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1

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

Microsoft Academic Search

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

B Thanvi; S Treadwell

2009-01-01

2

DAT imaging in drug-induced and psychogenic parkinsonism.  

PubMed

Parkinson's syndrome (PS) is frequently encountered in disorders associated with prominent degeneration of the nigrostriatal pathway as in Parkinson's disease, multisystem atrophy, and progressive supranuclear palsy (presynaptic PS). Drug-induced parkinsonism, a common, underdiagnosed health problem and psychogenic parkinsonism are causes of Parkinson's syndrome which, evidence suggests, occurs without degeneration of nigrostriatal structures. We review clinical features and results of DAT imaging in drug-induced parkinsonism and psychogenic parkinsonism. These two conditions normally give normal striatal DAT imaging results; an abnormal result in either case could exclude both conditions, corroborating a diagnosis of organic parkinsonism in uncertain cases. PMID:14531043

Tolosa, Eduardo; Coelho, Miguel; Gallardo, Marisol

2003-10-01

3

Clinical features and 123 I-FP-CIT SPECT imaging in drug-induced parkinsonism and Parkinson’s disease  

Microsoft Academic Search

Purpose  To determine clinical predictors and accuracy of 123I-FP-CIT SPECT imaging in the differentiation of drug-induced parkinsonism (DIP) and Parkinson’s disease (PD).\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Several clinical features and 123I-FP-CIT SPECT images in 32 patients with DIP, 25 patients with PD unmasked by antidopaminergic drugs (PDu) and 22 patients\\u000a with PD without a previous history of antidopaminergic treatment (PDc) were retrospectively evaluated.\\u000a \\u000a \\u000a \\u000a \\u000a Results  DIP and

Francisco J. Diaz-Corrales; Salome Sanz-Viedma; David Garcia-Solis; Teresa Escobar-Delgado; Pablo Mir

2010-01-01

4

Use of Hyposmia and Other Non-Motor Symptoms to Distinguish between Drug-Induced Parkinsonism and Parkinson's Disease.  

PubMed

Drug-induced Parkinsonism (DIP) secondary to antipsychotics and other dopamine antagonists is common and can be clinically indistinguishable from idiopathic Parkinson's disease (PD). Making the correct diagnosis is essential as it has important implications both for management of the underlying psychiatric condition and potentially lifelong therapy with antiparkinsonian agents. Additionally, because Parkinsonism does not always resolve with withdrawal of the offending agent or can recur years later, DIP may sometimes represent unmasking of incipient PD. The problem is increasing in scope as antipsychotic drugs are prescribed for a widening variety of indications, and understanding the factors that distinguish pharmacologic from degenerative Parkinsonism represents a significant unmet need. In this review, we discuss the rationale and evidence for using pre-clinical manifestations of PD, particularly non-motor symptoms, to distinguish between the conditions. PMID:24284418

Morley, James F; Duda, John E

2014-01-01

5

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

PubMed

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

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

2011-10-01

6

Quantifying drug induced dyskinesia in Parkinson's disease patients using standardized videos  

Microsoft Academic Search

This paper presents a video based method to quantify drug induced dyskinesias in Parkinson's disease (PD) patients. Dyskinetic movement in standard clinical videos of patients is analyzed by tracking landmark points on the video frames using non-rigid image registration. The novel application of Point Distribution Models (PDM) allows geometric variations and covariations of the landmark points to be captured from

Anusha S. Rao; Robert E. Bodenheimer; Thomas. L. Davis; Rui Li; Cissy Voight; Benoit M. Dawant

2008-01-01

7

Drugs for Parkinson's disease.  

PubMed

Levodopa combined with carbidopa is still the most effective treatment for symptoms of Parkinson's disease. Dopamine agonists, the next most effective class of drugs, can be used alone before the introduction of levodopa or as an adjunct to levodopa.Addition of a peripherally-acting COMT inhibitor or an MAO-B inhibitor to levodopa can reduce motor fluctuations in patients with advanced disease.Amantadine may have mild symptomatic benefit and can decrease levodopa-induced dyskinesias.Anticholinergics are rarely used because of their adverse effects, but can be a useful addition to levodopa for control of tremor and drooling.Subcutaneous apomorphine should be available for rescue use in patients with 'off' episodes. Deep brain stimulation is an option for patients with levodopa-induced motor complications and relatively intact cognition. PMID:24165688

2013-11-01

8

Generic vs. Branded Drugs for Parkinson's Disease  

MedlinePLUS

... Branded Drugs for Parkinson’s Disease Text Size Generic vs. Branded Drugs for Parkinson’s Disease Currently, there are ... 3 ratings) Print Topics in this section Generic vs. Branded Drugs for Parkinson’s Disease Carbidopa/levodopa Dopamine ...

9

Atypical antipsychotics in the treatment of drug-induced psychosis in Parkinson's disease.  

PubMed

Our experience with atypical antipsychotics in patients with PD is that their motor effects are not predictable. The multiple reports concerning clozapine's beneficial effects on tremor, dystonia, nocturnal akathisia, and dyskinesias all underscore this observation. However, the appearance of even minor degrees of parkinsonism in normal volunteers or schizophrenics should suggest that an antipsychotic will not be well-tolerated in patients with PD. The treatment of PD is probably the most stringent test of a drug's freedom from parkinsonian side effects. The data from trials in schizophrenia concerning parkinsonian effects cannot always be confidently interpreted. Virtually all subjects in these trials have been treated with typical neuroleptics until shortly before study entry. Because the parkinsonian side effects of these drugs may persist for several months, patients may still show declining levels of parkinsonism even when placed on a drug that induces it if this effect is milder than that induced by the pre-study neuroleptic. Depending on the pre-study drug used and the duration of the study, distinguishing placebo from a low-potency neuroleptic may be impossible. Furthermore, the standard measure of parkinsonism in psychiatric studies is the Simpson-Angus scale which is heavily weighted toward rigidity and may underscore bradykinesia, gait, and posture abnormalities. The prolactin response to an antipsychotic drug may turn out to be a good predictor of its freedom from parkinsonian side effects. That would fit with the data presented above of clozapine and quetiapine having less parkinsonian effects, olanzapine having more but variable effects and risperidone being poorly tolerated. With the data presented above, comprising a current review of all reports of the use of atypical antipsychotics in PD that we could locate, we can say little with certainty. The only drug with confirmed benefit without worsening parkinsonism is clozapine. Open-label trials involving over 400 patients and two multicenter, placebo-controlled, double-blind trials have demonstrated that it is effective in treating the psychosis. It improves tremor, does not worsen other motor functions to any significant extent, and is safe at low doses. Limited data provide conflicting information on both risperidone and olanzapine. Quetiapine seems to be well-tolerated with some, but definitely less, worsening of PD motor features than risperidone and olanzapine. Based on the current literature, our personal experience, and anecdotal experience of other PD specialists which we solicited, we will venture our own interpretation and recommendations. We think risperidone is poorly tolerated and should be used only as a last resort; that olanzapine is better than risperidone but will, in a majority of patients with PD, worsen motor function. We are optimistic, but not yet convinced, that quetiapine may prove to be as effective and better tolerated than clozapine. It will not require cumbersome monitoring because it does not induce a blood dyscrasia. We therefore recommend that DP be treated in the following manner. First, the anti-PD medications should be simplified and reduced as much as tolerated. We think, in general, side effects multiply more with increasing numbers of drugs than with drug dose, so that patients are more likely to tolerate a higher dose of levodopa than a lower dose of levodopa combined with other adjunctive anti-PD medications. In reducing anti-PD medications, we recommend tapering and stopping, if necessary, the drugs with the highest risk-to-benefit ratio first. Anticholinergics are stopped first, then selegiline, dopamine agonists, amantadine, and finally COMT inhibitors, which have no psychotomimetic action of their own. Finally, levodopa is reduced. Generally, a point is reached at which the anti-PD medications cannot be reduced without jeopardizing motor function. If psychosis persists at this point, then an antipsychotic is added. (ABS PMID:10752567

Friedman, J H; Factor, S A

2000-03-01

10

Drug treatment of Parkinson's disease  

PubMed Central

Parkinson's disease (PD) is a common neurodegenerative disease. While its cause remains elusive, much progress has been made regarding its treatment. Available drugs have a good symptomatic effect, but none has yet been shown to slow the progression of the disease in humans. The most efficacious drug is levodopa, but it remains unclear whether the symptomatic benefit is associated with neurotoxic effects and long-term deterioration. The long-term problem associated with levodopa is the appearance of dyskinesias, which is significantly delayed among patients treated with dopamine agonists as initial therapy. Less clear is the role of other drugs in PD, such as monoamine oxidase inhibitors (MAOIs), including selegiline and rasagiline, the putative N-meihyl-o-aspartaie (NMDA) receptor antagonists amantadine and memantine, and the muscarinic receptor blockers. All these may be used as initial therapy and delay the use of dopaminergic drugs, or can be added later to reduce specific symptoms (tremor or dyskinesias). Advanced PD is frequently associated with cognitive decline. To some extent, this can be helped by treatment with cholinesterase inhibitors such as rivastigmine. Similarly, hallucinations and delusions affect PD patients in the advanced stages of their disease. The use of classical neuroleptic drugs in these patients is contraindicated because of their extrapyramidal effects, but atypical drugs, and particularly clozapine, are very helpful. The big void in the therapy of PD lies in the more advanced stages. Several motor symptoms, like postural instability, dysphagia, and dysphonia, as well as dyskinesias, are poorly controlled by existing drugs. New therapies should also be developed against autonomic symptoms, particularly constipation.

Korczyn, Amos D.

2004-01-01

11

Benefits of monitoring plasma levodopa in Parkinson's disease patients with drug-induced chorea.  

PubMed

We studied the temporal patterns of chorea and plasma levodopa profiles in 30 patients with Parkinson's disease whose motor fluctuations were difficult to characterize and treat on the basis of observation alone. We were able to determine whether chorea was associated with high levodopa concentrations or low levodopa concentrations or both. We found the following patterns of levodopa-associated chorea: chorea due to inadequate levodopa levels, chorea due to biphasic levodopa absorption, chorea associated with either rapid or slow levodopa absorption, and chorea due to long-duration levodopa absorption mimicking a sustained-release preparation. Seven patients benefited after their dosing schedules were rearranged as a result of information gained from monitoring. We conclude that any patient with levodopa-associated chorea who cannot be regulated on the basis of observation alone should be studied with simultaneous plasma levodopa measurements and clinical monitoring to detect an unusual plasma levodopa pattern that may be improved by adjustment of dosing schedule. PMID:1892365

Sage, J I; Mark, M H; McHale, D M; Sonsalla, P K; Vitagliano, D

1991-06-01

12

Oxidative modification of peroxiredoxin is associated with drug-induced apoptotic signaling in experimental models of Parkinson disease.  

PubMed

The aim of this study was to investigate changes in protein profiles during the early phase of dopaminergic neuronal death using two-dimensional gel electrophoresis in conjunction with mass spectrometry. Several protein spots were identified whose expression was significantly altered following treatment of MN9D dopaminergic neuronal cells with 6-hydroxydopamine (6-OHDA). In particular, we detected oxidative modification of thioredoxin-dependent peroxidases (peroxiredoxins; PRX) in treated MN9D cells. Oxidative modification of PRX induced by 6-OHDA was blocked in the presence of N-acetylcysteine, suggesting that reactive oxygen species (ROS) generated by 6-OHDA induce oxidation of PRX. These findings were confirmed in primary cultures of mesencephalic neurons and in rat brain injected stereotaxically. Overexpression of PRX1 in MN9D cells (MN9D/PRX1) exerted neuroprotective effects against death induced by 6-OHDA through scavenging of ROS. Consequently, generation of both superoxide anion and hydrogen peroxide following 6-OHDA treatment was decreased in MN9D/PRX1. Furthermore, overexpression of PRX1 protected cells against 6-OHDA-induced activation of p38 MAPK and subsequent activation of caspase-3. In contrast, 6-OHDA-induced apoptotic death signals were enhanced by RNA interference-targeted reduction of PRX1 in MN9D cells. Taken together, our data suggest that the redox state of PRX may be intimately involved in 6-OHDA-induced dopaminergic neuronal cell death and also provide a molecular mechanism by which PRX1 exerts a protective role in experimental models of Parkinson disease. PMID:18250162

Lee, Young Mook; Park, Seong H; Shin, Dong-Ik; Hwang, Jee-Yeon; Park, Bokyung; Park, Yun-Jong; Lee, Tae H; Chae, Ho Z; Jin, Byung K; Oh, Tae H; Oh, Young J

2008-04-11

13

Continuous drug delivery in Parkinson's disease.  

PubMed

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

Senek, Marina; Nyholm, Dag

2014-01-01

14

Connecting Parkinson's disease and drug addiction: common players reveal unexpected disease connections and novel therapeutic approaches.  

PubMed

Parkinson´s disease (PD) is generally a sporadic disease, and only a small proportion of cases have a clear genetic component. During the last few years, a possible specific cause triggering death of dopaminergic neurons in the substantia nigra, drug of abuse-induced neurotoxicity, is being considered as a potential mechanism to develop PD, especially in the case of abuse of amphetamine and its derivatives. Recent evidences have shown pleiotrophin, a growth factor with important functions in remodeling and repair of injured neural tissue, as an important factor involved in the pathogenesis of both diseases by preventing neurodegeneration in Parkinson's disease, neurotoxicity induced by drug abuse and by its ability to modulate drugs addictive effects. This review discusses targeting growth factors such as glial-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) to treat Parkinson's disease and/or drug addiction and compiles recent evidences to propose the pleiotrophin/receptor protein tyrosine phosphatase ?/? signaling pathway as a new therapeutic target to treat Parkinson's disease and to prevent drug of abuse-induced neurotoxicity and addictive effects. PMID:21375485

Gramage, Esther; Herradón, Gonzalo

2011-01-01

15

Pharmacogenetics of Parkinson's Disease - Through Mechanisms of Drug Actions  

PubMed Central

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

Drozdzik, Marek; Bialecka, Monika; Kurzawski, Mateusz

2013-01-01

16

Levodopa in the treatment of Parkinson's disease: an old drug still going strong  

PubMed Central

After more than 40 years of clinical use, levodopa (LD) remains the gold standard of symptomatic efficacy in the drug treatment of Parkinson’s disease (PD). Compared with other available dopaminergic therapies, dopamine replacement with LD is associated with the greatest improvement in motor function. Long-term treatment with LD is, however, often complicated by the development of various types of motor response oscillations over the day, as well as drug-induced dyskinesias. Motor fluctuations can be improved by the addition of drugs such as entacapone or monoamine oxidase inhibitors, which extend the half-life of levodopa or dopamine, respectively. However, dyskinesia control still represents a major challenge. As a result, many neurologists have become cautious when prescribing therapy with LD. This review summarizes the available evidence regarding the use of LD to treat PD and will also address the issue of LD delivery as a critical factor for the drug’s propensity to induce motor complications.

Poewe, Werner; Antonini, Angelo; Zijlmans, Jan CM; Burkhard, Pierre R; Vingerhoets, Francois

2010-01-01

17

Environmental neurotoxin-induced progressive model of parkinsonism in rats  

PubMed Central

Objective Exposure to a number of drugs, chemicals or environmental factors can cause parkinsonism. Epidemiologic evidence supports a causal link between the consumption of flour made from the washed seeds of the plant, Cycas micronesica, by the Chamorro population of Guam and the development of Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC). Methods We now report that consumption of washed cycad flour pellets by Sprague-Dawley male rats induces progressive parkinsonism. Results Cycad-fed rats displayed motor abnormalities after two to three months of feeding such as spontaneous unilateral rotation, shuffling gait and stereotypy. Histological and biochemical examination of brains from cycad-fed rats revealed an initial decrease in the levels of dopamine and its metabolites in the striatum (STR), followed by neurodegeneration of dopaminergic (DAergic) cell bodies in the substantia nigra pars compacta (SNc). ?-synuclein (?-syn; proteinase K-resistant) and ubiquitin aggregates were found in the DAergic neurons of the SNc and neurites in the STR. In addition, we identified ?-syn aggregates in neurons of the locus coeruleus and cingulate cortex. No loss of motor neurons in the spinal cord was found after chronic consumption of cycad flour. In an organotypic slice culture of the rat substantia nigra and the striatum, an organic extract of cycad causes a selective loss of DA neurons and ?-synuclein aggregates in the substantia nigra. Interpretation Cycad-fed rats exhibit progressive behavioral, biochemical, and histological hallmarks of parkinsonism, coupled with a lack of fatality.

Shen, Wei-Bin; McDowell, Kimberly A.; Siebert, Aubrey A.; Clark, Sarah M.; Dugger, Natalie V.; Valentino, Kimberly M.; Jinnah, H. A.; Sztalryd, Carole; Fishman, Paul S.; Shaw, Christopher A.; Jafri, M. Samir; Yarowsky, Paul J.

2010-01-01

18

Pramipexole-induced antecollis in Parkinson's disease  

Microsoft Academic Search

We report a case of antecollis, or dropped head with Parkinson's disease (PD) induced by pramipexole, a nonergot dopamine agonist. An 80-year-old woman presented with progressively severe neck flexion, which developed within a few weeks of taking pramipexole at 3 mg\\/day. She had a disturbed gait and complained of difficulty in daily activity because of restricted visual field and severe stooped

Masahiko Suzuki; Toshiaki Hirai; Yasuhiko Ito; Tsuyoshi Sakamoto; Hisayoshi Oka; Akira Kurita; Kiyoharu Inoue

2008-01-01

19

Thrombocytopenia - drug induced  

MedlinePLUS

... your platelets, the condition is called drug-induced immune thrombocytopenia. Heparin, a blood thinner, is probably the most common cause of drug-induced immune thrombocytopenia. If a medicine prevents your bone marrow from ...

20

[Abnormal plasticity and drug effect in Parkinson's disease].  

PubMed

The repetitive transcranial magnetic stimulation (rTMS) has been studied as a method to induce plasticity changes in the human brain. And rTMS is expected as a therapeutic tool for Parkinson's disease, depression, intractable pain and others. We reported a new rTMS protocol, quadripulse stimulation (QPS), is more effective. QPS consists of repeated trains of four monophasic TMS pulses separated by inter-stimulus intervals of 5 ms (QPS-5) and 50 ms (QPS-50), inducing bidirectional motor cortical plasticity in an ISI dependent. QPS-5 leads to the potentiation effect. QPS-50 leads to a depression effect. We investigated the changes of plasticity induced by QPS in patients with Parkinson's disease and the healthy volunteer with oral administration of levodopa. In patients with Parkinson's disease the effect of QPS-5 and QPS-50 was attenuated at Off period. However, when the On period it was recovered. In healthy subjects, effect of QPS was enhanced by levodopa, both QPS-5 and QPS-50. PMID:23196564

Enomoto, Hiroyuki; Ugawa, Yoshikazu

2012-01-01

21

Piracetam and vinpocetine ameliorate rotenone-induced Parkinsonism in rats  

PubMed Central

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

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

2012-01-01

22

Present and future drug treatment for Parkinson's disease  

PubMed Central

Considerable advances made in defining the aetiology, pathogenesis, and pathology of Parkinson's disease (PD) have resulted in the development and rapid expansion of the pharmacopoeia available for treatment. Anticholinergics were used before the introduction of levodopa which is now the drug most commonly used. Dopamine agonists are effective when used alone or as an adjunct to levodopa, while monoamine oxidase B inhibitors improve motor function in early and advanced PD. However, treatment mainly addresses the dopaminergic features of the disease and leaves its progressive course unaffected; the drug treatment available for the management of non-motor symptoms is limited. This article seeks to set current treatment options in context, review emerging and novel drug treatments for PD, and assess the prospects for disease modification. Surgical therapies are not considered.

Schapira, A

2005-01-01

23

Potential of transdermal drug delivery in Parkinson's disease.  

PubMed

There has been a growing recognition that pulsatile stimulation of dopamine receptors may be an important mechanism in the generation of the motor fluctuations that often develop and compromise the effectiveness of long-term levodopa administration in persons with Parkinson's disease (PD). This has prompted investigation of treatment approaches that might provide more constant, and therefore physiological, dopamine receptor stimulation. Frequent levodopa administration, controlled-release levodopa preparations, inhibitors of levodopa metabolism, and duodenal, subcutaneous and even intravenous infusions of levodopa or dopamine agonists have all been employed with this goal in mind, but all have limitations. Transdermal drug delivery is a treatment approach that is not only capable of providing a constant rate of drug delivery, but is also non-invasive and relatively simple to use. However, developing a drug to be delivered transdermally for the treatment of PD has been anything but easy. Levodopa and many dopamine agonists are not sufficiently soluble to be administered via the transdermal route, and blind alleys have been encountered thus far in the investigation of suitably soluble drugs. Nevertheless, investigation continues and yet another candidate drug, rotigotine (N-0923), is currently under active investigation. Techniques designed to enhance skin permeation and thus improve the effectiveness of transdermal drug delivery are also potential sources for future treatment advances. PMID:12207550

Pfeiffer, Ronald F

2002-01-01

24

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

PubMed Central

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

Skibinski, Gaia; Finkbeiner, Steven

2013-01-01

25

Redefining Parkinson's Disease Research Using Induced Pluripotent Stem Cells  

PubMed Central

Parkinson’s disease (PD) is a movement disorder associated with the degeneration of nigral dopaminergic (DA) neurons. One of the greatest obstacles for PD research is the lack of patient-specific nigral DA neurons for mechanistic studies and drug discovery. The advent of induced pluripotent stem cells (iPSCs) has overcome this seemingly intractable problem and changed PD research in many profound ways. In this review, we discuss recent development in the generation and analyses of patient-specific iPSC-derived midbrain DA neurons. Results from this novel platform of human cellular models of PD have offered a tantalizing glimpse of the promising future of PD research. With the development of the latest genomic modification technologies, dopaminergic neuron differentiation methodologies, and cell transplantation studies, PD research is poised to enter a new phase that utilizes the human model system to identify the unique vulnerabilities of human nigral DA neurons and disease-modifying therapies based on such mechanistic studies.

Pu, Jiali; Jiang, Houbo; Zhang, Baorong; Feng, Jian

2012-01-01

26

Rhythm-specific modulation of the sensorimotor network in drug-naive patients with Parkinson's disease by levodopa.  

PubMed

Brain activity during rest is characterized by slow (0.01-0.1 Hz) fluctuations of blood oxygenation level-dependent functional magnetic resonance imaging signals. These fluctuations are organized as functional connectivity networks called resting-state networks, anatomically corresponding to specific neuronal circuits. As Parkinson's disease is mainly characterized by a dysfunction of the sensorimotor pathways, which can be influenced by levodopa administration, the present study investigated the functional connectivity changes within the sensorimotor resting-state network in drug-naïve patients with Parkinson's disease after acute levodopa administration. Using a double-blind placebo-controlled design, resting-state functional magnetic resonance imaging was carried out in 20 drug-naïve patients with Parkinson's disease, immediately before and 60 min after, oral administration of either levodopa or placebo. Control resting-state functional magnetic resonance imaging data were recorded in 18 age- and sex-matched healthy volunteers. Independent component analysis was performed to extract resting-state network maps and associated time-course spectral features. At the anatomical level, levodopa enhanced the sensorimotor network functional connectivity in the supplementary motor area, a region where drug-naïve patients with Parkinson's disease exhibited reduced signal fluctuations compared with untreated patients. At the spectral frequency level, levodopa stimulated these fluctuations in a selective frequency band of the sensorimotor network. The reported effects induced by levodopa on sensorimotor network topological and spectral features confirm that the sensorimotor system is a target of acute levodopa administration in drug-naïve patients with Parkinson's disease. Moreover, while the regional changes in supplementary motor area reflect the functional improvement in motor function, the rhythm-specific modulation induced by the dopamine precursor discloses a novel aspect of pharmacological stimulation in Parkinson's disease, adding further insight to the comprehension of levodopa action. PMID:23423673

Esposito, Fabrizio; Tessitore, Alessandro; Giordano, Alfonso; De Micco, Rosita; Paccone, Antonella; Conforti, Renta; Pignataro, Giuseppe; Annunziato, Lucio; Tedeschi, Gioacchino

2013-03-01

27

Drug-Induced Diarrhea  

Microsoft Academic Search

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

Bincy P. Abraham; Joseph H. Sellin

28

Drug-induced diarrhea  

Microsoft Academic Search

Many drugs have been known to cause diarrhea, although their mechanism of action has not been well desribed. The gastrointestinal\\u000a tract may become dysregulated when exposed to a drug that could disrupt mechanisms controlling mucosal permeability, transport,\\u000a motility, and gut metabolism. This review examines the mechanism by which drugs induce diarrhea within the broad classification\\u000a of watery, inflammatory, and fatty

Bincy Abraham; Joseph H. Sellin

2007-01-01

29

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

PubMed

The purpose of this study was to investigate whether a period of continuous theta burst stimulation (cTBS) induces cortical plasticity and thus improves bradykinesia of the upper limb in Parkinson's disease. In eight patients with Parkinson's disease (two females; mean age: 68.5 ± 5 years; disease duration: 4 ± 3 years) electrophysiological (motor evoked potentials, contralateral and ipsilateral silent period) and behavioural (Purdue pegboard test, UPDRS motor subscore) parameters were evaluated before (baseline condition) and after a 40-s period of (1) real or (2) sham continuous theta burst stimulation over the primary motor cortex contralateral to the more affected body side off dopaminergic drugs. Compared to baseline, cTBS did change neither measures of cortical excitability nor behavioural measures. cTBS over the primary motor cortex does not impact on cortical excitability or motor function of the upper limb in Parkinson's disease. We interpret these data to reflect impaired cortical plasticity in Parkinson's disease. This study is an important contribution to the knowledge about impaired plasticity in Parkinson's disease. PMID:20496035

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

2010-10-01

30

The influence of levodopa-induced dyskinesias on manual tracking in patients with Parkinson’s disease  

Microsoft Academic Search

The influence of peak-dose, levodopa-induced dyskinesias (LID) on manual tracking (MT) was examined in 10 dyskinetic patients\\u000a with Parkinson’s disease (DPD), and compared to 10 age\\/gender-matched non-dyskinetic patients with Parkinson’s disease (NDPD)\\u000a and 10 healthy controls. Whole-body movement (WBM) and MT performance were recorded simultaneously with a 6-degrees-of-freedom\\u000a magnetic motion tracker and forearm rotation sensors, respectively. Subjects were asked to match

Sarah Lemieux; Mehrdad Ghassemi; Mandar Jog; Roderick Edwards; Christian Duval

2007-01-01

31

Promises of novel multi-target neuroprotective and neurorestorative drugs for Parkinson's disease.  

PubMed

The cascade of neurotoxic events involved in neuronal degeneration suggests that it is naive to think mono-target drugs can induce disease modification by slowing the process of neurodegeneration in Parkinson's disease (PD). Employing the pharmacophore of rasagiline (N-propargyl-1-R-aminoindan), we have developed a series of novel multi-target neuroprotective drugs, including: (A) drugs [ladostigil, TV-3326 (N-propargyl-3R-aminoindan-5yl)-ethyl methylcarbamate)] with both cholinesterase-butyrylesterase (Ch-BuE) and brain-selective monamine oxidase-AB (MAO-AB) inhibitory activities and (B) iron chelator-radical scavenging drugs (M30) possessing brain-selective MAO-AB inhibitor activity and the neuroprotective-neurorescue propargylamine moiety of rasagiline. This was considered to be valid since brain MAO and iron increase in PD and aging, which could lead to oxidative stress-dependent neurodegeneration. The multi-target iron chelator, M30, has all the properties of ladostigil, but is not an acetylcholinesterase (CHE) inhibitor. However, M30 has both neuroprotective and neurorestorative activities for nigrostriatal dopamine neurons in post-lesion MPTP, lactacystin and 6-hydroxydopamine animal models of PD. The neurorestorative activity has been identified as being related to the ability of the drug to activate hypoxia-inducible factor (HIF) by inhibiting prolyl-4-hydroxylase. M30 regulates cell cycle arrest and induces the neurotrophins brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), erythropoietin (EPO), as well as glia-derived neurotrophic factor (GDNF). These unique multiple actions of M30 make it potentially useful as a disease modifying drug for the treatment of PD. PMID:24262165

Youdim, Moussa B H; Kupershmidt, Lana; Amit, Tamar; Weinreb, Orly

2014-01-01

32

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

PubMed

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

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

2014-02-01

33

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

PubMed Central

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

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

2013-01-01

34

Drug-induced esophagitis.  

PubMed

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

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

2009-01-01

35

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

PubMed Central

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

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

2014-01-01

36

Drug-induced vasculitis.  

PubMed

Vasculitis resulting from drug use includes a wide variety of clinical and pathologic conditions that are, in general, empirically defined and poorly understood. Further complicating our grasp of these disorders are ambiguous terms such as hypersensitivity vasculitis, allergic vasculitis, leukocytoclastic vasculitis, serum sickness, and others, which are often used interchangeably without clear definition. The clinical picture varies widely from self-limiting to progressive and even fatal illness. These syndromes have now been reported in association with newer classes of therapeutic agents including biologic response modifiers. Vasculitis affecting the central nervous system may be related to a variety of drugs and remains one of the more important syndrome sets within the spectrum of drug-induced vasculitis. These disorders are clinically important, because removal of the offending drug often is associated with regression of the vasculitic condition. PMID:8867537

Calabrese, L H; Duna, G F

1996-01-01

37

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

Microsoft Academic Search

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

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

2011-01-01

38

Drug treatment of Parkinson's disease. Time for phase II.  

PubMed

Parkinson's disease (PD) is a neurodegenerative syndrome for which at present no cure is available; therapy consists mainly of amelioration of the symptoms with L-Dopa and/or dopamine (DA) agonists. Development of an effective causal therapy should be focussed on preventing or at least retarding the neurodegenerative process underlying the disease. At the cellular level, PD is characterized by degeneration of neuromelanin-containing dopaminergic neurons in the substantia nigra. Neuromelanin formation is the outcome of a process generally known as DA autooxidation, a chain of oxidation reactions in which highly neurotoxic DA-quinones are produced. The level of these DA-quinones, as estimated by the occurrence of their cysteinyl conjugates, is reported to be increased in the Parkinsonian substantia nigra. Hence, stimulation of pathways implicated in the detoxication of DA-quinones in the brain may provide neuroprotection in PD. Besides their inactivation through non-enzymatic antioxidants such as ascorbic acid and glutathione, DA-quinones are efficiently inactivated enzymatically by NAD(P)H:quinone oxidoreductase (NQO) and glutathione transferase(s), both of which are expressed in the human substantia nigra. The activity of these enzymes, which belong to the group of phase II biotransformation enzymes, can be up-regulated by a large variety of compounds. These compounds, including dithiolethiones, phenolic anti-oxidants, and isothiocyanates, have been shown to be active both in vitro and in vivo. Thus, considering the role of phase II biotransformation enzymes, in particular NQO and glutathione transferase(s), in the detoxication of DA-quinones, we propose that phase II enzyme inducers warrant evaluation on their neuroprotective potential in PD. PMID:10704931

Drukarch, B; van Muiswinkel, F L

2000-05-01

39

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

PubMed Central

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

Hong, Lin; Sklar, Larry A.

