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Pharmacological Research Mar 2017Weak bases that readily penetrate through the lipid bilayer and accumulate inside the acidic organelles are known as lysosomotropic molecules. Many lysosomotropic... (Review)
Review
Weak bases that readily penetrate through the lipid bilayer and accumulate inside the acidic organelles are known as lysosomotropic molecules. Many lysosomotropic compounds exhibit therapeutic activity and are commonly used as antidepressant, antipsychotic, antihistamine, or antimalarial agents. Interestingly, studies also have shown increased sensitivity of cancer cells to certain lysosomotropic agents and suggested their mechanism of action as a promising approach for selective destruction of cancer cells. However, their chemotherapeutic utility may be limited due to various side effects. Hence, understanding the homeostatic alterations mediated by lysosomotropic compounds has significant importance for revealing their true therapeutic potential as well as toxicity. In this review, after briefly introducing the concept of lysosomotropism and classifying the lysosomotropic compounds into two major groups according to their cytotoxicity on cancer cells, we focused on the subcellular alterations mediated by class-II lysosomotropic compounds. Briefly, their effect on intracellular cholesterol homeostasis, autophagy and lysosomal sphingolipid metabolism was discussed. Accordingly, class-II lysosomotropic molecules inhibit intracellular cholesterol transport, leading to the accumulation of cholesterol inside the late endosomal-lysosomal cell compartments. However, the accumulated lysosomal cholesterol is invisible to the cellular homeostatic circuits, hence class-II lysosomotropic molecules also upregulate cholesterol synthesis pathway as a downstream event. Considering the fact that Niemann-Pick disease, a lysosomal cholesterol storage disorder, also triggers similar pathologic abnormalities, this review combines the knowledge obtained from the Niemann-Pick studies and lysosomotropic compounds. Taken together, this review is aimed at allowing readers a better understanding of subcellular alterations mediated by lysosomotropic drugs, as well as their potential therapeutic and/or toxic activities.
Topics: Animals; Cholesterol; Homeostasis; Humans; Lysosomes; Neoplasms; Pharmaceutical Preparations
PubMed: 28025106
DOI: 10.1016/j.phrs.2016.12.021 -
Annals of Clinical Psychiatry :... Aug 2017Several published studies have reported an association between antipsychotic medications, especially first-generation agents, and a decline in gray matter volume. This... (Review)
Review
BACKGROUND
Several published studies have reported an association between antipsychotic medications, especially first-generation agents, and a decline in gray matter volume. This prompted us to review the possible neurotoxic mechanisms of first-generation antipsychotics (FGAs), especially haloperidol, which has been widely used over the past several decades.
METHODS
A PubMed search was conducted using the keywords haloperidol, antipsychotic, neurotoxicity, apoptosis, oxidative stress, and neuroplasticity. No restrictions were placed on the date of the articles or language. Studies with a clearly described methodology were included.
RESULTS
Animal, cell culture, and human tissue studies were identified. Thirty reports met the criteria for the search. All studies included haloperidol; a few also included other FGAs (fluphenazine and perphenazine) and/or second-generation agents (SGAs) (aripiprazole, paliperidone, and risperidone). A neurotoxic effect of haloperidol and other FGAs was a common theme across all studies. Minimal (mainly at high doses) or no neurotoxic effects were noted in SGAs.
CONCLUSIONS
A review of the literature suggests that haloperidol exerts measurable neurotoxic effects at all doses via many molecular mechanisms that lead to neuronal death. A similar effect was observed in 2 other FGAs, but the effect in SGAs was much smaller and occurred mainly at high doses. A stronger binding to serotonin 5HT-2A receptors than to dopamine D2 receptors may have a neuroprotective effect among SGAs. Further studies are warranted to confirm these findings.
