disease were independent risk factors for the development of DILI. The risk of development of hepatitis is increased in the presence of one or more of these risk factors. PMID:25949974

  12. Role of tumor necrosis factor-alpha in methamphetamine-induced drug dependence and neurotoxicity.

    PubMed

    Nakajima, Akira; Yamada, Kiyofumi; Nagai, Taku; Uchiyama, Takehisa; Miyamoto, Yoshiaki; Mamiya, Takayoshi; He, Jue; Nitta, Atsumi; Mizuno, Makoto; Tran, Manh Hung; Seto, Aika; Yoshimura, Masako; Kitaichi, Kiyoyuki; Hasegawa, Takaaki; Saito, Kuniaki; Yamada, Yasuhiro; Seishima, Mitsuru; Sekikawa, Kenji; Kim, Hyoung-Chun; Nabeshima, Toshitaka

    2004-03-01

    Tumor necrosis factor-alpha (TNF-alpha), a proinflammatory cytokine, is now emerging as an important modulator of the function of the CNS. Methamphetamine (METH) is a widely abused psychostimulant that causes euphoria, hyperactivity, and drug dependence. High doses of METH cause long-term neurotoxicity in dopaminergic neurons. In this study, we investigated a role of TNF-alpha in METH-induced dependence and neurotoxicity. Repeated treatment with METH (2 mg/kg for 5 d) in rats induced a significant increase in TNF-alpha mRNA and protein expression in the brain. Exogenous TNF-alpha (1-4 microg) blocked locomotor-stimulating and rewarding effects of METH, as well as METH (4 mg/kg; four times at 2 hr intervals)-induced dopaminergic neurotoxicity in mice. To examine a role of endogenous TNF-alpha in behavioral and neurochemical effects of METH, we used mice with targeted deletions of the TNF-alpha gene. TNF-alpha-(-/-) mice showed enhanced responses to the locomotor-sensitizing, rewarding, and neurotoxic effects of METH compared with wild-type mice. We also examined the role of TNF-alpha in METH-induced dopamine (DA) release and uptake in vitro and in vivo in C57BL/6 mice. Exogenous TNF-alpha (4 microg) attenuated the METH-induced increase in extracellular striatal DA in vivo and potentiated striatal DA uptake into synaptosomes in vitro and in vivo. Furthermore, TNF-alpha activated vesicular DA uptake by itself and diminished the METH-induced decrease in vesicular DA uptake. Our findings suggest that TNF-alpha plays a neuroprotective role in METH-induced drug dependence and neurotoxicity by activating plasmalemmal and vesicular DA transporter as well as inhibiting METH-induced increase in extracellular DA levels. PMID:14999072

  13. Drug-induced modulation of locomotor hyperactivity induced by picrotoxin in nucleus accumbens.

    PubMed

    Morgenstern, R; Mende, T; Gold, R; Lemme, P; Oelssner, W

    1984-10-01

    Locomotor hyperactivity was induced in rats by bilateral injection of picrotoxin (PIC) into the nucleus accumbens (NAC) followed by intraperitoneal (IP) or intra-accumbens (IA) injection of agents affecting dopamine (DA), acetylcholine, serotonin, or GABA receptors. IP injection of haloperidol and diazepam attenuated PIC-induced hypermotility in a dose-dependent manner. Low (sedative) doses of the DA agonists apomorphine (APO) and lisuride, or pretreatment with reserpine abolished PIC-induced hypermotility. Independent of a preceding IA injection of PIC, higher IP doses of APO produced the well-known locomotor effect. LSD, and the atypical neuroleptic, sulpiride, potentiated PIC-induced hypermotility strongly whereas clozapine was ineffective. IA injection of carbachol or haloperidol, in doses which antagonized hypermotility induced by APO IP, did not influence PIC-induced hypermotility. The atypical neuroleptics, clozapine and sulpiride, and the benzodiazepine, diazepam, inhibited PIC-induced hypermotility. The results suggest that there is a complex involvement of GABA, DA and serotonin functions in the effectuation of PIC-induced hypermotility and that PIC-induced hypermotility may be affected by DA-sensitive structures situated outside the NAC. PMID:6504948

  14. Genetics of Parkinson’s Disease

    PubMed Central

    Klein, Christine; Westenberger, Ana

    2012-01-01

    Fifteen years of genetic research in Parkinson’s disease (PD) have led to the identification of several monogenic forms of the disorder and of numerous genetic risk factors increasing the risk to develop PD. Monogenic forms, caused by a single mutation in a dominantly or recessively inherited gene, are well-established, albeit relatively rare types of PD. They collectively account for about 30% of the familial and 3%–5% of the sporadic cases. In this article, we will summarize the current knowledge and understanding of the molecular genetics of PD. In brief, we will review familial forms of PD, basic genetic principles of inheritance (and their exceptions in PD), followed by current methods for the identification of PD genes and risk factors, and implications for genetic testing. PMID:22315721

  15. Drug-induced acute tubulointerstitial nephritis: a case with elevated urinary cadmium.

    PubMed

    Subat-Dezulovi?, Mirna; Slavi?, Irena; Rozmani?, Vojko; Persi?, Mladen; Medjimurec, Branka; S?ukanec-Spoljar, Mira

    2002-05-01

    Acute tubulointerstitial nephritis (ATIN) has many different causes, but is most frequently caused by drugs. We report a 13-year-old vegetarian girl with drug-induced ATIN, confirmed by renal biopsy, and simultaneous occurrence of elevated urinary cadmium. Four weeks prior to admission she had been treated with antibiotics and acetaminophen for respiratory infection, and remaining febrile, was treated with different "home-made" herbal mixtures. She presented with acute non-oliguric renal failure, tubular dysfunction, and sterile pyuria, but without skin rash or edema. Laboratory data showed a raised erythrocyte sedimentation rate, normal white blood count with eosinophilia, and a serum creatinine of 245 micromol/l. Urinalysis was remarkable for glycosuria, tubular proteinuria, and elevated beta(2)-microglobulin and N-acetyl-beta-D-glucosaminidase excretion. Immunoserological tests characteristic of acute glomerulonephritis and systemic diseases were negative. She was treated with steroids and her renal function improved. Follow-up analyses disclosed normal urinary cadmium and enzyme excretion within 6 months. Heavy metal analysis of herbal preparations that she had taken confirmed the presence of cadmium, but within approved concentrations. In conclusion, elevated urinary cadmium in the case of drug-induced ATIN may be assumed to be an accidental finding. However, consumption of different herbs containing cadmium and cadmium-induced nephro-toxicity could be the reason for such serious renal damage. PMID:12042900

  16. Genomic indicators in the blood predict drug-induced liver injury.

    PubMed

    Huang, J; Shi, W; Zhang, J; Chou, J W; Paules, R S; Gerrish, K; Li, J; Luo, J; Wolfinger, R D; Bao, W; Chu, T-M; Nikolsky, Y; Nikolskaya, T; Dosymbekov, D; Tsyganova, M O; Shi, L; Fan, X; Corton, J C; Chen, M; Cheng, Y; Tong, W; Fang, H; Bushel, P R

    2010-08-01

    Genomic biomarkers for the detection of drug-induced liver injury (DILI) from blood are urgently needed for monitoring drug safety. We used a unique data set as part of the Food and Drug Administration led MicroArray Quality Control Phase-II (MAQC-II) project consisting of gene expression data from the two tissues (blood and liver) to test cross-tissue predictability of genomic indicators to a form of chemically induced liver injury. We then use the genomic indicators from the blood as biomarkers for prediction of acetaminophen-induced liver injury and show that the cross-tissue predictability of a response to the pharmaceutical agent (accuracy as high as 92.1%) is better than, or at least comparable to, that of non-therapeutic compounds. We provide a database of gene expression for the highly informative predictors, which brings biological context to the possible mechanisms involved in DILI. Pathway-based predictors were associated with inflammation, angiogenesis, Toll-like receptor signaling, apoptosis, and mitochondrial damage. The results show for the first time and support the hypothesis that genomic indicators in the blood can serve as potential diagnostic biomarkers predictive of DILI. PMID:20676066

  17. Alveolar macrophage mediated pulmonary clearance suppressed by drug-induced phospholipidosis

    SciTech Connect

    Ferin, J.

    1982-01-01

    Drug-induced phopholipidosis in rats treated with chlorphentermine (CP) for 4-7 days suppressed totally alveolar pulmonary clearance in the first days after a TiO/sub 2/ aerosol exposure. Reversing phospholipidosis by treatment interruption led to a recovery of particle clearance. Morphological observations indicated that ''foam cells'' contained less TiO/sub 2/ particles than alveolar macrophages (AM) of control rats. Clearance of ZnO particles which seems not to be mediated by AM was not affected by CP treatment. A grand average retention curve based on data from control groups of past experiments suggests that alveolar clearance of TiO/sub 2/ particles has a phase 1 (T/sub 1///sub 2/ = 7 days) lasting about 2 weeks and a phase 2 (T/sub 1///sub 2/ = 69 days). The results with drug-induced phospholipidosis suggest that phase 1 is pratically totally AM-mediated. Drug-induced phospholipidosis is a promising method for the study of AM involvement in defensive functions.

  18. Genomic indicators in the blood predict drug-induced liver injury

    PubMed Central

    Huang, Jianping; Shi, Weiwei; Zhang, John; Chou, Jeff W.; Paules, Richard S.; Gerrish, Kevin; Li, Jianying; Luo, Jun; Wolfinger, Russell D.; Bao, Wenjun; Chu, Tzu-Ming; Nikolsky, Yuri; Nikolskaya, Tatiana; Dosymbekov, Damir; Tsyganova, Marina O.; Shi, Leming; Fan, Xiaohui; Corton, J. Christopher; Chen, Minjun; Cheng, Yiyu; Tong, Weida; Fang, Hong; Bushel, Pierre R.

