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Advances in Pharmacology (San Diego,... 2009Stimulant drugs acting at the dopamine transporter (DAT), like cocaine, are widely abused, yet effective medical treatments for this abuse have not been found. Analogs... (Review)
Review
Stimulant drugs acting at the dopamine transporter (DAT), like cocaine, are widely abused, yet effective medical treatments for this abuse have not been found. Analogs of benztropine (BZT) that, like cocaine, act at the DAT have effects that differ from cocaine and in some situations block the behavioral, neurochemical, and reinforcing actions of cocaine. Neurochemical studies of dopamine levels in brain and behavioral studies have demonstrated that BZT analogs have a relatively slow onset and reduced maximal effects compared to cocaine. Pharmacokinetic studies, however, indicated that the BZT analogs rapidly access the brain at concentrations above their in vitro binding affinities, while binding in vivo demonstrates apparent association rates for BZT analogs lower than that for cocaine. Additionally, the off-target effects of these compounds do not fully explain their differences from cocaine. Initial structure-activity studies indicated that BZT analogs bind to DAT differently from cocaine and these differences have been supported by site-directed mutagenesis studies of the DAT. In addition, BZT analog-mediated inhibition of uptake was more resistant to mutations producing inward conformational DAT changes than cocaine analogs. The BZT analogs have provided new insights into the relation between the molecular and behavioral actions of cocaine and the diversity of effects produced by dopamine transport inhibitors. Novel interactions of BZT analogs with the DAT suggest that these drugs may have a pharmacology that would be useful in their development as treatments for cocaine abuse.
Topics: Animals; Behavior; Cocaine-Related Disorders; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; Drug Discovery; Humans; Nervous System
PubMed: 20230764
DOI: 10.1016/S1054-3589(08)57007-4 -
WMJ : Official Publication of the State... May 2023Benztropine is an anticholinergic drug used as a therapy for Parkinson's disease and treatment for extrapyramidal side effects. While tardive dyskinesia is an...
INTRODUCTION
Benztropine is an anticholinergic drug used as a therapy for Parkinson's disease and treatment for extrapyramidal side effects. While tardive dyskinesia is an involuntary movement disorder that often occurs gradually after long-term use of medications, it does not commonly present acutely.
CASE PRESENTATION
A 31-year-old White woman experiencing psychosis presented with spontaneous, acute-onset dyskinesia induced with the withdrawal of benztropine. She had been followed in our academic outpatient clinic for medication management and intermittent psychotherapy.
DISCUSSION
The pathophysiology of tardive dyskinesia is not fully understood, but several hypotheses exist, including the involvement of changes in basal ganglia neuronal systems. To our knowledge, this is the first case report to document acute-onset dyskinesia associated with the withdrawal of benztropine.
CONCLUSION
his case report, which describes an atypical response to discontinuing benztropine, might offer the scientific community potential clues to better understand the pathophysiology of tardive dyskinesia.
Topics: Female; Humans; Adult; Benztropine; Tardive Dyskinesia; Dyskinesia, Drug-Induced; Antipsychotic Agents
PubMed: 37141483
DOI: No ID Found -
Frontiers in Cell and Developmental... 2022Obtaining oligodendroglial cells from dispensable tissues would be of great interest for autologous or immunocompatible cell replacement therapy in demyelinating...