Topics: Animals; Antipsychotic Agents; Cell Death; Haloperidol; Humans; Neurons
PubMed: 28738100
DOI: No ID Found -
Journal of B.U.ON. : Official Journal... 2020In the effort to improve treatment effectiveness in glioblastoma, this short note reviewed collected data on the pathophysiology of glioblastoma with particular... (Review)
Review
In the effort to improve treatment effectiveness in glioblastoma, this short note reviewed collected data on the pathophysiology of glioblastoma with particular reference to intersections with the pharmacology of perphenazine. That study identified five areas of potentially beneficial intersection. Data showed seemingly 5 independent perphenazine attributes of benefit to glioblastoma treatment - i) blocking dopamine receptor 2, ii) reducing centrifugal migration of subventricular zone cells by blocking dopamine receptor 3, iii) blocking serotonin receptor 7, iv) activation of protein phosphatase 2, and v) nausea reduction. Perphenazine is fully compatible with current chemoirradiation protocols and with the commonly used ancillary medicines used in clinical practice during the course of glioblastoma. All these attributes argue for a trial of perphenazine's addition to current standard treatment with temozolomide and irradiation. The subventricular zone seeds the brain with mutated cells that become recurrent glioblastoma after centrifugal migration. The current paper shows how perphenazine might reduce that contribution. Perphenazine is an old, generic, cheap, phenothiazine antipsychotic drug that has been in continuous clinical use worldwide since the 1950's. Clinical experience and research data over these decades have shown perphenazine to be well-tolerated in psychiatric populations, in normals, and in non-psychiatric, medically ill populations for whom perphenazine is used to reduce nausea. For now (Summer, 2020) the nature of glioblastoma requires a polypharmacy approach until/unless a core feature and means to address it can be identified in the future. Conclusions: Perphenazine possesses a remarkable constellation of attributes that recommend its use in GB treatment.
Topics: Dopamine Antagonists; Glioblastoma; Humans; Perphenazine
PubMed: 33099901
DOI: No ID Found -
The Cochrane Database of Systematic... Nov 2017Oral zuclopenthixol dihydrochloride (Clopixol) is an anti-psychotic treatment for people with psychotic symptoms, especially those with schizophrenia. It is associated... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Oral zuclopenthixol dihydrochloride (Clopixol) is an anti-psychotic treatment for people with psychotic symptoms, especially those with schizophrenia. It is associated with neuroleptic malignant syndrome, a prolongation of the QTc interval, extra-pyramidal reactions, venous thromboembolism and may modify insulin and glucose responses.
OBJECTIVES
To determine the effects of zuclopenthixol dihydrochloride for treatment of schizophrenia.
SEARCH METHODS
We searched the Cochrane Schizophrenia Group's Trials Register (latest search 09 June 2015). There were no language, date, document type, or publication status limitations for inclusion of records in the register.
SELECTION CRITERIA
All randomised controlled trials (RCTs) focusing on zuclopenthixol dihydrochloride for schizophrenia. We included trials meeting our inclusion criteria and reporting useable data.
DATA COLLECTION AND ANALYSIS
We extracted data independently. For binary outcomes, we calculated risk ratio (RR) and its 95% confidence interval (CI), on an intention-to-treat basis. For continuous data, we estimated the mean difference (MD) between groups and its 95% CI. We employed a random-effect model for analyses. We assessed risk of bias for included studies and created 'Summary of findings' tables using GRADE.