    2011-01-01

    Genomic biomarkers for the detection of drug-induced liver injury (DILI) from blood are urgently needed for monitoring drug safety. We used a unique data set as part of the Food and Drug Administration led MicroArray Quality Control Phase-II (MAQC-II) project consisting of gene expression data from the two tissues (blood and liver) to test cross-tissue predictability of genomic indicators to a form of chemically-induced liver injury. We then use the genomic indicators from the blood as biomarkers for prediction of acetaminophen-induced liver injury and show that the cross tissue predictability of a response to the pharmaceutical agent (accuracy as high as 92.1%) is better than, or at least comparable to, that of non-therapeutic compounds. We provide a database of gene expression for the highly informative predictors which brings biological context to the possible mechanisms involved in DILI. Pathway-based predictors were associated with inflammation, angiogenesis, Toll-like receptor signaling, apoptosis and mitochondrial damage. The results demonstrate for the first time and support the hypothesis that genomic indicators in the blood can serve as potential diagnostic biomarkers predictive of DILI. PMID:20676066

  19. Understanding the role of reactive metabolites in drug-induced hepatotoxicity: state of the science.

    PubMed

    Antoine, Daniel J; Williams, Dominic P; Park, B Kevin

    2008-11-01

    Drug-induced liver injury (DILI) represents a major impediment to the development of new drugs and is a leading cause of drug withdrawal. The occurrence of hepatotoxicity has been closely associated with the formation of chemically reactive metabolites. Huge investment has focused on the screening of chemically reactive metabolites to offer a pragmatic approach to produce safer drugs and also reduce drug attrition and prevent market place withdrawal. However, questions surrounding the importance of chemically reactive metabolites still remain. Increasing evidence now exists for the multi-factorial nature of DILI, in particular the role played by the host immune system or disease state in the pathogenesis of DILI. This review aims to evaluate the current measures for the prediction and diagnosis of DILI and to highlight investigations being made to understand the multidimensional nature. Some of the steps being made to generate improved physiological systems to identify more sensitive, reflective mechanism-based biomarkers to aid the earlier identification of DILI and develop safer medicines are also discussed. PMID:18950283

  20. Key factors of susceptibility to anti-tuberculosis drug-induced hepatotoxicity.

    PubMed

    Chen, Ru; Wang, Jing; Zhang, Yuan; Tang, Shaowen; Zhan, Siyan

    2015-06-01

    Anti-tuberculosis drug-induced hepatotoxicity (ATDH) is one of the leading adverse drug reactions during the course of tuberculosis treatment and poses a considerable challenge to clinicians and researchers. Previous studies have revealed the important contribution of drug metabolism and transporter enzymes to the complexity of ATDH. The emerging roles of immune response and oxidative stress resulting from reactive metabolite in the development of ATDH have also gained attention recently. Both non-genetic and genetic factors can have a significant impact on the susceptibility to ATDH, consequently altering the risk of hepatotoxicity in susceptible individuals. Non-genetic risk factors associated with ATDH include host factors, environment factors and drug-related factors. Genetic factors contributing to the susceptibility of ATDH involve genetic variations in bioactivation/toxification pathways via the cytochrome P450 enzymes (phase I), detoxification reactions by N-acetyl transferase 2, glutathione S-transferase and uridine diphosphate glucuronosyltransferase (phase II) and hepatic transport (phase III), together with immunological factors and antioxidant response. Better understanding of these factors may help to predict and prevent the occurrence of ATDH and develop more effective treatments. This review focuses on the mechanisms of ATDH and the key factors of susceptibility associated with drug metabolism, hepatic transport, immune response and oxidative stress. PMID:25693865

  1. MicroRNAs as Signaling Mediators and Biomarkers of Drug- and Chemical-induced Liver Injury

    PubMed Central

    McGill, Mitchell R.; Jaeschke, Hartmut

    2015-01-01

    Drug-induced liver injury (DILI) is major problem for both the drug industry and for clinicians. There are two basic categories of DILI: intrinsic and idiosyncratic. The former is the chief cause of acute liver failure in several developed countries, while the latter is the most common reason for post-marketing drug withdrawal and a major reason for failure to approve new drugs in the U.S. Although considerably more progress has been made in the study of intrinsic DILI, our understanding of both forms of drug hepatotoxicity remains incomplete. Recent work involving microRNAs (miRNAs) has advanced our knowledge of DILI in two ways: 1) possible roles of miRNAs in the pathophysiological mechanisms of DILI have been identified and 2) circulating miRNA profiles have shown promise for the detection and diagnosis of DILI in clinical settings. The purpose of this review is to summarize major findings in these two areas of research. Taken together, exciting progress has been made in the study of miRNAs in DILI. Possible mechanisms through which miRNA species contribute to the basic mechanisms of DILI are beginning to emerge, and new miRNA-based biomarkers have the potential to greatly improve diagnosis of liver injury and prediction of patient outcomes.

  2. Reversion of pH-Induced Physiological Drug Resistance: A Novel Function of Copolymeric Nanoparticles

    PubMed Central

    Li, Rutian; Xie, Li; Zhu, Zhenshu; Liu, Qin; Hu, Yong; Jiang, Xiqun; Yu, Lixia; Qian, Xiaoping; Guo, Wanhua; Ding, Yitao; Liu, Baorui

    2011-01-01

    Aims The extracellular pH of cancer cells is lower than the intracellular pH. Weakly basic anticancer drugs will be protonated extracellularly and display a decreased intracellular concentration. In this study, we show that copolymeric nanoparticles (NPs) are able to overcome this “pH-induced physiological drug resistance” (PIPDR) by delivering drugs to the cancer cells via endocytosis rather than passive diffussion. Materials and Methods As a model nanoparticle, Tetradrine (Tet, Pka 7.80) was incorporated into mPEG-PCL. The effectiveness of free Tet and Tet-NPs were compared at different extracellular pHs (pH values 6.8 and 7.4, respectively) by MTT assay, morphological observation and apoptotic analysis in vitro and on a murine model by tumor volume measurement, PET-CT scanning and side effect evaluation in vivo. Results The cytotoxicity of free Tet decreased prominently (P<0.05) when the extracellular pH decreased from 7.4 to 6.8. Meanwhile, the cytotoxicity of Tet-NPs was not significantly influenced by reduced pH. In vivo experiment also revealed that Tet-NPs reversed PIPDR more effectively than other existing methods and with much less side effects. Conclusion The reversion of PIPDR is a new discovered mechanism of copolymeric NPs. This study emphasized the importance of cancer microenvironmental factors in anticancer drug resistance and revealed the superiority of nanoscale drug carrier from a different aspect. PMID:21966359

  3. Melatonin enhances L-DOPA therapeutic effects, helps to reduce its dose, and protects dopaminergic neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism in mice.

    PubMed

    Naskar, Amit; Prabhakar, Visakh; Singh, Raghavendra; Dutta, Debashis; Mohanakumar, Kochupurackal P

    2015-04-01

    L-3,4-dihydroxyphenylalanine (L-DOPA) reduces symptoms of Parkinson's disease (PD), but suffers from serious side effects on long-term use. Melatonin (10-30 mg/kg, 6 doses at 10 hr intervals) was investigated to potentiate L-DOPA therapeutic effects in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in mice. Striatal tyrosine hydroxylase (TH) immunoreactivity, TH, and phosphorylated ser 40 TH (p-TH) protein levels were assayed on 7th day. Nigral TH-positive neurons stereology was conducted on serial sections 2.8 mm from bregma rostrally to 3.74 mm caudally. MPTP caused 39% and 58% decrease, respectively, in striatal fibers and TH protein levels, but 2.5-fold increase in p-TH levels. About 35% TH neurons were lost between 360 and 600 ?m from 940 ?m of the entire nigra analyzed, but no neurons were lost between 250 ?m rostrally and 220 ?m caudally. When L-DOPA in small doses (5-8 mg/kg) failed to affect MPTP-induced akinesia or catalepsy, co-administration of melatonin with L-DOPA attenuated these behaviors. Melatonin administration significantly attenuated MPTP-induced loss in striatal TH fibers (82%), TH (62%) and p-TH protein (100%) levels, and nigral neurons (87-100%). Melatonin failed to attenuate MPTP-induced striatal dopamine depletion. L-DOPA administration (5 mg/kg, once 40 min prior to sacrifice, p.o.) in MPTP- and melatonin-treated mice caused significant increase in striatal dopamine (31%), as compared to L-DOPA and MPTP-treated mice. This was equivalent to 8 mg/kg L-DOPA administration in parkinsonian mouse. Therefore, prolonged, effective use of L-DOPA in PD with lesser side effects could be achieved by treating with 60% lower doses of L-DOPA along with melatonin. PMID:25626558

  4. Neuroimaging in Parkinson’s Disease

    Microsoft Academic Search

    A. Jon Stoessl; Pacific Parkinson

    2011-01-01

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

  5. Prophylactic and therapeutic functions of drug combinations against noise-induced hearing loss

    PubMed Central

    Bao, Jianxin; Hungerford, Michelle; Luxmore, Randi; Ding, Dalian; Qiu, Ziyu; Lei, Debin; Yang, Aizhen; Liang, Ruqiang; Ohlemiller, Kevin K.

    2013-01-01

    Noise is the most common occupational and environmental hazard. Noise-induced hearing loss (NIHL) is the second most common form of sensorineural hearing deficit, after age-related hearing loss (presbycusis). Although promising approaches have been identified for reducing NIHL, currently there are no effective medications to prevent NIHL. Development of an efficacious treatment has been hampered by the complex array of cellular and molecular pathways involved in NIHL. We turned this difficulty into an advantage by asking whether NIHL could be effectively prevented by targeting multiple signaling pathways with a combination of drugs already approved by U.S. Food and Drug Administration (FDA). We previously found that antiepileptic drugs blocking T-type calcium channels had both prophylactic and therapeutic effects for NIHL. NIHL can also be reduced by an up-regulation of glucocorticoid (GC) signaling pathways. Based on these findings, we tested a combination therapy for NIHL that included ethosuximide and zonisamide (anticonvulsants) and dexamethasone and methylprednisolone (synthetic GCs) in mice under exposure conditions typically associated with dramatic permanent threshold shifts (PTS). We first examined possible prophylactic effects for each drug when administered alone two hours before noise, and calculated the median effective dose (ED50). We then tested for synergistic effects of two-drug combinations (anticonvulsant + GC), and identified combinations with the strongest synergy against NIHL, based on a previously established combination index (CI) metric. We repeated similar tests to determine their therapeutic effects when administered the same drugs 24 hours after the noise exposure. Our study shows the feasibility of developing pharmacological intervention in multiple pathways, and discovering drug combinations with optimal synergistic effects in preventing permanent NIHL. PMID:23792074

  6. Rotenone, Paraquat, and Parkinson’s Disease

    PubMed Central

    Tanner, Caroline M.; Kamel, Freya; Ross, G. Webster; Hoppin, Jane A.; Goldman, Samuel M.; Korell, Monica; Marras, Connie; Bhudhikanok, Grace S.; Kasten, Meike; Chade, Anabel R.; Comyns, Kathleen; Richards, Marie Barber; Meng, Cheryl; Priestley, Benjamin; Fernandez, Hubert H.; Cambi, Franca; Umbach, David M.; Blair, Aaron; Sandler, Dale P.; Langston, J. William

    2011-01-01

    Background Mitochondrial dysfunction and oxidative stress are pathophysiologic mechanisms implicated in experimental models and genetic forms of Parkinson’s disease (PD). Certain pesticides may affect these mechanisms, but no pesticide has been definitively associated with PD in humans. Objectives Our goal was to determine whether pesticides that cause mitochondrial dysfunction or oxidative stress are associated with PD or clinical features of parkinsonism in humans. Methods We assessed lifetime use of pesticides selected by mechanism in a case–control study nested in the Agricultural Health Study (AHS). PD was diagnosed by movement disorders specialists. Controls were a stratified random sample of all AHS participants frequency-matched to cases by age, sex, and state at approximately three controls: one case. Results In 110 PD cases and 358 controls, PD was associated with use of a group of pesticides that inhibit mitochondrial complex I [odds ratio (OR) = 1.7; 95% confidence interval (CI), 1.0–2.8] including rotenone (OR = 2.5; 95% CI, 1.3–4.7) and with use of a group of pesticides that cause oxidative stress (OR = 2.0; 95% CI, 1.2–3.6), including paraquat (OR = 2.5; 95% CI, 1.4–4.7). Conclusions PD was positively associated with two groups of pesticides defined by mechanisms implicated experimentally—those that impair mitochondrial function and those that increase oxidative stress—supporting a role for these mechanisms in PD pathophysiology. PMID:21269927

  7. Sensorimotor adaptation of speech in Parkinson’s disease

    PubMed Central

    Mollaei, Fatemeh; Shiller, Douglas M.; Gracco, Vincent L.