Obtaining oligodendroglial cells from dispensable tissues would be of great interest for autologous or immunocompatible cell replacement therapy in demyelinating diseases, as well as for studying myelin-related pathologies or testing therapeutic approaches in culture. We evaluated the feasibility of generating oligodendrocyte precursor cells (OPCs) from adult rat adipose tissue by expressing genes encoding transcription factors involved in oligodendroglial development. Adipose-derived mesenchymal cells were lentivirally transduced with tetracycline-inducible , , , and/or transgenes. Immunostaining with the OPC-specific O4 monoclonal antibody was used to mark oligodendroglial induction. O4- and myelin-associated glycoprotein (MAG)-positive cells emerged after 3 weeks when using the + + combination, followed in the ensuing weeks by GFAP-, O1 antigen-, p75NTR (low-affinity NGF receptor)-, and myelin proteins-positive cells. The O4 cell population progressively expanded, eventually constituting more than 70% of cells in culture by 5 months. transgene expression was essential for generating O4 cells but was insufficient for inducing a full oligodendroglial phenotype. Converted cells required continuous transgene expression to maintain their glial phenotype. Some vestigial characteristics of mesenchymal cells were maintained after conversion. Growth factor withdrawal and triiodothyronine (T) supplementation generated mature oligodendroglial phenotypes, while FBS supplementation produced GFAP- and p75NTR-rich cultures. Converted cells also showed functional characteristics of neural-derived OPCs, such as the expression of AMPA, NMDA, kainate, and dopaminergic receptors, as well as similar metabolic responses to differentiation-inducing drugs. When co-cultured with rat dorsal root ganglion neurons, the converted cells differentiated and ensheathed multiple axons. We propose that functional oligodendroglia can be efficiently generated from adult rat mesenchymal cells by direct phenotypic conversion.
PubMed: 35223826
DOI: 10.3389/fcell.2022.741499 -
Journal of Virology Oct 2015Filoviruses, consisting of Ebola virus (EBOV) and Marburg virus (MARV), are among the most lethal infectious threats to mankind. Infections by these viruses can cause...
UNLABELLED
Filoviruses, consisting of Ebola virus (EBOV) and Marburg virus (MARV), are among the most lethal infectious threats to mankind. Infections by these viruses can cause severe hemorrhagic fevers in humans and nonhuman primates with high mortality rates. Since there is currently no vaccine or antiviral therapy approved for humans, there is an urgent need to develop prophylactic and therapeutic options for use during filoviral outbreaks and bioterrorist attacks. One of the ideal targets against filoviral infection and diseases is at the entry step, which is mediated by the filoviral glycoprotein (GP). In this report, we screened a chemical library of small molecules and identified numerous inhibitors, which are known G protein-coupled receptor (GPCR) antagonists targeting different GPCRs, including histamine receptors, 5-HT (serotonin) receptors, muscarinic acetylcholine receptor, and adrenergic receptor. These inhibitors can effectively block replication of both infectious EBOV and MARV, indicating a broad antiviral activity of the GPCR antagonists. The time-of-addition experiment and microscopic studies suggest that GPCR antagonists block filoviral entry at a step following the initial attachment but prior to viral/cell membrane fusion. These results strongly suggest that GPCRs play a critical role in filoviral entry and GPCR antagonists can be developed as an effective anti-EBOV/MARV therapy.
IMPORTANCE
Infection of Ebola virus and Marburg virus can cause severe illness in humans with a high mortality rate, and currently there is no FDA-approved vaccine or therapeutic treatment available. The 2013-2015 epidemic in West Africa underscores a lack of our understanding in the infection and pathogenesis of these viruses and the urgency of drug discovery and development. In this study, we have identified numerous inhibitors that are known G protein-coupled receptor (GPCR) antagonists targeting different GPCRs. These inhibitors can effectively block replication of both infectious EBOV and MARV, indicating a broad antiviral activity of the GPCR antagonists. Our results strongly suggest that GPCRs play a critical role in filoviral entry and GPCR antagonists can be developed as an effective anti-EBOV/MARV therapy.
Topics: Animals; Antiviral Agents; Benztropine; Cell Line; Chlorocebus aethiops; Cyproheptadine; Ebolavirus; HEK293 Cells; Hemorrhagic Fever, Ebola; Heparin; High-Throughput Screening Assays; Humans; Macrolides; Marburg Virus Disease; Marburgvirus; Receptors, G-Protein-Coupled; Small Molecule Libraries; Vero Cells; Virus Internalization; Zidovudine
PubMed: 26202243
DOI: 10.1128/JVI.01337-15 -
The American Journal of Case Reports Jun 2020BACKGROUND Antipsychotic medications are associated with multiple adverse effects, including metabolic syndrome, prolonged QT interval, and extrapyramidal symptoms....