MAIN RESULTS
We included 20 trials, randomising 1850 participants. Data were reported for 12 comparisons, predominantly for the short term (up to 12 weeks) and inpatient populations. Overall risk of bias for included studies was low to unclear.Data were unavailable for many of our pre-stated outcomes of interest. No data were available, across all comparisons, for death, duration of stay in hospital and general functioning.Zuclopenthixol dihydrochloride versus: 1. placeboMovement disorders (EPSEs) were similar between groups (1 RCT, n = 28, RR 6.07 95% CI 0.86 to 43.04 very low-quality evidence). There was no clear difference in numbers leaving the study early (2 RCTs, n = 100, RR 0.29, 95% CI 0.01 to 6.60, very low-quality evidence). 2. chlorpromazineNo clear differences were found for the outcomes of global state (average CGI-SI endpoint score) (1 RCT, n = 60, MD 0.00, 95% CI -0.49 to 0.49) or movement disorders (EPSEs) (3 RCTs, n = 199, RR 0.94, 95% CI 0.61 to 1.45), both very low-quality evidence. More people left the study early for any reason from the zuclopenthixol group (6 RCTs, n = 766, RR 0.54, 95% CI 0.36 to 0.81, low-quality evidence). 3. chlorprothixeneThere was no clear difference in numbers leaving the study early for any reason (1 RCT, n = 20, RR 1.00, 95% CI 0.34 to 2.93, very low-quality evidence). 4. clozapineNo useable data were presented. 5. haloperidolNo clear differences between treatment groups were found for the outcomes global state score (average CGI endpoint score) (1 RCT, n = 49, MD 0.13, 95% CI -0.30 to 0.55) or leaving the study early (2 RCTs, n = 141, RR 0.99, 95% CI 0.72 to 1.35), both very low-quality evidence. 6. perphenazineThose receiving zuclopenthixol were more likely to require medication in the short term for EPSEs than perphenazine (1 RCT, n = 50, RR 1.90, 95% CI 1.12 to 3.22, very low-quality evidence). Similar numbers left the study early (2 RCTs, n = 104, RR 0.63, 95% CI 0.27 to 1.47, very low-quality evidence). 7. risperidoneThose receiving zuclopenthixol were more likely to require medications for EPSEs than risperidone (1 RCT, n = 98,RR 1.92, 95% CI 1.12 to 3.28, very low quality evidence). There was no clear difference in numbers leaving the study early ( 3 RCTs, n = 154, RR 1.30, 95% CI 0.84 to 2.02) or in mental state (average PANSS total endpoint score) (1 RCT, n = 25, MD -3.20, 95% CI -7.71 to 1.31), both very low-quality evidence). 8. sulpirideNo clear differences were found for global state (average CGI endpoint score) ( 1 RCT, n = 61, RR 1.18, 95% CI 0.49 to 2.85, very low-quality evidence), requiring hypnotics/sedatives (1 RCT, n = 61, RR 0.60, 95% CI 0.27 to 1.32, very low-quality evidence) or leaving the study early (1 RCT, n = 61, RR 2.07 95% CI 0.97 to 4.40, very low-quality evidence). 9. thiothixeneNo clear differences were found for the outcomes of 'global state (average CGI endpoint score) (1 RCT, n = 20, RR 0.50, 95% CI 0.17 to 1.46) or leaving the study early (1 RCT, n = 20, RR 0.57, 95% CI 0.24 to 1.35), both very low-quality evidence). 10. trifluoperazineNo useable data were presented. 11. zuclopenthixol depotThere was no clear difference in numbers leaving the study early (1 RCT, n = 46, RR 1.95, 95% CI 0.36 to 10.58, very low-quality evidence). 12. Zuclopenthixol dihydrochloride (cis z isomer) versus zuclopenthixol (cis z/trans e isomer)There were no clear differences in reported side-effects ( 1 RCT, n = 57, RR 1.34, 95% CI 0.82 to 2.18, very low-quality evidence) and in numbers leaving the study early (4 RCTs, n = 140, RR 2.15, 95% CI 0.49 to 9.41, very low-quality evidence).
AUTHORS' CONCLUSIONS
Zuclopenthixol dihydrochloride appears to cause more EPSEs than clozapine, risperidone or perphenazine, but there was no difference in EPSEs when compared to placebo or chlorpromazine. Similar numbers required hypnotics/sedatives when zuclopenthixol dihydrochloride was compared to sulpiride, and similar numbers of reported side-effects were found when its isomers were compared. The other comparisons did not report adverse-effect data.Reported data indicate zuclopenthixol dihydrochloride demonstrates no difference in mental or global states compared to placebo, chlorpromazine, chlorprothixene, clozapine, haloperidol, perphenazine, sulpiride, thiothixene, trifluoperazine, depot and isomers. Zuclopenthixol dihydrochloride, when compared with risperidone, is favoured when assessed using the PANSS in the short term, but not in the medium term.The data extracted from the included studies are mostly equivocal, and very low to low quality, making it difficult to draw firm conclusions. Prescribing practice is unlikely to change based on this meta-analysis. Recommending any particular course of action about side-effect medication other than monitoring, using rating scales and clinical assessment, and prescriptions on a case-by-case basis, is also not possible.There is a need for further studies covering this topic with more antipsychotic comparisons for currently relevant outcomes.