    2013-01-01

    Background The basal ganglia (BG) are involved in establishing motor plans for a wide range of behaviors. Parkinson’s disease (PD) is a manifestation of basal ganglia dysfunction associated with a deficit in sensorimotor integration and difficulty in acquiring new motor sequences, thereby affecting motor learning. Previous studies of sensorimotor integration and sensorimotor adaptation (SA) in PD have focused on limb movements using visual and force-field alterations.1–4 Methods Here we report the results from a SA experiment investigating the ability of PD patients to make speech motor adjustments to a constant and predictable auditory feedback manipulation. Participants produced speech while their auditory feedback was altered and maintained in a manner consistent with a change in tongue position. The degree of adaptation was associated with the severity of motor symptoms. Results The PD patients exhibited adaptation to the induced sensory error, however the degree of adaptation was reduced compared to healthy age-matched control participants. Conclusions The reduced capacity to adapt to a change in auditory feedback is consistent with reduced gain in the sensorimotor system for speech and with previous studies demonstrating limitations in the adaptation of limb movements following changes in visual feedback in PD patients. PMID:23861349

  8. Mitochondrial dysfunction and oxidative stress in Parkinson’s disease

    PubMed Central

    Subramaniam, Sudhakar Raja; Chesselet, Marie-Francoise

    2013-01-01

    Parkinson’s disease is a movement disorder that is characterized by the progressive degeneration of dopaminergic neurons in substantia nigra pars compacta resulting in dopamine deficiency in the striatum. Although majority of the PD cases are sporadic several genetic mutations have also been linked to the disease thus providing new opportunities to study the pathology of the illness. Studies in humans and various animal models of PD reveal that mitochondrial dysfunction might be a defect that occurs early in PD pathogenesis and appears to be a widespread feature in both sporadic and monogenic forms of PD. The general mitochondrial abnormalities linked with the disease include mitochondrial electron transport chain impairment, alterations in mitochondrial morphology and dynamics, mitochondrial DNA mutations and anomaly in calcium homeostasis. Mitochondria are vital organelles with multiple functions and their dysfunction can lead to a decline in energy production, generation of reactive oxygen species and induction of stress-induced apoptosis. In this review, we give an outline of mitochondrial functions that are affected in the pathogenesis of sporadic and familial PD, and hence provide insights that might be valuable for focused future research to exploit possible mitochondrial targets for neuroprotective interventions in PD. PMID:23643800

  9. ? - synuclein and Parkinson’s disease: the first roadblock

    PubMed Central

    Lin Chua, Christelle En; Tang, Bor Luen

    2006-01-01

    ?-synuclein gene mutations are major underlying genetic defects known in familial juvenile onset Parkinson’s disease (PD), and ?-synuclein is a major constituent of Lewy Bodies, the pathological hallmark of PD. The normal cellular function of ?-synuclein has been elusive, and its exact etiological mechanism in causing dopaminergic neuronal death in PD is also not clearly understood. Very recent reports now indicate that mutant or simply over-expressed ?-synuclein could cause damage by interfering with particular steps of neuronal membrane traffic. ?-synuclein selectively blocks endoplamic reticulum-to-Golgi transport, thus causing ER stress. A screen in a yeast revealed that ?-synuclein toxicity could be suppressed by over-expression of the small GTPase Ypt1/Rab1, and that over-expression of the latter rescues neuron loss in invertebrate and mammalian models of ?-synuclein-induced neurodegeneration. ?-synuclein may also serve a chaperone function for the proper folding of synaptic SNAREs that are important for neurotransmitter release. We discuss these recent results and the emerging pathophysiological interaction of ?-synuclein with components of neuronal membrane traffic.

  10. Parkinson's disease and the skin.

    PubMed

    Gregory, Ralph; Miller, Sarah

    2015-08-01

    The concept that the skin is a mirror of Parkinson's disease dates to the start of the last century. Despite dermatological disorders being recognised as a common non-motor symptom of Parkinson's disease, they are often overlooked. This article reviews the various skin disorders seen in Parkinson's disease and addresses the other dermatological questions that are frequently raised by those attending Parkinson's disease clinics. PMID:25862733

  11. Gait festination in Parkinson's disease

    Microsoft Academic Search

    N Giladi; H Shabtai; E Rozenberg; E Shabtai

    2001-01-01

    Background: Festinating gait (FSG) was first associated with parkinsonism by Sir James Parkinson, in his original essay on “The Shaking Palsy”. Its frequency and relation to other parkinsonian features have never been assessed.Objective: To study the relationships between gait festination and other parkinsonian clinical features among patients with Parkinson's disease (PD).Method: During an open lecture to patients with PD who

  12. Pharmacological stimulation of metabotropic glutamate receptor type 4 in a rat model of Parkinson's disease and l-DOPA-induced dyskinesia: Comparison between a positive allosteric modulator and an orthosteric agonist.

    PubMed

    Iderberg, Hanna; Maslava, Natallia; Thompson, Analisa D; Bubser, Michael; Niswender, Colleen M; Hopkins, Corey R; Lindsley, Craig W; Conn, P Jeffrey; Jones, Carrie K; Cenci, M Angela

    2015-08-01

    Metabotropic glutamate receptor 4 (mGlu4) negatively modulates GABA and glutamate release in the 'indirect pathway' of the basal ganglia, and has thus been proposed as a potential target to treat motor symptoms in Parkinson's disease. Here, we present an extensive comparison of the behavioural effects produced by the mGlu4 positive allosteric modulator (PAM), VU0364770, and the mGlu4 orthosteric agonist, LSP1-2111, in rats with unilateral 6-OHDA lesions. The compounds' activity was initially assessed in a test of haloperidol-induced catalepsy in intact rats, and effective doses were then evaluated in the hemiparkinsonian animal model. Neither of the two compounds modified the development of dyskinetic behaviours elicited by chronic treatment with full doses of l-DOPA. When given together with l-DOPA to rats with already established dyskinesias, neither VU0364770 nor LSP1-2111 modified the abnormal involuntary movement scores. VU0364770 potentiated, however, the motor stimulant effect of a subthreshold l-DOPA dose in certain behavioural tests, whereas LSP1-2111 lacked this ability. Taken together, these results indicate that a pharmacological stimulation of mGlu4 lacks intrinsic antidyskinetic activity, but may have DOPA-sparing activity in Parkinson's disease. For the latter indication, mGlu4 PAMs appear to provide a better option than orthosteric agonists. PMID:25749357

  13. Pharmacogenetic testing in idiosyncratic drug-induced liver injury: current role in clinical practice.

    PubMed

    Aithal, Guruprasad P

    2015-07-01

    In contrast to the studies that have explored association of genetic variants with other complex traits, those investigating hepatotoxicity have identified risk alleles with substantially higher risk ratios for the susceptibility to drug-induced liver injury (DILI). In addition, a relatively small number of human leukocyte antigen (HLA) alleles have overlapping associations with a variety of adverse reactions including DILI, cutaneous hypersensitivity and drug-induced pancreatitis. However, if used as a test prior to prescription to prevent potential adverse reaction, genotyping would have a very high negative predictive value, yet a low positive predictive value based on the low incidence of DILI. One potential consideration is to treat all relevant HLA genotypes as one panel covering different forms of adverse drug reactions, thereby improving the positive predictive value of the panel and widen its application. The majority of HLA alleles associated with DILI have a very high negative predictive value; therefore, they can be used to rule out hepatotoxicity caused by particular drugs. A high negative predictive value of a genetic test can be used to identify the correct agent underlying DILI when the patient had been exposed to two concomitant medications with a potential to cause DILI. Inclusion of genetic tests in the causality assessment of an event, where DILI is suspected, may improve consistency and precision of causality assessment tools. A recent clinical trial used N-acetyltransferase 2 genotyping to determine the appropriate dose of isoniazid in an anti-tuberculosis therapeutic regimen and demonstrated that pharmacogenetic-based clinical algorithms have the potential to improve efficacy of a drug and to reduce DILI. PMID:25809692

  14. Drug-induced hypersensitivity syndrome associated with Epstein-Barr virus infection.

    PubMed

    Descamps, V; Mahe, E; Houhou, N; Abramowitz, L; Rozenberg, F; Ranger-Rogez, S; Crickx, B

    2003-05-01

    Association of drug-induced hypersensitivity syndrome with viral infection is debated. Human herpesvirus 6 (HHV-6) reactivation has been the most frequently reported infection associated with this syndrome. However, a case of cytomegalovirus (CMV) infection was recently described associated with anticonvulsant-induced hypersensitivity syndrome. We report a case of severe allopurinol-induced hypersensitivity syndrome with pancreatitis associated with Epstein-Barr virus (EBV) infection. Active EBV infection was demonstrated in two consecutive serum samples by the presence of anti-EBV early antigen (EA) IgM antibodies and an increase in anti-EBV EA IgG antibodies, whereas no anti-EBV nuclear antigen IgG antibodies were detected. EBV DNA was detected by polymerase chain reaction (PCR) in peripheral blood mononuclear cells. Reactivation of HHV-6 was suggested only by the presence of anti-HHV-6 IgM antibodies, but HHV-6 DNA was not detected by PCR in the serum. Other viral investigations showed previous infection (CMV, rubella, measles, parvovirus B19), immunization after vaccination (hepatitis B virus), or absence of previous infection (hepatitis C virus, human immunodeficiency virus). We suggest that EBV infection may participate in some cases, as do the other herpesviruses HHV-6 or CMV, in the development of drug-induced hypersensitivity syndrome. PMID:12786838

  15. Intense pseudotransport of a cationic drug mediated by vacuolar ATPase: procainamide-induced autophagic cell vacuolization.