BACKGROUND Antipsychotic medications are associated with multiple adverse effects, including metabolic syndrome, prolonged QT interval, and extrapyramidal symptoms. Acute laryngeal dystonia (ALD) is a rare and lethal form of extrapyramidal reaction. CASE REPORT A 27-year-old woman with schizophrenia on risperidone presented to our Emergency Department with a sensation of choking and respiratory distress, mimicking a panic attack. She developed a generalized dystonic reaction in the hospital, leading to diagnosis risperidone-associated ALD as a cause of her initial problems. She was discharged with an emphasis on being compliant with anticholinergic medication. However, her persistent respiratory symptoms prompted us to revisit the management plan. Her risperidone dose was tapered down to discontinue and an alternate drug was chosen. CONCLUSIONS ALD must be considered as a differential diagnosis when patients on antipsychotic medications present with respiratory distress. Our case highlights the association of ALD with an atypical antipsychotic agent, risperidone. Prompt recognition of this entity is necessary to prevent complications and guide definitive management.
Topics: Adult; Antipsychotic Agents; Benztropine; Dystonia; Female; Humans; Laryngeal Diseases; Risperidone; Schizophrenia
PubMed: 32506071
DOI: 10.12659/AJCR.922393 -
The Cochrane Database of Systematic... 2003Anticholinergics were the first drugs available for the symptomatic treatment of Parkinson's disease and they are still widely used today, both as monotherapy and as... (Review)
Review
BACKGROUND
Anticholinergics were the first drugs available for the symptomatic treatment of Parkinson's disease and they are still widely used today, both as monotherapy and as part of combination regimes. They are commonly believed to be associated with a less favourable side effect profile than other antiparkinsonian drugs, in particular with respect to neuropsychiatric and cognitive adverse events. They have been claimed to exert a better effect on tremor than on other parkinsonian features.
OBJECTIVES
To determine the efficacy and tolerability of anticholinergics in the symptomatic treatment of Parkinson's disease compared to placebo or no treatment.
SEARCH STRATEGY
The literature search included electronic searches of the Cochrane Controlled Trials Register (The Cochrane Library, Issue 4, 2001), MEDLINE (1966 to 2001), Old Medline (1960-1965), Index Medicus (1927 - 1959), as well as handsearching the neurology literature including the reference lists of identified articles, other reviews and book chapters.
SELECTION CRITERIA
Randomised controlled trials of anticholinergic drugs versus placebo or no treatment in de-novo or advanced Parkinson's disease, either as monotherapy or as an add-on to other antiparkinsonian drugs were included. Trials of anticholinergic drugs that were never in general clinical use were excluded.
DATA COLLECTION AND ANALYSIS
Data was abstracted independently by two authors. Differences were settled by discussion among all authors. Data collected included patient characteristics, disease duration and severity, concomitant medication, interventions including duration and dose of anticholinergic treatment, outcome measures, rates of and reasons for withdrawals, and neuropsychiatric and cognitive adverse events.
MAIN RESULTS
The initial search yielded 14 potentially eligible studies, five of which were subsequently excluded. In three cases this was because they dealt with substances that had never been marketed or had not been licensed for as far as could be traced back. One trial had been published twice in different languages. One study was excluded based on the assessment of its methodological quality. The remaining nine studies were all of double-blind cross-over design and included 221 patients. Trial duration was between five and 20 weeks and drugs investigated were benzhexol (mean doses: 8 to 20 mg/d), orphenadrine (mean dose not reported), benztropine (mean dose not reported), bornaprine (8 to 8.25 mg/d), benapryzine (200 mg/d), and methixine (45 mg/d). Only one study involved two anticholinergic drugs. Outcome measures varied widely across studies and in many cases, the scales applied were the authors' own and were not defined in detail. Incomplete reporting of methodology and results was frequent. The heterogeneous study designs as well as incomplete reporting precluded combined statistical analysis. Five studies used both tremor and other parkinsonian features as outcome measures. Outcome measures in these five studies were too different for a combined analysis and results varied widely, from a significant improvement in tremor only to significant improvement in other features but not in tremor. All studies except one (dealing with methixine) found a significant improvement from baseline on the anticholinergic drug in at least one outcome measure. The difference between placebo and active drug was reported in four studies and was found to be significant in all cases. No study failed to show superiority of the anticholinergic over placebo. The occurrence of neuropsychiatric and cognitive adverse events was reported in all but three studies (in 35 patients on active drug versus 13 on placebo). The most frequently reported reason for drop-outs from studies was in patients on placebo due to withdrawal from pre-trial anticholinergic treatment.