Topics: Antipsychotic Agents; Clopenthixol; Humans; Movement Disorders; Randomized Controlled Trials as Topic; Schizophrenia
PubMed: 29144549
DOI: 10.1002/14651858.CD005474.pub2 -
The Cochrane Database of Systematic... Oct 2014Antipsychotic drugs are the core treatment for schizophrenia. Treatment guidelines state that there is no difference in efficacy between the various first-generation... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Antipsychotic drugs are the core treatment for schizophrenia. Treatment guidelines state that there is no difference in efficacy between the various first-generation antipsychotics, however, low-potency first-generation antipsychotic drugs are sometimes perceived as less efficacious than high-potency first-generation compounds by clinicians, and they also seem to differ in their side effects.
OBJECTIVES
To review the effects of high-potency, first-generation perphenazine compared with low-potency, first-generation antipsychotic drugs for people with schizophrenia.
SEARCH METHODS
We searched the Cochrane Schizophrenia Group Trials Register (October 2010).
SELECTION CRITERIA
We included all randomised controlled trials (RCTs) comparing perphenazine with first-generation, low-potency antipsychotic drugs for people with schizophrenia or schizophrenia-like psychoses.
DATA COLLECTION AND ANALYSIS
We extracted data independently. For dichotomous data we calculated risk ratios (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis and using a random-effects model.
MAIN RESULTS
The review currently includes four relevant randomised trials with 365 participants. The size of the included studies was between 42 and 158 participants with a study length between one and four months. Overall, the methods of sequence generation and allocation concealment were poorly reported. Most studies were rated as low risk of bias in terms of blinding. Overall, attrition bias in the studies was high.The effects of perphenazine and low-potency antipsychotic drugs seemed to be similar in terms of the primary outcome - response to treatment (perphenazine 58%, low-potency antipsychotics 59%, 2 RCTs, n = 138, RR 0.97 CI 0.74 to 1.26 - moderate quality of evidence). There was also no clear evidence of a difference in acceptability of treatment with the number of participants leaving the studies early due to any reason, however results were imprecise (perphenazine 30%, low-potency antipsychotics 28%, 3 RCTs, n = 323, RR 0.78 CI 0.35 to 1.76, very low quality of evidence).There were low numbers of studies available for the outcomes experiencing at least one adverse effect (perphenazine 33%, low-potency antipsychotics 47%, 2 RCTs, n = 165, RR 0.83 CI 0.36 to 1.95, low quality evidence) and experiencing at least one movement disorder (perphenazine 22%, low-potency first-generation antipsychotics 0%, 1 RCT, n = 69, RR 15.62 CI 0.94 to 260.49, low quality evidence), and the confidence intervals for the estimated effects did not exclude important differences. Akathisia was more frequent in the perphenazine group (perphenazine 25%, low-potency antipsychotics 22%, 2 RCTs, n = 227, RR 9.45 CI 1.69 to 52.88), whereas severe toxicity was less so (perphenazine 42%, low-potency antipsychotics 69%, 1 RCT, n = 96, RR 0.61 CI 0.41 to 0.89).There were three deaths in the low-potency group by four months but the difference between groups was not significant (perphenazine 0%, low-potency antipsychotics 2%, 1 RCT, n = 96, RR 0.14 CI 0.01 to 2.69, moderate quality evidence). No data were available for our prespecified outcomes of interest sedation or quality of life. Data were not available for other outcomes such as relapse, service use, costs and satisfaction with care.The event rates reported quote simple aggregates and are not based on the RRs.
AUTHORS' CONCLUSIONS
The results do not show a superiority in efficacy of high-potency perphenazine compared with low-potency first-generation antipsychotics. There is some evidence that perphenazine is more likely to cause akathisia and less likely to cause severe toxicity, but most adverse effect results were equivocal. The number of studies as well as the quality of studies is low, with quality of evidence for the main outcomes ranging from moderate to very low, so more randomised evidence would be needed for conclusions to be made.