    PubMed

    Morissette, Guillaume; Lodge, Robert; Marceau, François

    2008-05-01

    Cationic drugs frequently exhibit large apparent volumes of distribution, consistent with various forms of cellular sequestration. The contributions of organelles and metabolic processes that may mimic drug transport were defined in human vascular smooth muscle cells. We hypothesized that procainamide-induced vacuolar cytopathology is driven by intense pseudotransport mediated by the vacuolar (V)-ATPase and pursued the characterization of vesicular trafficking alterations in this model. Large amounts of procainamide were taken up by intact cells (maximal in 2 h, reversible upon washout, apparent KM 4.69 mM; fluorometric determination of cell-associated drug). Procainamide uptake was extensively prevented or reversed by pharmacological inhibition of the V-ATPase with bafilomycin A1 or FR 167356, decreased at low extracellular pH and preceded vacuolar cell morphology. However, the uptake of procainamide was unaffected by mitochondrial poisons that reduced the uptake of rhodamine 6G. Large vacuoles induced by millimolar procainamide were labeled with the late endosome/lysosome markers Rab7 and CD63 and the autophagy effector LC3; their osmotic formation (but not procainamide uptake) was reduced by extracellular mannitol and parallel to LC3 II formation. Procainamide-induced vacuolization is associated with defective endocytosis of fluorophore-labeled bovine serum albumin, but not with induction of the unfolded protein response. The contents of a vacuole subset slowly (> or =24 h) become positive for Nile red staining (phospholipidosis-like response). V-ATPase-driven ion trapping is a form of intense cation pseudotransport that concerns the uncharged form of the drugs, and is associated with a vacuolar, autophagic and evolutive cytopathology and profound effects on vesicular trafficking. PMID:18295291

  16. Intense pseudotransport of a cationic drug mediated by vacuolar ATPase: Procainamide-induced autophagic cell vacuolization

    SciTech Connect

    Morissette, Guillaume [Centre de recherche en Rhumatologie et Immunologie, Centre Hospitalier Universitaire de Quebec, Quebec QC, G1V 4G2 (Canada); Centre de recherche en Rhumatologie et Immunologie, Centre Hospitalier Universitaire de Quebec, Quebec QC, G1V 4G2 (Canada); Lodge, Robert [Centre de recherche en Infectiologie, Centre Hospitalier Universitaire de Quebec, Quebec QC, G1V 4G2 (Canada); Marceau, Francois [Centre de recherche en Rhumatologie et Immunologie, Centre Hospitalier Universitaire de Quebec, Quebec QC, G1V 4G2 (Canada); Centre de recherche en Rhumatologie et Immunologie, Centre Hospitalier Universitaire de Quebec, Quebec QC, G1V 4G2 (Canada)], E-mail: francois.marceau@crchul.ulaval.ca

    2008-05-01

    Cationic drugs frequently exhibit large apparent volumes of distribution, consistent with various forms of cellular sequestration. The contributions of organelles and metabolic processes that may mimic drug transport were defined in human vascular smooth muscle cells. We hypothesized that procainamide-induced vacuolar cytopathology is driven by intense pseudotransport mediated by the vacuolar (V)-ATPase and pursued the characterization of vesicular trafficking alterations in this model. Large amounts of procainamide were taken up by intact cells (maximal in 2 h, reversible upon washout, apparent K{sub M} 4.69 mM; fluorometric determination of cell-associated drug). Procainamide uptake was extensively prevented or reversed by pharmacological inhibition of the V-ATPase with bafilomycin A1 or FR 167356, decreased at low extracellular pH and preceded vacuolar cell morphology. However, the uptake of procainamide was unaffected by mitochondrial poisons that reduced the uptake of rhodamine 6G. Large vacuoles induced by millimolar procainamide were labeled with the late endosome/lysosome markers Rab7 and CD63 and the autophagy effector LC3; their osmotic formation (but not procainamide uptake) was reduced by extracellular mannitol and parallel to LC3 II formation. Procainamide-induced vacuolization is associated with defective endocytosis of fluorophore-labeled bovine serum albumin, but not with induction of the unfolded protein response. The contents of a vacuole subset slowly ({>=} 24 h) become positive for Nile red staining (phospholipidosis-like response). V-ATPase-driven ion trapping is a form of intense cation pseudotransport that concerns the uncharged form of the drugs, and is associated with a vacuolar, autophagic and evolutive cytopathology and profound effects on vesicular trafficking.

  17. Prediction of phospholipidosis-inducing potential of drugs by in vitro biochemical and physicochemical assays followed by multivariate analysis.

    PubMed

    Kuroda, Yukihiro; Saito, Madoka

    2010-03-01

    An in vitro method to predict phospholipidosis-inducing potential of cationic amphiphilic drugs (CADs) was developed using biochemical and physicochemical assays. The following parameters were applied to principal component analysis, as well as physicochemical parameters: pK(a) and clogP; dissociation constant of CADs from phospholipid, inhibition of enzymatic phospholipid degradation, and metabolic stability of CADs. In the score plot, phospholipidosis-inducing drugs (amiodarone, propranolol, imipramine, chloroquine) were plotted locally forming the subspace for positive CADs; while non-inducing drugs (chlorpromazine, chloramphenicol, disopyramide, lidocaine) were placed scattering out of the subspace, allowing a clear discrimination between both classes of CADs. CADs that often produce false results by conventional physicochemical or cell-based assay methods were accurately determined by our method. Basic and lipophilic disopyramide could be accurately predicted as a nonphospholipidogenic drug. Moreover, chlorpromazine, which is often falsely predicted as a phospholipidosis-inducing drug by in vitro methods, could be accurately determined. Because this method uses the pharmacokinetic parameters pK(a), clogP, and metabolic stability, which are usually obtained in the early stages of drug development, the method newly requires only the two parameters, binding to phospholipid, and inhibition of lipid degradation enzyme. Therefore, this method provides a cost-effective approach to predict phospholipidosis-inducing potential of a drug. PMID:19786086

  18. Two cases of amiodarone-induced thyrotoxicosis successfully treated with a short course of antithyroid drugs while amiodarone was continued.

    PubMed Central

    Trip, M D; Düren, D R; Wiersinga, W M

    1994-01-01

    Two patients with amiodarone-induced thyrotoxicosis were treated successfully with potassium perchlorate and carbimazole while treatment with amiodarone was continued. These antithyroid drugs were stopped after the patients had became clinically and biochemically euthyroid. During follow up, when treatment with amiodarone continued, thyrotoxicosis did not recur. Amiodarone-induced thyrotoxicosis seems to be a transient condition that can be treated successfully with a short course of antithyroid drugs without stopping amiodarone treatment. PMID:7946779

  19. Phenotypic screens for compounds that target the cellular pathologies underlying Parkinson’s Disease

    PubMed Central

    Tardiff, Daniel F.; Lindquist, Susan

    2012-01-01

    Parkinson’s Disease (PD) is a devastating neurodegenerative disease that affects over one million patients in the US. Yet, no disease modifying drugs exist, only those that temporarily alleviate symptoms. Because of its poorly defined and highly complex disease etiology, it is essential to embrace unbiased and innovative approaches for identifying new chemical entities that target the underlying toxicities associated with PD. Traditional target-based drug discovery paradigm can suffer from a bias towards a small number of potential targets. Phenotypic screening of both genetic and pharmacological PD models offers an alternative approach to discover compounds that target the initiating causes and effectors of cellular toxicity. The relative paucity of reported phenotypic screens illustrates the intrinsic difficulty in establishing model systems that are both biologically meaningful and adaptable to high-throughput screening. Parallel advances in PD models and in vivo screening technologies will help create opportunities for identifying new therapeutic leads with unanticipated, breakthrough mechanisms of action. PMID:23644949

  20. Detecting drug-induced prolongation of the QRS complex: New insights for cardiac safety assessment

    SciTech Connect

    Cros, C., E-mail: caroline.cros@hotmail.co.uk [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom); Skinner, M., E-mail: Matthew.Skinner@astrazeneca.com [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom); Moors, J. [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom)] [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom); Lainee, P. [Sanofi-Aventis R and D, 371, rue du Pr Joseph Blayac, 34184 Montpellier Cedex 04 (France)] [Sanofi-Aventis R and D, 371, rue du Pr Joseph Blayac, 34184 Montpellier Cedex 04 (France); Valentin, J.P. [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom)] [Safety Pharmacology, Global Safety Assessment, Safety Assessment UK, AstraZeneca R and D, Alderley Park, Macclesfield, SK10 4TG (United Kingdom)

    2012-12-01

    Background: Drugs slowing the conduction of the cardiac action potential and prolonging QRS complex duration by blocking the sodium current (I{sub Na}) may carry pro-arrhythmic risks. Due to the frequency-dependent block of I{sub Na}, this study assesses whether activity-related spontaneous increases in heart rate (HR) occurring during standard dog telemetry studies can be used to optimise the detection of class I antiarrhythmic-induced QRS prolongation. Methods: Telemetered dogs were orally dosed with quinidine (class Ia), mexiletine (class Ib) or flecainide (class Ic). QRS duration was determined standardly (5 beats averaged at rest) but also prior to and at the plateau of each acute increase in HR (3 beats averaged at steady state), and averaged over 1 h period from 1 h pre-dose to 5 h post-dose. Results: Compared to time-matched vehicle, at rest, only quinidine and flecainide induced increases in QRS duration (E{sub max} 13% and 20% respectively, P < 0.01–0.001) whereas mexiletine had no effect. Importantly, the increase in QRS duration was enhanced at peak HR with an additional effect of + 0.7 ± 0.5 ms (quinidine, NS), + 1.8 ± 0.8 ms (mexiletine, P < 0.05) and + 2.8 ± 0.8 ms (flecainide, P < 0.01) (calculated as QRS at basal HR-QRS at high HR). Conclusion: Electrocardiogram recordings during elevated HR, not considered during routine analysis optimised for detecting QT prolongation, can be used to sensitise the detection of QRS prolongation. This could prove useful when borderline QRS effects are detected. Analysing during acute increases in HR could also be useful for detecting drug-induced effects on other aspects of cardiac function. -- Highlights: ? We aimed to improve detection of drug-induced QRS prolongation in safety screening. ? We used telemetered dogs to test class I antiarrhythmics at low and high heart rate. ? At low heart rate only quinidine and flecainide induced an increase in QRS duration. ? At high heart rate the effects of two out of three antiarrhythmics were enhanced. ? Detection of a drug-induced prolongation of QRS was improved at high heart rate.

  1. Cancer-drug induced insulin resistance: innocent bystander or unusual suspect.

    PubMed

    Ariaans, G; de Jong, S; Gietema, J A; Lefrandt, J D; de Vries, E G E; Jalving, M

    2015-04-01

    Epidemiological and experimental evidence strongly suggests an association between type 2 diabetes mellitus and cancer. Insulin resistance, causing hyperinsulinaemia and eventually hyperglycaemia, appears to increase cancer incidence and disease progression. In addition, insulin resistance seems to reduce the efficacy of cancer therapy. Treatment with cancer therapeutics such as glucocorticoids, chemotherapy, hormonal therapies and targeted drugs can actually induce insulin resistance. The question arises whether cancer-therapy induced insulin resistance impairs anticancer treatment efficacy and disease outcome. Here, we review current literature regarding the incidence of cancer-therapy induced insulin resistance and describe the systemic and extra- and intracellular changes that occur in insulin signalling pathways and glucose metabolism. Subsequently, clinical and preclinical evidence for consequences of insulin resistance in terms of cancer progression and survival is presented. Finally, potential interventions including diabetes medication and limiting energy availability through diets and exercise are discussed. PMID:25724262

  2. Drug-loaded nanoparticles induce gene expression in human pluripotent stem cell derivatives

    PubMed Central

    Gajbhiye, Virendra; Escalante, Leah; Chen, Guojun; Laperle, Alex; Zheng, Qifeng; Steyer, Benjamin; Gong, Shaoqin; Saha, Krishanu

    2014-01-01

    Tissue engineering and advanced manufacturing of human stem cells requires a suite of tools to control gene expression spatiotemporally in culture. Inducible gene expression systems offer cell-extrinsic control, typically through addition of small molecules, but small molecule inducers typically contain few functional groups for further chemical modification. Doxycycline (DXC), a potent small molecule inducer of tetracycline (Tet) transgene systems, was conjugated to a hyperbranched dendritic polymer (Boltorn H40) and subsequently reacted with polyethylene glycol (PEG). The resulting PEG-H40-DXC nanoparticle exhibited pH-sensitive drug release behavior and successfully controlled gene expression in stem-cell-derived fibroblasts with a Tet-On system. While free DXC inhibited fibroblast proliferation and matrix metalloproteinase (MMP) activity, PEG-H40-DXC nanoparticles maintained higher fibroblast proliferation levels and MMP activity. The results demonstrate that the PEG-H40-DXC nanoparticle system provides an effective tool to controlling gene expression in human stem cell derivatives. PMID:24232694

  3. Quantitative profiling of caspase-cleaved substrates reveals different drug-induced and cell-type patterns in apoptosis

    PubMed Central

    Shimbo, Kazutaka; Hsu, Gerald W.; Nguyen, Huy; Mahrus, Sami; Trinidad, Jonathan C.; Burlingame, Alma L.; Wells, James A.