2014-01-01

40

Drug-Induced Hematologic Syndromes  

PubMed Central

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

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

2009-01-01

41

Toxin-Induced Models of Parkinson's Disease  

PubMed Central

Summary: Parkinson's disease (PD) is a common neurodegenerative disease that appears essentially as a sporadic condition. It results mainly from the death of dopaminergic neurons in the substantia nigra. PD etiology remains mysterious, whereas its pathogenesis begins to be understood as a multifactorial cascade of deleterious factors. Most insights into PD pathogenesis come from investigations performed in experimental models of PD, especially those produced by neurotoxins. Although a host of natural and synthetic molecules do exert deleterious effects on dopaminergic neurons, only a handful are used in living laboratory animals to recapitulate some of the hallmarks of PD. In this review, we discuss what we believe are the four most popular parkinsonian neurotoxins, namely 6-hydroxydopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, and paraquat. The main goal is to provide an updated summary of the main characteristics of each of these four neurotoxins. However, we also try to provide the reader with an idea about the various strengths and the weaknesses of these neurotoxic models.

Bove, Jordi; Prou, Delphine; Perier, Celine; Przedborski, Serge

2005-01-01

42

Levodopa-Induced Dyskinesias in Parkinson’s Disease: Etiology, Impact on Quality of Life, and Treatments  

Microsoft Academic Search

Levodopa is the most effective agent to alleviate motor dysfunction in Parkinson’s disease but its long-term use is associated with the development of dyskinesias. Although the pathogenic processes behind the development of levodopa-induced dyskinesias are still being elucidated, it appears that chronic administration of this short-lived agent results in nonphysiologic pulsatile stimulation of striatal neurons and abnormal firing patterns in

Elmyra V. Encarnacion; Robert A. Hauser

2008-01-01

43

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

PubMed

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

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

2013-11-01

44

Application of Several Multimedia Approaches to the Teaching of CNS Pharmacology: Parkinson's Disease and Antiparkinsonism Drugs.  

ERIC Educational Resources Information Center

A multimedia approach to drug therapy for Parkinson's Disease, part of a pharmacy school central nervous system course, integrated use of lecture, textbook, video/graphic technology, the movie "Awakenings," Internet and World Wide Web, and an interactive animated movie. A followup questionnaire found generally positive student attitudes toward the…

Faulkner, Thomas P.; Sprague, Jon E.

1996-01-01

45

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

Microsoft Academic Search

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

Andreas Schober

2004-01-01

46

Loss of thalamic serotonin transporters in early drug-naïve Parkinson’s disease patients is associated with tremor: an [ 123 I]?-CIT SPECT study  

Microsoft Academic Search

In vitro studies revealed serotonin transporter (5-HTT) decline in Parkinson’s disease (PD). Yet, few studies investigated\\u000a thalamic 5-HTT in vivo and its effect on PD heterogeneity. We analyzed thalamic [123I]?-CIT binding (mainly reflecting 5-HTT binding) in 32 drug-naïve PD patients and 13 controls with SPECT. Twenty-six patients\\u000a were examined twice (17 months apart). Based on UPDRS scores, we identified subgroups of

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

2008-01-01

47

Drug-induced liver injury  

Microsoft Academic Search

Drug-induced liver injury (DILI) accounts for 9.5% of all suspected adverse drug reactions (ADRs) and for a significant proportion of fatal ADRs. DILI may be a direct toxic effect or an immunological reaction to either the drug or an active metabolite. Drugs can cause a diverse array of liver injury, which may be acute or chronic. Adaptation to injurious effects,

Adam D. Farmer; Alison Brind

2011-01-01

48

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

PubMed Central

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

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

2013-01-01

49

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

Microsoft Academic Search

Objective: To compare the tremorlytic properties of pramipexole, a non-ergoline dopamine agonist to those of placebo as add on medication in patients with Parkinson's disease. Methods: Eighty four patients with early or advanced Parkinson's disease and marked, drug resistant tremor under a stable and optimised antiparkinsonian medication were included in a double blind, randomised, placebo controlled, multicentre study and assigned

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

2002-01-01

50

Management of levodopa-induced dyskinesias in Parkinson's disease  

Microsoft Academic Search

\\u000a Abstract\\u000a   Long-term administration of levodopa in Parkinson's disease (PD) can cause motor complications such as dyskinesias and motor\\u000a response fluctuations. An increased risk is associated with more severity and younger age at onset of PD, longer duration\\u000a of treatment, and higher levodopa dose. Levodopa-induced dyskinesias (LID) consist of peak-dose dyskinesia, biphasic dyskinesia,\\u000a and off-period dystonia. The pathophysiology of LID includes

Kenichi Kashihara

2007-01-01

51

Neuroprotective effects of nicotine against salsolinol-induced cytotoxicity: Implications for parkinson’s disease  

Microsoft Academic Search

Parkinson’s disease is associated with degeneration of dopaminergic cell bodies in the substantia nigra. It has been suggested\\u000a that salsolinol, an endogenous metabolite of dopamine, may be involved in this process. An inverse relationship between Parkinson’s\\u000a disease and smoking (nicotine intake) has been observed in epidemiological studies. Moreover, neuroprotective effects of nicotine\\u000a in various experimental models have been observed. In

Robert L. Copeland; Yaminah A. Leggett; Yasmine M. Kanaan; Robert E. Taylor; Yousef Tizabi

2005-01-01

52

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

PubMed Central

Background Overexpression and abnormal accumulation of aggregated ?-synuclein (?S) have been linked to Parkinson's disease (PD) and other synucleinopathies. ?S can misfold and adopt a variety of morphologies but recent studies implicate oligomeric forms as the most cytotoxic species. Both genetic mutations and chronic exposure to neurotoxins increase ?S aggregation and intracellular reactive oxygen species (ROS), leading to mitochondrial dysfunction and oxidative damage in PD cell models. Results Here we show that curcumin can alleviate ?S-induced toxicity, reduce ROS levels and protect cells against apoptosis. We also show that both intracellular overexpression of ?S and extracellular addition of oligomeric ?S increase ROS which induces apoptosis, suggesting that aggregated ?S may induce similar toxic effects whether it is generated intra- or extracellulary. Conclusions Since curcumin is a natural food pigment that can cross the blood brain barrier and has widespread medicinal uses, it has potential therapeutic value for treating PD and other neurodegenerative disorders.

2010-01-01

53

[Drug-induced hypercalcemia].  

PubMed

Drug-induced hypercalcemia is caused by increased bone resorption (vitamin D and vitamin A intoxication), increased calcium absorption in the gastrointestinal tract (vitamin D intoxication, excessive intake of calcium) or increased calcium reabsorption in the renal tubules (thiazide diuretics). When vitamin D (D(2) or D(3)) intoxication develops, the hypercalcemia persists for more than several months. Therefore, short-acting active vitamin D (1alpha-OHD(3), 1,25- (OH) (2)D(3)) are clinically used. Recently, various analogs of 1,25- (OH) (2)D(3) with potent differentiation stimulating activity on keratinocytes but insufficient calcium-movilizing activity have been developed (tacalcitol, calcipotriol, 22-oxacalcitriol). However, severe hypercalcemia may develop when these ointments were abundantly applied to patients with psoriasis since the agents can be easily absorbed through the skin lesions. PMID:16397353

Sato, Kanji

2006-01-01

54

Nicotinic receptor agonists reduce L-DOPA-induced dyskinesias in a monkey model of Parkinson's disease.  

PubMed

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

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

2013-10-01

55

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

PubMed Central

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

2011-01-01

56

An anti-Parkinson drug ropinirole depletes orexin from rat hypothalamic slice culture.  

PubMed

Non-ergot-type dopamine receptor agonists such as ropinirole are used for the treatment of Parkinson disease, but they occasionally show serious side effects including sleep attacks and daytime sleepiness. These symptoms are reminiscent of narcolepsy, a major sleep disorder. Because narcolepsy is thought to result from deficiency of a hypothalamic neuropeptide orexin, we examined whether ropinirole affected the integrity of orexin-containing neurons, using organotypic slice culture of rat hypothalamus. Application of ropinirole induced a significant decrease in the number of orexin-immunoreactive neurons. The same treatment showed no significant effect on the number of melanin-concentrating hormone-immunoreactive neurons. The decrease of orexin-immunoreactive neurons was reversible after washout of ropinirole and was not accompanied by induction of cell death. Antagonism of dopamine D(2) receptors and of serotonin 5-HT(1A) receptors attenuated the effect of ropinirole, suggesting involvement of these receptors in depletion of orexin. On the other hand, a moderate concentration of N-methyl-d-aspartate that excited orexin neurons counteracted the effect of ropinirole on the number of orexin-immunoreactive neurons. These results suggest that ropinirole can cause deficiency of orexin by inhibiting excitatory activities of orexin neurons, which may be relevant to the adverse actions of this drug on sleep and wakefulness. PMID:20727917

Michinaga, Shotaro; Hisatsune, Akinori; Isohama, Yoichiro; Katsuki, Hiroshi

2010-12-01

57

Levetiracetam for levodopa-induced dyskinesia in Parkinson’s disease: a randomized, double-blind, placebo-controlled trial  

Microsoft Academic Search

The aim of this study was to assess the efficacy, safety and tolerability of the antiepileptic compound levetiracetam (LEV)\\u000a for the treatment of levodopa-induced dyskinesia (LID) in Parkinson’s disease (PD). We thus performed a randomized, double-blind,\\u000a placebo-controlled, parallel-group pilot study in PD patients with moderate-to-severe LID on stable dopaminergic therapy.\\u000a Placebo or LEV was administered twice daily (titrated from 250

Martin WolzMatthias; Matthias Löhle; Karl Strecker; Uta Schwanebeck; Christine Schneider; Heinz Reichmann; Xina Grählert; Johannes Schwarz; Alexander Storch

2010-01-01

58

Toxin-Induced and Genetic Animal Models of Parkinson's Disease  

PubMed Central

Parkinson's disease (PD) is a common progressive neurodegenerative disorder. The major pathological hallmarks of PD are the selective loss of nigrostriatal dopaminergic neurons and the presence of intraneuronal aggregates termed Lewy bodies (LBs), but the pathophysiological mechanisms are not fully understood. Epidemiologically, environmental neurotoxins such as pesticides are promising candidates for causative factors of PD. Oxidative stress and mitochondrial dysfunction induced by these toxins could contribute to the progression of PD. While most cases of PD are sporadic, specific mutations in genes that cause familial forms of PD have led to provide new insights into its pathogenesis. This paper focuses on animal models of both toxin-induced and genetically determined PD that have provided significant insight for understanding this disease. We also discuss the validity, benefits, and limitations of representative models.

Hisahara, Shin; Shimohama, Shun

2011-01-01

59

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

PubMed

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

Jenner, Peter

2013-08-01

60

Manganese-induced Parkinsonism in a patient undergoing maintenance hemodialysis.  

PubMed

We report a rare case of manganese (Mn)-induced parkinsonism in a patient on maintenance hemodialysis therapy who complained of gait disturbance and dysarthria. His symptoms and abnormal magnetic resonance imaging (MRI) findings of the brain were thought to be caused, at least in part, by long-term ingestion of a health supplement (Chlorella extract) that contained 1.7 mg of Mn in the usual daily dose. Elevated serum and cerebrospinal fluid Mn levels were detected, and brain MRI showed areas of abnormal intensity in the bilateral basal ganglia (low intensity on T1-weighted images and high intensity on T2-weighted images). Edetic acid infusion therapy dramatically improved the MRI abnormalities, after which his symptoms gradually improved 4 months later. PMID:16183431

Ohtake, Takayasu; Negishi, Kousuke; Okamoto, Kouji; Oka, Machiko; Maesato, Kyoko; Moriya, Hidekazu; Kobayashi, Shuzo

2005-10-01

61

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

PubMed Central

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

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

2014-01-01

62

Drug-Induced Liver Injury  

Microsoft Academic Search

Many drugs and environmental chemicals are capable of evoking some degree of liver injury. The liver represents a primary\\u000a target for adverse drug reactions due to its central role in biotransformation and excretion of foreign compounds, its portal\\u000a location within the circulation exposing it to a wide variety of substances, and its anatomic and physiologic structure. Drug-induced\\u000a liver injury (DILI)

Michael Holt; Cynthia Ju

63

Drug-induced lupus erythematosus  

MedlinePLUS

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

64

Drug-induced pulmonary disease  

MedlinePLUS

Acute episodes usually go away within 48 - 72 hours after the medication has been stopped. Chronic symptoms may take longer to improve. Some drug-induced lung diseases, such as pulmonary fibrosis, ...

65

Drug-induced hepatic injury.  

PubMed

Drugs and other chemical toxins account for less than 5% of cases of jaundice or acute hepatitis and fewer cases of chronic liver disease, but they are an important cause of more severe types of hepatic injury. Drug reactions produce an array of hepatic lesions that mimic all known hepatobiliary diseases; this poses a diagnostic challenge for physicians and pathologists. Diagnosis of drug-induced hepatic injury is circumstantial, with positive rechallenge being the only factor that unequivocally implicates a particular agent. Nonetheless, other aspects of the temporal relationship between drug ingestion and adverse reaction, exclusion of other diseases, the presence of extrahepatic features of drug hypersensitivity and some findings on liver biopsy can lend support to the diagnosis. Some of these issues will be explored in this review by considering contemporary paradigms of drug-induced hepatic injury. Factors that predispose to dose-dependent hepatic injury will be considered in relation to acetaminophen, an example of acute hepatotoxicity, and methotrexate, an agent that can produce hepatic fibrosis. Flucloxacillin will be discussed as an example of drug-induced cholestatic hepatitis often associated with prolonged cholestasis and the vanishing bile duct syndrome. Minocycline and diclofenac will be mentioned as two drugs for which drug hepatitis is an exceedingly rare complication. Finally, the evidence that Chinese herbal medicines can be hepatotoxic will be reviewed. PMID:9407344

Farrell, G C

1997-10-01

66

Non-drug-induced nephrotoxicity  

Microsoft Academic Search

Several drugs and other compounds can induce acute and\\/or chronic nephrotoxicity. The goal of this study was to review clinical\\u000a features of nephrotoxicity induced by ‘atypical’ or ‘unconventional’ agents, such as environmental agents (metals, minerals,\\u000a animals), food agents (mushrooms, aristolochic acid, medicinal traditional herbals, dietary supplements, melamine), drugs,\\u000a and other products (ethylene glycol). Nephrotoxicity varies according to local background, dependent

Justine Bacchetta; Laurence Dubourg; Laurent Juillard; Pierre Cochat

2009-01-01

67

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

PubMed

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

Cesaro, P; Defebvre, L

2014-04-01

68

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

PubMed Central

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

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

2012-01-01

69

Protective Effect of Lycopene on Oxidative Stress and Cognitive Decline in Rotenone Induced Model of Parkinson’s Disease  

Microsoft Academic Search

Evidence from clinical and experimental studies indicate that oxidative stress is involved in pathogenesis of Parkinson’s\\u000a disease. The present study was designed to investigate the neuroprotective potential of lycopene on oxidative stress and neurobehavioral\\u000a abnormalities in rotenone induced PD. Rats were treated with rotenone (3 mg\\/kg body weight, intraperitoneally) for 30 days.\\u000a NADH dehydrogenase a marker of rotenone action was observed to

Harpreet Kaur; Shaveta Chauhan; Rajat Sandhir

70

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

PubMed Central

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

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

2012-01-01

71

Drug-induced lupus erythematosus.  

PubMed

Drug-induced lupus erythematosus (DILE) refers to a condition whose clinical, histological, and immunological features are similar to those seen in idiopathic lupus erythematosus but that occurs when certain drugs are taken and resolves after their withdrawal. Over 90 drugs have been linked to DILE to date and the list is growing. Like idiopathic lupus erythematosus, DILE has systemic, subacute cutaneous, and chronic cutaneous forms. A correct diagnosis is very important, as this condition usually resolves after withdrawal of the offending drug. PMID:23164669

Pretel, M; Marquès, L; España, A

2014-01-01

72

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

Microsoft Academic Search

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

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

2005-01-01

73

Drug-induced peripheral neuropathies.  

PubMed

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

Argov, Z; Mastaglia, F L

1979-03-10

74

Apoptosis induced by anticancer drugs  

Microsoft Academic Search

Most of the cytotoxic anticancer drugs in current use have been shown to induce apoptosis in susceptible cells. The fact that disparate agents, which interact with different targets, induce cell death with some common features (endonucleolytic cleavage of DNA, changes in chromatin condensation) suggests that cytotoxicity is determined by the ability of the cell to engage this so-called ‘programmed’ cell

John A. Hickman

1992-01-01

75

The Endotoxin-Induced Neuroinflammation Model of Parkinson's Disease  

PubMed Central

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

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

2011-01-01

76

Drug-Induced Urinary Calculi  

PubMed Central

Urinary calculi may be induced by a number of medications used to treat a variety of conditions. These medications may lead to metabolic abnormalities that facilitate the formation of stones. Drugs that induce metabolic calculi include loop diuretics; carbonic anhydrase inhibitors; and laxatives, when abused. Correcting the metabolic abnormality may eliminate or dramatically attenuate stone activity. Urinary calculi can also be induced by medications when the drugs crystallize and become the primary component of the stones. In this case, urinary supersaturation of the agent may promote formation of the calculi. Drugs that induce calculi via this process include magnesium trisilicate; ciprofloxacin; sulfa medications; triamterene; indinavir; and ephedrine, alone or in combination with guaifenesin. When this situation occurs, discontinuation of the medication is usually necessary.

Matlaga, Brian R; Shah, Ojas D; Assimos, Dean G

2003-01-01

77

Comparison of chronic analgesic drugs prevalence in Parkinson's disease, other chronic diseases and the general population.  

PubMed

Patients with Parkinson's disease (PD) frequently experienced pain. Nevertheless, there are no epidemiological data about frequency of pain in PD. We compare pain prevalence using analgesic prescription in PD patients, in the general population and in two samples of painful patients: diabetics and osteoarthritis patients in France. Data were obtained from the French System of Health Insurance for the year 2005. Medications (antiparkinsonian, antidiabetics drugs and osteoarthritis drugs) were used for identification of PD, diabetic and osteoarthritis patients. We estimated the prevalence of analgesic drugs prescription (at least one analgesic drug) and the prevalence of chronic analgesic drugs prescription (more than 90 DDD of analgesic drug). The study included 11,466 PD patients. PD patients significantly received more prescription of analgesics than the general population (82% versus 77%,) and fewer than patients with osteoarthritis (82% versus 90%). No significant difference was found between PD and diabetic patients. The chronic prescription of analgesic drugs was more prevalent in PD patients (33%) than in the general population (20%) and in diabetic patients (26%) and similar to that in osteoarthritis patients. PD patients were more exposed than the general population and diabetics to opiates, acetaminophen, and adjuvant analgesics chronic use. PMID:19062167

Brefel-Courbon, Christine; Grolleau, Sabrina; Thalamas, Claire; Bourrel, Robert; Allaria-Lapierre, Valérie; Loï, Robert; Micallef-Roll, Joelle; Lapeyre-Mestre, Maryse

2009-01-01

78

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

PubMed

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

Youdim, Moussa B H

2013-03-01

79

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

PubMed Central

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.

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

2014-01-01

80

Drug-induced Liver Injury  

PubMed Central

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

David, Stefan; Hamilton, James P

2011-01-01

81

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

PubMed Central

A major barrier to research on Parkinson's disease is inaccessibility of diseased tissue for study. One solution is to derive induced pluripotent stem cells from patients and differentiate them into neurons affected by disease. Triplication of SNCA, encoding ?-synuclein, causes a fully penetrant, aggressive form of Parkinson's disease with dementia. ?-Synuclein dysfunction is the critical pathogenic event in Parkinson's disease, multiple system atrophy and dementia with Lewy bodies. Here we produce multiple induced pluripotent stem cell lines from an SNCA triplication patient and an unaffected first-degree relative. When these cells are differentiated into midbrain dopaminergic neurons, those from the patient produce double the amount of ?-synuclein protein as neurons from the unaffected relative, precisely recapitulating the cause of Parkinson's disease in these individuals. This model represents a new experimental system to identify compounds that reduce levels of ?-synuclein, and to investigate the mechanistic basis of neurodegeneration caused by ?-synuclein dysfunction.

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

2011-01-01

82

Drug-induced corneal damage.  

PubMed

Corneal damage can have a variety of causes, including infections, chemical splashes, environmental factors (radiation, trauma, contact lenses, etc.), and systemic diseases (genetic, autoimmune, inflammatory, metabolic, etc.). A wide range of drugs can also damage the cornea. The severity of drug-induced corneal changes can range from simple asymptomatic deposits to irreversible, sight-threatening damage. Several factors can influence the onset of corneal lesions. Some factors, such as the dose, are treatment-related, while others such as contact lenses, are patient-related. A variety of mechanisms may be involved, including corneal dryness, changes in the corneal epithelium, impaired wound healing and deposits. Many drugs can damage the cornea through direct contact, after intraocular injection or instillation, including VEGF inhibitors, anti-inflammatory drugs, local anaesthetics, glaucoma drugs, fluoroquinolones, and preservatives. Some systemically administered drugs can also damage the cornea, notably cancer drugs, amiodarone and isotretinoin. Vulnerable patients should be informed of this risk if they are prescribed a drug with the potential to damage the cornea so that they can identify problems in a timely manner. It may be necessary to discontinue the suspect drug when signs and symptoms of corneal damage occur. PMID:24860895

2014-04-01

83

Drug Induced Interstitial Lung Disease  

PubMed Central

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

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

2012-01-01

84

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

PubMed

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

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

2014-01-01

85

Drugs induced pulmonary arterial hypertension.  

PubMed

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

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

2013-09-01

86

Parkinson's Disease  

MedlinePLUS

Parkinson’s Disease Introduction Parkinson’s disease is a common disease that affects muscle control. Parkinson’s disease affects about half a million people every year. The symptoms of Parkinson’s disease are easily treated. This ...

87

Drug-induced liver injury following positive drug rechallenge  

Microsoft Academic Search

Drug rechallenge (or reinitiation), following an event of drug-induced liver injury, can lead to serious or fatal liver injury. A retrospective review of a large pharmaceutical safety database was conducted to assess clinical outcomes of positive drug rechallenge following possible drug-induced liver injury.Positive rechallenge with suspect drug was reported in 770 of 36,795 hepatic adverse events. A total of 88

Julie I. Papay; Dawn Clines; Rezvan Rafi; Nancy Yuen; Susan D. Britt; John S. Walsh; Christine M. Hunt

2009-01-01

88

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

PubMed

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

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

2011-12-01

89

Involvement of Nitric Oxide in Maneb- and Paraquat-Induced Parkinson’s Disease Phenotype in Mouse: Is There Any Link with Lipid Peroxidation?  

Microsoft Academic Search

The study aimed to investigate the involvement of nitric oxide (NO) in maneb (MB)- and paraquat (PQ)-induced Parkinson’s disease\\u000a (PD) phenotype in mouse and its subsequent contribution to lipid peroxidation. Animals were treated intraperitoneally with\\u000a or without MB and PQ, twice a week for 3, 6 and 9 weeks. In some sets of experiments (9 weeks treated groups), the animals\\u000a were treated

Satya Prakash Gupta; Suman Patel; Sharawan Yadav; Anand Kumar Singh; Seema Singh; Mahendra Pratap Singh

2010-01-01

90

PLGA microparticles with zero-order release of the labile anti-Parkinson drug apomorphine.  

PubMed

The treatment of patients suffering from advanced Parkinson's disease is highly challenging, because the efficacy of the "gold standard" levodopa declines with time. Co-administration of the dopamine receptor agonist apomorphine is beneficial, but difficult due to the poor oral bioavailability and short half-life of this drug. In order to overcome these restrictions, PLGA-based microparticles allowing for controlled parenteral delivery of this morphine derivative were prepared using (solid-in-)oil-in-water extraction/evaporation techniques. Particular attention was paid to minimize spontaneous oxidation of the labile drug and to optimize the key features of the microparticles, including encapsulation efficiency, initial burst release and particle size. Various formulation and processing parameters were adjusted in this respect. The systems were thoroughly characterized using SEM, EDX, DSC, laser diffraction, headspace-GC as well as in vitro drug release measurements in agitated flasks and flow-through cells. Importantly, apomorphine could effectively be protected against degradation during microparticle preparation and within the delivery systems upon exposure to phosphate buffer pH 7.4 (containing 0.2% ascorbic acid) at 37 °C: 90% intact drug was released at a constant rate during about 10d. PMID:23313920

Regnier-Delplace, C; Thillaye du Boullay, O; Siepmann, F; Martin-Vaca, B; Degrave, N; Demonchaux, P; Jentzer, O; Bourissou, D; Siepmann, J

2013-02-25

91

Neuroprotection by a mitochondria-targeted drug in a Parkinson's disease model  

PubMed Central

The objective of this study was to assess the neuroprotective effects of a mitochondria-targeted antioxidant, Mito-Q10, the coenzyme-Q analog attached to a triphenylphosphonium cation that targets the antioxidant to mitochondria, in experimental models of Parkinson’s disease (PD). Primary mesencephalic neuronal cells and cultured dopaminergic cells were treated with 1-methyl-4-phenylpyridinium (MPP+), an active metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and mice were used for testing the efficacy of Mito-Q10. MPP+ treatment caused a dose-dependent loss of tyrosine hydroxylase and membrane potential and an increase in caspase-3 activation in dopaminergic cells, which were reversed by Mito-Q10. MPTP treatment induced a loss of striatal dopamine and its metabolites, inactivation of mitochondrial aconitase in the substantia nigra, and a loss of locomotor activity in mice. Treatment with Mito-Q10 significantly inhibited both MPP+- and MPTP-induced neurotoxicity in cell culture and mouse models. Collectively, these results indicate that mitochondrial targeting of antioxidants is a promising neuroprotective strategy in this preclinical mouse model of PD.

Ghosh, Anamitra; Chandran, Karunakaran; Kalivendi, Shasi V.; Joseph, Joy; Antholine, William E.; Hillard, Cecilia J.; Kanthasamy, Arthi; Kanthasamy, Anumantha; Kalyanaraman, Balaraman

2014-01-01

92

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

PubMed Central

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

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

2010-01-01

93

Drug-induced megaloblastic change.  

PubMed

Treatment with any drug which either directly or indirectly affects cellular DNA biosynthesis can result in megaloblastic change. This type of change results from an inadequate rate of DNA replication with a consequent rate of cell division of the erythrocyte series. Appearance of abnormal red cell precursors, i.e., megaloblasts, in the bone marrow, changes in the peripheral blood film, a raised mean corpusular volume, and, often, anemia signal these DNA biosynthetic changes. Drugs which block DNA biosynthesis are categorized according to their action on the following phases of the process: 1) DNA assembly; 2) ribonucleotide reduction; 3) thymidylate biosynthesis; 4) pyrimidine precursor biosynthesis; 5) purine precursor biosynthesis; and 6) mechanism unknown. A hierarchial diagram illustrates the sites of drug-induced inhibition of DNA biosynthesis. A table presents the drugs which induce megaloblastic change, their usage, their mechanism of action, and the risk of megaloblastosis occurring as a result of their usage. Protracted use of oral contraceptives(OCs) has been shown to produce megaloblastic anemia only infrequently. OCs can interfere with folate cofactor interactions, causing impaired DNA synthesis, however. Alcohol consumption leads to development of macrocytosis, megaloblastosis, and anemia either through folate deficiency or through marrow toxicity. PMID:6450011

Scott, J M; Weir, D G

1980-10-01

94

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

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.

2014-01-01

95

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

PubMed

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

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

2007-12-01

96

Drug-induced lupus erythematosus.  

PubMed

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

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

2014-06-01

97

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

PubMed

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

Gaki, Georgia S; Papavassiliou, Athanasios G

2014-06-01

98

Dementia in Parkinson’s Disease  

Microsoft Academic Search

Opinion statement  Dementia in Parkinson’s disease encompasses a spectrum relating to motor, psychiatric, and cognitive symptoms that are classified\\u000a as either Dementia with Lewy Bodies (DLB) (initial cognitive symptoms) or Parkinson’s Disease Dementia (PDD) (initial motor\\u000a signs preceding cognitive symptoms by at least a year). Anticholinergic and antipsychotic drugs have a high risk of adverse\\u000a cognitive and\\/or motor effects, so their

Avrom L. Kurtz; Daniel I. Kaufer

2011-01-01

99

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

PubMed

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

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

2012-07-15

100

Determination of drugs used as anti-Parkinson's disease drugs in urine and serum by capillary electrophoresis.  

PubMed

A new capillary electrophoresis method to determine simultaneously eight of the most important anti-Parkinson's disease compounds has been developed. The generic names of the drugs studied are benactyzine (BA), trihexyphenidyl (TP), fenpiverin (FP), diphemin (DF), scopolamine (BL), adiphenine (TS), diethylaminoethylester 1-phenylcyclopentane-1-carboxylate (EKK), and diethylaminoethylester tetramethoxydiphenylacetate (EKO). An untreated fused-silica capillary tube (75 microns i.d., 57 cm total length, 49.5 cm length to the detector) was used with detection at 190 nm. The optimal separation conditions were 50 mM phosphate buffer (pH 2.7) with 7 mM-beta-cyclodextrin, electrokinetic injection for 15 sec at 5 kV, temperature 25 degrees C, and 15-20 kV separation voltage. Complete separation of all compounds was achieved in less than 16 min. The procedure was applied for the determination in urine and serum. The limits of detection (LOD, S/N = 3) for serum were 209 (FP), 234 (EKO), 168 (DF), 182 (BA), 168 (TP), 220 (BL), 174 (TS), and 163 (EKK) ppb. The method can be used for the therapeutic drug monitoring of these central active cholinolytics in clinical laboratories. PMID:10797881

Vargas, G; Havel, J; Babácková, L; Patocka, J

1998-01-01

101

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

Microsoft Academic Search

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

Ranjeet Verma; Bimla Nehru

2009-01-01

102

Drug-induced pulmonary disease.  

PubMed

Drug-induced disease of any system or organ can be associated with high morbidity and mortality, and it is tremendously costly to the health care of our country. More than 100 medications are known to affect the lungs adversely, including the airways in the form of cough and asthma, the interstitium with interstitial pneumonitis and noncardiac pulmonary edema, and the pleura with pleural effusions. Patients commonly do not even know what medications they are taking, do not bring them to the physician's office for identification, and usually do not relate over-the-counter medications with any problems they have. They assume that all nonprescription drugs are safe. Patients also believe that if they are taking prescription medications at their discretion, meaning on an as-needed basis, then these medications are also not important. This situation stresses just how imperative it is for the physician to take an accurate drug history in all patients seen with unexplained medical situations. Cardiovascular drugs that most commonly produce a pulmonary abnormality are amiodarone, the angiotensin-converting enzyme inhibitors, and beta-blockers. Pulmonary complications will develop in 6% of patients taking amiodarone and 15% taking angiotensin-converting enzyme inhibitors, with the former associated with interstitial pneumonitis that can be fatal and the latter associated with an irritating cough that is not associated with any pathologic or physiologic sequelae of consequence. The beta-blockers can aggravate obstructive lung disease in any patient taking them. Of the antiinflammatory agents, acetylsalicyclic acid can produce several different airway and parenchymal complications, including aggrevation of asthma in up to 5% of patients with asthma, a noncardiac pulmonary edema when levels exceed 40 mg/dl, and a pseudosepsis syndrome. More than 200 products contain aspirin. Low-dose methotrexate is proving to be a problem because granulomatous interstitial pneumonitis develops in 5% of those patients receiving it. This condition occurs most often in patients receiving the drug for rheumatoid arthritis, but it has been reported in a few patients receiving it for refractory asthma. Chemotherapeutic drug-induced lung disease is almost always associated with fever, thus mimicking opportunistic infection, which is the most common cause of pulmonary complications in the immunocompromised host. However, in 10% to 15% of patients, the pulmonary infiltrate is due to an adverse effect from a chemotherapeutic agent. This complication is frequently fatal even when recognized early.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:8174459

Rosenow, E C

1994-05-01

103

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

PubMed

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

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

104

Successful subthalamic stimulation, but levodopa-induced dystonia, in a genetic Parkinson's disease.  