Topics: Adult; Antipsychotic Agents; Humans; Perphenazine; Randomized Controlled Trials as Topic; Schizophrenia
PubMed: 25290157
DOI: 10.1002/14651858.CD009369.pub2 -
CNS Drugs Sep 2016Somnolence is a common side effect of antipsychotics. To assess the incidence of this side effect, we performed a MEDLINE search for randomized, double-blinded, placebo-... (Review)
Review
Somnolence is a common side effect of antipsychotics. To assess the incidence of this side effect, we performed a MEDLINE search for randomized, double-blinded, placebo- or active-controlled studies of adult patients treated with antipsychotics for schizophrenia, mania, bipolar depression, or bipolar disorder. We extracted rates of somnolence from original publications and pooled them based on the dose of each antipsychotic in the same psychiatric condition, then estimated the absolute risk increase (ARI) and the number needed to harm (NNH) of an antipsychotic relative to placebo or an active comparator in the same psychiatric condition. According to the ARI in acute schizophrenia, bipolar mania, and bipolar depression, antipsychotics can be classified as high somnolence (clozapine), moderate somnolence (olanzapine, perphenazine, quetiapine, risperidone, ziprasidone), and low somnolence (aripiprazole, asenapine, haloperidol, lurasidone, paliperidone, cariprazine). The risk of somnolence with blonanserin, brexpiprazole, chlorpromazine, iloperidone, sertindole, and zotepine needs further investigation. The rates of somnolence were positively correlated to dose and duration for some antipsychotics, but not for others. Many factors, including antipsychotic per se, the method used to measure somnolence, patient population, study design, and dosing schedule, might affect the incidence of antipsychotic-induced somnolence. The mechanisms of antipsychotic-induced somnolence are likely multifactorial, although the blockade of histamine 1 receptors and α1 receptors may play a major role. The management of antipsychotic-induced somnolence should include sleep hygiene education, choosing an antipsychotic with a lower risk for somnolence, starting at a lower dose with a slower titration based on psychiatric diagnoses, adjusting doses when necessary, and minimizing concurrent somnolence-prone agents. Since most cases of somnolence were mild to moderate, allowing tolerance to develop over at least 4 weeks is reasonable before discontinuing an antipsychotic.
Topics: Adult; Antipsychotic Agents; Dose-Response Relationship, Drug; Humans; Incidence; Mental Disorders; Randomized Controlled Trials as Topic; Research Design; Sleep Stages; Time Factors
PubMed: 27372312
DOI: 10.1007/s40263-016-0352-5 -
Developmental Medicine and Child... Dec 2017To evaluate the actual evidence of efficacy of oral pharmacological treatments in the management of dyskinetic cerebral palsy (CP). (Review)
Review
AIM
To evaluate the actual evidence of efficacy of oral pharmacological treatments in the management of dyskinetic cerebral palsy (CP).
METHOD
A systematic review was performed according to the American Academy for Cerebral Palsy and Developmental Medicine (AACPDM) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology. Articles were searched for in PubMed/MEDLINE, Scopus, Web of Science, Cochrane Library, Database of Reviews of Effectiveness, OTSeeker, Physiotherapy Evidence Database, REHABDATA, and ClinicalTrials.gov.
RESULTS
Sixteen articles met the eligibility criteria. Eight studies on trihexyphenidyl and two on levodopa showed contradictory results. Low efficacy was reported for diazepam, dantrolene sodium, perphenazine, and etybenzatropine. Tetrabenazine, gabapentin and levetiracetam should be studied in more detail. The updated available evidence does not support any therapeutic algorithm for the management of dyskinetic CP.
INTERPRETATION
This lack of evidence is partially owing to the inconsistency of classifications of patients and of outcome measures used in the reviewed studies. Further randomized, double-blind, placebo-controlled pharmacological trials, optimized for different age groups, based on valid, reliable, and disease-specific rating scales are strongly needed. Outcome measures should be selected within the framework of the International Classification of Functioning, Disability and Health.