    2012-01-01

    Proapoptotic drugs are a mainstay of cancer drug treatment. These drugs stress cells and ultimately trigger the activation of caspases, cysteine-class proteases that cleave after aspartic acid and deconstruct the cell. It is well known that cells respond differently to proapoptotic cancer drug treatments. Here, using a global and unbiased quantitative N-terminomics technology, we show that ?500 products of caspase cleavage and their kinetics vary dramatically between cell type and cytotoxic drug treatment. It is likely that variations arise from differences in baseline proteome composition of the cell type and the alterations induced by drug treatments to yield a unique cohort of proteins that caspases finally target. Many targets are specific to both drug treatment and cell type, providing candidate-specific biomarkers for apoptosis. For example, in multiple myeloma cells treated with the proteasome inhibitor bortezomib, levels of activating transcription factor-4 increase dramatically early in drug treatment and then decrease upon cleavage by activated caspases. Thus, caspase-derived cleavage products are a sensitive reflection of cell-type and drug-induced stress, and provide useful fingerprints for mechanisms of drug action and response. PMID:22802652

  4. [Psychotropic drugs induced weight gain: a review of the literature concerning epidemiological data, mechanisms and management].

    PubMed

    Ruetsch, O; Viala, A; Bardou, H; Martin, P; Vacheron, M N

    2005-01-01

    Weight gain is associated with the use of many psychotropic medications, including antidepressants, mood stabilizers, antipsychotic drugs, and may have serious long term consequences: it can increase health risks, specifically from overweight (BMI = 25-29.9 kg/m2) to obesity (BMI > or =30 kg/m2), according to Body Mass Index (BMI), and the morbidity associated therewith in a substantial part of patients (hypertension, coronary heart desease, ischemic stroke, impaired glucose tolerance, diabetes mellitus, dyslipidemia, respiratory problems, osteoarthritis, cancer); according to patients, psychosocial consequences such as a sense of demoralization, physical discomfort and being the target of substantial social stigma are so intolerable that they may discontinue the treatment even if it is effective. The paper reviews actual epidemiological data concerning drug induced weight gain and associated health problems in psychiatric patients : there is a high risk of overweight, obesity, impaired glucose tolerance, diabetes mellitus, premature death, in patients with schizophrenia or bipolar disorder; and the effects of specific drugs on body weight: Tricyclic Antidepressants (TCA) induced weight gain correlated positively with dosage and duration of treatment, more pronounced with amitriptyline ; Selective Serotonin Reuptake Inhibitors (SSRI) decrease transiently bodyweight during the first few weeks of treatment and may then increase bodyweight; weight gain appears to be most prominent with some mood stabilizers (lithium, valproate); atypical antipsychotics tend to cause more weight gain than conventional ones and weight gain, diabetes, dyslipidemia, seem to be most severe with clozapine and olanzapine. Conceming the underlying mechanisms of drug induced weight gain, medications might interfere with central nervous functions regulating energy balance; patients report about: increase of appetite for sweet and fatty foods or "food craving" (antidepressants, mood stabilizers, antipsychotic drugs) and weight gain despite reduced appetite which can be explained by an altered resting metabolic rate (TCA, SSRI, Monoaminoxidase Inhibitors MAO I). According to current concepts, appetite and feeding are regulated by a complex of neurotransmitters, neuromodulators, cytokines and hormones interacting with the hypothalamus, including the leptin and the tumor necrosis factor system. The pharmacologic mechanisms underlying weight gain are presently poorly understood: maybe the different activities at some receptor systems may induce it, but also genetic predisposition. Understanding of the metabolic consequences of psychotropic drugs (weight gain, diabetes, dyslipidemia) is essential: the insulin-like effect of lithium is known; treatment with antipsychotic medications increases the risk of impaired glucose tolerance and diabetes mellitus. Several management options of weight gain are available from choosing or switching to another drug, dietary advices, increasing physical activities, behavioural treatment, but the best approach seems to attempt to prevent the weight gain : patients beginning maintenance therapy should be informed of that risk, and nutritional assessment and counselling should be a routine part of treatment management, associated with monitoring of weight, BMI, blood pressure, biological parameters (baseline and three months monitoring of fasting glucose level, fasting cholesterol and triglyceride levels, glycosylated haemoglobin). Psychiatrics must pay attention to concomitant medications and individual factors underlying overweight and obesity. Weight gain has been described since the discovery and the use of the firstpsychotropic drugs, but seems to intensify with especially some of the second generation antipsychotic medications ; understanding of the side effects of psychotropic drugs, including their metabolic consequences (weight gain, diabetes, dyslipidemia) is essential for the psychiatrics to avoid on the one hand a risk of lack of compliance, a discontinuation of the pharmacological medication and also

  5. BCL2 Expression Delays Drug-induced Apoptosis but Does Not Increase Clonogenic Survival after Drug Treatment in HeLa Cells1

    Microsoft Academic Search

    Dong X. Yin; Robert T. Schimke

    1995-01-01

    Apoptosis is a major form of cell death induced by chemotherapeutic drugs. Overexpression of the proto-oncogene bcl-2 can prevent apoptosis in various types of cells. We have constructed a HeLa S3 cell line in which the expression of bcl-2 can be controlled by the concentration of tetracy- cline in the medium. Using this system, we show that apoptosis induced by

  6. Methodology for the development of a drug library based upon collision-induced fragmentation for the identification of toxicologically relevant drugs in plasma samples

    Microsoft Academic Search

    A. G. A. M Lips; W Lameijer; R. H Fokkens; N. M. M Nibbering

    2001-01-01

    The possibility of creating a robust mass spectral library with use of high-performance liquid chromatography–atmospheric pressure–electrospray ionization (HPLC–AP–ESI) for the identification of drugs misused in cases of clinical toxicology has been examined. Factors reported as influencing the fragmentation induced by “source transport region collision induced dissociation” (CID) have been tested in this study (i.e. solvent, pH, different acids or buffer

  7. Cutaneous adverse drug reaction type erythema multiforme major induced by eslicarbazepine

    PubMed Central

    Massot, Andreu; Gimenez-Arnau, Ana

    2014-01-01

    Severe skin reactions occur less frequently with eslicarbazepine (ESL) than with the other aromatic anticonvulsants. We report the first case of cutaneous adverse drug reaction (CADR) to ESL and co-sensitization between ESL and betalactams. A 41-year-old white woman developed focal epilepsy due to a meningioma that was removed. As post-operatory complication, she suffered meningitis as well as a maculo-papular erythema caused by the treatment with meropenem. Subsequently, ESL was started and gradually increased until 800 mg/day. Twenty-five days later, the patient developed an Erythema Multiforme Major (EMM). Strong positive immediate reaction was induced by prick test with carbamazepine (CBZ) and ESL at 0.01 and 0.1% within 15 and 30 minutes; however the delayed reading at 48 hours was negative. The patient was not carrier of the HLA alleles A3101 and B1502 associated with CBZ induced EMM. The hypersensitivity pathogenic mechanism of EMM is unclear and a delayed hypersensitivity process is speculated. However, the patch and intradermal tests in our patient did not show a delayed reaction but an immediate cutaneous one. A first allergic episode may elicit a massive nonspecific activation of the immune system, providing an enhanced expression of co-stimulatory molecules that decreases the level of tolerance to other drugs. When prescribing ESL, we suggest ruling out previous CADR, especially to CBZ and oxcarbazepine but also other chemically unrelated drugs such as beta-lactams. PMID:25422574

  8. Twelve cases of drug-induced blepharospasm improved within 2 months of psychotropic cessation

    PubMed Central

    Emoto, Yuko; Emoto, Hirofumi; Oishi, Eriko; Hikita, Syunichi; Wakakura, Masato

    2011-01-01

    Background: To determine whether psychotropic cessation in patients with drug-induced blepharospasm improves motor symptoms. Methods: In patients with drug-induced blepharospasm, we withdrew part or all of their psychotropic medication and assessed motor symptoms using the Jankovic rating scale (0 = none, 1 = noticeable, 2 = mild, 3 = moderate, 4 = severe) at first presentation and after cessation. Results: Twelve patients (eleven women and one man, mean age 60.4 years) were enrolled. Psychotropics were administered before the onset of blepharospasm in all patients. The mean duration of treatment with psychotropic medication was 47.3 (range 3–120) months. Jankovic rating scale at initial presentation was 3 in eleven patients and 2 in one patient. After cessation, blepharospasm started to improve in all cases within 2 months (average 3.9 weeks). While the effect of psychotropic cessation was variable, the symptoms eventually improved to more than 2 on the rating scale. Three of the twelve patients underwent a single botulinum neurotoxin injection and were withdrawn from therapy after cessation. Conclusion: Psychotropic drugs can cause blepharospasm in some cases. Clinicians should consider reducing psychotropic medication as far as possible in patients with blepharospasm taking these agents. PMID:21753898

  9. Drug-induced liver injury due to varenicline: a case report

    PubMed Central

    2012-01-01

    Background Liver injury due to prescription and nonprescription medications is an expanding public health concern in the United States, with drug-induced liver injury (DILI) being the single most common reason for regulatory actions instituted by the Food and Drug Administration against certain medications and supplements. Case presentation A 69-year-old Latino man was referred to Hepatology Clinic for urgent evaluation of new onset jaundice, nausea and fatigue associated with a >40-fold increase in his transaminase levels and elevated INR and alkaline phosphatase. The patient had received a new prescription for varenicline to aid with smoking cessation approximately 3 weeks prior to his evaluation in Hepatology Clinic. Within 5?days of starting the varenicline, the patient developed new onset of nausea, vomiting, malaise and deep jaundice. The varenicline was discontinued on day 5 by the patient. Hepatologic evaluation revealed no evidence of acute viral hepatitis, autoimmune, metabolic or alcohol-related liver disorders. The patient’s past medical history was notable, however, for chronic hepatitis C. His liver enzymes and synthetic function completely normalized 9?weeks after discontinuation of the varenicline. Conclusion This report represents the second documented cases of drug-induced liver injury related to varenicline therapy, highlighting the need for clinician awareness regarding potential hepatotoxicity of varenicline, particularly among patients with pre-existing liver disease. PMID:22681894