REVIEWER'S CONCLUSIONS
As monotherapy or as an adjunct to other antiparkinsonian drugs, anticholinergics are more effective than placebo in improving motor function in Parkinson's disease. Neuropsychiatric and cognitive adverse events occur more frequently on anticholinergics than on placebo and are a more common reason for withdrawal than lack of efficacy. Results regarding a potentially better effect of the anticholinergic drug on tremor than on other outcome measures are conflicting and data do not strongly support a differential clinical effect on individual parkinsonian features. Data is insufficient to allow comparisons in efficacy or tolerability between individual anticholinergic drugs.
Topics: Cholinergic Antagonists; Humans; Muscarinic Antagonists; Parkinson Disease; Randomized Controlled Trials as Topic
PubMed: 12804486
DOI: 10.1002/14651858.CD003735 -
Cureus Jun 2022The limited psychiatric bedspace due to the COVID-19 pandemic and the lack of access to an up-to-date medication regimen delayed the recognition of the diagnosis and...
The limited psychiatric bedspace due to the COVID-19 pandemic and the lack of access to an up-to-date medication regimen delayed the recognition of the diagnosis and treatment for a 40-year-old man with schizoaffective disorder, bipolar type, who traveled from his home city and abruptly discontinued his prescription of clozapine. He developed a cholinergic rebound syndrome including delirium and extrapyramidal symptoms (EPS). The delay included time spent in two different medical hospitals: one awaiting psychiatric bedspace, and secondly, when the patient's cholinergic rebound syndrome was misdiagnosed as acute alcohol withdrawal. Once the etiology was recognized, he was promptly treated with anticholinergic medication (benztropine) and retitrated to his outpatient dose of clozapine leading to the resolution of symptoms including delirium and EPS. This case will discuss the challenges of continuity of care in delirious, psychotic, or otherwise confused patients, including contributions from the COVID-19 pandemic. A medication card or other improvements in medication databases that may reduce delays in treatment are discussed.
PubMed: 35812573
DOI: 10.7759/cureus.25765 -
Medicine Dec 2023This case report presents a unique acute dystonic reaction (ADR) induced by metoclopramide in a 6-year-old male patient with pertussis-associated vomiting. The rarity of...
INTRODUCTION
This case report presents a unique acute dystonic reaction (ADR) induced by metoclopramide in a 6-year-old male patient with pertussis-associated vomiting. The rarity of such a reaction in pediatric patients underscores the significance of this case in contributing to the scientific literature. This report highlights the need for heightened awareness of the potential adverse effects of medications commonly used in pediatrics and emphasizes the importance of tailored interventions for this population.
MAIN SYMPTOMS AND IMPORTANT CLINICAL FINDINGS
Following the administration of metoclopramide for vomiting associated with pertussis cough, the patient exhibited distressing symptoms, including torticollis, facial grimacing, and tongue protrusion. These involuntary movements were promptly recognized, leading to the suspicion of an ADR. The clinical findings underscore the importance of vigilant monitoring for extrapyramidal symptoms following medication administration, especially in children.
THE MAIN DIAGNOSES, THERAPEUTIC INTERVENTIONS, AND OUTCOMES
The primary diagnosis of ADR induced by metoclopramide was confirmed, prompting the cessation of the medication and the initiation of anticholinergic therapy with benztropine. This intervention rapidly resolved the patient's symptoms, highlighting the importance of tailored and swift therapeutic strategies. The outcome demonstrated the efficacy of timely intervention in managing ADR in pediatric patients.
CONCLUSION
The main takeaway lesson from this case lies in the critical need for healthcare practitioners to remain vigilant for potential adverse reactions in pediatric patients, even when prescribing commonly used medications. The successful management of this case underscores the importance of prompt recognition, appropriate interventions, and continuous monitoring. Ultimately, this case contributes to the scientific literature by highlighting the unique manifestation of ADR in a pediatric patient, reinforcing the significance of individualized patient care and medication safety.