PubMed

Recently, it is under scrutiny the possibility to anticipate the stereotactic implantation of the subthalamic nucleus (STN) even in relatively mild Parkinson's disease (PD) patients with an unsatisfying response to drugs. In addition, it is debated whether levodopa (LD) and deep brain stimulation (DBS) are congruent or, instead, mutually exclusive. A 56-year-old LRRK2-positive PD patient, with 7 years of disease history, dominated by severe left resting tremor, was submitted to bilateral implantation of the subthalamic nucleus (STN). Before surgery, the combination of LD and dopamine agonists failed to handle tremor unless administered at doses, which induced undesirable adverse events. STN deep brain stimulation (DBS) abolished tremor but did not provide satisfying control of hypokinetic-rigid symptoms. The condition STIM-ON plus LD, albeit transiently beneficial, installed a painful dystonia developing slowly after 24-36 h. Only a chronic therapy combining rotigotine plus STN-DBS proved effective without side effects. This case report, based upon the surprising difference between the therapeutic response to the combination of LD and dopamine agonist (before surgery) and the combination of DBS and agonist after surgery, emphasizes how STIM and LD target different motor domains through mechanisms with differential plasticity and confirms the efficacy of STN-DBS in LRKK2 patients. PMID:22437494

Stefani, Alessandro; Marzetti, Francesco; Pierantozzi, Mariangela; Petrucci, Simona; Olivola, Enrica; Galati, Salvatore; Bassi, Mario Stampanoni; Imbriani, Paola; Valente, Enza Maria; Pastore, Francesco Saverio

2013-03-01

105

Drug-naive patients with Parkinson’s disease in Hoehn and Yahr stages I and II show a bilateral decrease in striatal dopamine transporters as revealed by [ 123 I]?-CIT SPECT  

Microsoft Academic Search

Ten healthy subjects and 16 patients with early Parkinson’s disease (PD) were examined with single photon emission computed\\u000a tomography (SPECT) and [123I]?-CIT, a ligand for the dopamine (DA) transporter. Only drug-naive patients were examined since the expression of and binding\\u000a to DA transporters may be influenced by dopaminergic medication. The main finding was a significant reduction in [123I]?-CIT binding in

G. Tissingh; P. Bergmans; J. Booij; A. Winogrodzka; E. A. van Royen; J. C. Stoof; E. C. Wolters

1997-01-01

106

Hypothesis: A role for EBV-induced molecular mimicry in Parkinson's disease.  

PubMed

Current concepts regarding the pathogenesis of Parkinson's disease support a model whereby environmental factors conspire with a permissive genetic background to initiate the disease. The identity of the responsible environmental trigger has remained elusive. There is incontrovertible evidence that aggregation of the neuronal protein alpha-synuclein is central to disease pathogenesis. A novel hypothesis of Parkinson's pathogenesis, articulated by Braak and colleagues, implicates a pathogen acting in the olfactory mucosa and gastrointestinal tract as the inciting agent. In this point-of-view article, we hypothesize that ?-synuclein aggregation in Parkinson's disease is an Epstein-Barr virus (EBV)-induced autoimmune phenomenon. Specifically, we have shown evidence for molecular mimicry between the C-terminal region of ?-synuclein and a repeat region in the latent membrane protein 1 encoded by EBV. We hypothesize that, in genetically-susceptible individuals, anti-EBV latent membrane protein antibodies targeting the critical repeat region cross react with the homologous epitope on ?-synuclein and induce its oligomerization. Consistent with the Braak's proposed pattern of spread, we contend that axon terminals in the lamina propria of the gut are among the initial targets, with subsequent spread of pathology to the CNS. While at this time, we can only provide evidence from the literature and preliminary findings from our own laboratory, we hope that our hypothesis will stimulate the development of tractable experimental systems that can be exploited to test it. Further support for an EBV-induced immune pathogenesis for Parkinson's disease could have profound therapeutic implications. PMID:24726430

Woulfe, John M; Gray, Madison T; Gray, Douglas A; Munoz, David G; Middeldorp, Jaap M

2014-07-01

107

[Drug treatment is beneficial also for elderly patients with Parkinson disease. Important to consider also other co-existing diseases].  

PubMed

Parkinson's disease is a relatively common disorder in elderly patients. With carefully performed treatment a considerable improvement can be seen also in patients of high age. L-dopa as well as other antiparkinsonian drugs should be used in lower doses than those subscribed for younger patients. Cognitive decline implies a certain risk for mental confusion, in which case the dose of the causing agent has to be lowered or the treatment interrupted. PMID:11330147

Granérus, A K

2001-03-28

108

Ropinirole-induced Pisa syndrome in Parkinson disease.  

PubMed

Pisa syndrome (PS), also known as pleurothotonus, is an abnormal posture characterized by lateral flexion of the trunk that typically disappears in supine position. In Parkinson disease (PD), an abnormal forward flexion of the trunk (defined as camptocormia) is a common observation and has been interpreted as a sign of dystonia. Few reports have described PS mainly related to dopaminergic therapy in this kind of patients.Levodopa/carbidopa, levodopa/benserazide, levodopa/carbidopa/entacapone, pergolide, and pramipexole may cause PS, whereas no reports for ropinirole have been described.Here, we describe a case of a patient with PD who developed severe and reversible PS due to ropinirole intake. PMID:24614668

Galati, Salvatore; Möller, Jens Carsten; Städler, Claudio

2014-01-01

109

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

NASA Astrophysics Data System (ADS)

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

Jaramillo Raquejo, Daniela

2013-05-01

110

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

Microsoft Academic Search

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

Hideo Tohgi; Satoshi Takahashi; Takashi Abe; Kimiaki Utsugisawa

2001-01-01

111

Mapping of brain function after MPTP-induced neurotoxicity in a primate Parkinson's disease model  

Microsoft Academic Search

Neurophysiological studies of the brain in normal and Parkinson's disease (PD) patients have indicated intricate connections for basal ganglia-induced control of signaling into the motor cortex. To investigate if similar mechanisms are controlling function in the primate brain (Macaca fascicularis) after MPTP-induced neurotoxicity, we conducted PET studies of cerebral blood flow, oxygen and glucose metabolism, dopamine transporter, and D2 receptor

Anna-Liisa Brownell; Kelly Canales; Y. Iris Chen; Bruce G Jenkins; Christopher Owen; Elijahu Livni; Meixiang Yu; Francesca Cicchetti; Rosario Sanchez-Pernaute; Ole Isacson

2003-01-01

112

Dieldrin-induced neurotoxicity: relevance to Parkinson's disease pathogenesis.  

PubMed

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 genetic factors in the disease. Thus, understanding the interplay between genes and environment in PD may be critical to unlocking the mysteries of this 200-year-old neurodegenerative disease. Pesticides and metals are the most common classes of environmental chemicals that promote dopaminergic degeneration. The organochlorine pesticide dieldrin has been found in human PD postmortem brain tissues, suggesting that this pesticide has potential to promote nigral cell death. Though dieldrin has been banned, humans continue to be exposed to the pesticide through contaminated dairy products and meats due to the persistent accumulation of the pesticide in the environment. This review summarizes various neurotoxic studies conducted in both cell culture and animals models following dieldrin exposure and discusses their relevance to key pathological mechanisms associated with nigral dopaminergic degeneration including oxidative stress, mitochondrial dysfunction, protein aggregation, and apoptosis. PMID:16112328

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

2005-08-01

113

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

Microsoft Academic Search

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

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

2007-01-01

114

Drug-Induced (Thalidomide) Malformations  

PubMed Central

Phocomelia (flipper-like limbs) has long been recognized as a rare malformation. Numerous cases of phocomelia and other congenital malformations have recently been reported in the United Kingdom, Australia, Europe and Canada in which the common factor appears to have been the administration of the hypnotic compound thalidomide during early pregnancy. Two additional cases of infants born with phocomelia, amelia and alimentary abnormalities are presented. In both of these cases the administration of thalidomide was initiated early during pregnancy (five to eight weeks after the last normal menstrual period) and maintained for several weeks. Thalidomide (alpha-phthalimido glutarimide) is related chemically to other glutarimides currently in clinical use. The possibility that these compounds and/or their metabolites may induce teratogenic effects warrants consideration. Emphasis is added to the view that caution should be exercised when prescribing new drugs. ImagesFig. 1Fig. 2

Ing, George M.; Olman, C. L.; Oyd, John R.

1962-01-01

115

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

SciTech Connect

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

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

2010-02-15

116

Parkinson's Disease  

MedlinePLUS

... Deep Brain Stimulation Consortium Meeting Summary Parkinson's Disease Cell Biology Meeting Summary Parkinson's Disease Cell Biology Meeting Summary Udall Centers Meeting—Expediting Parkinson’s Disease ...

117

Neuroprotection by a mitochondria-targeted drug in a Parkinson's disease model.  

PubMed

The objective of this study was to assess the neuroprotective effects of a mitochondria-targeted antioxidant, Mito-Q(10), the coenzyme-Q analog attached to a triphenylphosphonium cation that targets the antioxidant to mitochondria, in experimental models of Parkinson's disease (PD). Primary mesencephalic neuronal cells and cultured dopaminergic cells were treated with 1-methyl-4-phenylpyridinium (MPP(+)), an active metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and mice were used for testing the efficacy of Mito-Q(10). MPP(+) treatment caused a dose-dependent loss of tyrosine hydroxylase and membrane potential and an increase in caspase-3 activation in dopaminergic cells, which were reversed by Mito-Q(10). MPTP treatment induced a loss of striatal dopamine and its metabolites, inactivation of mitochondrial aconitase in the substantia nigra, and a loss of locomotor activity in mice. Treatment with Mito-Q(10) significantly inhibited both MPP(+)- and MPTP-induced neurotoxicity in cell culture and mouse models. Collectively, these results indicate that mitochondrial targeting of antioxidants is a promising neuroprotective strategy in this preclinical mouse model of PD. PMID:20828611

Ghosh, Anamitra; Chandran, Karunakaran; Kalivendi, Shasi V; Joseph, Joy; Antholine, William E; Hillard, Cecilia J; Kanthasamy, Arthi; Kanthasamy, Anumantha; Kalyanaraman, Balaraman

2010-12-01

118

Basal ganglia hypoactivity during grip force in drug naïve Parkinson's disease.  

PubMed

The basal ganglia (BG) are impaired in Parkinson's disease (PD), but it remains unclear which nuclei are impaired during the performance of motor tasks in early-stage PD. Therefore, this study was conducted to determine which nuclei function abnormally, and whether cortical structures are also affected by early-stage PD. The study also determined if cerebellar hyperactivity is found early in the course of PD. Blood oxygenation level dependent activation was compared between 14 early-stage drug-naïve PD patients and 14 controls performing two precision grip force tasks using functional magnetic resonance imaging at 3 T. The grip tasks used in this study were chosen because both tasks are known to provide robust activation in BG nuclei, and the two tasks were similar except that the 2-s task required more switching between contraction and relaxation than the 4-s task. The 4-s task revealed that PD patients were hypoactive relative to controls only in putamen and external globus pallidus, and thalamus. In the 2-s task, PD patients were hypoactive throughout all BG nuclei, thalamus, M1, and supplementary motor area. There were no differences in cerebellar activation between groups during either task. Regions of interest analysis revealed that the hypoactivity observed in PD patients during the 2-s task became more pronounced over time as patients performed the task. This suggests that a motor task that requires switching can accentuate abnormal activity throughout all BG nuclei of early-stage, drug-naive PD, and that the abnormal activity becomes more pronounced with repeated task performance in these patients. PMID:20225221

Spraker, Matthew B; Prodoehl, Janey; Corcos, Daniel M; Comella, Cynthia L; Vaillancourt, David E

2010-12-01

119

Memory impairment induced by low doses of reserpine in rats: possible relationship with emotional processing deficits in Parkinson disease.  

PubMed

We have recently verified that the monoamine-depleting drug reserpine--at doses that do not modify motor function--impairs memory in a rodent model of aversive discrimination. In this study, the effects of reserpine (0.1-0.5 mg/kg) on the performance of rats in object recognition, spatial working memory (spontaneous alternation) and emotional memory (contextual freezing conditioning) tasks were investigated. While object recognition and spontaneous alternation behavior were not affected by reserpine treatment, contextual fear conditioning was impaired. Together with previous studies, these results suggest that low doses of reserpine would preferentially induce deficits in tasks involved with emotional contexts. Possible relationships with cognitive and emotional processing deficits in Parkinson disease are discussed. PMID:18579275

Fernandes, Valéria S; Ribeiro, Alessandra M; Melo, Thieza G; Godinho, Monique; Barbosa, Flavio F; Medeiros, Danielle S; Munguba, Hermany; Silva, Regina H

2008-08-01

120

Increased reflection impulsivity in patients with ephedrone induced Parkinsonism  

PubMed Central

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.

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

121

Grinspan's syndrome: a drug-induced phenomenon?  

PubMed

Three cases of apparently drug-induced Grinspan's syndrome involving the triad of oral lichen planus, diabetes mellitus, and hypertension are reported. Because drug therapy for diabetes mellitus and hypertension is capable of producing lichenoid reactions of the oral mucosa, the question arises as to whether Grinspan's syndrome is an iatrogenically induced syndrome. PMID:2290647

Lamey, P J; Gibson, J; Barclay, S C; Miller, S

1990-08-01

122

Drug-induced acute interstitial nephritis  

Microsoft Academic Search

Acute interstitial nephritis (AIN) is a common cause of acute kidney injury. Many etiologies of AIN have been recognized—including allergic\\/drug-induced, infectious, autoimmune\\/systemic, and idiopathic forms of disease. The most common etiology of AIN is drug-induced disease, which is thought to underlie 60–70% of cases. Multiple agents from many different classes of drugs can cause AIN, and the clinical presentation and

Mark A. Perazella; Glen S. Markowitz

2010-01-01

123

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

PubMed

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

Steiger, M

2008-01-01

124

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

PubMed Central

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

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

2012-01-01

125

Dopamine-Induced Nonmotor Symptoms of Parkinson's Disease  

PubMed Central

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

Park, Ariane; Stacy, Mark

2011-01-01

126

M30, a brain permeable multitarget neurorestorative drug in post nigrostriatal dopamine neuron lesion of parkinsonism animal models.  

PubMed

The anti-Parkinson iron chelator brain selective monoamine oxidase (MAO) AB inhibitor M30 [5-(N-methyl-N-propargylaminomethyl)-8-hydroxyquinoline] was shown to possess neuroprotective activities in vitro and in vivo, against several insults applicable to several neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease (PD) and ALS. We examined the effect of M30 on a pre-existing lesion induced by the parkinsonism-inducing toxin, MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). In this neurorescue/neurorestorative paradigm, M30 was orally administered to mice for 14 days (2.5-5 mg/kg/day) following post MPTP or lactacystin lesion and was shown to significantly elevate striatal dopamine, serotonin and noradrenaline levels, reduce their metabolism, and elevate tyrosine-hydroxylase protein levels. Importantly, M30 elevated MPTP-reduced dopaminergic and transferrin receptor cell count in the substantia nigra pars compacta (SNpc). Finally, M30 was shown to decrease mitosis and elevate HIF (hypoxia induced factor) which regulates the neurotrophins BDNF, GDNF, VEGF and erythropoietin by elevating their brain levels, thus providing additional protection. These findings indicates that brain-permeable M30 has neurorestorative activity, which may clearly be of clinical importance for the treatment of PD. PMID:22166418

Youdim, Moussa B H

2012-01-01

127

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

PubMed Central

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.

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

2010-01-01

128

Intrastriatal injections of KN-93 ameliorates levodopa-induced dyskinesia in a rat model of Parkinson's disease  

PubMed Central

Background Levodopa remains the most effective drug for the treatment of Parkinson’s disease (PD). However, long-term levodopa treatment is associated with the emergence of levodopa-induced dyskinesia (LID), which has hampered its use for PD treatment. The mechanisms of LID are only partially understood. A previous study showed that KN-93, a Ca2+/calmodulin-dependent protein kinase II (CaMKII) inhibitor, could be used to ameliorate LID in rats. However, the precise mechanisms by which KN-93 acts as an antidyskinetic are not fully understood. Methods In the present study, a rat model of PD was induced by 6-hydroxydopamine (OHDA) injections. Then, the successfully lesioned rats were intrastriatally administered with a different dose of KN-93 (1 ?g, 2 ?g, or 5 ?g) prior to levodopa treatment. Abnormal involuntary movements (AIMs) scores and apomorphine-induced rotations were measured in PD rats. Phosphorylated levels of GluR1 at Serine-845 (pGluR1S845) levels were determined by western blot. Arc and Penk levels were measured by real-time polymerase chain reaction (PCR). Results We found that both 2 ?g and 5 ?g KN-93 treatment lowered AIMs scores in levodopa priming PD rats without affecting the antiparkinsonian effect of levodopa. In agreement with behavioral analysis, KN-93 treatment (2 ?g) reduced pGluR1S845 levels in PD rats. Moreover, KN-93 treatment (2 ?g) reduced the expression of Gad1 and Nur77 in PD rats. Conclusion These data indicated that intrastriatal injections of KN-93 were beneficial in reducing the expression of LID by lowering the expression of pGluR1S845 via suppressing the activation of CaMKII in PD rats. Decreased expression of pGluR1S845 further reduced the expression of Gad1 and Nur77 in PD rats.

Yang, Xinxin; Wu, Na; Song, Lu; Liu, Zhenguo

2013-01-01

129

Secondary parkinsonism  

MedlinePLUS

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

130

Drug-induced liver injury and drug development: industry perspective.  

PubMed

Despite intensive ongoing research, drug-induced live injury (DILI) remains a serious issue for care providers and patients, and has been a major cause of drug withdrawal and non-approval by regulatory authorities in the past 50 years. Consequently, DILI remains a major concern for the pharmaceutical industry and a leading cause for attrition during drug development. In most instances, severe DILI is an uncommon idiosyncratic reaction, which typically does not present during preclinical phases or early clinical phases of drug development. In the majority of cases, drugs that caused severe DILI in humans have not shown clear and consistent hepatotoxic signals in preclinical assessment including animal studies, cell cultures, or other methods. Despite intensive efforts to develop better biomarkers that would help in predicting DILI risk in earlier phases of drug development, such biomarkers are currently not supported by sufficient evidence and are not yet available for routine use by drug makers. Due to the lack of effective and accurate methods for prediction of idiosyncratic DILI during preclinical phases of drug development, different drug makers have adopted different approaches, which are often not supported by strong systematic evidence. Based on growing experience, it is becoming increasingly evident that milder forms of liver injury occurring during clinical development, when assessed correctly, may significantly enhance our ability to predict the drug's potential to cause more severe liver injury postmarketing. Strategies based on this concept have been adopted by many drug makers, and are being increasingly implemented during drug development. Meticulous causality assessment of individual hepatic cases and adherence to strict hepatic discontinuation rules are critical components of this approach and have to rely on thorough clinical evaluation and occasionally on assessment by liver experts experienced with DILI and drug development. PMID:24879986

Regev, Arie

2014-05-01

131

Manganese-Induced Parkinsonism due to Ephedrone Abuse  

PubMed Central

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

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

2011-01-01

132

Drug-induced gingival enlargement: an overview.  

PubMed

The first documented case of drug-induced gingival enlargement was reported in 1939. Since that time, specific medications have been associated with this condition. Although the biologic mechanisms responsible for drug-mediated gingival enlargement remain unclear, a multifactorial etiology is considered to be responsible, with contributing factors including age, genetic predisposition, and local conditions. While the role of plaque remains to be completely elucidated, there is abundant clinical evidence demonstrating at least partial resolution of drug-induced gingival enlargement following improved plaque control. Variations in drug kinetics, gingival crevicular fluid concentrations, protein synthesis, and the presence of growth factors also might contribute to the mechanism of gingival overgrowth. PMID:23991852

Moffitt, Michelle L; Bencivenni, Davide; Cohen, Robert E

2013-05-01

133

Induced pluripotent stem cell technology and direct conversion: new possibilities to study and treat Parkinson's disease.  

PubMed

Recent developments in in vitro disease modeling and regenerative medicine have placed induced pluripotent stem cells (iPSCs) in the center of attention as a unique source to study Parkinson's disease. After only 5 years of intensive research, human iPSCs can be generated without viral integration and under xeno-free conditions. This, combined with increasingly sophisticated methods to differentiate iPSCs into functional dopaminergic (DA) neurons, led us to recapitulate the most important findings concerning the use of iPSC technology as a prospective tool to treat symptoms of Parkinson's disease as well as to obtain insight in disease related cell pathogenesis. Moreover, we touch upon some of the latest discoveries in which patient-derived autologous DA neurons come into even more direct reach thanks to a method that allows transdifferentiation of fibroblasts into DA neurons. PMID:22529017

Roessler, Reinhard; Boddeke, Erik; Copray, Sjef

2013-08-01

134

Dopaminergic induced changes in cognitive and motor processing in Parkinson's disease: an electrophysiological investigation.  

PubMed Central

Event-related potentials and reaction time measures to auditory discrimination tasks of graded difficulty were used to separate cognitive from motor processing time in 27 patients with newly diagnosed, previously untreated Parkinson's disease and later on optimal levodopa treatment. Before treatment event-related potential P3 and task performance were normal but the reaction time was prolonged compared with age matched controls. After treatment P3 latency was significantly prolonged and the reaction time reduced suggesting a dopamine induced dissociation between cognitive and motor processing. In early Parkinson's disease cognitive processing time remains normal but the motor processing time is prolonged. Dopamine replacement is followed by significantly reduced motor processing time despite increased cognitive processing time. Motor processing may reflect the dopamine status of the putamen whereas dopaminergic over-stimulation of other regions may adversely affect cognitive processing in patients treated with levodopa.

Prasher, D; Findley, L

1991-01-01

135

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

PubMed Central

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

Oh, Young J.

2013-01-01

136

Mechanisms of drug-induced liver injury  

Microsoft Academic Search

The idiosyncratic nature and poor prognosis of drug-induced liver injury (DILI) make this type of reaction a major safety\\u000a issue during drug development, as well as the most common cause for the withdrawal of drugs from the pharmaceutical market.\\u000a The key to predicting and preventing DILI is understanding the underlying mechanisms. DILI is initiated by direct hepatotoxic\\u000a effects of a

Michael P. Holt; Cynthia Ju

2006-01-01

137

Nonsteroidal antiinflammatory drug-induced colonic stricture  

Microsoft Academic Search

Summary Nonsteroidal antiinflammatory drugs (NSAIDs) are widely prescribed drugs that can result in gastroduodenal ulceration. Adverse effects upon the small and large intestine are now more often recognized. Small intestinal obstruction secondary to both mucosal diaphragms and broad-based stenoses is reported, but colonic strictures appear to be less common. A case of NSAID-induced colonic stricture leading to large bowel obstruction

Michael H. E. Robinson; Timothy Wheatley; Ian H. Leach

1995-01-01

138

Drug-Induced Respiratory Disorders.  

National Technical Information Service (NTIS)

In this note the writer adds niridazole (Ambilhar) to the list of drugs that can cause severe pulmonary sensitivity reactions. He cites a case which involved, treatment of Schistosoma mansoni infection.

Z. Farid S. Bassily A. Hassan

1973-01-01

139

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

PubMed

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

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

2013-12-01

140

Drug metabolite profiling and elucidation of drug-induced hepatotoxicity.  

PubMed

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

Tang, Wei

2007-06-01

141

Role of Serotonin Neurons in L-DOPA- and Graft-Induced Dyskinesia in a Rat Model of Parkinson's Disease  

PubMed Central

L-DOPA, the most effective drug to treat motor symptoms of Parkinson's disease, causes abnormal involuntary movements, limiting its use in advanced stages of the disease. An increasing body of evidence points to the serotonin system as a key player in the appearance of L-DOPA-induced dyskinesia (LID). In fact, exogenously administered L-DOPA can be taken up by serotonin neurons, converted to dopamine and released as a false transmitter, contributing to pulsatile stimulation of striatal dopamine receptors. Accordingly, destruction of serotonin fibers or silencing serotonin neurons by serotonin agonists could counteract LID in animal models. Recent clinical work has also shown that serotonin neurons are present in the caudate/putamen of patients grafted with embryonic ventral mesencephalic cells, producing intense serotonin hyperinnervation. These patients experience graft-induced dyskinesia (GID), a type of dyskinesia phenotypically similar to the one induced by L-DOPA but independent from its administration. Interestingly, the 5-HT1A receptor agonist buspirone has been shown to suppress GID in these patients, suggesting that serotonin neurons might be involved in the etiology of GID as for LID. In this paper we will discuss the experimental and clinical evidence supporting the involvement of the serotonin system in both LID and GID.

Shin, Eunju; Tronci, Elisabetta; Carta, Manolo

2012-01-01

142

Effects of ceftriaxone on the behavioral and neuronal changes in an MPTP-induced Parkinson's disease rat model.  

PubMed

Hyperactivity of the glutamatergic system is involved in excitotoxicity and neurodegeneration in Parkinson's disease (PD) and treatment with drugs modulating glutamatergic activity may have beneficial effects. Ceftriaxone has been reported to increase glutamate uptake by increasing glutamate transporter expression. The aim of this study was to determine the effects of ceftriaxone on working memory, object recognition, and neurodegeneration in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD rat model. MPTP was stereotaxically injected into the substantia nigra pars compacta (SNc) of male Wistar rats. Then, starting the next day (day 1), the rats were injected daily with either ceftriaxone (200mg/kg/day, i.p.) or saline for 14 days and underwent a T-maze test on days 8-10 and an object recognition test on days 12-14. MPTP-lesioned rats showed impairments of working memory in the T-maze test and of recognition function in the object recognition test. The treatment of ceftriaxone decreased the above MPTP-induced cognitive deficits. Furthermore, this study provides evidence that ceftriaxone inhibits MPTP lesion-induced dopaminergic degeneration in the nigrostriatal system, microglial activation in the SNc, and cell loss in the hippocampal CA1 area. In conclusion, these data support the idea that hyperactivity of the glutamatergic system is involved in the pathophysiology of PD and suggest that ceftriaxone may be a promising pharmacological tool for the development of new treatments for the dementia associated with PD. PMID:24755306

Ho, Shih-Chun; Hsu, Chih-Chuan; Pawlak, Cornelius Rainer; Tikhonova, Maria A; Lai, Te-Jen; Amstislavskaya, Tamara G; Ho, Ying-Jui

2014-07-15

143

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

PubMed

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

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

2014-02-01

144

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

Microsoft Academic Search

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

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

2009-01-01

145

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

PubMed Central

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

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

2010-01-01

146

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

PubMed

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

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

2013-09-15

147

A mutation in Drosophila methuselah resists paraquat induced Parkinson-like phenotypes.  

PubMed

Parkinson's disease (PD) is a prevalent and devastating neurodegenerative disorder having limited cure options and strong association with the loss of dopaminergic neurons in the substantia nigra region of the mid brain. Etiology of PD includes both genetic and environmental factors. Paraquat (PQ), a widely used herbicide, is known to be associated with pathogenesis of PD. We report that a mutation in Drosophila methuselah (mth(1)), which is associated with aging, has a role in preventing dopaminergic neuronal cell death in PQ-exposed organism. Exposed mth(1) flies exhibit significant resistance against PQ-induced Parkinson's phenotypes and behavior in terms of oxidative stress, dopaminergic neuronal degeneration, locomotor performance, dopamine content, phosphorylated JNK, pFOXO, Hid, and cleaved caspase-3 levels. Conversely, over-expression of mth in dopaminergic neurons makes the exposed organism more vulnerable to oxidative stress, neuronal cell death, and behavioral deficit. The study suggests that lesser activation of JNK-mediated apoptosis in dopaminergic neurons of exposed mth(1) flies protects the organism from PQ-induced damage, which may be causally linked to a common mechanism for PQ-induced neurodegeneration. PMID:24819147

Shukla, Arvind K; Pragya, Prakash; Chaouhan, Hitesh S; Patel, D K; Abdin, M Z; Kar Chowdhuri, Debapratim

2014-10-01

148

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

PubMed Central

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

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

2010-01-01

149

Remission-inducing drugs in rheumatoid arthritis.  

PubMed Central

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

Anastassiades, T. P.

1980-01-01

150

Drug-induced rash: nuisance or threat?  

PubMed

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

Wick, Jeannette Y

2013-03-01

151

Drug-induced liver injury  

Microsoft Academic Search

Cholestasis is the failure of bile to reach duodenum due to three different mechanisms: a. alteration of bile secretion by\\u000a hepatocytes into the canaliculus with or without liver cell damage; b. obstruction of the intrahepatic bile ducts caused by\\u000a diseases of ductules or small\\/medium bile ducts; c. obstruction of extrahepatic bile ducts. This short review focuses on drugs\\u000a which may

Claude Degott

1997-01-01

152

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

PubMed

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

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

153

Neuroprotection by a mitochondria-targeted drug in a Parkinson's disease model  

Microsoft Academic Search

The objective of this study was to assess the neuroprotective effects of a mitochondria-targeted antioxidant, Mito-Q10, the coenzyme-Q analog attached to a triphenylphosphonium cation that targets the antioxidant to mitochondria, in experimental models of Parkinson's disease (PD). Primary mesencephalic neuronal cells and cultured dopaminergic cells were treated with 1-methyl-4-phenylpyridinium (MPP+), an active metabolite of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and mice

Anamitra Ghosh; Karunakaran Chandran; Shasi V. Kalivendi; Joy Joseph; William E. Antholine; Cecilia J. Hillard; Arthi Kanthasamy; Anumantha Kanthasamy; Balaraman Kalyanaraman

2010-01-01

154

Altered thalamic response to levodopa in Parkinson's patients with dopa-induced dyskinesias  

PubMed Central

Parkinson’s disease (PD) is a progressive neurologic condition characterized by tremor, slowness, stiffness, and unstable posture. Degeneration of dopamine-producing neurons in the substantia nigra causes PD. Treatment with levodopa, a precursor of dopamine, initially ameliorates the clinical manifestations of PD. However, chronic levodopa treatment can produce severe involuntary movements (so-called dopa-induced dyskinesias or DID), limiting treatment. Pallidotomy, placement of a surgical lesion in the internal segment of the globus pallidus, reduces DID. Because this result is inconsistent with current theories of both basal ganglia function and DID, it prompted us to investigate the brain’s response to levodopa. We measured regional cerebral blood flow response to levodopa with positron-emission tomography in 6 PD patients with DID, 10 chronically treated PD patients without DID, 17 dopa-naïve PD patients, and 11 normals. The dose of levodopa was chosen to produce clinical benefit without inducing DID. This strategy allowed us to examine the brain response to levodopa across groups without the confounding effect of differences in motor behavior. We found that the DID group had a significantly greater response in ventrolateral thalamus than the other groups. This was associated with decreased activity in primary motor cortex. These findings are consistent with increased inhibitory output from the internal segment of the globus pallidus to thalamus after levodopa administration. They provide a physiological explanation for the clinical efficacy of pallidotomy and new insights into the physiology of the basal ganglia.

Hershey, Tamara; Black, Kevin J.; Stambuk, Mikula K.; Carl, Juanita L.; McGee-Minnich, Lori A.; Perlmutter, Joel S.