  10. FXR antagonism of NSAIDs contributes to drug-induced liver injury identified by systems pharmacology approach

    PubMed Central

    Lu, Weiqiang; Cheng, Feixiong; Jiang, Jing; Zhang, Chen; Deng, Xiaokang; Xu, Zhongyu; Zou, Shien; Shen, Xu; Tang, Yun; Huang, Jin

    2015-01-01

    Non-steroidal anti-inflammatory drugs (NSAIDs) are worldwide used drugs for analgesic, antipyretic, and anti-inflammatory therapeutics. However, NSAIDs often cause several serious liver injuries, such as drug-induced liver injury (DILI), and the molecular mechanisms of DILI have not been clearly elucidated. In this study, we developed a systems pharmacology approach to explore the mechanism-of-action of NSAIDs. We found that the Farnesoid X Receptor (FXR) antagonism of NSAIDs is a potential molecular mechanism of DILI through systematic network analysis and in vitro assays. Specially, the quantitative real-time PCR assay reveals that indomethacin and ibuprofen regulate FXR downstream target gene expression in HepG2 cells. Furthermore, the western blot shows that FXR antagonism by indomethacin induces the phosphorylation of STAT3 (signal transducer and activator of transcription 3), promotes the activation of caspase9, and finally causes DILI. In summary, our systems pharmacology approach provided novel insights into molecular mechanisms of DILI for NSAIDs, which may propel the ways toward the design of novel anti-inflammatory pharmacotherapeutics. PMID:25631039

  11. Probing the anticancer-drug-binding-induced microenvironment alterations in subdomain IIA of human serum albumin.

    PubMed

    Xu, Xiaoqing; Qian, Yingdan; Wu, Ping; Zhang, Hui; Cai, Chenxin

    2015-05-01

    The binding interaction of anticancer drug (using 5-fluorouracil (FU) as an example) with the model protein human serum albumin (HSA), and the FU-binding-induced microenvironment alterations in subdomain IIA of HSA molecule were studied by a combination of spectroscopic techniques and molecular docking method. The results indicated that the nature of forces involved in binding interaction between HSA and FU molecule were mainly van der Waal's forces and hydrogen bonding interactions. These interactions resulted in the formation of FU-HSA complex, making the local microenvironment in subdomain IIA of the protein more hydrophobic than its native state. Moreover, the interaction caused the large conformation changes of HSA, leading to the increase of the compact ?-helix structures at low concentration of FU (less than 150 ?M). However, the high concentration of FU (higher than 150 ?M) made the compact ?-helix structure decreasing, probably due to the protein undergoing some sort of distortion. Molecular docking study revealed that FU could enter the inside a hydrophobic cavity of subdomain IIA (Sudlow's site I) in proximity of Trp214 residue with the formation of specific hydrogen bonding with Trp214 and Lys199 residues, causing the fluorescence quenching of Trp214 through a static quenching mechanism. The study essentially provides an effective way for investigating the microenvironment alterations of protein induced by the drug molecules, and this approach can further be used in development of biomedicines and assessment of the safety-engineered drug delivery. PMID:25612933

  12. Dynamic in vivo analysis of drug induced actin cytoskeleton degradation by digital holographic microscopy

    NASA Astrophysics Data System (ADS)

    Schnekenburger, Juergen; Bredebusch, Ilona; Langehanenberg, Patrik; Domschke, Wolfram; von Bally, Gert; Kemper, Björn

    2007-07-01

    The actin cytoskeleton mediates a variety of crucial cellular functions as migration, intracellular transport, exocytosis, endocytosis and force generation. The highly dynamic actin fibers are therefore targets for several drugs and toxins. However the study of actin interfering processes by standard microscopy techniques fails in the detailed resolution of dynamic spatial alterations required for a deeper understanding of toxic effects. Here we applied digital holographic microscopy in the online functional analysis of the actin cytoskeleton disrupting marine toxin Latrunculin B. SEM and fluorescence microscopy showed rapid Latrunculin B induced alterations in cell morphology and actin fiber degradation in pancreas tumor cells. The dynamic digital holographic in vivo analysis of the drug dependent cellular processes demonstrated differences in the actin cytoskeleton stability of highly differentiated and dedifferentiated pancreas tumor cell lines. The spatial resolution of the morphological alterations revealed unequal changes in cell morphology. While cells with a low metastatic potential showed Latrunculin B induced cell collapse within 4 h the metastatic tumor cells were increased in cell volume indicating Latrunculin B effects also on cell water content. These data demonstrate that marker free, non-destructive online analysis of cellular morphology and dynamic spatial processes in living cells by digital holography offers new insights in actin dependent cellular mechanisms. Digital holographic microscopy was shown to be a versatile tool in the screening of toxic drug effects and cancer cell biology.

  13. Induced pluripotent stem cell-derived cardiomyocytes for cardiovascular disease modeling and drug screening

    PubMed Central

    2013-01-01

    Human induced pluripotent stem cells (hiPSCs) have emerged as a novel tool for drug discovery and therapy in cardiovascular medicine. hiPSCs are functionally similar to human embryonic stem cells (hESCs) and can be derived autologously without the ethical challenges associated with hESCs. Given the limited regenerative capacity of the human heart following myocardial injury, cardiomyocytes derived from hiPSCs (hiPSC-CMs) have garnered significant attention from basic and translational scientists as a promising cell source for replacement therapy. However, ongoing issues such as cell immaturity, scale of production, inter-line variability, and cell purity will need to be resolved before human clinical trials can begin. Meanwhile, the use of hiPSCs to explore cellular mechanisms of cardiovascular diseases in vitro has proven to be extremely valuable. For example, hiPSC-CMs have been shown to recapitulate disease phenotypes from patients with monogenic cardiovascular disorders. Furthermore, patient-derived hiPSC-CMs are now providing new insights regarding drug efficacy and toxicity. This review will highlight recent advances in utilizing hiPSC-CMs for cardiac disease modeling in vitro and as a platform for drug validation. The advantages and disadvantages of using hiPSC-CMs for drug screening purposes will be explored as well. PMID:24476344

  14. Drugs to Block Cytokine Signaling for the Prevention and Treatment of Inflammation-Induced Preterm Birth

    PubMed Central

    Ng, Pearl Y.; Ireland, Demelza J.; Keelan, Jeffrey A.

    2015-01-01

    Preterm birth (PTB) at less than 37?weeks of gestation is the leading cause of neonatal morbidity and mortality. Intrauterine infection (IUI) due to microbial invasion of the amniotic cavity is the leading cause of early PTB (<32?weeks). Commensal genital tract Ureaplasma and Mycoplasma species, as well as Gram-positive and Gram-negative bacteria, have been associated with IUI-induced PTB. Bacterial activation of Toll-like receptors and other pattern recognition receptors initiates a cascade of inflammatory signaling via the NF-?B and p38 mitogen-activated protein kinase (MAPK) signaling pathways, prematurely activating parturition. Antenatal antibiotic treatment has had limited success in preventing PTB or fetal inflammation. Administration of anti-inflammatory drugs with antibiotics could be a viable therapeutic option to prevent PTB and fetal complications in women at risk of IUI and inflammation. In this mini-review, we will discuss the potential for anti-inflammatory drugs in obstetric care, focusing on the class of drugs termed “cytokine suppressive anti-inflammatory drugs” or CSAIDs. These inhibitors work by specifically targeting the NF-?B and p38 MAPK inflammatory signaling pathways. Several CSAIDs are discussed, together with clinical and toxicological considerations associated with the administration of anti-inflammatory agents in pregnancy. PMID:25941525

  15. Metabolomics approaches for discovering biomarkers of drug-induced hepatotoxicity and nephrotoxicity

    SciTech Connect

    Beger, Richard D., E-mail: richard.beger@fda.hhs.go [Division of Systems Toxicology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR 72079-9502 (United States); Sun, Jinchun; Schnackenberg, Laura K. [Division of Systems Toxicology, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR 72079-9502 (United States)

    2010-03-01

    Hepatotoxicity and nephrotoxicity are two major reasons that drugs are withdrawn post-market, and hence it is of major concern to both the FDA and pharmaceutical companies. The number of cases of serious adverse effects (SAEs) in marketed drugs has climbed faster than the number of total drug prescriptions issued. In some cases, preclinical animal studies fail to identify the potential toxicity of a new chemical entity (NCE) under development. The current clinical chemistry biomarkers of liver and kidney injury are inadequate in terms of sensitivity and/or specificity, prompting the need to discover new translational specific biomarkers of organ injury. Metabolomics along with genomics and proteomics technologies have the capability of providing translational diagnostic and prognostic biomarkers specific for early stages of liver and kidney injury. Metabolomics has several advantages over the other omics platforms such as ease of sample preparation, data acquisition and use of biofluids collected through minimally invasive procedures in preclinical and clinical studies. The metabolomics platform is reviewed with particular emphasis on applications involving drug-induced hepatotoxicity and nephrotoxicity. Analytical platforms for metabolomics, chemometrics for mining metabolomics data and the applications of the metabolomics technologies are covered in detail with emphasis on recent work in the field.

  16. Sleep disturbances in Parkinsonism.

    PubMed

    Askenasy, J J M

    2003-02-01

    The present article is meant to suggest an approach to the guidelines for the therapy of sleep disturbances in Parkinson's Disease (PD) patients.The factors affecting the quality of life in PD patients are depression, sleep disturbances and dependence. A large review of the literature on sleep disturbances in PD patients, provided the basis for the following classification of the sleep-arousal disturbances in PD patients. We suggest a model based on 3 steps in the treatment of sleep disturbances in PD patients. This model allowing the patient, the spouse or the caregiver a quiet sleep at night, may postpone the retirement and the institutionalization of the PD patient. I. Correct diagnosis of sleep disorders based on detailed anamnesis of the patient and of the spouse or of the caregiver. One week recording on a symptom diary (log) by the patient or the caregiver. Correct diagnosis of sleep disorders co morbidities. Selection of the most appropriate sleep test among: polysomnography (PSG), multiple sleep latency test (MSLT), multiple wake latency test (MWLT), Epworth Sleepiness Scale, actigraphy or video-PSG. II. The nonspecific therapeutic approach consists in: a) Checking the sleep effect on motor performance, is it beneficial, worse or neutral. b) Psycho-physical assistance. c) Dopaminergic adjustment is necessary owing to the progression of the nigrostriatal degeneration and the increased sensitivity of the terminals, which alter the normal modulator mechanisms of the motor centers in PD patients. Among the many neurotransmitters of the nigro-striatal pathway one can distinguish two with a major influence on REM and NonREM sleep. REM sleep corresponds to an increased cholinergic receptor activity and a decreased dopaminergic activity. This is the reason why REM sleep deprivation by suppressing cholinergic receptor activity ameliorates PD motor symptoms. L-Dopa and its agonists by suppressing cholinergic receptors suppress REM sleep. The permanent adjustment according to the progression of the degenerative process of the disease will diminishe aggravation. The following types of sleep-arousal disturbances have to be considered in PD patients: - Sleep Disturbances, Light Fragmented Sleep (LFS), Abnormal Motor Activity During Sleep (AMADS), REM Behavior Disorders (RBD), Sleep Related Breathing Disorders (SRBD), Sleep Related Hallucinations (SRH), Sleep Related Psychotic Behavior (SRPB). - Arousal Disturbances, Sleep Attacks (SA), Excessive Daytime Sleepiness (EDS), Each syndrome has to receive a score according to its severity. III. The specific therapy consists in: LFS: Benzodiazepines & Nondiazepines. AMADS: Clonazepam, Opioid, Apomorphine infusion; RBD: Clonazepam and dopaminergic agonists; SRBD: CPAP, UPPP, nasal interventions, losing weight; SRH: Clozapine, Risperidone; SRPD: Nortriptyline, Clozapine, Olanzepine; SA-adjustment; EDS-arousing drugs. Each therapeutic approach must be tailored to the individual PD patient. PMID:12589574