WHAT THIS PAPER ADDS
Evidence to prove (or disprove) the efficacy of oral drugs in dyskinetic cerebral palsy is low. The most investigated drugs, trihexyphenidyl and levodopa, show contradictory results. Tetrabenazine, levetiracetam, and gabapentin efficacy should be studied in more detail. Lack of evidence is partially due to the inconsistency of classifications and outcome measures used. Outcome measures should be selected within the framework of the International Classification of Functioning, Disability and Health in next clinical trials.
Topics: Anticonvulsants; Cerebral Palsy; Dyskinesias; Humans; Neurotransmitter Agents; Outcome Assessment, Health Care
PubMed: 28872668
DOI: 10.1111/dmcn.13532 -
The Lancet. Psychiatry Apr 2018Antipsychotic drugs improve schizophrenia symptoms and reduce the frequency of relapse, but treatment response is highly variable. Little is known about the genetic... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Antipsychotic drugs improve schizophrenia symptoms and reduce the frequency of relapse, but treatment response is highly variable. Little is known about the genetic factors associated with treatment response. We did a genome-wide association study of antipsychotic treatment response in patients with schizophrenia.
METHODS
The discovery cohort comprised patients with schizophrenia from 32 psychiatric hospitals in China that are part of the Chinese Antipsychotics Pharmacogenomics Consortium. Patients who met inclusion criteria were randomly assigned (1:1:1:1:1:1) to six groups (olanzapine, risperidone, quetiapine, aripiprazole, ziprasidone, and haloperidol or perphenazine; those assigned to haloperidol or perphenazine were subsequently assigned [1:1] to one or the other) for 6 weeks. Antipsychotic response was quantified with percentage change on the Positive and Negative Syndrome Scale. Single-nucleotide polymorphisms (SNPs) were tested for their association with treatment response. Linkage-disequilibrium-independent SNPs that exhibited potential associations (ie, p<1 × 10) were tested in a validation cohort comprising patients from the Chinese Antipsychotics Pharmacogenetics Consortium from five collaborative hospitals, who were treated with olanzapine, risperidone, or aripiprazole for 8 weeks.
FINDINGS
The discovery cohort contained 2413 patients and the validation cohort 1379 patients. In the discovery cohort, we identified three novel SNPs (rs72790443 in MEGF10 [p=1·37 × 10], rs1471786 in SLC1A1 [p=1·77 × 10], and rs9291547 in PCDH7 [p=4·48 × 10]) that were associated with antipsychotic treatment response at a genome-wide significance level. These associations were confirmed in the validation cohort (p<0·05). In the combined sample of the discovery and validation cohorts, we identified five novel loci showing genome-wide significant associations with general antipsychotic treatment response (rs72790443 in MEGF10 [p=1·40 × 10], rs1471786 in SLC1A1 [p=2·33 × 10], rs9291547 in PCDH7 [p=3·24 × 10], rs12711680 in CNTNAP5 [p=2·12 × 10], and rs6444970 in TNIK [p=4·85 × 10]). In antipsychotic-specific groups, after the combination of results from both samples, the rs2239063 SNP in CACNA1C was associated with treatment response to olanzapine (p=1·10 × 10), rs16921385 in SLC1A1 was associated with treatment response to risperidone (p=4·40 × 10), and rs17022006 in CNTN4 was associated with treatment response to aripiprazole (p=2·58 × 10).
INTERPRETATION
We have identified genes related to synaptic function, neurotransmitter receptors, and schizophrenia risk that are associated with response to antipsychotics. These findings improve understanding of the mechanisms underlying treatment responses, and the identified biomarkers could eventually guide choice of antipsychotic in patients with schizophrenia.
FUNDING
National Key Technology R&D Program of China, National Natural Science Foundation of China.