1998-01-01

155

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

PubMed

Gap junctional communication plays an important role in various models of brain pathology, but the changes of gap junctions in Parkinsonism are still not understood. In this study, we show that a major gap junctional protein, connexin43 (Cx43), in astrocytes is enhanced both in a rat Parkinson's disease (PD) model induced with rotenone, a widely used pesticide that inhibits mitochondrial complex I, and in vitro in cultured astrocytes stimulated with rotenone. Enhancement of Cx43 protein levels in rotenone-treated cultured astrocytes occurred in parallel with an increase in gap junctional intercellular communication, but was not accompanied with an increase in Cx43 mRNA levels. Furthermore, the rotenone-induced increase of Cx43 protein levels both in vitro and in vivo was associated with increased levels of phosphorylated Cx43, which is required for gap junctional intercellular communication. In our rat PD model, phosphorylated Cx43 was selectively enhanced in the basal ganglia regions, which contain DA neurons or their terminal areas. The increase of Cx43 levels was lower in the substantia nigra pars compacta and the striatum than in the substantia nigra pars reticulata and the globus pallidus. Our findings indicate that modulation of Cx43 protein, and consequently gap junctional cellular communication, in astrocytes may play an important role in PD pathology. PMID:19232380

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

2009-04-21

156

Immune Mechanisms in Drug-Induced Hepatotoxicity  

Microsoft Academic Search

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

Zhang-Xu Liu; Neil Kaplowitz

157

Drug-Induced Nephrotoxicity and Its Biomarkers  

PubMed Central

Nephrotoxicity occurs when kidney-specific detoxification and excretion do not work properly due to the damage or destruction of kidney function by exogenous or endogenous toxicants. Exposure to drugs often results in toxicity in kidney which represents the major control system maintaining homeostasis of body and thus is especially susceptible to xenobiotics. Understanding the toxic mechanisms for nephrotoxicity provides useful information on the development of drugs with therapeutic benefi ts with reduced side effects. Mechanisms for drug-induced nephrotoxicity include changes in glomerular hemodynamics, tubular cell toxicity, inflammation, crystal nephropathy, rhabdomyolysis, and thrombotic microangiopathy. Biomarkers have been identifi ed for the assessment of nephrotoxicity. The discovery and development of novel biomarkers that can diagnose kidney damage earlier and more accurately are needed for effective prevention of drug-induced nephrotoxicity. Although some of them fail to confer specificity and sensitivity, several promising candidates of biomarkers were recently proved for assessment of nephrotoxicity. In this review, we summarize mechanisms of drug-induced nephrotoxicity and present the list of drugs that cause nephrotoxicity and biomarkers that can be used for early assessment of nephrotoxicity.

Kim, Sun Young; Moon, Aree

2012-01-01

158

Drug Induced Hypersensitivity and the HLA Complex  

PubMed Central

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

Alfirevic, Ana; Pirmohamed, Munir

2011-01-01

159

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

PubMed Central

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

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

2013-01-01

160

Non-Steroidal Anti-Inflammatory Drugs in Alzheimer's Disease and Parkinson's Disease: Reconsidering the Role of Neuroinflammation  

PubMed Central

Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases with age as the greatest risk factor. As the general population experiences extended life span, preparation for the prevention and treatment of these and other age-associated neurological diseases are warranted. Since epidemiological studies suggested that non-steroidal anti-inflammatory drug (NSAID) use decreased risk for AD and PD, increasing attention has been devoted to understanding the costs and benefits of the innate neuroinflammatory response to functional recovery following pathology onset. This review will provide a general overview on the role of neuroinflammation in these neurodegenerative diseases and an update on NSAID treatment in recent experimental animal models, epidemiological analyses, and clinical trials.

Moore, Amy H.; Bigbee, Matthew J.; Boynton, Grace E.; Wakeham, Colin M.; Rosenheim, Hilary M.; Staral, Christopher J.; Morrissey, James L.; Hund, Amanda K.

2010-01-01

161

Poly(ADP-ribose) polymerase activation mediates 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism  

PubMed Central

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a neurotoxin that causes parkinsonism in humans and nonhuman animals, and its use has led to greater understanding of the pathogenesis of Parkinson’s disease. However, its molecular targets have not been defined. We show that mice lacking the gene for poly(ADP-ribose) polymerase (PARP), which catalyzes the attachment of ADP ribose units from NAD to nuclear proteins after DNA damage, are dramatically spared from MPTP neurotoxicity. MPTP potently activates PARP exclusively in vulnerable dopamine containing neurons of the substantia nigra. MPTP elicits a novel pattern of poly(ADP-ribosyl)ation of nuclear proteins that completely depends on neuronally derived nitric oxide. Thus, NO, DNA damage, and PARP activation play a critical role in MPTP-induced parkinsonism and suggest that inhibitors of PARP may have protective benefit in the treatment of Parkinson’s disease.

Mandir, Allen S.; Przedborski, Serge; Jackson-Lewis, Vernice; Wang, Zhao-Qi; Simbulan-Rosenthal, Cynthia M.; Smulson, Mark E.; Hoffman, Brian E.; Guastella, Daniel B.; Dawson, Valina L.; Dawson, Ted M.

1999-01-01

162

Tetrabenazine improves levodopa-induced peak-dose dyskinesias in patients with Parkinson's disease.  

PubMed

Since levodopa-induced peak dyskinesias (LIDs) may reflect, in part, a disproportionate phasic release of dopamine from synaptic vesicles, we examined the ability of the vesicular depletor tetrabenazine (TBZ) to reduce LIDs in 10 dyskinetic advanced Parkinson's disease (PD) patients. After basal evaluation, the patients received, through a slow titration, oral TBZ twice a day for six weeks (up to 50 mg daily) before being re-assessed after a challenge with levodopa. The primary outcome measure was the change in the Unified Parkinson's Disease Rating Scale (UPDRS) dyskinesia score (items 32 to 34). TBZ was well tolerated. A clear treatment effect on LIDs emerged (up to 45%, p<0.05). In two patients a little worsening of motor performance necessitated an increase of the antiparkinsonian therapy, which did not worsen peak-dose LIDs. The patients experienced a clear benefit in terms of their quality of life. In this open-label pilot study, orally administered TBZ resulted in objective and subjective improvements in LIDs. Larger pharmacological studies are in progress. PMID:24125559

Brusa, L; Orlacchio, A; Stefani, A; Galati, S; Pierantozzi, M; Iani, C; Mercuri, N B

2013-01-01

163

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

PubMed Central

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.

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

164

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

PubMed Central

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

Kim, Grace K.

2010-01-01

165

Orthostatic Hypotension in Drug-Na?ve Patients with Parkinson's Disease  

PubMed Central

Background and Purpose Orthostatic hypotension (OH) is known to be present even in patients with early Parkinson’s disease (PD). To affirm the presence of OH and find correlation between OH and other dysautonomic symptoms in PD, this study has done in newly-diagnosed PD patients. Methods Forty-five non-demented patients with no prior history of treatment for PD were recruited (17 men, 63.8 ± 10.1 years of age). All the patients were evaluated for OH before starting medications. Autonomic symptoms were evaluated with structured questionnaires. Clinical characteristics of PD were evaluated (median Hoehn and Yahr stage 2.0 (1–3), 1.3 ± 1.1 years of disease duration), and comorbid medical conditions that could affect blood pressure were also recorded. Results OH was prevalent, and eighteen patients (40%) showed orthostatic hypotension, and twenty-seven (60%) did not (normotensive group). There was no significant difference in demographic and clinical characteristics between groups. The presence or severity of symptoms of autonomic dysfunction in the OH group also not differed from those of the normotensive group. Conclusions OH was prevalent even in the early stage of PD, and was not related to presence or severity of any other symptoms of autonomic dysfunction. Our findings suggest that clinicians should pay attention to OH from the early stage of disease.

Bae, Hyo-Jin; Cheon, Sang-Myung; Kim, Jae Woo

2011-01-01

166

Posttraumatic parkinsonism.  

PubMed

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

Formisano, Rita; Zasler, Nathan D

2014-01-01

167

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

PubMed

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

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

2013-09-01

168

Levodopa-induced alterations in speech rate in advanced Parkinson's disease.  

PubMed

The effect of speech rate on overall intelligibility in Parkinson's Disease (PD) is still a matter of debate. A comparison of the results of previous studies on speech rate in PD is hampered by methodological differences. In this study, we evaluated the effects of levodopa on speech rate and on its variability in a standardized reading task. Twenty-five patients were studied before and after levodopa administration while reading a standardized text. In accordance with previous studies, no significant improvement of speech rate was found. Rather an increased variability of speech rate in the on-medication state could be demonstrated. It is possible that this increased variability may be the consequence of respiratory deficits due to levodopa-induced dyskinesia or an increase of dysfluencies. However, the effects of defective auditory feedback and disturbed executive function cannot be ruled out. PMID:16776432

De Letter, Miet; Santens, Patrick; De Bodt, Marc; Boon, Paul; Van Borsel, John

2006-03-01

169

Identification of differentially expressed proteins in striatum of maneb-and paraquat-induced Parkinson's disease phenotype in mouse  

Microsoft Academic Search

Behavioral, phenotypic and biochemical changes induced by maneb+paraquat (MB+PQ) in experimental animals have shown their role in the etiologies of Parkinson's disease (PD); however, MB+PQ induced neuronal damage at genome and proteome level have not yet been clearly understood. The present study was undertaken to investigate the differential protein expression patterns in control and MB+PQ treated mouse striatum and to

Suman Patel; Ashima Sinha; Mahendra Pratap Singh

2007-01-01

170

Event-based prospective memory in newly diagnosed, drug-naive Parkinson's disease patients.  

PubMed

The present study investigated memory for intention in individuals with Parkinson's disease (PD) who were newly diagnosed and not yet treated to avoid the effect of therapy as a potential confounding variable. A comprehensive neuropsychological battery and an event-based prospective memory task were administered to 41 subjects with de novo PD and 40 control subjects. Separate scores were computed for correct execution of intended action (prospective component) and recall of intention (retrospective component). PD patients performed marginally worse (p = .053) than controls on the prospective component of the task. On the other hand, the performance of the two groups was comparable for the retrospective component. Neuropsychological findings revealed lower performance of the PD group in episodic memory and in some measures of executive functions. These results suggested a subtle prospective memory dysfunction present at the initial stage of PD, which may be related to disruption of fronto-striatal circuitry. PMID:22014082

Pagni, Cristina; Frosini, Daniela; Ceravolo, Roberto; Giunti, Giulia; Unti, Elisa; Poletti, Michele; McClintock, Shawn M; Murri, Luigi; Bonuccelli, Ubaldo; Tognoni, Gloria

2011-11-01

171

James Parkinson: Parkinson's disease.  

PubMed

Parkinson's disease is a condition that anyone with a modicum of medical knowledge can recognise in the street--as indeed how it was studied by James Parkinson himself. Its three characteristic features are: 1. Increase in the tone of the voluntary muscles (rigidity). 2. Slowness of movement (bradykinesis). 3. Tremor (the characteristic 'pill rolling' movements of the fingers). PMID:24312998

Ellis, Harold

2013-11-01

172

[Drug-induced impairment of renal function].  

PubMed

Acute kidney injury (AKI) of any origin is a common complication/disease in hospitalized patients, going along with significantly increased mortality and morbidity, as well as hospitalization duration and expenses. Drug-induced AKI is usually seen in patients with concurrent risk factors such as existing kidney disease, dehydration with or without hypotension, older age or diabetes mellitus. In cases with multiple risk factors or therapies the triggering drug is often impossible to define. Hemodynamic alterations, intrinsic tubulointerstitial damages and intrarenal (i. e. tubular) obstructions as a result of drug precipitations are the pathophysiological basis of this disease entity. Clinically the AKI is perceived as the most important problem, due to the development of hyperhydration (including pulmonary edema) and reduced/lacking clearance of toxic metabolites. The prognosis of drug-induced AKI is usually good, especially if the agents are stopped early in the process, but nevertheless some patients experience severe acute AKI requiring dialysis with/without subsequent restoration. Considering and recognizing potential risk factors may help to identify patients at risk and lead to introduction of prophylactic actions. Identification of risk factors and the introduction of prevention strategies should be an integral part of everybody's daily clinical work, especially in intensive care medicine due to the high susceptibility to AKI. PMID:22971974

Krüger, B; Benck, U; Singer, T; Krämer, B K

2012-09-01

173

Use of toxicogenomics to understand mechanisms of drug-induced hepatotoxicity during drug discovery and development  

Microsoft Academic Search

Hepatotoxicity is a common cause of failure in drug discovery and development and is also frequently the source of adverse drug reactions. Therefore, a better prediction, characterization and understanding of drug-induced hepatotoxicity could result in safer drugs and a more efficient drug discovery and development process. Among the ‘omics technologies, toxicogenomics (or the use of gene expression profiling in toxicology)

Eric A. G. Blomme; Yi Yang; Jeffrey F. Waring

2009-01-01

174

Neuroprotective effect of curcumin on hippocampal injury in 6-OHDA-induced Parkinson's disease rat.  

PubMed

Clinically, Parkinson's disease (PD)-related neuronal lesions commonly occur. The purpose of this study is to investigate potential therapeutic effect of curcumin against hippocampal damage of 6-hydroxydopamine (6-OHDA)-PD rat model. These results showed that curcumin significantly increased the body weight of 6-OHDA-impaired rats (P<0.01), and reversed the anhedonia in rats induced by 6-OHDA impairment (P<0.01). Meanwhile, behavioral manifestations of curcumin-treated PD rats were effectively ameliorated as shown in open field test (P<0.01). In addition, curcumin increased the contents of monoaminergic neurotransmitters (P<0.01), such as dopamine (DA) and norepinephrine (NE), in hippocampal homogenate through high performance liquid chromatography (HPLC) assay. Curcumin effectively alleviated the 6-OHDA-induced hippocampal damage as observed in hematoxylin-eosin (H&E) staining. Furthermore, curcumin obviously up-regulated hippocampal brain derived neurotrophic factor (BDNF), TrkB, phosphatidylinositide 3-kinases (PI3K) protein expressions, respectively as shown in Western blot analysis. These findings demonstrated that curcumin mediated the neuroprotection against 6-OHDA-induced hippocampus neurons in rats, which the underlying mechanism is involved in activating BDNF/TrkB-dependent pathway for promoting neural regeneration of hippocampal tissue. PMID:24642369

Yang, Jiaqing; Song, Shilei; Li, Jian; Liang, Tao

2014-06-01

175

Neuroprotection of pramipexole in UPS impairment induced animal model of Parkinson's disease.  

PubMed

Pramipexole (PPX), a dopamine (DA) receptor D3 preferring agonist, has been used as monotherapy or adjunct therapy to treat Parkinson's disease (PD) for many years. Several in vitro and in vivo studies in neurotoxin-induced DA neuron injury models have reported that PPX may possess neuroprotective properties. The present study is to evaluate the neuroprotection of PPX in a sustained DA neuron degeneration model of PD induced by ubiquitin-proteasome system (UPS) impairment. Adult C57BL/6 mice were treated with PPX (low dose 0.1 mg/kg or high dose 0.5 mg/kg, i.p, twice a day) started 7 days before, and continued after microinjection of proteasome inhibitor lactacystin in the medial forebrain bundle for a total 4 weeks. Animal behavior observation, and pathological and biochemical assays were conducted to determine the neuroprotective effects of PPX. We report here that PPX treatment significantly improves rotarod performance, attenuates DA neuron loss and striatal DA reduction, and alleviates proteasomal inhibition and microglial activation in the substantia nigra of lactacystin-lesioned mice. PPX can increase the levels of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor and induce an activation of autophagy. Furthermore, pretreatment with D3 receptor antagonist U99194 can significantly block the PPX-mediated neuroprotection. These results suggest that multiple molecular pathways may be attributed to the neuroprotective effects of PPX in the UPS impairment model of PD. PMID:20635141

Li, Chao; Guo, Yuan; Xie, Wenjie; Li, Xingang; Janokovic, Joseph; Le, Weidong

2010-10-01

176

Neuroprotective effect of hydroxysafflor yellow A on 6-hydroxydopamine-induced Parkinson's disease in rats.  

PubMed

Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting predominantly the dopaminergic mesotelencephalic system. Enormous progress has been made in the treatment of PD. Our previous study has shown that hydroxysafflor yellow A (HSYA) could attenuate the neurotoxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice. In the present work, we examined whether HSYA had the neuroprotective effect on dopaminergic neurons of substantia nigra in a rat model of PD. Adult Sprague-Dawley rats were unilaterally injected with 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle. The PD rats were treated with HSYA (2 or 8 mg/kg) via caudal vein injection daily for 4 weeks. Rotational tests showed that HSYA significantly attenuated apomorphine-induced turns in 6-OHDA-induced PD rats. HSYA treatment resulted in a significant protection against the loss of tyrosine hydroxylase-positive cells. Our data showed that HSYA also increased the levels of dopamine and its metabolites, glial cell line-derived neurotrophic factor and brain-derived neurotrophic factor in striatum of PD rats. In conclusion, these results supported a role for HSYA in preserving dopamine neuron integrity and motor function in a rodent model of PD, and implied a potential neuroprotective role for HSYA in this disease. PMID:23791614

Han, Bing; Hu, Jia; Shen, Jingyu; Gao, Yonglin; Lu, Yan; Wang, Tian

2013-08-15

177

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

PubMed

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

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

2013-11-01

178

Mirtazapine has a therapeutic potency in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice model of Parkinson's disease  

PubMed Central

Background Mirtazapine, a noradrenergic and specific serotonergic antidepressant (NaSSA), shows multiple pharmacological actions such as inhibiting presynaptic ?2 noradrenaline receptor (NAR) and selectively activating 5-hydroxytriptamine (5-HT) 1A receptor (5-HT1AR). Mirtazapine was also reported to increase dopamine release in the cortical neurons with 5-HT dependent manner. To examine whether mirtazapine has a therapeutic potency in Parkinson’s disease (PD), we examined this compound in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice model of PD. Results Male C57BL/6 mice were subjected to MPTP treatment to establish a PD model. Mirtazapine was administered once a day for 3 days after MPTP treatment. MPTP-induced motor dysfunction, assessed by beam-walking and rota-rod tests, was significantly improved by administration of mirtazapine. Biochemical examinations by high performance liquid chromatography and western blot analysis suggested mirtazapine facilitated utilization of dopamine by increasing turnover and protein expression of transporters, without affecting on neurodegenerative process by MPTP. These therapeutic effects of mirtazapine were reduced by administration of WAY100635, an inhibitor for 5HT1AR, or of clonidine, a selective agonist for ?2-NAR, or of prazosin, an inhibitor for ?1-NAR, respectively. Conclusion Our results showed mirtazapine had a therapeutic potency against PD in a mouse model. Because PD patients sometimes show depression together, it will be a useful drug for a future PD treatment.

2014-01-01

179

Quantitative Electromyographic Analysis of Reaction Time to External Auditory Stimuli in Drug-Naïve Parkinson's Disease  

PubMed Central

Evaluation of motor symptoms in Parkinson's disease (PD) is still based on clinical rating scales by clinicians. Reaction time (RT) is the time interval between a specific stimulus and the start of muscle response. The aim of this study was to identify the characteristics of RT responses in PD patients using electromyography (EMG) and to elucidate the relationship between RT and clinical features of PD. The EMG activity of 31 PD patients was recorded during isometric muscle contraction. RT was defined as the time latency between an auditory beep and responsive EMG activity. PD patients demonstrated significant delays in both initiation and termination of muscle contraction compared with controls. Cardinal motor symptoms of PD were closely correlated with RT. RT was longer in more-affected side and in more-advanced PD stages. Frontal cognitive function, which is indicative of motor programming and movement regulation and perseveration, was also closely related with RT. In conclusion, greater RT is the characteristic motor features of PD and it could be used as a sensitive tool for motor function assessment in PD patients. Further investigations are required to clarify the clinical impact of the RT on the activity of daily living of patients with PD.

Kwon, Do-Young; Park, Byung Kyu; Kim, Ji Won; Eom, Gwang-Moon; Hong, Junghwa; Koh, Seong-Beom; Park, Kun-Woo

2014-01-01

180

Daytime sleepiness in Parkinson's disease: perception, influence of drugs, and mood disorder.  

PubMed

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

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

2014-01-01

181

Excessive daytime sleepiness in patients with Parkinson's disease.  

PubMed

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

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

2011-03-01

182

Oxidative-stress-induced apoptosis in PBLs of two patients with Parkinson disease secondary to alpha-synuclein mutation.  

PubMed

Alpha-synuclein has been implicated in the pathology of certain neurodegenerative diseases, including Parkinson disease (PD). Although the precise physiological and pathological role of alpha-synuclein is unclear, overexpression of the protein or its mutants may reduce cell viability. In this study we evaluated the apoptotic response to oxidative stress induced by 2-deoxy-d-ribose (dRib) in peripheral blood lymphocytes (PBLs) of two siblings with Parkinson disease secondary to A53T alpha-synuclein mutation. PBLs exposed to oxidative stress showed a higher percentage of apoptotic cells in PD patients than in controls. However in cells of PD patients, the increase of apoptotic response was lower than in controls, suggesting that cells of PD patients have greater "resistance" to oxidative stress. We conclude that other environmental agents could play a key role in inducing programmed cell death in cells of PD patients with mutant alpha-synuclein. PMID:18061619

Battisti, Carla; Formichi, Patrizia; Radi, Elena; Federico, Antonio

2008-04-15

183

Homocysteine Intracerebroventricular Injection Induces Apoptosis in the Substantia Nigra Cells and Parkinson's Disease LikeBehavior in Rats.  

PubMed

Parkinson's disease is a degenerative disorder of the central nervous system. The motor symptoms of Parkinson's disease result from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain; the cause of this cell death is unknown. Homocysteine (Hcy) is a non-protein amino acid. It is a homologue of the amino acid cysteine. The elevated levels of homocysteine in plasma have been associated with a number of disease states. Hcy (2 µmol / µl) was injected intracerebroventricular (i.c.v) in rats, five days later, the locomotor activity was measured with open field apparatus, Also apoptosis was investigated in substantia nigra cells by immunohistochemical analysis. Hcy could decrease locomotor activities significantly in rats as well as it could induce apoptosis in substantia nigra cells. These results suggest that Hcy is a neurotoxic metabolite and may induce cell death in some nuclei in the brain. PMID:24551795

Ataie, Amin; Ataee, Ramin; Mansoury, Zahra; Aghajanpour, Mohsen

2013-01-01

184

Striatal plasticity in Parkinson's disease and L-dopa induced dyskinesia.  

PubMed

Striatal function adapts to the loss of nigrostriatal dopaminergic input in Parkinson's disease (PD) to initially maintain voluntary movement, but subsequently changes in response to drug treatment leading to the onset of motor complications, notably dyskinesia. Alterations in presynaptic dopaminergic function coupled to changes in the response of post-synaptic dopaminergic receptors causing alterations in striatal output underlie attempts at compensation and the control of movement in early PD. However, eventually compensation fails and persistent changes in striatal function ensue that involve morphological, biochemical and electrophysiological change. Key alterations occur in cholinergic and glutamatergic transmission in the striatum and there are changes in motor programming controlled by events involving LTP/LTD. Dopamine replacement therapy with L-dopa modifies altered striatal function and restores motor function but non-physiological dopamine receptor stimulation leads to altered signalling through D1 and D2 receptor systems and changes in striatal function causing abnormalities of LTP/LTD mediated through glutamatergic/nitric oxide (NO) mechanisms. These lead to the onset of dyskinesia and underlie the priming process that characterise dyskinesia and its persistence. PMID:22166408

Iravani, M M; McCreary, A C; Jenner, P

2012-01-01

185

Drug-induced nodular regenerative hyperplasia.  

PubMed

Drug-induced nodular regenerative hyperplasia is an uncommon injury with unique pathophysiology, clinical, and diagnostic considerations. This injury is characteristically asymptomatic in its early phases with only mild elevations in transaminases (< 3× upper limit of normal [ULN]). The latency period is typically more than 6 months. Once clinically apparent, it is marked by complications of portal hypertension, including hypersplenism, ascites, and variceal bleeding, with little or no hepatic dysfunction. Hence, it is an important cause of noncirrhotic portal hypertension. The most commonly associated drugs include thiopurines, chemotherapeutic agents, and antiretroviral agents. Diagnosis is aided by the recognition of noncirrhotic portal hypertension, a detailed history of prior drug exposure, and exclusion of the other causes of nodular regenerative hyperplasia. Clinical history, abdominal imaging, and hepatic hemodynamic studies provide important diagnostic clues, but histologic examination remains the diagnostic gold standard. Therapeutic intervention is aimed at earliest discontinuation of the offending agent and of portal hypertension complications. The natural history varies widely, and portal hypertension can progresses despite drug discontinuation. PMID:24879987

Ghabril, Marwan; Vuppalanchi, Raj

2014-05-01

186

Mechanisms of drug induced QT interval prolongation.  

PubMed

The long QT syndrome (LQTS) is characterized by a prolonged QT interval, as well as a propensity to develop syncope and sudden cardiac death caused by the malignant polymorphic ventricular arrhythmia called torsades de pointes (TdP). The QT interval is measured from the onset of the QRS complex to the end of the T wave and can be affected by both ventricular conduction velocities as well as by the velocity of repolarization. In most cases, QT prolongation is caused by factors that prolong the duration of the action potential, mainly by delaying the repolarization phase 3. The molecular mechanism is partially known. There are two well described mechanisms: blocking of the ion channel cavity of HERG; or causing an abnormal protein trafficking required for the location of HERG subunits in cell membrane. Both of them impair the I(Kr) current. However the blockade of ion channels is not the only condition to generate TdP. Other factors may play an important role, e.g. myocardium heterogeneity, drug-drug interaction, genetic polymorphism, and Electrolyte disturbances. Several drugs had been subject of withdrawal because QT-prolongation and arrhythmia. Understanding of processes involved in drug-induced QT prolongation is needed for the study and prevention of life-threatening arrhythmias. PMID:20210718

Ponte, Marcelo Luis; Keller, Guillermo Alberto; Di Girolamo, Guillermo

2010-01-01

187

MPTP-induced model of Parkinson's disease in heat shock protein 70.1 knockout mice.  

PubMed

Heat shock proteins (HSPs), molecular chaperones that assist in protein folding, have become a research focus in Parkinson's disease (PD) since the pathogenesis of PD is characterized by intracellular protein misfolding and inclusion body formation. This study investigated the effect of the knockout (KO) of the Hsp70.1 (approved gene symbol Hspa1b) gene on the sensitivity of murine nigrostriatal dopaminergic neurons to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced toxicity. We confirmed changes in motor coordination and tyrosine hydroxylase (TH) immunoreactivity in the substantia nigra following MPTP treatment of C57BL/6 normal mice and Hspa1b KO mice. MPTP treatment led to motor control impairment and induced TH-positive dopaminergic neurodegeneration in normal mice. Compared to untreated normal mice, rotarod duration and the density of TH-positive neurons in the substantia nigra were also significantly lower in untreated KO mice (p<0.01). MPTP-treated KO mice had markedly decreased rotarod duration and reduced density of TH-positive neurons, compared to MPTP-treated normal mice. These results indicate that Hspa1b KO mice are more vulnerable to the neurotoxic effects of MPTP and are consistent with the hypothesis that HSPs represent an important molecular target for neuroprotective strategies in the treatment of PD. PMID:22446746

Park, Hyun Kyung; Cho, Ah Rang; Lee, Seung Chul; Ban, Ju Yeon

2012-06-01

188

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

PubMed Central

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

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

2011-01-01

189

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

PubMed

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

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

2011-01-01

190

Parkinson's disease patient-derived induced pluripotent stem cells free of viral reprogramming factors.  

PubMed

Induced pluripotent stem cells (iPSCs) derived from somatic cells of patients represent a powerful tool for biomedical research and may provide a source for replacement therapies. However, the use of viruses encoding the reprogramming factors represents a major limitation of the current technology since even low vector expression may alter the differentiation potential of the iPSCs or induce malignant transformation. Here, we show that fibroblasts from five patients with idiopathic Parkinson's disease can be efficiently reprogrammed and subsequently differentiated into dopaminergic neurons. Moreover, we derived hiPSCs free of reprogramming factors using Cre-recombinase excisable viruses. Factor-free hiPSCs maintain a pluripotent state and show a global gene expression profile, more closely related to hESCs than to hiPSCs carrying the transgenes. Our results indicate that residual transgene expression in virus-carrying hiPSCs can affect their molecular characteristics and that factor-free hiPSCs therefore represent a more suitable source of cells for modeling of human disease. PMID:19269371

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

2009-03-01

191

Survival and differentiation of transplanted neural stem cells in mice brain with MPTP-induced Parkinson disease  

Microsoft Academic Search

AIM: To determine survival and differentiation of cultured neural stem cells (NSCs) into viable and functional neurons upon transplantation into mice brain of MPTP-induced Parkinson disease (PD). METHODS: Mouse model of PD was established with two subcutaneous (sc) injections of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 40 mg\\/kg) twice, 16 h apart. NSCs isolated from rat embryo midbrain were cultured in clonal density. After

LI Xue-Kun; GUO An-Chen; ZUO Ping-Ping

2003-01-01

192

Oxidative-stress-induced apoptosis in PBLs of two patients with Parkinson disease secondary to alpha-synuclein mutation  

Microsoft Academic Search

Alpha-synuclein has been implicated in the pathology of certain neurodegenerative diseases, including Parkinson disease (PD). Although the precise physiological and pathological role of alpha-synuclein is unclear, overexpression of the protein or its mutants may reduce cell viability. In this study we evaluated the apoptotic response to oxidative stress induced by 2-deoxy-d-ribose (dRib) in peripheral blood lymphocytes (PBLs) of two siblings

Carla Battisti; Patrizia Formichi; Elena Radi; Antonio Federico

2008-01-01

193

The natural history of histologically proved drug induced liver disease  

Microsoft Academic Search

BACKGROUNDThe long term outcome of drug related liver disease is unknown.AIMSTo study the natural history of histologically proved drug induced hepatotoxicity.METHODS110 patients with liver biopsies coded either as drug induced liver disease or hepatitis\\/cholestasis of unknown aetiology were identified from hospital records 1978–1996. Review of case notes and histology identified 44 patients with definite drug induced hepatotoxicity. Forty surviving patients

P G Aithal; C P Day

1999-01-01

194

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

PubMed

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

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

2013-01-01

195

Tauroursodeoxycholic acid prevents MPTP-induced dopaminergic cell death in a mouse model of Parkinson's disease.  

PubMed

Mitochondrial dysfunction and oxidative stress are implicated in the neurodegenerative process in Parkinson's disease (PD). Moreover, c-Jun N-terminal kinase (JNK) plays an important role in dopaminergic neuronal death in substantia nigra pars compacta. Tauroursodeoxycholic acid (TUDCA) acts as a mitochondrial stabilizer and anti-apoptotic agent in several models of neurodegenerative diseases. Here, we investigated the role of TUDCA in preventing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurodegeneration in a mouse model of PD. We evaluated whether TUDCA modulates MPTP-induced degeneration of dopaminergic neurons in the nigrostriatal axis, and if that can be explained by regulation of JNK phosphorylation, reactive oxygen species (ROS) production, glutathione S-transferase (GST) catalytic activation, and Akt signaling, using C57BL/6 glutathione S-transferase pi (GSTP) null mice. TUDCA efficiently protected against MPTP-induced dopaminergic degeneration. We have previously demonstrated that exacerbated JNK activation in GSTP null mice resulted in increased susceptibility to MPTP neurotoxicity. Interestingly, pre-treatment with TUDCA prevented MPTP-induced JNK phosphorylation in mouse midbrain and striatum. Moreover, the anti-oxidative role of TUDCA was demonstrated in vivo by impairment of ROS production in the presence of MPTP. Finally, results herein suggest that the survival pathway activated by TUDCA involves Akt signaling, including downstream Bad phosphorylation and NF-?B activation. We conclude that TUDCA is neuroprotective in an in vivo model of PD, acting mainly by modulation of JNK activity and cellular redox thresholds, together with activation of the Akt pro-survival pathway. These results open new perspectives for the pharmacological use of TUDCA, as a modulator of neurodegeneration in PD. PMID:22773138

Castro-Caldas, M; Carvalho, A Neves; Rodrigues, E; Henderson, C J; Wolf, C R; Rodrigues, C M P; Gama, M J

2012-10-01

196

Non-drug induced gingival enlargement.  