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

    PubMed

    Schulte, Claudia; Gasser, Thomas

    2011-01-01

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

  18. Drug-induced DNA repair: X-ray structure of a DNA-ditercalinium complex

    SciTech Connect

    Gao, Qi; Williams, L.D.; Egli, M.; Rabinovich, D.; Rich, A. (Massachusetts Inst. of Tech., Cambridge (United States)); Chen, Shunle; Quigley, G.J. (Hunter College, New York, NY (United States))

    1991-03-15

    Ditercalinium is a synthetic anticancer drug that binds to DNA by bis-intercalation and activates DNA repair processes. In prokaryotes, noncovalent DNA-ditercalinium complexes are incorrectly recognized by the uvrABC repair system as covalent lesions on DNA. In eukaryotes, mitochondrial DNA is degraded by excess and futile DNA repair. Using x-ray crystallography, the authors have determined, to 1.7 {angstrom} resolution, the three-dimensional structure of a complex of ditercalinium bound to the double-stranded DNA fragment (d(CGCG)){sub 2}. The DNA in the complex with ditercalinium is kinked (by 15{degrees}) and severely unsound (by 36{degrees}) with exceptionally wide major and minor grooves. Recognition of the DNA-ditercalinium complex by uvrABC in prokaryotes, and by mitochondrial DNA repair systems in eukaryotes, might be related to drug-induced distortion of the DNA helix.

  19. Computational investigation of drug action on human-induced stem cell-derived cardiomyocytes.

    PubMed

    Frotscher, Ralf; Koch, Jan-Peter; Staat, Manfred

    2015-07-01

    We compare experimental and computational results for the actions of the cardioactive drugs Lidocaine, Verapamil, Veratridine, and Bay K 8644 on a tissue monolayer consisting of mainly fibroblasts and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSc-CM). The choice of the computational models is justified and literature data is collected to model drug action as accurately as possible. The focus of this work is to evaluate the validity and capability of existing models for native human cells with respect to the simulation of pharmaceutical treatment of monolayers and hiPSc-CM. From the comparison of experimental and computational results, we derive suggestions for model improvements which are intended to computationally support the interpretation of experimental results obtained for hiPSc-CM. PMID:25807216

  20. Drug-Induced Amnesia Hurts Recognition, but Only for Memories That Can Be Unitized

    PubMed Central

    Reder, Lynne M.; Oates, Joyce M.; Thornton, Edward R.; Quinlan, Joseph J.; Kaufer, Abigail; Sauer, Jennifer

    2008-01-01

    Midazolam is a drug that creates temporary anterograde amnesia. In a within-subjects, double-blind experiment, participants studied a list of stimuli after receiving an injection of midazolam in one session and after receiving saline in another session. The lists consisted of three types of stimuli: words, photographs, and abstract pictures. Recognition memory was tested at the end of each session. Memory was reliably poorer in the midazolam condition than the saline condition, but this amnesic effect was significantly smaller for pictorial stimuli than for words and almost nonexistent for abstract pictures. We argue that the less familiar the stimulus, the less likely it is to be associated with an experimental context. These data bolster our claim that unitization increases the chances of episodic binding and that drug-induced amnesia prevents episodic binding regardless of unitization. PMID:16866739

  1. Clinical features, diagnosis, and natural history of drug-induced liver injury.

    PubMed

    Hayashi, Paul H; Fontana, Robert J

    2014-05-01

    Patients with idiosyncratic drug-induced liver injury (DILI) can pose substantial diagnostic, prognostic, and therapeutic challenges to the practicing gastroenterologist. The presentation of DILI may vary from asymptomatic liver enzyme elevation to acute liver failure. Although most DILI resolves following drug discontinuation, up to 20% of patients progress to chronic DILI further challenging the clinicians diagnostic and management skills. Also, some medications can lead to advanced fibrosis, encephalopathy, and portal hypertension without significant elevation in liver enzymes during exposure. Finally, there are no objective tests to definitively diagnose DILI. Although causality assessment instruments are available, none are widely accepted or used in clinical practice. Therefore, the diagnosis of DILI depends on thorough and accurate history taking, follow-up of the patient's clinical course and excluding more common causes of liver injury. In this review, we discuss the variable clinical presentations, course, and diagnostic methods used to establish a diagnosis and prognosis in DILI. PMID:24879979

  2. Imaging nigral pathology and clinical progression in Parkinson's disease

    PubMed Central

    Du, Guangwei; Lewis, Mechelle M.; Sen, Suman; Wang, Jianli; Shaffer, Michele L.; Styner, Martin; Yang, Qing X.; Huang, Xuemei

    2012-01-01

    Background The pattern of dopamine cell loss in Parkinson's disease is known to be prominent in the ventrolateral and caudal substantia nigra, but less severe in the dorsal and rostral region. Both diffusion tensor imaging and R2* relaxometry of the substantia nigra have been reported as potential markers for Parkinson's disease, but their relative ability to mark disease progression and differences in pathophysiological bases remains unclear. Methods High resolution T2-weigthed, R2*, and diffusion tensor imaging were obtained from 28 controls and 40 Parkinson's disease subjects [15 early-stage (disease duration?1 year), 14 mid-stage (duration 2-5 years), and 11 late-stage (duration>5 years)]. Fractional anisotropy and R2* values in both rostral and caudal substantia nigra were obtained for all subjects, and clinical measures (disease duration; levodopa-equivalent daily dosage; “off”-drug Unified Parkinson's Disease Rating Scale motor score) were obtained for Parkinson's subjects. Results There was no correlation between fractional anisotropy and clinical measures, whereas R2* was strongly associated with disease progression. Compared to controls, fractional anisotropy in caudal substantia nigra was significantly decreased in Parkinson's disease patients of all stages, whereas in rostral substantia nigra it was decreased significantly only in the late-stage group. R2* in both substantia nigra regions was significantly increased in the mid-stage and late-stage, but not early-stage, of Parkinson's disease subjects. Conclusions These findings suggest that fractional anisotropy changes may mark early pathological changes in caudal substantia nigra, whereas the changes in R2* may more closely track Parkinson's disease's clinical progression after symptom onset. PMID:23008179

  3. Prevention of gastric mucosal injury induced by anti-platelet drugs by famotidine.

    PubMed

    Uotani, Takahiro; Sugimoto, Mitsushige; Nishino, Masafumi; Ichikawa, Hitomi; Sahara, Shu; Yamade, Mihoko; Iwaizumi, Moriya; Yamada, Takanori; Osawa, Satoshi; Sugimoto, Ken; Umemura, Kazuo; Watanabe, Hiroshi; Miyajima, Hiroaki; Furuta, Takahisa

    2014-08-01

    Anti-platelet drug-induced gastric mucosal injury correlates with intragastric pH. Our aim was to investigate prophylaxis effects of famotidine, one of the representative histamine-2 receptor antagonists (H2RA), on gastric mucosal injury induced by dual therapy with low-dose aspirin and clopidogrel in relation to Helicobacter pylori (H. pylori) infection and CYP2C19 genotypes. This study was conducted for 20 healthy Japanese volunteers (10 H. pylori-positive and 10-negative subjects) with 100?mg aspirin plus 75?mg clopidogrel (AC) once-daily dosing and AC plus 20?mg famotidine twice-daily dosing (ACH). Mucosal injury was endoscopically assessed on day 3 and 7 and 24-hour intragastric pH and antiplatelet-function test was performed on day 7. Median pH in ACH was similar between CYP2C19 extensive metabolizer (EM) and intermediate metabolizer (IM)/poor metabolizer (PM) and was significantly higher in H. pylori-positive than negative subjects (P?drug-induced gastric injury was alleviated by famotidine without attenuation of anti-platelet functions irrespective of H. pylori and CYP2C19 genotypes. PMID:24615745

  4. Characteristics of Idiosyncratic Drug-induced Liver Injury in Children: Results From the DILIN Prospective Study

    PubMed Central

    Molleston, Jean P.; Fontana, Robert J.; Lopez, M. James; Kleiner, David E.; Gu, Jiezhun; Chalasani, Naga

    2013-01-01

    Background The spectrum and severity of idiosyncratic drug-induced liver injury (DILI) in children are not well established. Patients and Methods The DILIN (Drug-Induced Liver Injury Network) Prospective Study is a longitudinal multicenter study designed to determine the etiologies, risk factors, and outcomes of suspected DILI. Between September 2004 and September 2009, 30 children ages 2 to 18 years with suspected DILI who met eligibility criteria were enrolled and studied for at least 6 months. Results Mean age was 14 years; 70% were girls. Antimicrobial (50%) and central nervous system agents (40%) were the most commonly implicated drug classes, with minocycline (4), isoniazid (3), azithromycin (3), atomoxetine (3), and lamotrigine (3) the leading agents. Median time from drug initiation to symptom onset was 32 days. Peak (median) liver chemistries were aspartate aminotransferase 503 U/L, alanine aminotransferase 727 U/L, alkaline phosphatase 331 U/L, and total bilirubin 3.9 mg/dL. Autoantibodies were common (64%). Liver injury pattern was hepatocellular 78%, cholestatic 13%, and mixed 9%. The DILI episode was scored: mild 32%, moderate 44%, severe 20%, and fatal (within 6 months) 4%. Causality assessment was definite 36%, very likely 36%, probable 16%, possible 8%, and unlikely 4%. Seven percent had persistent liver test abnormalities at 6-month follow-up suggesting chronic DILI. Liver biopsies from 12 children most frequently demonstrated chronic hepatitis or bile duct injury. Conclusions Idiosyncratic DILI in children is most commonly caused by antimicrobial or central nervous system agents and usually presents with a hepatocellular injury pattern. The majority of patients recover, but morbidity and infrequent mortality are seen. PMID:21788760