Topics: Male; Humans; Child; Metoclopramide; Whooping Cough; Vomiting; Dyskinesias; Torticollis
PubMed: 38050314
DOI: 10.1097/MD.0000000000036140 -
Journal of Neurochemistry Sep 2006Two atypical inhibitors of the dopamine transporter, benztropine, used in the treatment of Parkinson's disease, and bupropion, used as an antidepressant, show very... (Comparative Study)
Comparative Study
Two atypical inhibitors of the dopamine transporter, benztropine, used in the treatment of Parkinson's disease, and bupropion, used as an antidepressant, show very different psychostimulant effects when compared with another inhibitor, cocaine. Taking advantage of the differential sensitivity of the dopamine and the norepinephrine transporters (DAT and NET) to benztropine and bupropion, we have used site-directed mutagenesis to produce gain-of-function mutants in NET which demonstrate that Ala279 in the trans-membrane domain 5 (TM5) and Ser359 in the TM7 of DAT are responsible for the higher sensitivity of DAT to both bupropion and benztropine. Substitution of these two DAT residues into the NET background does not alter the potency of NET-selective inhibitors, such as desipramine. The results from experiments examining the ability of DAT-selective inhibitors to displace [3H]nisoxetine binding in NET gain-of-function mutants suggest that Ser359 contributes to the initial binding of the inhibitor, and that Ala279 may influence subsequent steps involved in the blockade of translocation. Thus, these studies begin to identify residues that are important for the unique molecular interactions of benztropine and bupropion with the DAT, and that ultimately may contribute to the distinct behavioral actions of these drugs.
Topics: Alanine; Animals; Benztropine; Binding, Competitive; Biological Transport; Bupropion; COS Cells; Chlorocebus aethiops; Dopamine; Dopamine Plasma Membrane Transport Proteins; Dopamine Uptake Inhibitors; Dose-Response Relationship, Drug; Drug Interactions; Fluoxetine; Models, Molecular; Mutagenesis, Site-Directed; Norepinephrine Plasma Membrane Transport Proteins; Radioligand Assay; Serine; Transfection; Tritium
PubMed: 16923164
DOI: 10.1111/j.1471-4159.2006.04060.x -
Frontiers in Immunology 2018Though promoting remyelination in multiple sclerosis (MS) has emerged as a promising therapeutic strategy, it does not address inflammatory signals that continue to...
Though promoting remyelination in multiple sclerosis (MS) has emerged as a promising therapeutic strategy, it does not address inflammatory signals that continue to induce neuronal damage and inhibit effectiveness of repair mechanisms. Our lab has previously characterized the immunomodulatory tetrapeptide, tuftsin, which induces an anti-inflammatory shift in microglia and macrophages. This targeted anti-inflammatory agent improves physical deficits in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Here, we sought to determine whether tuftsin is also effective in combination with benztropine, an FDA-approved drug that stimulates remyelination, in both EAE and in the cuprizone model of demyelination. We show that combining these two agents to promote anti-inflammatory and remyelinating mechanisms alleviates symptoms in EAE and lessens pathological hallmarks in both MS models. Importantly, tuftsin is required to transform the inflammatory CNS environment normally present in EAE/MS into one of an anti-inflammatory nature, and benztropine is required in the cuprizone model to improve remyelination. Our data further support tuftsin's beneficial immunomodulatory activity in the context of EAE, and show that when studying remyelination in the absence of an autoimmune insult, tuftsin still activated microglia toward an anti-inflammatory fate, but benztropine was necessary for significant repair of the damaged myelin. Overall, tuftsin effectively combined with benztropine to significantly improve MS-like pathologies in both models.
Topics: Animals; Benztropine; Cuprizone; Disease Models, Animal; Drug Therapy, Combination; Encephalomyelitis, Autoimmune, Experimental; Mice; Multiple Sclerosis; Myelin Sheath; Tuftsin
PubMed: 30555470
DOI: 10.3389/fimmu.2018.02784