PubMed

Gingival enlargement refers to an increase in the size of the gingival tissue. The etiology varies, and often is multifactorial; however, local and systemic conditions, disease, and idiopathic factors may contribute to gingival enlargement. Tissue consistency can vary from soft and spongy to dense, typically appearing darker in shade compared to the drug-induced gingival enlargement. Treatment modalities usually involve surgical removal of excess tissue, non-surgical debridement, use of chemotherapeutic agents, and/or elimination or mitigation of contributing factors and conditions. PMID:23928447

Moffitt, Michelle L; Cohen, Robert E

2013-08-01

197

A Granulomatous Drug Eruption Induced by Entecavir  

PubMed Central

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

Yoon, Jimi; Park, Donghwa

2013-01-01

198

Milestones in Parkinson's disease therapeutics.  

PubMed

In the mid-1980s, the treatment of Parkinson's disease was quite exclusively centered on dopatherapy and was focusing on dopamine systems and motor symptoms. A few dopamine agonists and a monoamine oxidase B inhibitor (selegiline) were used as adjuncts in advanced Parkinson's disease. In the early 2010s, levodopa remains the gold standard. New insights into the organization of the basal ganglia paved the way for deep brain stimulation, especially of the subthalamic nucleus, providing spectacular improvement of drug-refractory levodopa-induced motor complications. Novel dopamine agonists (pramipexole, ropinirole, rotigotine), catecholmethyltransferase inhibitors (entacapone), and monoamine oxidase B inhibitors (rasagiline) have also been developed to provide more continuous oral delivery of dopaminergic stimulation in order to improve motor outcomes. Using dopamine agonists early, before levodopa, proved to delay the onset of dyskinesia, although this is achieved at the price of potentially disabling daytime somnolence or impulse control disorders. The demonstration of an antidyskinetic effect of the glutamate antagonist amantadine opened the door for novel nondopaminergic approaches of Parkinson's disease therapy. More recently, nonmotor symptoms (depression, dementia, and psychosis) have been the focus of the first randomized controlled trials in this field. Despite therapeutic advances, Parkinson's disease continues to be a relentlessly progressive disorder leading to severe disability. Neuroprotective interventions able to modify the progression of Parkinson's disease have stood out as a failed therapeutic goal over the last 2 decades, despite potentially encouraging results with compounds like rasagiline. Newer molecular targets, new animal models, novel clinical trial designs, and biomarkers to assess disease modification have created hope for future therapeutic interventions. PMID:21626552

Rascol, Olivier; Lozano, Andres; Stern, Matthew; Poewe, Werner

2011-05-01

199

Cellular Imaging Predictions of Clinical Drug-Induced Liver Injury  

Microsoft Academic Search

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

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

2008-01-01

200

Mechanism of copper(II)-induced misfolding of Parkinson's disease protein  

PubMed Central

?-synuclein (aS) is a natively unfolded pre-synaptic protein found in all Parkinson's disease patients as the major component of fibrillar plaques. Metal ions, and especially Cu(II), have been demonstrated to accelerate aggregation of aS into fibrillar plaques, the precursors to Lewy bodies. In this work, copper binding to aS is investigated by a combination of quantum and molecular mechanics simulations. Starting from the experimentally observed attachment site, several optimized structures of Cu-binding geometries are examined. The most energetically favorable attachment results in significant allosteric changes, making aS more susceptible to misfolding. Indeed, an inverse kinematics investigation of the configuration space uncovers a dynamically stable ?-sheet conformation of Cu-aS that serves as a nucleation point for a second ?-strand. Based on these findings, we propose an atomistic mechanism of copper-induced misfolding of aS as an initial event in the formation of Lewy bodies and thus in PD pathogenesis.

Rose, Frisco; Hodak, Miroslav; Bernholc, Jerzy

2011-01-01

201

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

PubMed

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

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

2013-05-01

202

Gastrodin protects apoptotic dopaminergic neurons in a toxin-induced Parkinson's disease model.  

PubMed

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

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

2013-01-01

203

Neuronal drug transporters in platinum drugs-induced peripheral neurotoxicity.  

PubMed

To gain a better insight into the neurotoxicity of platinum drugs, it is important to increase our knowledge over the phenomena allowing their entry into dorsal root ganglia neurons. A deeper understanding of platinum-drug transport mechanisms in neurons would represent not only a step forward in the pathogenetic interpretation of their neurotoxicity, but would also disclose possible treatment options to prevent this severe side-effect achievable through modulation of transporter activity. Copper transporters and organic cation transporters have been identified as putative targets for the pharmacological modulation of neuronal cell accumulation of platinum drugs and damage, and this possibility has been demonstrated by animal studies. The modulation of drug transporter activity is a promising strategy to limit the neurotoxicity of platinum drugs, provided that a) complete characterization of drug transporters is obtained and b) selective neuronal activity is targeted without reducing anticancer drug efficacy. PMID:24403505

Cavaletti, Guido; Ceresa, Cecilia; Nicolini, Gabriella; Marmiroli, Paola

2014-01-01

204

Pharmacogenetics of drug-induced liver injury.  

PubMed

Recent progress in research on drug-induced liver injury (DILI) has been determined by key developments in two areas. First, new technologies allow the identification of genetic risk factors with improved sensitivity, specificity, and efficiency. Second, new mechanistic concepts of DILI emphasize the importance of unspecific "downstream" events following drug-specific initial "upstream" hepatocyte injury and of complex interactions between environmental and genetic risk factors. The integration of genetic and mechanistic concepts is essential for current research approaches, and genetic studies of DILI now focus on targets that affect the function and transcriptional regulation of genes relating not only to drug metabolism but also to human leukocyte antigens (HLAs), cytokines, oxidative stress, and hepatobiliary transporters. Risk factors affecting unspecific downstream mechanisms may be identified using pooled DILI cases caused by various drugs. The power to detect variants that confer a low risk can be increased by recruitment of strictly selected cases through large networks, whereas controls may also be obtained from genotyped reference populations. The first genomewide studies of DILI identified HLA variants as risk factors for hepatotoxicity associated with flucloxacillin and ximelagatran, and their design has defined a new standard for pharmacogenetic studies. From a clinical and regulatory point of view, there is a need for genetic tests that identify patients at increased hepatotoxic risk. However, DILI is a rare complex disease, and pharmacogenetic studies have so far not been able to identify interactions of several risk factors defining a high population-attributable risk and clinically relevant absolute risk for DILI. PMID:20607838

Russmann, Stefan; Jetter, Alexander; Kullak-Ublick, Gerd A

2010-08-01

205

Drug Effects Upon Performance under Task-Induced Stress.  

National Technical Information Service (NTIS)

An experiment was performed to test the interaction between drug/placebo effects and incentive conditions under task-induced stress. Sixty-three student volunteers served in a factorially designed experiment varying level of incentive, drug condition, and...

P. M. Hurst M. F. Weidner

1966-01-01

206

Chlorotoxin-modified stealth liposomes encapsulating levodopa for the targeting delivery against Parkinson's disease in the MPTP-induced mice model.  

PubMed

Chlorotoxin (ClTx), originally isolated from scorpion venom of Leiurus quinquestriatus, is a 36-amino acid peptide and specifically binds to the brain gliomas and proliferating vascular endothelial cells. In this paper, it was first used to establish the ClTx-modified stealth liposomes (ClTx-LS) encapsulating levodopa (LD) for the targeting drug delivery against the Parkinson's disease (PD). After the DSPE-PEG-ClTx was synthesized and identified, the ClTx-LS system was prepared and characterized. Its targeting capability was studied in vitro and in vivo, and finally its anti-PD activity was evaluated, with non-modified liposomes (LS) as control. It was demonstrated through flow cytometry and confocal microscopy that ClTx modification highly facilitated the uptake of LS by brain microvascular endothelial cells in vitro. After intraperitoneal injection to mice, the active targeting system loaded with LD significantly increased the distribution of dopamine and dihydroxyphenyl acetic acid, the metabolites of LD, in the substantia nigra and striata. In the methyl-phenyl-tetrahydropyridine (MPTP)-induced PD mice model, LD-loaded ClTx-LS significantly attenuated the serious behavioral disorders and diminished the MPTP-induced loss of tyrosine hydroxylase-positive dopaminergic neurons. In conclusion, ClTx-modified LS might serve as a targeting delivery system to transport more drugs into the brain for a better PD therapy. PMID:22149216

Xiang, Yu; Wu, Qian; Liang, Liang; Wang, Xueqing; Wang, Jiancheng; Zhang, Xuan; Pu, Xiaoping; Zhang, Qiang

2012-01-01

207

Protein Oxidation Triggers the Unfolded Protein Response and Neuronal Injury in Chemically Induced Parkinson Disease  

Microsoft Academic Search

The recent identification of genetic mutations linked to Parkinson’s disease (PD), such as ?-synuclein, parkin, and LRRK2,\\u000a has highlighted the role of aberrant protein handling and degradation in this disorder. Moreover, a growing body of data suggests\\u000a that environmental toxins that mimic PD also exhibit faulty protein handling, providing a mechanistic link between toxicity\\u000a and the identified PD mutations. In

Alison I. Bernstein; Karen L. O’Malley

208

From Manganism to Manganese-Induced Parkinsonism: A Conceptual Model Based on the Evolution of Exposure  

Microsoft Academic Search

Manganism is a distinct medical condition from Parkinson’s disease. Manganese exposure scenarios in the last century generally\\u000a have changed from the acute, high-level exposure conditions responsible for the occurrence of manganism to chronic exposure\\u000a to much lower levels. Such chronic exposures may progressively extend the site of manganese deposition and toxicity from the\\u000a globus pallidus to the entire area of

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

2009-01-01

209

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

PubMed

This review addresses two questions. First, why does clozapine apparently occupy low levels of dopamine D2 receptors in patients, in contrast to all other antipsychotic drugs which occupy 70-80% of brain dopamine D2 receptors? Second, what is the receptor basis of action of antipsychotic drugs which elicit low levels of Parkinsonism? Antipsychotic doses of clozapine occupy between 0% and 50% of D2 receptors, as measured in patients by a variety of radioligands. It has recently been found, however, that the percent occupancy of a receptor by a drug depends on the radioligand used to measure that receptor. Based on this new finding, this review concludes that clozapine clinically occupies high levels of D2 receptors in the absence of any radioligand. This occupancy is estimated to be of the order of 70-80% in the dopamine-rich region of the human striatum, and even higher in the limbic D2-containing regions which are low in endogenous synaptic dopamine. This conclusion arises from two different approaches. One approach is to relate the reported clozapine occupancies in the human striatum with the dissociation constants of the various radioligands at the D2 receptor. This relation extrapolates to approximately 70-80% occupancy by clozapine when clozapine competes with endogenous dopamine at the D2 receptor. The second approach is to calculate the D2 occupancy of each antipsychotic drug, using the average spinal fluid concentration and the correct dissociation constant of the antipsychotic, thereby revealing that all antipsychotic drugs, including clozapine, occupy approximately 70-80% of dopamine D2 receptors in the human striatum, and possibly higher in the limbic regions. As determined by the new dissociation constants, antipsychotic drugs which elicit Parkinsonism (trifluperazine, chlorpromazine, raclopride, haloperidol, fluphenazine, risperidone) bind more tightly than dopamine to D2, while those antipsychotic drugs which elicit little or no Parkinsonism (melperone, seroquel, perlapine, clozapine, remoxipride, molindone, sulpiride, olanzapine, sertindole) bind more loosely than dopamine to D2 receptors. Compared to the tightly bound antipsychotic drugs, the more loosely bound antipsychotics generally require higher clinical doses, require fewer days for clinical adjustment, but may dissociate from the D2 receptor more rapidly and could lead to clinical relapse somewhat earlier than that found with the traditional tightly bound antipsychotic drugs. PMID:9577836

Seeman, P; Tallerico, T

1998-03-01

210

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

PubMed

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

Rokosik, Sandra L; Napier, T Celeste

2012-05-01

211

Neuroprotective Effects of Tetramethylpyrazine against Dopaminergic Neuron Injury in a Rat Model of Parkinson's Disease Induced by MPTP  

PubMed Central

Parkinson's disease (PD) is the second most prevalent progressive neurodegenerative disease. Although several hypotheses have been proposed to explain the pathogenesis of PD, apoptotic cell death and oxidative stress are the most prevalent mechanisms. Tetramethylpyrazine (TMP) is a biological component that has been extracted from Ligusticum wallichii Franchat (ChuanXiong), which exhibits anti-apoptotic and antioxidant roles. In the current study, we aimed to investigate the possible protective effect of TMP against dopaminergic neuron injury in a rat model of Parkinson's disease induced by MPTP and to elucidate probable molecular mechanisms. The results showed that TMP could notably prevent MPTP-induced dopaminergic neurons damage, reflected by improvement of motor deficits, enhancement of TH expression and the content of dopamine and its metabolite, DOPAC. We observed MPTP-induced activation of mitochondrial apoptotic death pathway, evidenced by up-regulation of Bax, down-regulation of Bcl-2, release of cytochrome c and cleavage of caspase 3, which was significantly inhibited by TMP. Moreover, TMP could prevent MPTP-increased TBARS level and MPTP-decreased GSH level, indicating the antioxidant role of TMP in PD model. And the antioxidant role of TMP attributes to the prevention of MPTP-induced reduction of Nrf2 and GCLc expression. In conclusion, in MPTP-induced PD model, TMP prevents the down-regulation of Nrf2 and GCLc, maintaining redox balance and inhibiting apoptosis, leading to the attenuation of dopaminergic neuron damage. The effectiveness of TMP in treating PD potentially leads to interesting therapeutic perspectives.

Lu, Chen; Zhang, Jin; Shi, Xiaopeng; Miao, Shan; Bi, Linlin; Zhang, Song; Yang, Qian; Zhou, Xuanxuan; Zhang, Meng; Xie, Yanhua; Miao, Qing; Wang, Siwang

2014-01-01

212

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

PubMed

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

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

2012-08-01

213

Young-Onset Parkinson's  

MedlinePLUS

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

214

Low dosage of rasagiline and epigallocatechin gallate synergistically restored the nigrostriatal axis in MPTP-induced parkinsonism.  

PubMed

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 in animal parkinsonism. Methods/Results: We show by high-performance liquid chromatography, immunohistochemistry and Western blot analyses that the combination of rasagiline and EGCG, at subliminal doses which have no profound protective effect, acts synergistically to restore the nigrostriatal axis in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. A detailed analysis revealed a complementary action of these drugs, differentially acting at MPTP-injured molecules/targets in the substantia nigra (SN): induction of brain-derived neurotrophic factor by rasagiline, increased membranal levels of the protein kinase C alpha-isoform by EGCG and a synergistic replenishment of their downstream effector, the serine/threonine kinase Akt/protein kinase B, suggesting that this kinase might represent one point of convergence of the distinct mechanisms of action of the drug cocktail. Conclusion: These results provide molecular evidence that activation of multiple brain targets by the combination of rasagiline and EGCG may synergistically contribute to the rescue of the dopamine neurons in the SN and replenishment of striatal dopamine. This may have important implications for rasagiline-treated PD patients who could further benefit from an adjunct administration of EGCG. PMID:20197647

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

2010-01-01

215

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

PubMed Central

In animals, sporadic injections of the mitochondrial toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) selectively damage dopaminergic neurons but do not fully reproduce the features of human Parkinson's disease. We have now developed a mouse Parkinson's disease model that is based on continuous MPTP administration with an osmotic minipump and mimics many features of the human disease. Although both sporadic and continuous MPTP administration led to severe striatal dopamine depletion and nigral cell loss, we find that only continuous administration of MPTP produced progressive behavioral changes and triggered formation of nigral inclusions immunoreactive for ubiquitin and ?-synuclein. Moreover, only continuous MPTP infusions caused long-lasting activation of glucose uptake and inhibition of the ubiquitin-proteasome system. In mice lacking ?-synuclein, continuous MPTP delivery still induced metabolic activation, but induction of behavioral symptoms and neuronal cell death were almost completely alleviated. Furthermore, the inhibition of the ubiquitinproteasome system and the production of inclusion bodies were reduced. These data suggest that continuous low-level exposure of mice to MPTP causes a Parkinson-like syndrome in an ?-synuclein-dependent manner.

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

2005-01-01

216

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

PubMed

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

Khurana, Navneet; Gajbhiye, Asmita

2013-12-01

217

An update on drug induced liver injury.  

PubMed

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

Rangnekar, A S; Fontana, R J

2011-06-01

218

Evaluation of the Short Parkinson's Evaluation Scale: a new friendly scale for the evaluation of Parkinson's disease in clinical drug trials.  

PubMed

The extensive use of the Unified Parkinson's Disease Rating Scale (UPDRS) has revealed low interrater reliability in some items and redundancy in others. In view of these shortcomings, we have structured a new scale that includes a zero-to three-point scale for each item in the evaluation of PD. The mental axis includes memory, thought disorders, and depression. Activities of daily living (ADL) includes eight items: speech, eating, feeding, dressing, hygiene, handwriting, walking, and turning in bed. The motor examination includes eight items: speech, tremor, rest and posture, rigidity, finger tapping, arising from chair, gait, and postural stability. Complications of therapy were also included: dyskinesias, dystonia, motor fluctuations, and freezing episodes, collected by history. In addition, a global scoring for motor fluctuations that should complement the Hoehn and Yahr Scale was incorporated. In this report, we present a statistical analysis of the ADL, motor evaluation, and complications of therapy sections. Concerning the interrater reliability mean, Kendall's W values were >0.9 for most of the items in the Short Parkinson's Evaluation Scale (SPES). Kendall's W <0.8 (motor evaluation) was found for two items of the SPES and nine items of the UPDRS. The mean interrater reliability for both scales across all seven centers (seven Kendall's W for seven centers) (Mann-Whitney test) showed no statistical differences between the scales. Spearman's correlations between items of both scales were significant. Factor analysis of the SPES and UPDRS data revealed a four-factor solution that explained approximately 60% of the data. All participating centers found the SPES easier to apply and quicker to complete, when compared with the UPDRS. The results obtained strongly favor the introduction of SPES for clinical practice. PMID:9260730

Rabey, J M; Bass, H; Bonuccelli, U; Brooks, D; Klotz, P; Korczyn, A D; Kraus, P; Martinez-Martin, P; Morrish, P; Van Sauten, W; Van Hilten, B

1997-08-01

219

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

PubMed

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

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

220

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

PubMed

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

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

1989-12-01

221

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

PubMed

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

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

2012-02-01

222

Melatonin or silymarin reduces maneb- and paraquat-induced Parkinson's disease phenotype in the mouse.  

PubMed

Oxidative stress is reported as one of the most widely accepted mechanisms of maneb (MB)- and paraquat (PQ)-induced nigrostriatal dopaminergic neurodegeneration leading to the Parkinson's disease (PD) phenotype. The study investigated the effects of silymarin, an antioxidant of plant origin, and melatonin, an indoleamine produced in all species, in MB- and PQ-induced mouse model of PD. The mice were treated intraperitoneally daily with silymarin (40mg/kg) or melatonin (30mg/kg) along with respective controls for 9wk. Subsets of these animals were also treated with MB (30mg/kg) and PQ (10mg/kg), twice a week, for 9wk, 2hr after silymarin/melatonin treatment. Locomotor activities along with striatal dopamine content, tyrosine hydroxylase (TH) immunoreactivity, number of degenerating neurons, lipid peroxidation and nitrite content were estimated. Additionally, mRNA expression of vesicular monoamine transporter, cytochrome P-450 2E1 (CYP2E1), and glutathione-S-transferase A4-4 (GSTA4-4), catalytic activities of CYP2E1 and GSTA4-4 and protein expressions of unphosphorylated and phosphorylated p53 (p53 and P-p53), Bax and caspase 9 were measured in control and MB- and PQ-treated mice with either silymarin or melatonin treatments. Silymarin/melatonin significantly offset MB- and PQ-mediated reductions in locomotor activities, dopamine content, TH immunoreactivity, VMAT 2 mRNA expression and the expression of p53 protein. Silymarin/melatonin attenuated the increases in lipid peroxidation, number of degenerating neurons, nitrite content, mRNA expressions of cytochrome P-450 2E1 (CYP2E1) and GSTA4-4, catalytic activities of CYP2E1 and GST and P-p53, Bax and caspase 9 protein expressions. The results demonstrate that silymarin and melatonin offer nigrostriatal dopaminergic neuroprotection against MB- and PQ-induced PD by the modulation of oxidative stress and apoptotic machinery. PMID:20964710

Singhal, Naveen Kumar; Srivastava, Garima; Patel, Devendra Kumar; Jain, Swatantra Kumar; Singh, Mahendra Pratap

2011-03-01

223

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

PubMed Central

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

Stewart, J

2000-01-01

224

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

Microsoft Academic Search

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

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

2011-01-01

225

Clinical and laboratory characteristics of drug-induced vasculitic syndromes.  

PubMed

Clinical recognition of drug-induced vasculitic and lupus-like syndromes is very important because continued use of the offending drug can lead to irreversible and life-threatening vasculitic organ damage (e.g. end-stage renal disease or pulmonary haemorrhage). Withdrawal of the drug often leads to spontaneous recovery, meaning that immunosuppressive therapy can be avoided. The presence of myeloperoxidase-antineutrophil cytoplasmic antibodies, IgM anticardiolipin antibody, and antihistone antibodies in combination was found to be characteristic of drug-induced vasculitic syndromes caused by the antithyroid drugs propylthiouracil and methimazol. Clinically, skin vasculitis and arthralgias predominated and renal vasculitis was rare. PMID:16207347

Wiik, Allan

2005-01-01

226

Clinical and laboratory characteristics of drug-induced vasculitic syndromes  

PubMed Central

Clinical recognition of drug-induced vasculitic and lupus-like syndromes is very important because continued use of the offending drug can lead to irreversible and life-threatening vasculitic organ damage (e.g. end-stage renal disease or pulmonary haemorrhage). Withdrawal of the drug often leads to spontaneous recovery, meaning that immunosuppressive therapy can be avoided. The presence of myeloperoxidase–antineutrophil cytoplasmic antibodies, IgM anticardiolipin antibody, and antihistone antibodies in combination was found to be characteristic of drug-induced vasculitic syndromes caused by the antithyroid drugs propylthiouracil and methimazol. Clinically, skin vasculitis and arthralgias predominated and renal vasculitis was rare.

Wiik, Allan

2005-01-01

227

Nonsteroidal anti-inflammatory drug-induced hepatotoxicity.  

PubMed

Nonsteroidal anti-inflammatory drugs are among the most common drugs associated with drug-induced liver injury, with an estimated incidence of between 3 and 23 per 100,000 patient years. Nimesulide, sulindac, and diclofenac seem to be associated with the highest risk and the only risk factor consistently identified is the concomitant use of other hepatotoxic drugs. Diclofenac-induced liver injury is a paradigm for drug-related hepatotoxicity. Recent studies suggest that genetic factors favoring the formation and accumulation of the reactive acylglucuronide metabolite of diclofenac and an enhanced immune response to the metabolite-protein adducts are associated with increased susceptibility to hepatotoxicity. PMID:17723920

Aithal, Guruprasad P; Day, Christopher P

2007-08-01

228

Mechanisms of drug-induced proarrhythmia in clinical practice  

PubMed Central

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

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

2013-01-01

229

Drug-induced renal calculi: epidemiology, prevention and management.  

PubMed

Drug-induced calculi represent 1-2% of all renal calculi. The drugs reported to produce calculi formation may be divided into two groups. The first one includes poorly soluble drugs with high urine excretion that favours crystallisation in the urine. Among poorly soluble molecules, triamterene was the leading cause of drug-containing urinary calculi in the 1970s, and it is still currently responsible for a significant number of calculi. In the last decade, drugs used for the treatment of HIV-infected patients, namely indinavir and sulfadiazine, have become the most frequent cause of drug-containing urinary calculi. Besides these drugs, about twenty other molecules may induce nephrolithiasis in patients receiving long-term treatment or high doses. Calculi analysis by physical methods, including infrared spectroscopy or x-ray diffraction, is needed to demonstrate the presence of the drug or its metabolites within the calculi. The second group includes drugs that provoke urinary calculi as a consequence of their metabolic effects. Here, diagnosis relies on careful clinical inquiry because physical methods are ineffective to differentiate between urinary calculi induced by the metabolic effects of a drug and common metabolic calculi. The incidence of such calculi, especially those resulting from calcium/vitamin D supplementation, is probably underestimated. Although drug-induced urinary calculi most often complicate high-dose, long-duration drug treatments, there also exist specific patient risk factors in relation to urine pH, urine output and other parameters, which provide a basis for preventive or curative treatment of calculi. Better awareness of the possible occurrence of lithogenic complications, preventive measures based on drug solubility characteristics and close surveillance of patients on long-term treatment with drugs with lithogenic potential, especially those with a history of urolithiasis, should reduce the incidence of drug-induced nephrolithiasis. PMID:14871169

Daudon, Michel; Jungers, Paul

2004-01-01

230

Diagnosis, management and prevention of drug-induced liver injury  

Microsoft Academic Search

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

S Verma; N Kaplowitz

2009-01-01

231

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. ...

232

Signal Transduction Pathways Involved in Drug-Induced Liver Injury  

Microsoft Academic Search

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

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

233

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

PubMed

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

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

2013-04-01

234

Synuclein induces apoptosis by altered expression in human peripheral lymphocytes in Parkinson's disease  

Microsoft Academic Search

Though the etiology of Parkinson's disease (PD) remains unclear, ?-synuclein (?-SN) is regarded as a major causative agent of PD. Several lines of evidence indicate that immunological abnormalities are associated with PD for unknown reasons. The present study was performed to assess whether peripheral blood mononuclear cells (PBMCs) show altered ?-SN expression in PD patients and to identify its functions,

Seonghan Kim; Beom S. Jeon; Chaejeong Heo; Pil Seon Im; Tae-Beom Ahn; Ji-Heui Seo; Hye-Sun Kim; Cheol Hyoung Park; Se Hoon Choi; Seo-Hyun Cho; Wang Jae Lee; Yoo-Hun Suh

2004-01-01

235

Adverse drug reactions induced by valproic acid.  

PubMed

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

Nanau, Radu M; Neuman, Manuela G

2013-10-01

236

Antituberculosis drug-induced hepatotoxicity in children  

PubMed Central

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

Donald, Peter R

2011-01-01

237

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

PubMed

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

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

2011-01-01

238

Hallucinations and sleep disturbances in Parkinson's disease.  

PubMed

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

Kulisevsky, Jaime; Roldan, Eliana

2004-10-26

239

Drug-induced QT interval prolongation: mechanisms and clinical management  

PubMed Central

The prolonged QT interval is both widely seen and associated with the potentially deadly rhythm, Torsades de Pointes (TdP). While it can occur spontaneously in the congenital form, there is a wide array of drugs that have been implicated in the prolongation of the QT interval. Some of these drugs have either been restricted or withdrawn from the market due to the increased incidence of fatal polymorphic ventricular tachycardia. The list of drugs that cause QT prolongation continues to grow, and an updated list of specific drugs that prolong the QT interval can be found at www.qtdrugs.org. This review focuses on the mechanism of drug-induced QT prolongation, risk factors for TdP, culprit drugs, prevention and monitoring of prolonged drug-induced QT prolongation and treatment strategies.

Nachimuthu, Senthil; Assar, Manish D.

2012-01-01

240

A Tribute to Charlie Chaplin: Induced Positive Affect Improves Reward-Based Decision-Learning in Parkinson's Disease  

PubMed Central

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

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

2012-01-01

241

Resveratrol potentiates cytochrome P450 2 d22-mediated neuroprotection in maneb- and paraquat-induced parkinsonism in the mouse.  

PubMed

A strong association between polymorphisms of the cytochrome P450 (CYP/Cyp) 2D6 gene and risk to Parkinson's disease (PD) is well established. The present study investigated the neuroprotective potential of Cyp2d22, a mouse ortholog of human CYP2D6, in maneb- and paraquat-induced parkinsonism and the mechanisms involved therein along with the effects of resveratrol on various parameters associated with Cyp2d22-mediated neuroprotection. The animals were treated intraperitoneally with resveratrol (10mg/kg, daily) and paraquat (10mg/kg) alone or in combination with maneb (30 mg/kg), twice a week, for 9 weeks, along with their respective controls. The subsets of animals were also treated intraperitoneally with a Cyp2d22 inhibitor, ketoconazole (100mg/kg, daily). Maneb and paraquat reduced Cyp2d22 and vesicular monoamine transporter type 2 (VMAT-2) expressions, the number of tyrosine hydroxylase-positive cells, and dopamine content and increased paraquat accumulation in the nigrostriatal tissues, oxidative stress, microglial activation, neuroinflammation, and apoptosis. Cyp2d22 inhibitor significantly exacerbated all these neurodegenerative indexes. Resveratrol cotreatment, partially but significantly, ameliorated the neurodegenerative changes by altering Cyp2d22 expression and paraquat accumulation. The results obtained in the study demonstrate that Cyp2d22 offers neuroprotection in maneb- and paraquat-induced dopaminergic neurodegeneration and resveratrol enhances its neuroprotective credentials by influencing Cyp2d22 expression and paraquat accumulation. PMID:22334051

Srivastava, Garima; Dixit, Anubhuti; Yadav, Sharawan; Patel, Devendra Kumar; Prakash, Om; Singh, Mahendra Pratap

2012-04-15

242

Identification of drugs inducing phospholipidosis by novel in vitro data.  

PubMed

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

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

2012-11-01

243

Identification of Drugs Inducing Phospholipidosis by Novel in vitro Data  

PubMed Central

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.

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

2012-01-01

244

Drug-Induced Hepatotoxicity: Metabolic, Genetic and Immunological Basis  

PubMed Central

Drug-induced hepatotoxicity is a significant cause of acute liver failure and is usually the primary reason that therapeutic drugs are removed from the commercial market. Multiple mechanisms can culminate in drug hepatotoxicity. Metabolism, genetics and immunology separately and in concert play distinct and overlapping roles in this process. This review will cover papers we feel have addressed these mechanisms of drug-induced hepatotoxicity in adults following the consumption of commonly used medications. The aim is to generate discussion around “trigger point” papers where the investigators generated new science or provided additional contribution to existing science. Hopefully these discussions will assist in uncovering key areas that need further attention.

Njoku, Dolores B.

2014-01-01

245

Drug-induced subacute cutaneous lupus erythematosus associated with omeprazole.  

PubMed

Subacute cutaneous lupus erythematosus (SCLE) is characterized by annular scaly erythematous plaques in a photosensitive distribution, and the presence of anti-Ro (SSA) and/or anti-La (SSB) antibodies. Most cases of SCLE are idiopathic, but occasional cases may be drug-induced or associated with a hereditary deficiency of complement components. We report two cases of drug-induced SCLE precipitated by the proton pump inhibitor, omeprazole. Drug-induced disease should be considered in all atypical or extensive cases of SCLE, especially in elderly patients. PMID:20738320

Toms-Whittle, L M; John, L H; Buckley, D A

2011-04-01

246

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

PubMed Central

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

Murer, Mario Gustavo; Moratalla, Rosario

2011-01-01

247

Non-oral drug delivery in Parkinson's disease: a summary from the symposium at the 7th International Congress of Parkinson's Disease and Movement Disorders. 10-14 November 2002, Miami, FL, USA.  