Topics: Adult; Antipsychotic Agents; Cadherins; Cell Adhesion Molecules, Neuronal; China; Contactins; Excitatory Amino Acid Transporter 3; Female; Genome-Wide Association Study; Germinal Center Kinases; Humans; Logistic Models; Male; Membrane Proteins; Pharmacogenetics; Polymorphism, Single Nucleotide; Protein Serine-Threonine Kinases; Protocadherins; Schizophrenia; Treatment Outcome
PubMed: 29503163
DOI: 10.1016/S2215-0366(18)30049-X -
Neuro-degenerative Diseases 2020Orthostatic tremor (OT) is not an uncommon symptom in various neurodegenerative diseases. However, the nature and pathophysiology of OT involve a complex network of... (Review)
Review
Orthostatic tremor (OT) is not an uncommon symptom in various neurodegenerative diseases. However, the nature and pathophysiology of OT involve a complex network of tremors and dopaminergic pathways. We assessed patients who complained of prominent leg tremors described as "shaky leg." We analyzed their characteristics and evaluated them with neuroimaging and electrophysiological tools. A total of 23 patients who experienced an uncomfortable symptom of leg tremor were retrospectively enrolled from April 2014 to October 2019. Previous medical history, brain MRI, and surface electromyography (EMG) data were analyzed. The [18F]-FP-CIT brain positron emission tomography (PET) and the Unified Parkinson's Disease Rating Scale (UPDRS) were assessed for patients who showed parkinsonism. The causes of OT varied: parkinsonism (n = 5), idiopathic causes (n = 4), secondary causes (n = 3, trauma, brain lesion, arteriovenous malformation), drug reactions (n = 3, valproate, perphenazine, haloperidol), other neurological disorders (n = 5, essential tremor, dystonia, restless leg syndrome, REM sleep behavior disorder, dementia), alcohol withdrawal (n = 1), functional movement disorder (n = 1), and an unknown cause (n = 1). The frequency range varied (2.6-15 Hz) and according to the new consensus statement on the classification of OT, 4 patients had primary OT, 2 had "primary OT plus," 12 had slow OT, and 5 had orthostatic myoclonus. The prognosis associated with the use of medication was generally poor; however, clonazepam and levodopa were the most effective drugs. In conclusion, we found that different types of OT and orthostatic myoclonus were diagnosed by electrophysiological evaluation and neuroimaging tools even if they showed the same symptoms as "shaky leg." In addition, it is possible to roughly estimate the response to medication according to the type of OT and the cause. To clarify the pathophysiology of OT, a large number of longitudinal cohort studies and detailed neuroimaging and electrophysiological evaluations are needed.
Topics: Aged; Dizziness; Humans; Middle Aged; Neurodegenerative Diseases; Retrospective Studies; Tremor
PubMed: 32911473
DOI: 10.1159/000509411 -
Frontiers in Oncology 2015Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that is required for normal cell growth and development. PP2A is a potent tumor suppressor, which is... (Review)
Review
Protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that is required for normal cell growth and development. PP2A is a potent tumor suppressor, which is inactivated in cancer cells as a result of genetic deletions and mutations. In myeloid leukemias, genes encoding PP2A subunits are generally intact. Instead, PP2A is functionally inhibited by post-translational modifications of its catalytic C subunit, and interactions with negative regulators by its regulatory B and scaffold A subunits. Here, we review the molecular mechanisms of genetic and functional inactivation of PP2A in human cancers, with a particular focus on human acute myeloid leukemias (AML). By analyzing expression of genes encoding PP2A subunits using transcriptome sequencing, we find that PP2A dysregulation in AML is characterized by silencing and overexpression of distinct A scaffold and B regulatory subunits, respectively. We review the mechanisms of functional PP2A activation by drugs such as fingolimod, forskolin, OP449, and perphenazine. This analysis yields two non-mutually exclusive mechanisms for therapeutic PP2A re-activation: (i) allosteric activation of the phosphatase activity, and (ii) stabilization of active holo-enzyme assembly and displacement of negative regulatory factors from A and B subunits. Future studies should allow the development of specific and potent pharmacologic activators of PP2A, and definition of susceptible disease subsets based on specific mechanisms of PP2A dysregulation.
PubMed: 25699237
DOI: 10.3389/fonc.2015.00016