  5. Supervised prediction of drug-induced nephrotoxicity based on interleukin-6 and -8 expression levels

    PubMed Central

    2014-01-01

    Background Drug-induced nephrotoxicity causes acute kidney injury and chronic kidney diseases, and is a major reason for late-stage failures in the clinical trials of new drugs. Therefore, early, pre-clinical prediction of nephrotoxicity could help to prioritize drug candidates for further evaluations, and increase the success rates of clinical trials. Recently, an in vitro model for predicting renal-proximal-tubular-cell (PTC) toxicity based on the expression levels of two inflammatory markers, interleukin (IL)-6 and -8, has been described. However, this and other existing models usually use linear and manually determined thresholds to predict nephrotoxicity. Automated machine learning algorithms may improve these models, and produce more accurate and unbiased predictions. Results Here, we report a systematic comparison of the performances of four supervised classifiers, namely random forest, support vector machine, k-nearest-neighbor and naive Bayes classifiers, in predicting PTC toxicity based on IL-6 and -8 expression levels. Using a dataset of human primary PTCs treated with 41 well-characterized compounds that are toxic or not toxic to PTC, we found that random forest classifiers have the highest cross-validated classification performance (mean balanced accuracy = 87.8%, sensitivity = 89.4%, and specificity = 85.9%). Furthermore, we also found that IL-8 is more predictive than IL-6, but a combination of both markers gives higher classification accuracy. Finally, we also show that random forest classifiers trained automatically on the whole dataset have higher mean balanced accuracy than a previous threshold-based classifier constructed for the same dataset (99.3% vs. 80.7%). Conclusions Our results suggest that a random forest classifier can be used to automatically predict drug-induced PTC toxicity based on the expression levels of IL-6 and -8. PMID:25521947

  6. Effects of childhood maltreatment on the neural correlates of stress- and drug cue-induced cocaine craving.

    PubMed

    Elton, Amanda; Smitherman, Sonet; Young, Jonathan; Kilts, Clinton D

    2015-07-01

    Childhood adversity negatively influences all stages of the addiction process and is associated with persistent alterations in neuroendocrine, autonomic and brain responses to stress. We sought to characterize the impact of childhood abuse and neglect on the neural correlates of stress- and drug cue-induced drug craving associated with cocaine addiction. Cocaine-dependent men with (n?=?20) and without (n?=?18) moderate to severe childhood maltreatment histories underwent functional magnetic resonance imaging during script-guided mental imagery of personalized stress, drug use and neutral experiences. Compared to the neutral script, the stress and drug use scripts activated striatal, prefrontal, posterior cingulate, temporal and cerebellar regions consistent with prior studies of induced states of stress and drug craving. For the stress script, maltreated men exhibited reduced activation of the anterior precuneus and supplementary motor area (SMA); the interaction of maltreatment severity and stress-induced craving responses predicted lesser rostral anterior cingulate cortex activation. For the drug use script, maltreated men exhibited greater left dorsolateral prefrontal cortex activation. The interaction of maltreatment severity and craving responses was associated with greater activation of the visual cortex and SMA, whereas a maltreatment-by-anxiety interaction effect included lesser ventromedial prefrontal cortex activation. The outcomes indicate an association of childhood maltreatment with a heightened appetitive anticipatory response to drug cues and a diminished engagement of regulatory and controlled action selection processes in response to stress- or drug cue-induced drug craving and anxiety responses for cocaine-dependent men. These findings provide novel insights into possible brain mechanisms by which childhood maltreatment heightens risk for relapse in drug-dependent individuals. PMID:25214317

  7. Nuclear microscopy in Parkinson's disease

    NASA Astrophysics Data System (ADS)

    Watt, F.; Lee, T.; Thong, P. S. P.; Tang, S. M.

    1995-09-01

    Rats have been subjected to unilateral lesioning with the selective neurotoxin 6-OHDA in order to induce Parkinsonism. Analysis using the NUS Nuclear Microscope facility have shown that iron levels are raised by an average of 26% in the lesioned subtantia nigra region of the brain compared with the non-lesioned side. In addition the background tissue level of iron is also elevated by 31% in the lesioned side, indicating that there is a general increase in iron levels as a result of the lesioning. This result is consistent with the other observations that other diseases of the brain are frequently associated with altered iron levels (eg. progressive nuclear palsy, multiple system atrophy, Alzheimers disease, multiple sclerosis).

  8. Drug-induced premature chromosome condensation (PCC) protocols: cytogenetic approaches in mitotic chromosome and interphase chromatin.

    PubMed

    Gotoh, Eisuke

    2015-01-01

    Chromosome analysis is a fundamental technique which is used in wide areas of cytogenetic study including karyotyping species, hereditary diseases diagnosis, or chromosome biology study. Chromosomes are usually prepared from mitotic cells arrested by colcemid block protocol. However, obtaining mitotic chromosomes is often hampered under several circumstances. As a result, cytogenetic analysis will be sometimes difficult or even impossible in such cases. Premature chromosome condensation (PCC) (see Note 1) is an alternative method that has proved to be a unique and useful way in chromosome analysis. Former, PCC has been achieved following cell fusion method (cell-fusion PCC) mediated either by fusogenic viruses (e.g., Sendai virus) or cell fusion chemicals (e.g., polyethylene glycol), but the cell fusion PCC has several drawbacks. The novel drug-induced PCC using protein phosphatase inhibitors was introduced about 20 years ago. This method is much simpler and easier even than the conventional mitotic chromosome preparation protocol use with colcemid block and furthermore obtained PCC index (equivalent to mitotic index for metaphase chromosome) is usually much higher than colcemid block method. Moreover, this method allows the interphase chromatin to be condensed to visualize like mitotic chromosomes. Therefore drug-induced PCC has opened the way for chromosome analysis not only in metaphase chromosomes but also in interphase chromatin. The drug-induced PCC has thus proven the usefulness in cytogenetics and other cell biology fields. For this second edition version, updated modifications/changes are supplemented in Subheadings 2, 3, and 4, and a new section describing the application of PCC in chromosome science fields is added with citation of updated references. PMID:25827875

  9. Effectiveness of malic acid 1% in patients with xerostomia induced by antihypertensive drugs

    PubMed Central

    Guardia, Javier; Aguilar-Salvatierra, Antonio; Cabrera-Ayala, Maribel; Maté-Sánchez de-Val, José E.; Calvo-Guirado, José L.

    2013-01-01

    Objectives: Assessing the clinical effectiveness of a topical sialogogue on spray (malic acid, 1%) in the treatment of xerostomia induced by antihypertensive drugs. Study Design: This research has been carried out through a randomized double-blind clinical trial. 45 patients suffering from hypertensive drugs-induced xerostomia were divided into 2 groups: the first group (25 patients) received a topical sialogogue on spray (malic acid, 1%) whereas the second group (20 patients) received a placebo. Both of them were administered on demand for 2 weeks. Dry Mouth Questionnaire (DMQ) was used in order to evaluate xerostomia levels before and after product/placebo application. Unstimulated and stimulated salivary flows rates, before and after application, were measured. All the statistical analyses were performed by using SPSS software v17.0. Different DMQ scores at the earliest and final stage of the trial were analysed by using Mann-Whitney U test, whereas Student’s T-test was used to analyse salivary flows. Critical p-value was established at p<0.05. Results: DMQ scores increased significantly (clinical recovery) from 1.21 to 3.36 points (p<0.05) after malic acid (1%) application whereas DMQ scores increased from 1.18 to 1.34 points (p>0.05) after placebo application. After two weeks of treatment with malic acid, unstimulated salivary flow increased from 0.17 to 0.242 mL/min whereas the stimulated one increased from 0.66 to 0.92 mL/min (p<0.05). After placebo application unstimulated flow ranged from 0.152 to 0.146 mL/min and stimulated flow increased from 0.67 to 0.70 mL/min (p>0.05). Conclusions: Malic acid 1% spray improved antihypertensive-induced xerostomia and stimulated the production of saliva. Key words:Xerostomia, hyposialia, malic acid, antihypertensive drugs. PMID:22926481

  10. Characterization of Two Models of Drug-Induced Constipation in Mice and Evaluation of Mustard Oil in These Models

    Microsoft Academic Search

    Ryosuke Kojima; Hitoshi Doihara; Katsura Nozawa; Eri Kawabata-Shoda; Toshihide Yokoyama; Hiroyuki Ito

    2009-01-01

    Although it is known that both clonidine and loperamide cause delayed colonic transit in mice, these models of drug-induced experimental constipation have not yet been fully characterized. Therefore, the aims of this study were to validate the clonidine- and loperamide-induced delays of colonic transit in mice as models of atonic and spastic constipation, respectively, and to evaluate the effect of

  11. Identifying the translational gap in the evaluation of drug-induced QTc interval prolongation

    PubMed Central

    Chain, Anne SY; Dubois, Vincent FS; Danhof, Meindert; Sturkenboom, Miriam CJM; Della Pasqua, Oscar

    2013-01-01

    Aims Given the similarities in QTc response between dogs and humans, dogs are used in pre-clinical cardiovascular safety studies. The objective of our investigation was to characterize the PKPD relationships and identify translational gaps across species following the administration of three compounds known to cause QTc interval prolongation, namely cisapride, d, l-sotalol and moxifloxacin. Methods Pharmacokinetic and pharmacodynamic data from experiments in conscious dogs and clinical trials were included in this analysis. First, pharmacokinetic modelling and deconvolution methods were applied to derive drug concentrations at the time of each QT measurement. A Bayesian PKPD model was then used to describe QT prolongation, allowing discrimination of drug-specific effects from other physiological factors known to alter QT interval duration. A threshold of ?10 ms was used to explore the probability of prolongation after drug administration. Results A linear relationship was found to best describe the pro-arrhythmic effects of cisapride, d,l-sotalol and moxifloxacin both in dogs and in humans. The drug-specific parameter (slope) in dogs was statistically significantly different from humans. Despite such differences, our results show that the probability of QTc prolongation ?10 ms in dogs nears 100% for all three compounds at the therapeutic exposure range in humans. Conclusions Our findings indicate that the slope of PKPD relationship in conscious dogs may be used as the basis for the prediction of drug-induced QTc prolongation in humans. Furthermore, the risk of QTc prolongation can be expressed in terms of the probability associated with an increase ?10 ms, allowing direct inferences about the clinical relevance of the pro-arrhythmic potential of a molecule. PMID:23351036

  12. Evaluation of blood-brain barrier transport and CNS drug metabolism in diseased and control brain after intravenous L-DOPA in a unilateral rat model of Parkinson's disease

    PubMed Central

    2012-01-01

    Background Changes in blood-brain barrier (BBB) functionality have been implicated in Parkinson's disease. This study aimed to investigate BBB transport of L-DOPA transport in conjunction with its intra-brain conversion, in both control and diseased cerebral hemispheres in the unilateral rat rotenone model of Parkinson's disease. Methods In Lewis rats, at 14 days after unilateral infusion of rotenone into the medial forebrain bundle, L-DOPA was administered intravenously (10, 25 or 50 mg/kg). Serial blood samples and brain striatal microdialysates were analysed for L-DOPA, and the dopamine metabolites DOPAC and HVA. Ex-vivo brain tissue was analyzed for changes in tyrosine hydroxylase staining as a biomarker for Parkinson's disease severity. Data were analysed by population pharmacokinetic analysis (NONMEM) to compare BBB transport of L-DOPA in conjunction with the conversion of L-DOPA into DOPAC and HVA, in control and diseased cerebral hemisphere. Results Plasma pharmacokinetics of L-DOPA could be described by a 3-compartmental model. In r