PubMed

This symposium reviewed the issues of non-oral therapy in the late stage Parkinson's disease (PD). The accepted standard treatment of PD is oral levodopa or oral dopamine agonists. However, the long-term complications and limitations of this treatment might be improved by changing therapy from the present pulsatile stimulation to a more constant stimulation of central dopamine receptors. Stimulation of these receptors may be possible with non-oral drug delivery treatments. Many of these non-oral options have been evaluated during the last few decades to find a more continuous drug delivery. The non-oral treatment options include invasive measures such as intraduodenal levodopa, subcutaneous apomorphin and most recently, the non-invasive transdermal (patch) delivery system, with the novel dopamine agonist rotigotine (Aderis Pharmaceuticals Inc.). The benefits of the non-oral, more continuous dopaminergic treatment of PD needs to be demonstrated in clinical trials and long-term clinical practice, before they can be considered as potential replacements of the standard oral therapy. PMID:12667123

Behrens, Stephan; Sommerville, Kenneth

2003-04-01

248

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

PubMed

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

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

2010-11-01

249

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

PubMed

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

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

2006-09-01

250

Manic behaviour induced by deep-brain stimulation in Parkinson's disease: evidence of substantia nigra implication?  

PubMed Central

We report the case of a patient who had benefited from bilateral subthalamic nucleus deep brain stimulation for Parkinson's disease and who presented acute and reproducible manic behaviour when stimulated mainly in the substantia nigra. A positron emission tomography scan showed an activation of the right dorsolateral prefrontal and inferior temporal cortex, the left anterior cingulate cortex and a deactivation of the left insula. This suggests that changes in cortical activation related to mania are subcortically driven, involving notably the substantia nigra.

Ulla, M; Thobois, S; Lemaire, J-J; Schmitt, A; Derost, P; Broussolle, E; Llorca, P-M; Durif, F

2006-01-01

251

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

PubMed Central

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

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

2013-01-01

252

An approach to drug induced delirium in the elderly  

PubMed Central

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

Alagiakrishnan, K; Wiens, C

2004-01-01

253

Loss of thalamic serotonin transporters in early drug-na?ve Parkinson's disease patients is associated with tremor: an [123I]?-CIT SPECT study  

PubMed Central

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

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

2008-01-01

254

Drug-induced acne and rose pearl: similarities*  

PubMed Central

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.

Pontello Junior, Rubens; Kondo, Rogerio Nabor

2013-01-01

255

Drug-induced Osteoporosis: Mechanisms and Clinical Implications  

Microsoft Academic Search

Drug-induced osteoporosis is common and has a significant impact on the prognosis of patients suffering from chronic debilitating diseases. Glucocorticoids are the drugs causing osteoporotic fractures most frequently, but osteoporosis with fractures is observed also in women treated with aromatase inhibitors for breast cancer, in men receiving anti-androgen therapy for prostate cancer, in postmenopausal women treated with high doses of

Gherardo Mazziotti; Ernesto Canalis; Andrea Giustina

2010-01-01

256

Prevention of Drug-Induced Agranulocytosis with Free Radical Scavengers.  

National Technical Information Service (NTIS)

A method is provided of preventing an occurrence of granulocytopenia or agranulocytosis as a drug-induced side-effect in a patient. The method entails co-administering to the patient (1) an active drug other than clozapine with which granulocytopenia or a...

R. P. Mason

1991-01-01

257

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

PubMed Central

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

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

2014-01-01

258

DRUG-INDUCED IMMUNE THROMBOCYTOPENIA: PATHOGENESIS, DIAGNOSIS AND MANAGEMENT  

PubMed Central

SUMMARY Drug-induced immune thrombocytopenia (DITP) can be triggered by a wide range of medications. Although many cases of DITP are mild, some are characterized by life-threatening bleeding symptoms. The pathogenesis of DITP is complex in that at least six different mechanisms have been proposed by which drug-induced antibodies can promote platelet destruction. It is possible in many cases to identify antibodies that react with platelets in the presence of the sensitizing drug, but the required testing is technically demanding and not widely available. Therefore, a decision on whether to discontinue an implicated medication in a patient suspected of having DITP must be made on clinical grounds. An algorithms is available that can be helpful in assessing the likelihood that a particular drug caused thrombocytopenia, but the most important single determinant in managing a patient is a high index of suspicion and a careful history of drug exposure in an individual who presents with acute, often severe thrombocytopenia of unknown etiology. How drugs induce platelet-reactive antibodies and how, once formed, the antibodies cause platelet destruction following exposure to the drug is poorly understood. Further studies to address these issues and characterize more completely the range of drugs and drug metabolites that can cause DITP are needed.

Aster, Richard H; Curtis, Brian R; McFarland, Janice G; Bougie, Daniel W

2010-01-01

259

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

PubMed Central

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

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

2013-01-01

260

Manganese: a transition metal protects nigrostriatal neurons from oxidative stress in the iron-induced animal model of parkinsonism.  

PubMed

It has been suggested that transition metals such as iron and manganese produce oxidative injury to the dopaminergic nigrostriatal system. which may play a critical role in the pathogenesis of Parkinson's disease. Intranigral infusion of ferrous citrate (0 to 8.4 nmol, i.n.) acutely increased lipid peroxidation in the substantia nigra and dopamine turnover in the caudate nucleus. Subsequently, it caused a severe depletion of dopamine levels in the rat caudate nucleus. In contrast to iron's pro-oxidant effect, manganese (up to 30 nmol, i.n.) causes neither lipid peroxidation nor nigral injury/dopamine depletion. Manganese (1.05 to 4.2 nmol, i.n.) dose-dependently protected nigral neurons from iron-induced oxidative injury and dopamine depletion. Manganese also suppressed acute increase in dopamine turnover and contralateral turning behaviour induced by iron. In brain homogenates manganese (0 to 10 microM) concentration-dependently inhibited propagation of lipid peroxidation caused by iron (0 to 5 microM). Without the contribution of manganese-superoxide dismutase manganese was still effective in sodium azide and/or heat-pretreated brain homogenates. Surprisingly, iron but not manganese, catalysed the Fenton reaction or the conversion of hydrogen peroxide to hydroxyl radicals. The results indicate that iron and manganese are two transition metals mediating opposite effects in the nigrostriatal system, as pro-oxidant and antioxidant, respectively. In conclusion, intranigral infusion of iron, but not manganese, provides an animal model for studying the pathophysiological role of oxidant and oxidative stress in nigrostriatal degeneration and Parkinsonism. The present results further suggest that the atypical antioxidative properties of manganese may protect substantia nigra compacta neurons from iron-induced oxidative stress. PMID:9681949

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

1998-08-01

261

[Drug-induced fever: a diagnosis to remember].  

PubMed

Drug fever (DF) is a febrile reaction induced by a drug without additional clinical features like skin eruption. This adverse drug reaction is probably common but under diagnosed. While its outcome is generally favourable, DF generates unnecessary diagnostic procedures as well as hospitalisations or hospitalisation prolongations. Clinical presentation and biological findings are not specific. Fever is generally well tolerated but may be accompanied by general symptoms mimicking sepsis. Moderate biological disorders could be expected, including elevation or decrease in white blood cell count, eosinophilia, liver cytolysis, and increased C-reactive protein. An infection should be systematically ruled out. Clinical or biological signs of severity should question DF diagnosis. When DF is suspected, the involved drug(s) should be stopped after a reliable assessment of imputability. Antibiotics represent the most often implicated drugs. Fever disappearance after discontinuing the suspected drug is the cornerstone of DF diagnosis. Before stopping the administration of the suspected drug(s), a risk/benefit ratio assessment is necessary. Consistently, it may be complicated to stop an antimicrobial drug when treating an infection or an immunosuppressive drug if required. PMID:23490338

Vodovar, D; Le Beller, C; Lillo-Le-Louet, A; Hanslik, T; Megarbane, B

2014-03-01

262

Histopathological and immunohistochemical features of drug-induced exanthems.  

PubMed

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

Lisi, P; Pelliccia, S; Bellini, V

2014-04-01

263

Pulmonary and generalized lysosomal storage induced by amphiphilic drugs.  

PubMed Central

Administration of amphiphilic drugs to experimental animals causes formation of myelinoid bodies in many cell types, accumulation of foamy macrophages in pulmonary alveoli and pulmonary alveolar proteinosis. These changes are the result of an interaction between the drugs and phospholipids which leads to an alteration in physicochemical properties of the phospholipids. Impairment of the digestion of altered pulmonary secretions in phagosomes of macrophages results in accumulation of foam cells in pulmonary alveoli. Impairment of the metabolism of altered phospholipids removed by autophagy induces an accumulation of myelinoid bodies. The administration of amphiphilic compounds thus causes pulmonary intra-alveolar histiocytosis which is a part of a drug-induced lysosomal storage or generalized lipidosis. The accumulation of drug-lipid complexes in myelinoid bodies and in pulmonary foam cells may lead to alteration of cellular functioning and to clinical disease. Currently over 50 amphiphilic drugs are known. Unique pharmacological properties necessitate clinical use of some of these drugs. The occurrence and severity of potential clinical side effects depend on the nature of each drug, dosage and duration of treatment, simultaneous administration of other drugs and foods, individual metabolic pattern of the patient and other factors. Further studies on factors preventing and potentiating adverse effects of amphiphilic drugs are indicated. Images FIGURE 1. FIGURE 2. FIGURE 3. FIGURE 4. FIGURE 5. FIGURE 6. FIGURE 7. FIGURE 8. FIGURE 9. FIGURE 10.

Hruban, Z

1984-01-01

264

Can stress trigger Parkinson's disease?  

PubMed

In this manuscript we summarize the role of chronic stress as a potential trigger factor for Parkinson's disease. Underlying mechanisms and stress-induced changes to the neuronal networks have been highlighted. Examples of stress induced reversible symptoms that resemble parkinsonism in humans and in animal models raise the question whether emotional stress can cause striatal degeneration in susceptible patients. A Pubmed literature review searching for the terms 'Stress', 'Distress and Parkinson's disease', 'Emotional Distress and Parkinson's disease', 'Stress and Parkinson's disease', 'Prodromal Parkinson's disease', 'Non motor symptoms and Parkinson's disease', 'Paradoxical kinesia', 'Psychogenic parkinsonism', 'Functional somatic syndromes', 'Chronic fatigue syndrome', 'Irritable bowel syndrome', 'Fibromyalgia', 'Dopamine and fibromyalgia', 'Dopamine and chronic fatigue syndrome' and 'Dopamine and irritable bowel syndrome' was carried out until April 2013. Articles were also identified through searches of the authors' own files. Only papers published in English were reviewed. The final reference list was generated on the basis of originality and relevance to the broad scope of this viewpoint. PMID:24259593

Djamshidian, Atbin; Lees, Andrew J

2014-08-01

265

Drug Induced Arousal and Fear Appeals.  

ERIC Educational Resources Information Center

It is hypothesized that the drug, epinephrine, used in conjunction with a fear arousing film on the consquences of smoking would be more effective than either alone in increasing fear and negative attitudes toward smoking and, resultantly, in reducing cigarette consumption. The experimenters assigned 119 subjects to the four cells of a 2x2…

Deckner, C. William; Rogers, Ronald W.

266

Association between Physical Restraint and Drug-Induced Liver Injury  

Microsoft Academic Search

Objective: As animal models have suggested enhancement of xenobiotic-induced hepatotoxicity due to restraint stress, a case-control study was undertaken to investigate the effects of physical restraint on the development of drug-induced liver injury (DILI) in a psychiatric intensive care unit. Method: Demographic and clinical characteristics were compared between restrained patients (n = 106) and nonrestrained patients (n = 528) admitted

Kotaro Hatta; Nobuto Shibata; Tsuneyoshi Ota; Chie Usui; Masanobu Ito; Hiroyuki Nakamura; Heii Arai

2007-01-01

267

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

PubMed Central

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

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

2013-01-01

268

L-dopa induces under-damped visually guided motor responses in Parkinson's disease.  

PubMed

Parkinson's disease preferentially affects internally generated movements, e.g., movements recalled from memory, while externally cued movements are relatively preserved. However, L-dopa may have effects on visually guided movements as well as error-related processing. Fourteen Parkinson's disease (PD) subjects (on and off L-dopa medication) as well as ten normal controls performed a tracking task using a joystick. During discrete 30 s blocks, the visual feedback of the actual tracking errors were attenuated, amplified or unaltered. Second order dynamical system models, with the desired trajectory as the input and the actual motor performance as the output, were used to characterize the motor performance by the each subject under each condition. Although the overall root-mean-square tracking error did not significantly differ between groups, the nature of the motor performance differed significantly across groups. A clear dissociation was made between manipulations of error feedback--which altered the natural frequency of the models--and the effects of L-dopa, which affected damping. Compared to normal controls, PD subjects were significantly overdamped before medication and underdamped after medication. We interpret our results as being suggestive of L: -dopa normalization of compensatory overactive cerebellar activity in PD. PMID:20143051

Au, Wing-Lok; Lei, Ni; Oishi, Meeko M K; McKeown, Martin J

2010-05-01

269

Rotigotine transdermal system for the treatment of Parkinson's disease  

Microsoft Academic Search

Background: Levodopa has been the cornerstone of the treatment of Parkinson's disease (PD) for >30 years, but long-term levodopa therapy is associated with development of such motor complications as motor fluctuations, dyskinesias, and drug-induced involuntary movements. Rotigotine is a dopamine agonist with high affinity for the D2 receptor. Rotigotine transdermal system, the first such system approved by the US Food

David Q. Pham; Anna Nogid

2008-01-01

270

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

Microsoft Academic Search

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

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

2010-01-01

271

Mitochondrial involvement in drug-induced liver injury.  

PubMed

Mitochondrial dysfunction is a major mechanism of liver injury. A parent drug or its reactive metabolite can trigger outer mitochondrial membrane permeabilization or rupture due to mitochondrial permeability transition. The latter can severely deplete ATP and cause liver cell necrosis, or it can instead lead to apoptosis by releasing cytochrome c, which activates caspases in the cytosol. Necrosis and apoptosis can trigger cytolytic hepatitis resulting in lethal fulminant hepatitis in some patients. Other drugs severely inhibit mitochondrial function and trigger extensive microvesicular steatosis, hypoglycaemia, coma, and death. Milder and more prolonged forms of drug-induced mitochondrial dysfunction can also cause macrovacuolar steatosis. Although this is a benign liver lesion in the short-term, it can progress to steatohepatitis and then to cirrhosis. Patient susceptibility to drug-induced mitochondrial dysfunction and liver injury can sometimes be explained by genetic or acquired variations in drug metabolism and/or elimination that increase the concentration of the toxic species (parent drug or metabolite). Susceptibility may also be increased by the presence of another condition, which also impairs mitochondrial function, such as an inborn mitochondrial cytopathy, beta-oxidation defect, certain viral infections, pregnancy, or the obesity-associated metabolic syndrome. Liver injury due to mitochondrial dysfunction can have important consequences for pharmaceutical companies. It has led to the interruption of clinical trials, the recall of several drugs after marketing, or the introduction of severe black box warnings by drug agencies. Pharmaceutical companies should systematically investigate mitochondrial effects during lead selection or preclinical safety studies. PMID:20020267

Pessayre, Dominique; Mansouri, Abdellah; Berson, Alain; Fromenty, Bernard

2010-01-01

272

Aged monkeys as a partial model for Parkinson's disease  

PubMed Central

Parkinson's Disease (PD) and the natural aging process share a number of biochemical mechanisms, including reduced function of dopaminergic systems. The present study aims to determine the extent that motor and behavioral changes in aged monkeys resemble parkinsonism induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. The behavioral and physiological changes in PD are believed to result largely from selective depletion of dopamine in the nigrostriatal system. In the present study, ten aged female monkeys were compared with three groups: 9 untreated young adult female monkeys, 10 young adult male monkeys and 13 older male monkeys that had been exposed to MPTP. Trained observers, blind as to age and drug condition and without knowledge of the hypotheses, scored the monkeys using the Parkinson's factor score (Parkscore), which has been validated by a high correlation with post mortem striatal dopamine (DA) concentrations. The aged animals had higher scores on the Parkscore compared with the young adults, with most of its component behavioral items showing significance (tremor, eating problems, delayed initiation of movement, and poverty of movement). L-Dopa and DA-agonists did not clearly reverse the principal measure of parkinsonism. DA concentrations post mortem were 63% lower in 3 aged monkeys in the ventral putamen compared with 4 young adults, with greater reductions in putamen than in caudate (45%). We conclude that aged monkeys, unexposed to MPTP, show a similar profile of parkinsonism to that seen after the neurotoxin exposure to MPTP in young adult monkeys. The pattern of greater DA depletion in putamen than in caudate in aged monkeys is the same as in human Parkinson's disease and contrasts with the greater depletion in caudate seen after MPTP. Aged monkeys of this species reflect many facets of Parkinson's disease, but like older humans do not improve with standard dopamine replacement pharmacotherapies.

Hurley, P.J.; Elsworth, J.D.; Whittaker, M.C.; Roth, R.H.; Redmond, D.E.

2011-01-01

273

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

PubMed Central

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

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

2011-01-01

274

Excessive Sensitivity to Uncertain Visual Input in L-DOPA-Induced Dyskinesias in Parkinson's Disease: Further Implications for Cerebellar Involvement  

PubMed Central

When faced with visual uncertainty during motor performance, humans rely more on predictive forward models and proprioception and attribute lesser importance to the ambiguous visual feedback. Though disrupted predictive control is typical of patients with cerebellar disease, sensorimotor deficits associated with the involuntary and often unconscious nature of l-DOPA-induced dyskinesias in Parkinson’s disease (PD) suggests dyskinetic subjects may also demonstrate impaired predictive motor control. Methods: We investigated the motor performance of 9 dyskinetic and 10 non-dyskinetic PD subjects on and off l-DOPA, and of 10 age-matched control subjects, during a large-amplitude, overlearned, visually guided tracking task. Ambiguous visual feedback was introduced by adding “jitter” to a moving target that followed a Lissajous pattern. Root mean square (RMS) tracking error was calculated, and ANOVA, robust multivariate linear regression, and linear dynamical system analyses were used to determine the contribution of speed and ambiguity to tracking performance. Results: Increasing target ambiguity and speed contributed significantly more to the RMS error of dyskinetic subjects off medication. l-DOPA improved the RMS tracking performance of both PD groups. At higher speeds, controls and PDs without dyskinesia were able to effectively de-weight ambiguous visual information. Conclusion: PDs’ visually guided motor performance degrades with visual jitter and speed of movement to a greater degree compared to age-matched controls. However, there are fundamental differences in PDs with and without dyskinesia: subjects without dyskinesia are generally slow, and less responsive to dynamic changes in motor task requirements, but in PDs with dyskinesia, there was a trade-off between overall performance and inappropriate reliance on ambiguous visual feedback. This is likely associated with functional changes in posterior parietal–ponto–cerebellar pathways.

Stevenson, James K. R.; Lee, Chonho; Lee, Bu-Sung; TalebiFard, Pouria; Ty, Edna; Aseeva, Kristina; Oishi, Meeko M. K.; McKeown, Martin J.

2013-01-01

275

Identification of differentially expressed proteins in striatum of maneb-and paraquat-induced Parkinson's disease phenotype in mouse.  

PubMed

Behavioral, phenotypic and biochemical changes induced by maneb+paraquat (MB+PQ) in experimental animals have shown their role in the etiologies of Parkinson's disease (PD); however, MB+PQ induced neuronal damage at genome and proteome level have not yet been clearly understood. The present study was undertaken to investigate the differential protein expression patterns in control and MB+PQ treated mouse striatum and to identify differentially expressed proteins. Animals were treated with and without MB+PQ, twice a week for three, six and nine weeks and proteome profiles of striatum were compared. Three differentially expressed proteins were identified as complexin-I, alpha-enolase and glia maturation factor-beta (GMF-beta) using 2D-PAGE and mass spectrometry. The differential expressions were also confirmed at transcription level by semi-quantitative RT-PCR. The results suggest the involvement of complexin-I, alpha-enolase and GMF-beta in MB+PQ induced PD phenotype in mouse. PMID:17532186

Patel, Suman; Sinha, Ashima; Singh, Mahendra Pratap

2007-01-01

276

Oncoprotein Akt/PKB induces trophic effects in murine models of Parkinson's disease  

PubMed Central

Despite promising preclinical studies, neurotrophic factors have not yet achieved an established role in the treatment of human neurodegenerative diseases. One impediment has been the difficulty in providing these macromolecules in sufficient quantity and duration at affected sites. An alternative approach is to directly activate, by viral vector transduction, intracellular signaling pathways that mediate neurotrophic effects. We have evaluated this approach in dopamine neurons of the substantia nigra, neurons affected in Parkinson's disease, by adeno-associated virus 1 transduction with a gene encoding a myristoylated, constitutively active form of the oncoprotein Akt/PKB. Adeno-associated virus Myr-Akt has pronounced trophic effects on dopamine neurons of adult and aged mice, including increases in neuron size, phenotypic markers, and sprouting. Transduction confers almost complete protection against apoptotic cell death in a highly destructive neurotoxin model. Activation of intracellular neurotrophic signaling pathways by vector transfer is a feasible approach to neuroprotection and restorative treatment of neurodegenerative disease.

Ries, Vincent; Henchcliffe, Claire; Kareva, Tatyana; Rzhetskaya, Margarita; Bland, Ross; During, Matthew J.; Kholodilov, Nikolai; Burke, Robert E.

2006-01-01

277

Extrapontine Myelinolysis-Induced Parkinsonism in a Patient with Adrenal Crisis  

PubMed Central

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

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

2012-01-01

278

Drug-induced injury in the gastrointestinal tract.  

PubMed

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

Panarelli, Nicole C

2014-03-01

279

Drug-induced angioedema: experience of Italian emergency departments.  

PubMed

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

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

2014-06-01

280

Idiosyncratic Drug-Induced Liver Injury: A Clinical Update  

Microsoft Academic Search

Drug-induced liver injury (DILI) is a rare but potentially devastating adverse drug reaction. Its presentation can range from\\u000a asymptomatic elevation in liver biochemistries to fulminant liver failure. Over the past decade, clinical and research interest\\u000a in the field of idiosyncratic DILI has been intense, and several new findings have been reported. In this article, we provide\\u000a an update on implicated

Haripriya Maddur; Naga Chalasani

2011-01-01

281

Cannabidiol inhibits the hyperlocomotion induced by psychotomimetic drugs in mice  

Microsoft Academic Search

Cannabidiol is a non-psychotomimetic compound from Cannabis sativa. It is proposed as a possible antipsychotic drug, since it can prevent some psychotomimetic-like effects of ?9-tetrahydrocannabinol or apomorphine. Therefore, the aim of this work was to test the hypothesis that cannabidiol would inhibit the hyperlocomotion induced by two psychotomimetic drugs, d-amphetamine or ketamine. Male Swiss mice received i.p. injections of haloperidol

Fabrício A. Moreira; Francisco S. Guimarães

2005-01-01

282

Drug-induced granulomatous interstitial nephritis in a pediatric patient  

Microsoft Academic Search

Acute interstitial nephritis (AIN) is a known cause of acute renal failure in children. In most instances, drug therapy is\\u000a the offending agent. Although granuloma formation has been observed in drug-induced interstitial nephritis, it is not a commonly\\u000a associated manifestation. This is a case of a 15-year-old white female with Tetralogy of Fallot and pulmonary atresia who\\u000a developed acute renal

James E. Tong; David N. Howell; John W. Foreman

2007-01-01

283

Drug-induced hepatotoxicity test using ?-glutamylcysteine synthetase knockdown rat  

Microsoft Academic Search

Idiosyncratic drug-induced liver injury (DILI) is a major clinical problem for drug development. It is generally known that DILI is mainly caused by hepatic glutathione (GSH) depletion. The glutathione S-transferase activity of rodent is higher than that of human, which could make the prediction of DILI more difficult. Recently, we reported that an experimental rat model of GSH-depletion displayed high

Mayu Morita; Sho Akai; Hiroko Hosomi; Koichi Tsuneyama; Miki Nakajima; Tsuyoshi Yokoi

2009-01-01

284

Nonsteroidal anti-inflammatory drug-induced hepatoxicity.  

PubMed

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

Unzueta, Alberto; Vargas, Hugo E

2013-11-01

285

Drug-Induced Solar Urticaria due to Repirinast  

Microsoft Academic Search

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\\/ cm of UVA, and the provocation test confirmed

Y. Kurumaji; M. Shono

1994-01-01

286

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

PubMed

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

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

2013-08-29

287

P-Glycoprotein Mediated Efflux Limits the Transport of the Novel Anti-Parkinson's Disease Candidate Drug FLZ across the Physiological and PD Pathological In Vitro BBB Models  

PubMed Central

FLZ, a novel anti-Parkinson's disease (PD) candidate drug, has shown poor blood-brain barrier (BBB) penetration based on the pharmacokinetic study using rat brain. P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are two important transporters obstructing substrates entry into the CNS as well as in relation to PD neuropathology. However, it is unclear whether P-gp and BCRP are involved in low BBB permeability of FLZ and what the differences of FLZ brain penetration are between normal and Parkinson's conditions. For this purpose, in vitro BBB models mimicking physiological and PD pathological-related BBB properties were constructed by C6 astroglial cells co-cultured with primary normal or PD rat cerebral microvessel endothelial cells (rCMECs) and in vitro permeability experiments of FLZ were carried out. High transepithelial electrical resistance (TEER) and low permeability for sodium fluorescein (NaF) confirmed the BBB functionality of the two models. Significantly greater expressions of P-gp and BCRP were detected in PD rCMECs associated with the lower in vitro BBB permeability of FLZ in pathological BBB model compared with physiological model. In transport studies only P-gp blocker effectively inhibited the efflux of FLZ, which was consistent with the in vivo permeability data. This result was also confirmed by ATPase assays, suggesting FLZ is a substrate for P-gp but not BCRP. The present study first established in vitro BBB models reproducing PD-related changes of BBB functions in vivo and demonstrated that poor brain penetration of FLZ and low BBB permeability were due to the P-gp transport.

Liu, Qian; Hou, Jinfeng; Chen, Xiaoguang; Liu, Gengtao; Zhang, Dan; Sun, Hua; Zhang, Jinlan

2014-01-01

288

Genuine and drug-induced synesthesia: a comparison.  

PubMed

Despite some principal similarities, there is no systematic comparison between the different types of synesthesia (genuine, acquired and drug-induced). This comprehensive review compares the three principal types of synesthesia and focuses on their phenomenological features and their relation to different etiological models. Implications of this comparison for the validity of the different etiological models are discussed. Comparison of the three forms of synesthesia show many more differences than similarities. This is in contrast to their representation in the literature, where they are discussed in many respects as being virtually similar. Noteworthy is the much broader spectrum and intensity with the typical drug-induced synesthesias compared to genuine and acquired synesthesias. A major implication of the phenomenological comparison in regard to the etiological models is that genuine and acquired synesthesias point to morphological substrates, while drug-induced synesthesia appears to be based on functional changes of brain activity. PMID:22521474

Sinke, Christopher; Halpern, John H; Zedler, Markus; Neufeld, Janina; Emrich, Hinderk M; Passie, Torsten

2012-09-01

289

A strategy for risk management of drug-induced phospholipidosis.  

PubMed

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

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

2009-12-01

290

Gamma hydroxybutyrate--a coma inducing recreational drug.  

PubMed Central

The effects of gamma hydroxybutyrate, a coma inducing recreational drug, are described and illustrated by case reports of five patients presenting to accident and emergency (A&E). All had depressed levels of consciousness. There was strong circumstantial evidence of gamma hydroxybutyrate ingestion in all cases, and laboratory evidence in two. All recovered and supportive treatment. gamma Hydroxybutyrate has become a fashionable recreational drug. The majority of people who have ingested it will recover spontaneously without long term sequelae but its toxic effects may be dramatic while they last, particularly when it is taken with other drugs or alcohol. Images Figure 3 Figure 1

Ryan, J M; Stell, I

1997-01-01

291

In silico modeling to predict drug-induced phospholipidosis.  

PubMed

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

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

2013-06-01

292

Glucuronidation of Drugs and Drug-Induced Toxicity in Humanized UDP-Glucuronosyltransferase 1 Mice.  

PubMed

UDP-glucuronosyltransferases (UGTs) are phase II drug-metabolizing enzymes that catalyze glucuronidation of various drugs. Although experimental rodents are used in preclinical studies to predict glucuronidation and toxicity of drugs in humans, species differences in glucuronidation and drug-induced toxicity have been reported. Humanized UGT1 mice in which the original Ugt1 locus was disrupted and replaced with the human UGT1 locus (hUGT1 mice) were recently developed. In this study, acyl-glucuronidations of etodolac, diclofenac, and ibuprofen in liver microsomes of hUGT1 mice were examined and compared with those of humans and regular mice. The kinetics of etodolac, diclofenac, and ibuprofen acyl-glucuronidation in hUGT1 mice were almost comparable to those in humans, rather than in mice. We further investigated the hepatotoxicity of ibuprofen in hUGT1 mice and regular mice by measuring serum alanine amino transferase (ALT) levels. Because ALT levels were increased at 6 hours after dosing in hUGT1 mice and at 24 hours after dosing in regular mice, the onset pattern of ibuprofen-induced liver toxicity in hUGT1 mice was different from that in regular mice. These data suggest that hUGT1 mice can be valuable tools for understanding glucuronidations of drugs and drug-induced toxicity in humans. PMID:24764149

Kutsuno, Yuki; Itoh, Tomoo; Tukey, Robert H; Fujiwara, Ryoichi

2014-07-01

293

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

PubMed

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

Champy, Pierre; Höglinger, Günter U; Féger, Jean; Gleye, Christophe; Hocquemiller, Reynald; Laurens, Alain; Guérineau, Vincent; Laprévote, Olivier; Medja, Fadia; Lombès, Anne; Michel, Patrick P; Lannuzel, Annie; Hirsch, Etienne C; Ruberg, Merle

2004-01-01

294

Malignant melanoma and levodopa in Parkinson's disease: causality or coincidence?  

Microsoft Academic Search

Levodopa is the major drug used in the treatment of patients with Parkinson's disease. However, levodopa continues to be ‘contra-indicated’ for patients with Parkinson's disease associated with malignant melanoma. Case reports have suggested that levodopa has a causal relationship with malignant melanoma due to their shared dopamine biochemical pathway. Clinical characteristics of 54 patients with both Parkinson's disease and melanoma

Katherine H Fiala; Jacqueline Whetteckey; Bala V Manyam

2003-01-01

295

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

SciTech Connect

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

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

2009-10-15

296

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

PubMed Central

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

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

2009-01-01

297

Spontaneous reports on drug-induced pancreatitis in Denmark from 1968 to 1999  

Microsoft Academic Search

Objectives: To present an update on drug-induced pancreatitis reported to the Danish Committee on Adverse Drug Reactions. Design: Retrospective study of spontaneous case reports to the Danish reporting system on adverse drug reactions. Methods: All cases of suspected drug-induced pancreatitis reported to the Danish Committee on Adverse Drug Reactions from 1968 to 1999 were analysed. Three cases were excluded leaving

Vibeke Andersen; Jesper Sonne; Morten Andersen

2001-01-01

298

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

PubMed

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

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

2012-01-01

299

Characterization of PINK1 (PTEN-induced putative kinase 1) mutations associated with Parkinson disease in mammalian cells and Drosophila.  

PubMed

Mutations in PINK1 (PTEN-induced putative kinase 1) are tightly linked to autosomal recessive Parkinson disease (PD). Although more than 50 mutations in PINK1 have been discovered, the role of these mutations in PD pathogenesis remains poorly understood. Here, we characterized 17 representative PINK1 pathogenic mutations in both mammalian cells and Drosophila. These mutations did not affect the typical cleavage patterns and subcellular localization of PINK1 under both normal and damaged mitochondria conditions in mammalian cells. However, PINK1 mutations in the kinase domain failed to translocate Parkin to mitochondria and to induce mitochondrial aggregation. Consistent with the mammalian data, Drosophila PINK1 mutants with mutations in the kinase domain (G426D and L464P) did not genetically interact with Parkin. Furthermore, PINK1-null flies expressing the transgenic G426D mutant displayed defective phenotypes with increasing age, whereas L464P mutant-expressing flies exhibited the phenotypes at an earlier age. Collectively, these results strongly support the hypothesis that the kinase activity of PINK1 is essential for its function and for regulating downstream Parkin functions in mitochondria. We believe that this study provides the basis for understanding the molecular and physiological functions of various PINK1 mutations and provides insights into the pathogenic mechanisms of PINK1-linked PD. PMID:23303188

Song, Saera; Jang, Seoyeon; Park, Jeehye; Bang, Sunhoe; Choi, Sekyu; Kwon, Kyum-Yil; Zhuang, Xiaoxi; Kim, Eunjoon; Chung, Jongkyeong

2013-02-22

300

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

PubMed

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

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

301

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

Microsoft Academic Search

The aim of the present study was to explore the neuroprotective effects and mechanisms of action of dl-3-n-butylphthalide (NBP) in a 1-methyl-4-phenylpyridiniumion (MPP+)-induced cellular model of Parkinson's disease (PD). NBP was extracted from seeds of Apium graveolens Linn. (Chinese celery). MPP+ treatment of PC12 cells caused reduced viability, formation of reactive oxygen, and disruption of mitochondrial membrane potential. Our results

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

2010-01-01

302

Drug-induced lysosomal storage of sulphated glycosaminoglycans  

Microsoft Academic Search

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

Jens Fischer; Heinz Lüllmann; Renate Lüllmann-Rauch

1996-01-01

303

Equithesin: a hibernation-inducing drug?  

PubMed

1. Hibernating insectivore species (hedgehogs) and non-hibernating rodents (guinea pig and rat) were anaesthetized with 'equithesin' (a mixture of chloral hydrate, magnesium sulphate, and pentobarbitone sodium). 2. The physiological responses shown by the hedgehogs were similar to those observed in hedgehogs during a natural or cold-induced hibernation. 3. These responses included a strong reduction in body temperature, heart rate, respiration and oxygen consumption, and brain activity. 4. Such responses to equithesin were not observed in the non-hibernating rodent species. 5. These results suggest that equithesin is a potential tool for hibernation research. PMID:1360383

Batzri-Izraeli, R; Wollberg, Z; Dmi'el, R

1992-10-01

304

Drug-induced burning mouth syndrome: a new etiological diagnosis.  

PubMed

Burning mouth syndrome (BMS) is defined as a burning sensation of the oral mucosa, in the absence of specific oral lesions. The underlying etiology remains unclear. Peripheral alterations may be related to the density or reactive capacity of the oral mucosal membrane receptors - these being largely influenced by BMS-related risk factors such as stress, anxiety, the female gender, climacterium and advanced age. The present study compiles the cases of BMS induced by drugs reported in the literature, and attempts to draw a series of conclusions. A search was conducted in the PubMed database using the following key words: burning mouth syndrome, drug-induced, antihypertensive and chemically-induced. The search was carried out in April 2007. The literature yielded clinical cases in which oral burning sensation is described after the administration of drugs belonging to different therapeutic groups: antiretrovirals, antiseizure drugs, hormones and particularly antihypertensive medication. Curiously, among the different types of antihypertensive drugs, BMS was only associated with those compounds that act upon the angiotensin-renin system. PMID:18305436

Salort-Llorca, César; Mínguez-Serra, María Paz; Silvestre, Francisco Javier

2008-03-01

305

Drug-induced sleep endoscopy: a two drug comparison and simultaneous polysomnography.  

PubMed

The purpose of the present study was to compare pharyngeal and polysomnographical findings during drug-induced sleep endoscopy (DISE) performed with either propofol or midazolam as a single sedative agent. It is prospective, non-randomized, double-blinded case series study. Sixteen patients with sleep disordered breathing were sedated first with propofol and after full wake up with midazolam. Simultaneous polysomnography (PSG) was performed. We compared the zones of obstruction and vibration found with both drugs using the VOTE classification. Simultaneous PSG findings are also compared. There were 15 men and one woman; the mean age was 42.7 years old, mean body mass index 26.9 kg/m(2). Average DISE duration was 20 min with Propofol and 14.3 min with Midazolam. The induced sleep stage obtained was N2 with both drugs. Outpatient physical exam did not correlate with drug-induced sleep findings. There was a good correlation between DISE results with both drugs in all the areas of collapse except the velum (p < 0.005). Using a continuous perfusion, there is a good agreement in the findings observed in DISE performed with propofol and midazolam and PSG. PMID:23665745

Carrasco Llatas, Marina; Agostini Porras, Gabriela; Cuesta González, Maria Teresa; Rodrigo Sanbartolomé, Adelaida; Giner Bayarri, Pau; Gómez-Pajares, Fernando; Dalmau Galofre, José

2014-01-01

306

The selective alpha1 adrenoceptor antagonist HEAT reduces L-DOPA-induced dyskinesia in a rat model of Parkinson's disease.  

PubMed

In Parkinson's disease (PD), the long term use of L-DOPA results in major adverse effects including dyskinesia or abnormal involuntary movements. The present study focuses on the effect of the selective alpha(1) adrenoceptor antagonist HEAT (2-[[beta-(-4-hydroxyphenyl)ethyl]aminomethyl]-1-tetralone) in the 6-hydroxydopamine rat model of L-DOPA-induced dyskinesia. We demonstrate that the selective alpha(1) adrenoceptor antagonist HEAT (1 and 2 mg kg(-1)), the alpha(2) adrenoceptor antagonist idazoxan (9 mg kg(-1)), and the nonselective beta(1)/beta(2) adrenoceptor antagonist propranolol (20 mg kg(-1)) alleviate dyskinetic movements induced by L-DOPA. Furthermore, the adrenoceptor antagonists at the doses used did not influence exploratory behavior in the open field system indicating that the antidyskinetic effect is not due to a reduction in general motor activity. Intrastriatal administration of the selective alpha(1) adrenoceptor agonist cirazoline via reverse in vivo microdialysis did not induce dyskinesia. Additionally, we measured plasma, brain, and CSF levels of HEAT. HEAT is a CNS active compound with a brain/plasma and CSF/plasma ratio of 4.29 and 0.15, respectively, which is appropriate for the investigation of alpha(1)-mediated mechanisms in CNS disorders. In conclusion, these results demonstrated for the first time that a alpha(1) adrenoceptor antagonist reduced L-DOPA-induced dyskinesia in a rat model. Further studies assessing the risk benefit in comparison to existing therapies are needed before considering alpha(1) adrenoceptor antagonists as a target for the development of new antidyskinetic compounds. PMID:19771592

Buck, Kerstin; Ferger, Boris

2010-02-01

307

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

PubMed Central

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.

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

2013-01-01

308

The role of nitric oxide on visual-evoked potentials in MPTP-induced Parkinsonism in mice.  

PubMed

The present study aimed to elucidate visual evoked potentials (VEP) changes in MPTP induced Parkinson's disease (PD) and investigate the possible benefical effects of neuronal (n) and inducible (i) nitric oxide synthase (NOS) inhibitors on altered VEPs, lipid peroxidation and apoptosis. 3months old C57BL/6 mice were randomly divided into 6 groups which included control (C), 7-nitra indazole treated (7-NI), S-methylisothiourea (SMT) treated, 1,2,3,6-tetrahydropyridine (MPTP) treated, 7-NI+MPTP treated and SMT+MPTP treated. Motor activity of mice was evaluated via the pole test. At the end of the experimental period VEPs were recorded, brain and retina tissues were removed for biochemical analysis. Dopaminergic neuron death at substantia nigra (SN) was determined by immunohistochemical analysis of tyrosine hydroxylase (TH). Immunohistochemical staining was also performed to determine iNOS and nNOS in all tissue sections. Mice with experimental PD exhibited decreased motor activity. Dopaminergic cell death at pars compacta of SN (SNpc) was significantly increased in MPTP treated group compared to control. Diminished Parkinsonism symptoms were observed in 7-NI+MPTP and SMT+MPTP groups. Treatment with 7-NI and SMT decreased dopaminergic cell death in MPTP treated mice. Caspase-3 activity, nitrite/nitrate and 4-hydroxynonenal (4-HNE) levels were significantly increased in SN of MPTP treated mice compared to control. Treatment with 7-NI and SMT significantly decreased elevated caspase-3 activity, nitrite/nitrate and 4-HNE levels in SN of MPTP treated mice. No significant difference in above parameters were observed in the retina. VEP latencies were significantly prolonged in MPTP group compared to control group. 7-NI and SMT treatment caused a significant decrease in VEP latencies in MPTP treated mice compared to none treated MPTP group. This data shows that 7-NI and SMT improves prolonged VEP latencies. The protective effects of 7-NI and SMT on VEP alterations can be related to decreased dopaminergic cell death and reduced lipid peroxidation. PMID:24795109

Aras, Sinem; Tanriover, Gamze; Aslan, Mutay; Yargicoglu, Piraye; Agar, Aysel

2014-06-01

309

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

PubMed Central

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

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

2012-01-01

310

Drug-Induced Liver Injury due to Cancer Chemotherapeutic Agents.  

PubMed

Drug-induced liver injury (DILI) due to chemotherapeutic drugs is a significant cause of morbidity and mortality. Most cases of chemotherapy-induced hepatotoxicity are idiosyncratic and do not have a unique clinical or histological signature that is distinct from other agents that cause DILI. The major mechanisms underlying chemotherapy-related hepatotoxicity are based on the production of reactive metabolites generated by phase I oxidation reactions, immunological injury, or alterations in mitochondrial function. Underlying liver disease and hepatic involvement by tumor are important modifiers of liver injury, and reversibility is not universal after drug cessation. Chemotherapy can also exacerbate underlying liver disease, particularly hepatitis B, leading to worsening hepatic function. Diagnosing DILI due to chemotherapeutic agents is particularly challenging because competing etiologies, such as hepatotoxicity from other medications, opportunistic infections, radiation therapy, and pre-existing liver disease, are frequent. PMID:24879981

Bahirwani, Ranjeeta; Reddy, K Rajender

2014-05-01

311

Drug induced xerostomia in elderly individuals: An institutional study  

PubMed Central

Introduction: With better health care facilities and nutritional levels the average life expectancy of Indian population has been on the rise over the years. Most of the geriatric population is under long-term medication. Aim: The aim of this study was to evaluate the synergistic effect of multiple xerostomia drugs. Materials and Methods: Unstimulated saliva was measured in 60 geriatric patients, and xerostomia questionnaire and quality-of-life scale were also administered. Results: There was a very highly significant reduction in the salivary flow rates of patients under multiple xerostomia-inducing drugs. Conclusion: The synergistic effect of the xerostomia inducing medication could be the possible factor responsible for reduced salivary flow in elderly individuals using such drugs

Shetty, Shishir Ram; Bhowmick, Sunanda; Castelino, Renita; Babu, Subhas

2012-01-01

312

Drug-induced acne and rose pearl: similarities.  

PubMed

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

Pontello, Rubens; Kondo, Rogerio Nabor

2013-01-01

313

Incidence of drug-induced liver injury in medical inpatients  

Microsoft Academic Search

Objectives: Drug-induced liver injury (DILI) is a common concern. However, data on DILI epidemi- ology in inpatients are sparse. Methods: To investigate the incidence of DILI, we screened all patients in the pharmacoepidemiological inpatient database according to the CIOMS (Council for International Organisation of Medical Science) criteria, which consist of the evaluation of some clinical chem- istry laboratory liver parameters

Yvonne Meier; Marzia Cavallaro; Malgorzata Roos; Christiane Pauli-Magnus; Gerd Folkers; Peter J. Meier; Karin Fattinger

2005-01-01

314

The clinical benefit of imaging striatal dopamine transporters with [123I]FP-CIT SPET in differentiating patients with presynaptic parkinsonism from those with other forms of parkinsonism.  

PubMed

[123I]FP-CIT (N-omega-fluoropropyl-2 beta-carbomethoxy-3 beta-(4-iodophenyl)nortropane) has been developed successfully as a radioligand for single-photon emission tomography (SPET) imaging of dopamine transporters, which are situated in the membrane of dopaminergic neurons. Imaging of these transporters has shown promise as a clinical tool to detect degeneration of the dopaminergic nigrostriatal pathway. Several "presynaptic parkinsonian" syndromes, such as Parkinson's disease or multiple system atrophy, are characterised by degeneration of the nigrostriatal pathway. [123I]FP-CIT SPET imaging studies have shown the ability to detect loss of striatal dopamine transporters in such syndromes. However, in clinical practice it is sometimes difficult, but important, to discriminate patients with "presynaptic parkinsonism" from those with other forms of parkinsonism not characterised by loss of presynaptic dopaminergic cells (e.g. psychogenic parkinsonism or drug-induced postsynaptic parkinsonism). In these inconclusive cases, it may be of value to confirm or exclude the existence of degeneration of nigrostriatal dopaminergic cells by using imaging techniques such as [123I]FP-CIT SPET. Using [123I]FP-CIT SPET, we have imaged the striatal dopamine transporters in a group of patients with inconclusive forms of parkinsonism, and, moreover, have been able to perform clinical follow-up of these patients 2-4 years after imaging. In 33 inconclusive cases, ratios of specific to non-specific binding were calculated for the caudate nucleus and putamen following [123I]FP-CIT SPET imaging and compared with ratios obtained in healthy controls. In nine of the patients, degeneration of the nigrostriatal pathway was found scintigraphically and in all these cases, presynaptic parkinsonism was confirmed by clinical follow-up. In the other 24 subjects no degeneration was found scintigraphically. Forms of parkinsonism other than the presynaptic were confirmed at follow-up in 19 cases, and in three cases no conclusive diagnosis was established, but presynaptic parkinsonism was excluded clinically. A clinical diagnosis of presynaptic parkinsonism was established in two cases: one case of multiple system atrophy (in this patient loss of dopamine D2 receptors was found with [123I]iodobenzamide SPET performed 2 weeks after [123I]FP-CIT imaging) and one case of Parkinson's disease. Our data suggest that the positive predictive value of [123I]FP-CIT imaging is very high, and although the negative predictive value is lower, dopamine transporter imaging offers the prospect of a quick, objective method to confirm or exclude presynaptic parkinsonism in inconclusive cases. PMID:11315592

Booij, J; Speelman, J D; Horstink, M W; Wolters, E C

2001-03-01

315

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

PubMed

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

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

2012-06-01

316

Circulating KL-6 levels in patients with drug induced pneumonitis  

PubMed Central

Background: The circulating level of KL-6/MUC1 is a sensitive marker for various interstitial lung diseases. Previous case reports have suggested that KL-6 may also be increased in some patients with drug induced pneumonitis. A study was undertaken to determine whether serum KL-6 could be a marker for particular types of drug induced pneumonitis. Methods: The findings of high resolution computed tomographic (HRCT) chest scans of 30 patients with drug induced pneumonitis were reviewed separately by two independent observers. The pneumonitis was classified into four predominant patterns: widespread bilateral consolidation (diffuse alveolar damage, DAD; n=7), fibrosis with or without consolidation (chronic interstitial pneumonia, CIP; n=11), consolidation without fibrosis (bronchiolitis obliterans organising pneumonia or eosinophilic pneumonia, BOOP/EP; n=8), and diffuse ground glass opacities without fibrosis (hypersensitivity pneumonitis, HP; n=4). Serum KL-6 levels were measured by a sandwich enzyme linked immunosorbent assay. Results: The overall sensitivity of serum KL-6 in detecting drug induced lung disease was 53.3%, which was lower than its sensitivity in detecting other interstitial lung diseases. However, the KL-6 level was increased in most patients with a DAD or CIP pattern (16/18; 88.9%) and was closely correlated with their clinical course. In contrast, serum KL-6 levels were within the normal range in all patients with a BOOP/EP or HP pattern. Conclusions: Particular patterns detected by HRCT scanning, such as DAD and CIP but not the BOOP/EP or HP patterns, are associated with increased circulating KL-6 levels in drug induced pneumonitis. Serum KL-6 levels may reflect the clinical activity of the particular disorders.

Ohnishi, H; Yokoyama, A; Yasuhara, Y; Watanabe, A; Naka, T; Hamada, H; Abe, M; Nishimura, K; Higaki, J; Ikezoe, J; Kohno, N

2003-01-01

317

Region-specific protein abundance changes in the brain of MPTP-induced Parkinson's disease mouse model.  

PubMed

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 potential nigrostriatal-specific and other region-specific protein abundance changes. The combined analyses resulted in the identification of 4,895 nonredundant 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 substantial MPTP-induced abundance changes across different brain regions. A total of 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 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. Ubiquitin specific protease (USP9X), a deubiquination enzyme involved in the protection of proteins from degradation and promotion of the TGF-beta pathway, exhibited altered abundance 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. PMID:20155936

Zhang, Xu; Zhou, Jian-Ying; 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, Wei-Jun; Smith, Richard D

2010-03-01

318

PACAP protects against salsolinol-induced toxicity in dopaminergic SH-SY5Y cells: implication for Parkinson's disease.  

PubMed

Pituitary adenylate cyclase-activating polypeptide (PACAP) is an endogenous 38 amino acid containing neuropeptide with various cytoprotective functions including neuroprotection. Administration of PACAP has been shown to reduce damage induced by ischemia, trauma, or exogenous toxic substances. Moreover, mice deficient in PACAP are more vulnerable to damaging insults. In this study, we sought to determine whether PACAP may also be protective against salsolinol-induced toxicity in SH-SY5Y cells and, if so, elucidate its mechanism(s) of action. Salsolinol (SALS) is an endogenous dopamine metabolite with selective toxicity to nigral dopaminergic neurons, which are directly implicated in Parkinson's disease (PD). SH-SY5Y cells, derived from human neuroblastoma cells, express high levels of dopaminergic activity and are used extensively as a model to study these neurons. Exposure of SH-SY5Y cells to 400 ?M SALS for 24 h resulted in approximately 50 % cell death that was mediated by apoptosis as determined by cell flow cytometry and increases in caspase-3 levels. Cellular toxicity was also associated with reductions in brain-derived neurotrophic factor and phosphorylated cyclic AMP response element-binding protein. Pretreatment with PACAP dose-dependently attenuated SALS-induced toxicity and the associated apoptosis and the chemical changes. PACAP receptor antagonist PACAP6-38, in turn, dose-dependently blocked the effects of PACAP. Neither PACAP nor PACAP antagonist had any effect of its own on cellular viability. These results suggest the protective effects of PACAP in a cellular model of PD. Hence, PACAP or its agonists could be of therapeutic benefit in PD. PMID:23625270

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

2013-07-01

319

Naphthazarin has a protective effect on the 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine-induced Parkinson's disease model.  

PubMed

"Neurohormesis" refers to a response to a moderate level of stress that enhances the ability of the nervous systems to resist more severe stress that might be lethal or cause dysfunction or disease. Neurohormetic phytochemicals, such as, resveratrol, sulforaphane, curcumin, and catechins, protect neurons against injury and disease. Naphthoquinones, such as, juglone and plumbagin, induce robust hormetic stress responses. However, the possibility that subtoxic dose of 5,8-dihydroxy-1,4-naphthoquinone (naphthazarin) may protect against brain diseases via the activation of an adaptive stress response pathway in the brain has not been investigated. In this study, we examined the neurohormetic effect of a subtoxic dose of naphthazarin in a Parkinson's disease model. It was found that, under these conditions, naphthazarin enhanced movement ability, prevented loss of dopaminergic neurons, and attenuated neuroinflammation in a 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine-induced Parkinson's disease model. Furthermore, it was found that the neuroprotective effect of naphthazarin was mediated by the suppression of astroglial activation in response to 1-methyl-4-phenylpyridine treatment. In conclusion, we suggest that naphthazarin, in view of its hormetic effect on neuroprotection, be viewed as a potential treatment for Parkinson's disease and other neurodegenerative diseases associated with neuroinflammation. PMID:22513651

Choi, Seon Young; Son, Tae Gen; Park, Hee Ra; Jang, Young Jung; Oh, Shin Bi; Jin, Bora; Lee, Jaewon

2012-09-01

320

Prevention of Drug-induced Memory Impairment by Immunopharmacotherapy  

PubMed Central

One approach to treating drug abuse uses anti-drug antibodies to immunize subjects against the illicit substance rather than administering therapeutics that target the specific CNS site of action. At present, passive vaccination has recognized efficacy in treating certain gross symptoms of drug misuse, namely motor activation, self-administration, and overdose. However, the potential for antibodies to prevent drug-induced changes involving finer cognitive processes, such as benzodiazepine-associated amnesia, remains unexplored. To address this concept, a flunitrazepam hapten was synthesized and employed in the generation of a panel of high affinity monoclonal antibodies. Anti-flunitrazepam mAb RCA3A3 (Kd,app= 200 nM) was tested in a mouse model of passive immunization and subsequent mole-equivalent challenge with flunitrazepam. Not only was flunitrazepam-induced sedation prevented, but immunization also conferred protection to memory consolidation as assessed through contextual and cued fear conditioning paradigms. These results provide evidence that immunopharmacotherapeutic blockade of drug intoxication also preserves complex cognitive function.

Treweek, Jennifer B.; Sun, Chengzao; Mayorov, Alexander V.; Qi, Longwu; Levy, Coree L.; Roberts, Amanda J.; Dickerson, Tobin J.; Janda, Kim D.

2009-01-01

321

Drug-induced pulmonary arterial hypertension: a recent outbreak.  

PubMed

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

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

2013-09-01

322

Familial Parkinson's Disease Mutant E46K ?-Synuclein Localizes to Membranous Structures, Forms Aggregates, and Induces Toxicity in Yeast Models  

PubMed Central

In Parkinson's disease (PD), midbrain dopaminergic neuronal death is linked to the accumulation of aggregated ?-synuclein. The familial PD mutant form of ?-synuclein, E46K, has not been thoroughly evaluated yet in an organismal model system. Here, we report that E46K resembled wild-type (WT) ?-synuclein in Saccharomyces cerevisiae in that it predominantly localized to the plasma membrane, and it did not induce significant toxicity or accumulation. In contrast, in Schizosaccharomyces pombe, E46K did not associate with the plasma membrane. Instead, in one strain, it extensively aggregated in the cytoplasm and was as toxic as WT. Remarkably, in another strain, E46K extensively associated with the endomembrane system and was more toxic than WT. Our studies recapitulate and extend aggregation and phospholipid membrane association properties of E46K previously observed in vitro and cell culture. Furthermore, it supports the notion that E46K generates toxicity partly due to increased association with endomembrane systems within cells.

Fiske, Michael; White, Michael; Valtierra, Stephanie; Herrera, Sara; Solvang, Keith; Konnikova, Alina; DebBurman, Shubhik

2011-01-01

323

Mutant alpha-synuclein-induced degeneration is reduced by parkin in a fly model of Parkinson's disease.  

PubMed

Parkinson's disease (PD) patients show a characteristic loss of motor control caused by the degeneration of dopaminergic neurons. Mutations in the genes that encode alpha-synuclein and parkin have been linked to inherited forms of this disease. The parkin protein functions as a ubiquitin ligase that targets proteins for degradation. Expression of isoforms of human alpha-synuclein in the Drosophila melanogaster nervous system forms the basis of an excellent genetic model that recapitulates phenotypic and behavioural features of PD. Using this model, we analysed the effect of parkin co-expression on the climbing ability of aging flies, their life span, and their retinal degeneration. We have determined that co-expression of parkin can suppress phenotypes caused by expression of mutant alpha-synuclein. In the developing eye, parkin reduces retinal degeneration. When co-expressed in the dopaminergic neurons, the ability to climb is extended over time. If conserved in humans, we suggest that upregulation of parkin may prove a method of suppression for PD induced by mutant forms of alpha-synuclein. PMID:16767175

Haywood, Annika F M; Staveley, Brian E

2006-05-01

324

L-DOPA treatment reverses the motor alterations induced by manganese exposure as a Parkinson disease experimental model.  

PubMed

This investigation was designed to determine whether l-DOPA treatment improves the motor alterations observed after divalent and trivalent manganese (Mn) mixture inhalation on mice to ensure that the alterations are of dopaminergic origin. CD-1 male mice inhaled a mixture of 0.04 M manganese chloride (MnCl(2)) and manganese acetate (Mn(OAc)(3)), 1h twice a week for 5 months. Before Mn exposure, animals were trained to perform motor function tests and were evaluated each week after the exposure. Overall behavior was assessed by ratings and by videotaped analyses; by the end of Mn exposure period, 10 mice were orally treated with 7.5mg/kg L-DOPA. After 5 months of Mn-mixture inhalation striatal dopamine content decreased 71%, mice developed evident deficits in motor performance manifested as akinesia, postural instability and action tremor; these alterations were reverted with L-DOPA treatment. Our results suggest that the motor alterations induced by the inhalation of the combination of MnCl(2)/Mn(OAc)(3) are related to nigrostriatal dopaminergic function providing new light on the understanding of manganese neurotoxicity as a suitable Parkinson disease experimental model. PMID:20079802

Ordoñez-Librado, Jose Luis; Anaya-Martinez, Veronica; Gutierrez-Valdez, Ana Luisa; Montiel-Flores, Enrique; Corona, David Reyes; Martinez-Fong, Daniel; Avila-Costa, Maria Rosa

2010-03-01

325

Loss of thalamic serotonin transporters in early drug-naïve Parkinson's disease patients is associated with tremor: an [(123)I]beta-CIT SPECT study.  

PubMed

In vitro studies revealed serotonin transporter (5-HTT) decline in Parkinson's disease (PD). Yet, few studies investigated thalamic 5-HTT in vivo and its effect on PD heterogeneity. We analyzed thalamic [(123)I]beta-CIT binding (mainly reflecting 5-HTT binding) in 32 drug-naïve PD patients and 13 controls with SPECT. Twenty-six patients were examined twice (17 months apart). Based on UPDRS scores, we identified subgroups of patients with moderate/severe tremor (PD(T)) and without tremor (PD(WT)) at the time of clinical diagnosis. Additionally, depressive symptoms were evaluated using the Beck Depression Inventory (BDI) at baseline. Mean thalamic specific to non-specific [(123)I]beta-CIT binding ratio was lower in patients when compared to controls, and further decreased during follow-up. At baseline, average thalamic ratio was significantly lower in the PD(T) than in the PD(WT) subgroup. No correlation was found between BDI scores and thalamic binding ratios. Our findings show decline of [(123)I]beta-CIT binding to thalamic 5-HTT in PD and its possible contribution to tremor onset. PMID:18335163

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

2008-05-01

326

In vitro validation of drug-induced phospholipidosis.  

PubMed

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

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

2012-01-01

327

Auditory hallucinations in Parkinson’s disease  

Microsoft Academic Search

Whereas visual hallucinations are often found among patients with Parkinson’s disease, the occurrence of auditory hallucinations has never been systematically documented. The occurrence, past and present, of auditory hallucinations has been studied in 121 consecutive patients with Parkinson’s disease attending a movement disorders clinic. The cognitive state was evaluated using the short mental test (SMT). Hallucinations were reported for 45

Rivka Inzelberg; Svetlana Kipervasser; Amos D Korczyn

1998-01-01

328

Drug-induced gingival overgrowth: a case report.  

PubMed

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

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

2012-01-01

329

[Talc-induced pulmonary granulomas in drug addicts].  

PubMed

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

Latartseva, L N; Kryvenko, O N

2013-01-01

330

Retrospective evaluation of adverse drug reactions induced by antihypertensive treatment  

PubMed Central

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.

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

2013-01-01

331

A systematic review of drug induced ocular reactions in diabetes  

PubMed Central

AIMS—To conduct a systematic review of drug induced adverse ocular effects in diabetes to determine if this approach identified any previously unrecognised adverse drug effects; to make a preliminary assessment of the feasibility of this approach in identifying adverse drug reactions; and to assess the current accessibility of this information to prescribing physicians.?METHODS—Literature search of online biomedical databases. The search strategy linked eye disorders with adverse drug reactions and diabetes. Source journals were classified as medical, pharmaceutical, diabetes related, or ophthalmological. It was determined whether the reactions identified were recorded in drug datasheets and the British National Formulary.?RESULTS—63 references fulfilled the selection criteria, of which 45 were considered to be relevant to the study. The majority of these were case reports but cross sectional surveys, case-control and cohort studies, and review articles were also identified. 61% of the reactions were not recorded in the British National Formulary and 41% were not recorded in the datasheets. 55% appeared in specialist ophthalmology journals.?CONCLUSIONS—This is a feasible approach to the identification of adverse drug reactions. Adverse reactions not listed in the most commonly used reference sources were found. The majority were published in specialist ophthalmology journals which might not be seen by prescribing physicians.??

Hampson, J; Harvey, J

2000-01-01

332

Cancer Evolution under Drug-Induced Stress-Gradients  

NASA Astrophysics Data System (ADS)

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

Lambert, Guillaume; Austin, Robert H.

2011-03-01

333

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

ERIC Educational Resources Information Center

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

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

2013-01-01

334

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

PubMed Central

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.

2014-01-01

335

Management of Psychiatric Symptoms of Parkinson’s Disease  

Microsoft Academic Search

Depression and hallucination are the two main psychiatric symptoms in parkinsonian patients. Depressive features in Parkinson patients are very close to those of endogenous depression, except for a relative lack of anxiety, irritability, suicidal ideations, delusions and circadian rhythm. Pharmacotherapy with antidepressants is most reliable in the treatment of parkinsonian depressives, although levodopa or other antiparkinsonian drugs may relieve a

Koho Miyoshi; Akinori Ueki; Osamu Nagano

1996-01-01

336

[Drug-induced pneumonitis associated PABRON-GOLD].  

PubMed

A 75-year-old man had for many years taken the commercially sold medicine PABRON-S whenever he caught a cold. He caught a cold and took the drug six days before admission. When PABRON-S was not available, he took PABRON-GOLD and experienced dyspnea the next day. A roentgenogram at another hospital revealed bilateral diffuse lung shadows. He was referred to our hospital. A thoracic CT scan showed bilateral interstitial shadows. Bronchoalveolar lavage fluid contained inflammatory cells including neutrophils and lymphocytes. Examination of a transbronchial lung biopsy specimen showed infiltration of mononuclear cells into the thick alveolar wall and interstitum. A drug lymphocyte stimulation test with PABRON-GOLD was positive. Based on these findings, we believe that this patient had drug-induced pneumonitis caused by PABRON-GOLD. He was treated with a steroid hormone and his symptoms resolved immediately, the abnormal roentgenographic shadows remained longer. PMID:9071160

Nomura, M; Fujimura, M; Matsuda, T; Kitagawa, M

1997-01-01

337

Drug-induced gingival overgrowth: The nemesis of gingiva unravelled  

PubMed Central

Drug-induced gingival overgrowth or enlargement manifests as abnormal growth of the gingiva due to an adverse drug reaction (ADR) in patients treated with anticonvulsants, immunosuppressants, and calcium channel blockers. As gingival enlargement develops, it affects the normal oral hygiene practice and may interfere with masticatory functions. It gradually becomes a source of pain and the condition often leads to disfiguration. Within the group of patients that develop this unwanted effect, there appears to be variability in the extent and severity of the gingival changes. It would seem pertinent to identify and explore possible risk factors and relating them with the treatment plan. This article throws light on respective drugs and their association with gingival overgrowth and approaches to treatment based on current knowledge and investigative observations.

Bharti, Vipin; Bansal, Chhaya

2013-01-01

338

Drug-induced loss of unstably amplified genes.  

PubMed

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

Wani, M A; Snapka, R M

1990-01-01

339

Drug-induced gingival overgrowth: The nemesis of gingiva unravelled.  

PubMed

Drug-induced gingival overgrowth or enlargement manifests as abnormal growth of the gingiva due to an adverse drug reaction (ADR) in patients treated with anticonvulsants, immunosuppressants, and calcium channel blockers. As gingival enlargement develops, it affects the normal oral hygiene practice and may interfere with masticatory functions. It gradually becomes a source of pain and the condition often leads to disfiguration. Within the group of patients that develop this unwanted effect, there appears to be variability in the extent and severity of the gingival changes. It would seem pertinent to identify and explore possible risk factors and relating them with the treatment plan. This article throws light on respective drugs and their association with gingival overgrowth and approaches to treatment based on current knowledge and investigative observations. PMID:23869123

Bharti, Vipin; Bansal, Chhaya

2013-03-01

340

Cardiac imaging approaches to evaluate drug-induced myocardial dysfunction  

PubMed Central

The ability to make informed benefit-risk assessments for potentially cardiotoxic new compounds is of considerable interest and importance at the public health, drug development, and individual patient levels. Cardiac imaging approaches in the evaluation of drug-induced myocardial dysfunction will likely play an increasing role. However, the optimal choice of myocardial imaging modality and the recommended frequency of monitoring are undefined. These decisions are complicated by the array of imaging techniques, which have varying sensitivities, specificities, availabilities, local expertise, safety, and costs, and by the variable time-course of tissue damage, functional myocardial depression, or recovery of function. This White Paper summarizes scientific discussions of members of the Cardiac Safety Research Consortium on the main factors to consider when selecting nonclinical and clinical cardiac function imaging techniques in drug development. We focus on 3 commonly used imaging modalities in the evaluation of cardiac function: echocardiography, magnetic resonance imaging, and radionuclide (nuclear) imaging and highlight areas for future research.

Christian, Jennifer B.; Finkle, John K.; Ky, Bonnie; Douglas, Pamela S.; Gutstein, David E.; Hockings, Paul D.; Lainee, Pierre; Lenihan, Daniel J.; Mason, Jay W.; Sager, Philip T.; Todaro, Thomas G.; Hicks, Karen A.; Kane, Robert C.; Ko, Hon-Sum; Lindenfeld, JoAnn; Michelson, Eric L.; Milligan, James; Munley, Jiefen Y.; Raichlen, Joel S.; Shahlaee, Amir; Strnadova, Colette; Ye, Brenda; Turner, J. Rick

2013-01-01

341

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

Microsoft Academic Search

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

V A J Maria; R M M Victorino

1997-01-01

342

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

PubMed Central

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

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

1994-01-01

343

Drug target validation: Lethal infection blocked by inducible peptide  

NASA Astrophysics Data System (ADS)

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

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

2000-01-01

344

Surgical Treatment of Dyskinesia in Parkinson's Disease  

PubMed Central

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

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

2014-01-01

345

Drug induced toxic epidermal necrolysis: two case reports  

PubMed Central

Introduction Among the various drug induced dermatological entities toxic epidermal necrolysis and Stevens-Johnson’s syndrome occupy a primary place in terms of mortality. Prompt recognition of these conditions, immediate drug withdrawal and institution of appropriate treatment plays a vital role in reducing mortality. Drugs are by far the most common cause of toxic epidermal necrolysis, in which large sheets of skin are lost from the body surface making redundant the barrier function of the skin, with its resultant complications. The use of systemic corticosteroids in the treatment of toxic epidermal necrolysis has always been controversial, some consider corticosteroids life-saving while others believe that they increase mortality. Case presentation We describe two cases of drug-induced toxic epidermal necrolysis, a male and a female, both caucasoids of Pakistani origin, one treated without any steroids and the other with them, who made complete recovery without any major complications or sequelae. Conclusion The administration of systemic corticosteriods did not cause any major changes in outcome in our cases.

Raza, Naeem; Qadir, Fozi

2009-01-01

346

Risk Factors for Idiosyncratic Drug-Induced Liver Injury  

PubMed Central

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

CHALASANI, NAGA; BJORNSSON, EINAR

2011-01-01

347

The role of metabolic activation in drug-induced hepatotoxicity.  

PubMed

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

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

2005-01-01

348

Parkinson's Disease  

Microsoft Academic Search

Parkinson's disease (PD) results primarily from the death of dopaminergic neurons in the substantia nigra. Current PD medications treat symptoms; none halt or retard dopaminergic neuron degeneration. The main obstacle to developing neuroprotective therapies is a limited understanding of the key molecular events that provoke neurodegeneration. The discovery of PD genes has led to the hypothesis that misfolding of proteins

William Dauer; Serge Przedborski

2003-01-01

349

FDG positron emission tomography imaging of drug-induced pneumonitis  

Microsoft Academic Search

Several studies have reported the findings of fluorine-18-labeled fluoro-2-deoxy-d-glucose positron emission tomography (FDG-PET) in benign lung disease with diffuse pulmonary injury; however, the characteristics\\u000a and effectiveness of FDG-PET imaging for interstitial pneumonitis have not been substantiated. We report two cases of drug-induced\\u000a pneumonitis in two patients treated for breast cancer who were diagnosed by FDG-PET examination. Both the cases showed

Miwa Morikawa; Yoshiki Demura; Shiro Mizuno; Shingo Ameshima; Takeshi Ishizaki; Hidehiko Okazawa

2008-01-01

350

Pathophysiology and diagnosis of cancer drug induced cardiomyopathy  

Microsoft Academic Search

The clinical manifestations of anti-cancer drug associated cardiac side effects are diverse and can range from acutely induced\\u000a cardiac arrhythmias to Q–T interval prolongation, changes in coronary vasomotion with consecutive myocardial ischemia, myocarditis,\\u000a pericarditis, severe contractile dysfunction, and potentially fatal heart failure. The pathophysiology of these adverse effects\\u000a is similarly heterogeneous and the identification of potential mechanisms is frequently difficult

Christian Zuppinger; Francesco Timolati; Thomas M. Suter

2007-01-01

351

Cellular imaging predictions of clinical drug-induced liver injury.  

PubMed

Drug-induced liver injury (DILI) is the most common adverse event causing drug nonapprovals and drug withdrawals. Using drugs as test agents and measuring a panel of cellular phenotypes that are directly linked to key mechanisms of hepatotoxicity, we have developed an in vitro testing strategy that is predictive of many clinical outcomes of DILI. Mitochondrial damage, oxidative stress, and intracellular glutathione, all measured by high content cellular imaging in primary human hepatocyte cultures, are the three most important features contributing to the hepatotoxicity prediction. When applied to over 300 drugs and chemicals including many that caused rare and idiosyncratic liver toxicity in humans, our testing strategy has a true-positive rate of 50-60% and an exceptionally low false-positive rate of 0-5%. These in vitro predictions can augment the performance of the combined traditional preclinical animal tests by identifying idiosyncratic human hepatotoxicants such as nimesulide, telithromycin, nefazodone, troglitazone, tetracycline, sulindac, zileuton, labetalol, diclofenac, chlorzoxazone, dantrolene, and many others. Our findings provide insight to key DILI mechanisms, and suggest a new approach in hepatotoxicity testing of pharmaceuticals. PMID:18524759

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

2008-09-01

352

Excessive daytime sleepiness and unintended sleep in Parkinson's disease.  

PubMed

Patients with Parkinson's disease and parkinsonian syndromes (eg, dementia with Lewy body disease, multisystem atrophy, and Shy-Drager syndrome) suffer from daytime sleepiness. This sleepiness is common and very real, often approaching levels observed in the prototypical disorder of sudden-onset sleep, namely narcolepsy/cataplexy. Physicians need to be vigilant in assessing parkinsonian patients for sleepiness because treatment can dramatically enhance quality of life and prevent the significant morbidity and mortality that attends daytime sleepiness. Male patients with advanced disease, cognitive impairment, drug-induced psychosis, and orthostatic hypotension are most at risk for developing pathologic sleepiness. Because primary sleep disorders can coexist with parkinsonism (eg, sleep apnea, insufficient or interrupted sleep), these potential causes should be carefully assessed with polysomnography and treated appropriately. Dopaminomimetics exacerbate sleepiness in a small subset of patients in a dose-dependent fashion. Nonetheless, the primary pathologies involved in parkinsonism appear to be the greatest contributors to daytime sleepiness. Sleepiness in parkinsonism, especially a narcolepsy-like phenotype, may necessitate treatment with wake-promoting agents such as bupropion, modafinil, or traditional psychostimulants. PMID:16522272

Rye, David B

2006-03-01

353

Cytokine expression and signaling in drug-induced cellular senescence.  

PubMed

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

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

2010-01-14

354

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

PubMed Central

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

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

2013-01-01

355

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

Microsoft Academic Search

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

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

2009-01-01

356

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

PubMed

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

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

2014-08-22

357

Parkinson's Disease and Parkinsonism: Neuropathology  

PubMed Central

Parkinsonism, the clinical term for a disorder with prominent bradykinesia and variable associated extrapyramidal signs and symptoms, is accompanied by degeneration of the nigrostriatal dopaminergic system, with neuronal loss and reactive gliosis in the substantia nigra found at autopsy. Parkinsonism is pathologically heterogeneous, with the most common pathologic substrates related to abnormalities in the presynaptic protein ?-synuclein or the microtubule binding protein tau. In idiopathic Parkinson’s disease (PD), ?-synuclein accumulates in neuronal perikarya (Lewy bodies) and neuronal processes (Lewy neurites). The disease process is multifocal and involves select central nervous system neurons and peripheral autonomic nervous system neurons. The particular set of neurons affected determines nonmotor clinical presentations. Multiple system atrophy (MSA) is the other major ?-synucleinopathy. It is also associated with autonomic dysfunction and in some cases with cerebellar signs. The hallmark histopathologic feature of MSA is accumulation of ?-synuclein within glial cytoplasmic inclusions (GCI). The most common of the Parkinsonian tauopathies is progressive supranuclear palsy (PSP), which is clinically associated with severe postural instability leading to early falls. The tau pathology of PSP also affects both neurons and glia. Given the population frequency of PD, ?-synuclein pathology similar to that in PD, but not accompanied by neuronal loss, is relatively common (10% of people over 65 years of age) in neurologically normal individuals, leading to proposed staging schemes for PD progression. Although MSA-like and PSP-like pathology can be detected in neurologically normal individuals, such cases are too infrequent to permit assessment of patterns of disease progression.

Dickson, Dennis W.

2012-01-01

358

Treatment of Parkinson's disease.  

PubMed Central

Pharmacotherapy with levodopa for Parkinson's disease provides symptomatic benefit, but fluctuations in (or loss of) response may eventually occur. Dopamine agonists are also helpful and, when taken with low doses of levodopa, often provide sustained benefit with fewer side effects; novel agonists and new methods for their administration are therefore under study. Other therapeutic strategies are being explored, including the use of type B monoamine oxidase inhibitors to reduce the metabolic breakdown of dopamine, catechol-O-methyltransferase inhibitors to retard the breakdown of levodopa, norepinephrine precursors to compensate for deficiency of this neurotransmitter, glutamate antagonists to counteract the effects of the subthalamic nucleus, and various neurotrophic factors to influence dopaminergic nigrostriatal cells. Surgical procedures involving pallidotomy are sometimes helpful. Those involving cerebral transplantation of adrenal medullary or fetal mesencephalic tissue have yielded mixed results; benefits may relate to the presence of growth factors in the transplanted tissue. The transplantation of genetically engineered cell lines will probably become the optimal transplantation procedure. The cause of Parkinson's disease may relate to oxidant stress and the generation of free radicals. It is not clear whether treatment with selegiline hydrochloride (a type B monoamine oxidase inhibitor) delays the progression of Parkinson's disease, because the drug also exerts a mild symptomatic effect. Daily treatment with vitamin E (a scavenger of free radicals) does not influence disease progression, perhaps because of limited penetration into the brain. Images

Aminoff, M J

1994-01-01

359

Methamphetamine and Parkinson's disease.  

PubMed

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

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

2013-01-01

360

Methamphetamine and Parkinson's Disease  

PubMed Central

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

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

2013-01-01

361

Modulation of levodopa-induced motor response complications by NMDA antagonists in Parkinson's disease  

Microsoft Academic Search

The complex dopamine-glutamate interactions within the basal ganglia are disrupted by chronic nigrostriatal denervation and standard replacement therapy with levodopa. Acute N-methyl-d-aspartate (NMDA) receptor blockade is able to overcome the changes in dopamine D1- and D2-dependent responses and the progressive shortening in the duration of response induced by long-term exposure to levodopa in 6-hydroxydopamine-lesioned rats. Preliminary results further suggest that

Pierre J. Blanchet; Stella M. Papa; Leo Verhagen Metman; M. Maral Mouradian; Thomas N. Chase

1997-01-01

362

Drug-induced liver injury: present and future  

PubMed Central

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

Suk, Ki Tae

2012-01-01

363

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

PubMed Central

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.

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

2011-01-01

364

Imaging Mass Spectrometry Reveals Elevated Nigral Levels of Dynorphin Neuropeptides in L-DOPA-Induced Dyskinesia in Rat Model of Parkinson's Disease  

PubMed Central

L-DOPA-induced dyskinesia is a troublesome complication of L-DOPA pharmacotherapy of Parkinson's disease and has been associated with disturbed brain opioid transmission. However, so far the results of clinical and preclinical studies on the effects of opioids agonists and antagonists have been contradictory at best. Prodynorphin mRNA levels correlate well with the severity of dyskinesia in animal models of Parkinson's disease; however the identities of the actual neuroactive opioid effectors in their target basal ganglia output structures have not yet been determined. For the first time MALDI-TOF imaging mass spectrometry (IMS) was used for unbiased assessment and topographical elucidation of prodynorphin-derived peptides in the substantia nigra of a unilateral rat model of Parkinson's disease and L-DOPA induced dyskinesia. Nigral levels of dynorphin B and alpha-neoendorphin strongly correlated with the severity of dyskinesia. Even if dynorphin peptide levels were elevated in both the medial and lateral part of the substantia nigra, MALDI IMS analysis revealed that the most prominent changes were localized to the lateral part of the substantia nigra. MALDI IMS is advantageous compared with traditional molecular methods, such as radioimmunoassay, in that neither the molecular identity analyzed, nor the specific localization needs to be predetermined. Indeed, MALDI IMS revealed that the bioconverted metabolite leu-enkephalin-arg also correlated positively with severity of dyskinesia. Multiplexing DynB and leu-enkephalin-arg ion images revealed small (0.25 by 0.5 mm) nigral subregions with complementing ion intensities, indicating localized peptide release followed by bioconversion. The nigral dynorphins associated with L-DOPA-induced dyskinesia were not those with high affinity to kappa opioid receptors, but consisted of shorter peptides, mainly dynorphin B and alpha-neoendorphin that are known to bind and activate mu and delta opioid receptors. This suggests that mu and/or delta subtype-selective opioid receptor antagonists may be clinically relevant for reducing L-DOPA-induced dyskinesia in Parkinson's disease.

Ljungdahl, Anna; Hanrieder, Jorg; Falth, Maria; Bergquist, Jonas; Andersson, Malin

2011-01-01

365

Current approaches to the treatment of Parkinson's disease  

PubMed Central

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

Jankovic, Joseph; Aguilar, L Giselle

2008-01-01

366

A unique case of coincidence of early onset Parkinson's disease and multiple sclerosis.  

PubMed

We report on a patient who developed left arm rest/postural tremor at age 24 and responded well to trihexyphenidyl. One year later spastic paraparesis appeared, and multiple sclerosis was diagnosed on the basis of clinical, radiological, and laboratory evidence. Although paraparesis improved after immunosuppressant therapy, a complete picture of an asymmetric parkinsonian syndrome gradually developed. Excellent response to levodopa, drug-induced dyskinesias, and DaTSCAN revealing pathology congruent with Parkinson's disease (PD) indicate a coincidental etiopathogenetic relationship of both clinical entities: multiple sclerosis and PD. Genetic analyses focusing on autosomal recessive parkinsonism (parkin, DJ1, and PINK1) were negative. To the best of our knowledge, only 15 cases of parkinsonism in association with multiple sclerosis have been reported, and their relationship has been interpreted to be either causal or coincidental. This is the first report of a coincidence of both entities, in which the parkinsonian syndrome developed first and before age 30. PMID:17914725

Valkovic, Peter; Krastev, Georgi; Mako, Miroslav; Leitner, Petra; Gasser, Thomas

2007-11-15

367

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

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

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

2014-08-01

368

Drug-induced liver injury with autoimmune features.  

PubMed

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

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

2014-05-01

369

Drug-induced vascular lesions of the liver.  

PubMed

The vascular lesions of the liver described in association with drug and toxic substance exposure are reviewed, with special reference to the abnormalities of the following: (1) the hepatic venous efferent system (ie, large and small hepatic vein obstruction); (2) the sinusoids (ie, sinusoidal dilatation, peliosis, perisinusoidal fibrosis); (3) the portal vein and its branches; and (4) the hepatic arterial tree. Drug-induced vascular tumors of the liver and vascular changes observed within nonvascular tumors of the liver are also envisaged. Finally, the pathophysiologic mechanisms of all these lesions are considered. The awareness of this type of hepatotoxicity and the knowledge of its epidemiology seem to be essential for both its early detection and prevention. PMID:6338851

Zafrani, E S; von Pinaudeau, Y; Dhumeaux, D

1983-03-01

370

Drug-induced liver injury in older adults  

PubMed Central

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

Mitchell, Sarah J.

2010-01-01

371

Fungicidal Drugs Induce a Common Oxidative Damage Cellular Death Pathway  

PubMed Central

Summary Amphotericin, miconazole and ciclopirox are antifungal agents from three different drug classes that can effectively kill planktonic yeast, yet their complete fungicidal mechanisms are not fully understood. Here we employ a systems biology approach to identify a common oxidative damage cellular death pathway triggered by these representative fungicides in Candida albicans and Saccharomyces cerevisiae. This mechanism utilizes a signaling cascade involving the GTPases Ras1/2 and Protein Kinase A, and culminates in death through the production of toxic ROS in a tricarboxylic acid cycle- and respiratory chain-dependent manner. We also show that the metabolome of C. albicans is altered by antifungal drug treatment, exhibiting a shift from fermentation to respiration, a jump in the AMP/ATP ratio, and elevated production of sugars; this coincides with elevated mitochondrial activity. Lastly, we demonstrate that DNA damage plays a critical role in antifungal-induced cellular death and that blocking DNA repair mechanisms potentiates fungicidal activity.

Belenky, Peter; Camacho, Diogo; Collins, James J.

2013-01-01

372

Drug-induced solar urticaria due to repirinast.  

PubMed

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

Kurumaji, Y; Shono, M

1994-01-01

373

Beta-endorphin and drug-induced reward and reinforcement.  

PubMed

Although drugs of abuse have different acute mechanisms of action, their brain pathways of reward exhibit common functional effects upon both acute and chronic administration. Long known for its analgesic effect, the opioid beta-endorphin is now shown to induce euphoria, and to have rewarding and reinforcing properties. In this review, we will summarize the present neurobiological and behavioral evidences that support involvement of beta-endorphin in drug-induced reward and reinforcement. Currently, evidence supports a prominent role for beta-endorphin in the reward pathways of cocaine and alcohol. The existing information indicating the importance of beta-endorphin neurotransmission in mediating the reward pathways of nicotine and THC, is thus far circumstantial. The studies described herein employed diverse techniques, such as biochemical measurements of beta-endorphin in various brain sites and plasma, and behavioral measurements, conducted following elimination (via administration of anti-beta-endorphin antibodies or using mutant mice) or augmentation (by intracerebral administration) of beta-endorphin. We suggest that the reward pathways for different addictive drugs converge to a common pathway in which beta-endorphin is a modulating element. Beta-endorphin is involved also with distress. However, reviewing the data collected so far implies a discrete role, beyond that of a stress response, for beta-endorphin in mediating the substance of abuse reward pathway. This may occur via interacting with the mesolimbic dopaminergic system and also by its interesting effects on learning and memory. The functional meaning of beta-endorphin in the process of drug-seeking behavior is discussed. PMID:18602444

Roth-Deri, Ilana; Green-Sadan, Tamar; Yadid, Gal

2008-09-01

374

Influence of Mast Cells in Drug-Induced Gingival Overgrowth  

PubMed Central

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

Yeap, Swee Keong; Alitheen, Noorjahan Banu

2013-01-01

375

Influence of mast cells in drug-induced gingival overgrowth.  

PubMed

Mast cells (MCs) are multifunctional effector cells that were originally thought to be involved in allergic disorders. Now it is known that they contain an array of mediators with a multitude of effects on many other cells. MCs have become a recent concern in drug-induced gingival overgrowth (DIGO), an unwanted outcome of systemic medication. Most of the studies have confirmed the significant presence of inflammation as a prerequisite for the overgrowth to occur. The inflammatory changes within the gingival tissue appear to influence the interaction between the inducing drug and the fibroblast activity. The development of antibodies to MC-specific enzymes, tryptase and chymase, has facilitated the study of mast cells in DIGO. Many immunohistochemical studies involving MCs have been conducted; as a result, DIGO tissues are found to have increased the number of MCs in the gingiva, especially in the area of fibrosis. At the cellular level, gingival fibrogenesis is initiated by several mediators which induce the recruitment of a large number of inflammatory cells, including MCs. The purpose of this paper is to access the roles played by MCs in gingival overgrowth to hypothesize a relationship between these highly specialized cells in the pathogenesis of DIGO. PMID:23431239

Subramani, Tamilselvan; Rathnavelu, Vidhya; Yeap, Swee Keong; Alitheen, Noorjahan Banu

2013-01-01

376

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

Microsoft Academic Search

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

Marc P Pusztaszeri; Byron L Cryer; Robert M Genta

2007-01-01

377

Sleep disturbances in Parkinson’s disease  

Microsoft Academic Search

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

Cynthia L. Comella

2003-01-01

378

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

Microsoft Academic Search

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

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

2012-01-01

379

DRUG INDUCED PHOSPHOLIPIDOSIS: AN ACQUIRED LYSOSOMAL STORAGE DISORDER  

PubMed Central

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.

Shayman, James A.; Abe, Akira

2012-01-01

380

[Pharmacogenetics in Parkinson's disease treatment].  

PubMed

The authors present the current opinion on the significance of molecular biology in individualized therapy. Pharmacogenetics is a new branch of clinical pharmacology dealing with the influence of genetic factors on drugs with special focus on interpersonal differences to drug response. The article includes basic rules of pharmacogenetics as well as its use in clinical practice. Individualized treatment of Parkinson's disease is not widely known although interpersonal differences to drug response is clearly stated. There is some evidence that varied efficacy of treatment and risk of motor and mental complications can be of genetic origin. Some results concerning the relationship between genetic polymorphism of COMT, DRD2, DAT, CCK, MTHFR and successful and safe treatment of Parkinson's disease are presented. PMID:18512170

Bia?ecka, Monika; K?odowska-Duda, Gabriela; Kurzawski, Mateusz; Dro?dzik, Marek

2008-01-01

381

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

PubMed

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

Donato, M Teresa; Gómez-Lechón, M José

2012-10-01

382

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

PubMed

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

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

2012-09-01

383

Circulating microRNAs, potential biomarkers for drug-induced liver injury  

Microsoft Academic Search

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

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

2009-01-01

384

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

PubMed

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

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

2012-11-01

385

Generation of Pig Induced Pluripotent Stem Cells with a Drug-Inducible System  

Microsoft Academic Search

Domesticated ungulate pluripotent embryonic stem (ES) cell lines would be useful for generating precise gene-modified animals. To date, many efforts have been made to establish domesticated ungulate pluripotent ES cells from early embryos without success. Here, we report the generation of porcine-induced pluripotent stem (iPS) cells using drug-inducible expression of defined factors. We showed that porcine iPS cells expressed alkaline

Zhao Wu; Jijun Chen; Jiangtao Ren; Lei Bao; Jing Liao; Chun Cui; Linjun Rao; Hui Li; Yijun Gu; Huiming Dai; Hui Zhu; Xiaokun Teng; Lu Cheng; Lei Xiao

2009-01-01

386

Perioperative management of patients with Parkinson's disease.  

PubMed

Parkinson's disease is the second most common neurodegenerative disease worldwide, leading to a wide range of disability and medical complications. Managing patients with Parkinson's disease in the perioperative hospital setting can be particularly challenging. Suboptimal management can lead to medical complications, prolonged hospital stays, and delayed recovery. This review aims to address the most important issues related to caring for patients with Parkinson's disease perioperatively who are undergoing emergent or planned general surgery. It also intends to help hospitalists, internists, and other health care providers mitigate potential in-hospital morbidity and prevent prolonged recovery. Challenges in managing patients with Parkinson's disease in the perioperative hospital setting include disruption of medication schedules, "nothing by mouth" status, reduced mobility, and medication interactions and their side effects. Patients with Parkinson's disease are more prone to immobility and developing dysphagia, respiratory dysfunction, urinary retention, and psychiatric symptoms. These issues lead to higher rates of pneumonia, urinary tract infections, deconditioning, and falls compared with patients without Parkinson's disease, as well as prolonged hospital stays and a greater need for post-hospitalization rehabilitation. Steps can be taken to decrease these complications, including minimizing nothing by mouth status duration, using alternative routes of drugs administration when unable to give medications orally, avoiding drug interactions and medications that can worsen parkinsonism, assessing swallowing ability frequently, encouraging incentive spirometry, performing bladder scans, avoiding Foley catheters, and providing aggressive physical therapy. Knowing and anticipating these potential complications allow hospital physicians to mitigate nosocomial morbidity and shorten recovery times and hospital stays. PMID:24333200

Katus, Linn; Shtilbans, Alexander

2014-04-01

387

Prolonged drug-induced hypothermia in experimental stroke.  

PubMed

In experimental and human stroke, hypothermia is strongly related to a favorable outcome. Previous attempts to manipulate the core temperature in focal cerebral ischemia have been based on mechanical cooling. The purpose of the study is to establish a model for long-term drug-induced hypothermia in focal ischemia by pharmacological alteration of the central thermoregulatory set-point. We tested the hypothesis that the dopaminergic agonist Talipexole, which induces hypothermia, reduces infarct size. Body temperature was monitored by a radio-pill-implant. Rats had reversible occlusion of the middle cerebral artery (MCAO) for 30 minutes. Thirty minutes after reflow, the experimental group of rats (n = 10) received an intravenous bolus injection of Talipexole followed by a continuous infusion of Talipexole during the following 24 hours. The control group of rats (n = 10) received a similar treatment regimen with saline only. All rats were killed 7 days after MCAO. Infarct volume was quantified stereologically. The mean body temperature (35.6 + 1.0 degrees C) during 24 hours after bolus injection of Talipexole was significantly lower than in control rats (37.3 +/- 0.5 degrees C), P < .05. Infarct volumes were significantly lower in the Talipexole group (4.7 +/- 1.9 mm3) than in the control group (8.8 +/- 4.7 mm3), P < .04. In the Talipexole treated rats we also observed a significant hypokalemia (P = .001) and a significantly lower index of relative degree of movement (P < .02). Our study shows that the core body temperature was reduced by 1.7 degrees C for 24 hours after MCAO in rats treated with Talipexole. This treatment induced a significant reduction of infarct volume at 7 days after focal ischemia by 47%. We suggest that the reduction in infarct volume is related to drug-induced hypothermia. The hypokalemia in the hypothermic rats is possibly explained by the observed lower degree of movement. PMID:17903912

Johansen, Flemming Fryd; Jørgensen, Henrik Stig; Reith, Jakob

2003-01-01

388

Controlled release of rasagiline mesylate promotes neuroprotection in a rotenone-induced advanced model of Parkinson's disease.  

PubMed

Microencapsulation of rasagiline mesylate (RM) into PLGA microspheres was performed by method A (O/W emulsion) and method B (W/O/W double emulsion). The best formulation regarding process yield, encapsulation efficiency and in vitro drug release was that prepared with method A, which exhibited constant drug release for two weeks (K(0)=62.3 ?g/day/20mg microspheres). Exposure of SKN-AS cells to peroxide-induced oxidative stress (1 mM) resulted in cell apoptosis which was significantly reduced by RM (40.7-102.5 ?M) as determined by cell viability, ROS production and DNA fragmentation. Daily doses of rotenone (2 mg/kg) given i.p. to rats for 45 days induced neuronal and behavioral changes similar to those occurring in PD. Once an advanced stage of PD was achieved, animals received RM in saline (1 mg/kg/day) or encapsulated within PLGA microspheres (amount of microspheres equivalent to 15 mg/kg RM given on days 15 and 30). After 45 days RM showed a robust effect on all analytical outcomes evaluated with non-statistically significant differences found between its administration in solution or within microparticles however; with this controlled release system administration of RM could be performed every two weeks thereby making this new therapeutic system an interesting approach for the treatment of PD. PMID:22985602

Fernández, M; Barcia, E; Fernández-Carballido, A; Garcia, L; Slowing, K; Negro, S

2012-11-15

389

Over-Pressure Suppresses Ultrasonic-Induced Drug Uptake  

PubMed Central

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.

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

2012-01-01

390

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

PubMed

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

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

2014-07-01

391

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

Federal Register 2010, 2011, 2012, 2013

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

2013-01-28

392

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

Microsoft Academic Search

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

Lauren C. Costantini; Douglas Cole; Ole Isacson

2001-01-01

393

Anticancer Agent Shikonin Is an Incompetent Inducer of Cancer Drug Resistance  

PubMed Central

Purpose Cancer drug resistance is a major obstacle for the success of chemotherapy. Since most clinical anticancer drugs could induce drug resistance, it is desired to develop candidate drugs that are highly efficacious but incompetent to induce drug resistance. Numerous previous studies have proven that shikonin and its analogs not only are highly tumoricidal but also can bypass drug-transporter and apoptotic defect mediated drug resistance. The purpose of this study is to investigate if or not shikonin is a weak inducer of cancer drug resistance. Experimental Design Different cell lines (K562, MCF-7, and a MDR cell line K562/Adr), after repeatedly treated with shikonin for 18 months, were assayed for drug resistance and gene expression profiling. Results After 18-month treatment, cells only developed a mere 2-fold resistance to shikonin and a marginal resistance to cisplatin and paclitaxel, without cross resistance to shikonin analogs and other anticancer agents. Gene expression profiles demonstrated that cancer cells did strongly respond to shikonin treatment but failed to effectively mobilize drug resistant machineries. Shikonin-induced weak resistance was associated with the up-regulation of ?II-tubulin, which physically interacted with shikonin. Conclusion Taken together, apart from potent anticancer activity, shikonin and its analogs are weak inducers of cancer drug resistance and can circumvent cancer drug resistance. These merits make shikonin and its analogs potential candidates for cancer therapy with advantages of avoiding induction of drug resistance and bypassing existing drug resistance.

Wu, Hao; Xie, Jiansheng; Pan, Qiangrong; Wang, Beibei; Hu, Danqing; Hu, Xun

2013-01-01

394

A case of acute onset parkinsonism  

PubMed Central

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

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

2013-01-01

395

Targeting the Intrinsically Disordered Structural Ensemble of ?-Synuclein by Small Molecules as a Potential Therapeutic Strategy for Parkinson's Disease  

PubMed Central

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

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