- Parkinson's Disease: Biomarkers, Treatment, and Risk Factors. [Review]
- FNFront Neurosci 2018; 12:612
- Parkinson's disease (PD) is a progressive neurodegenerative disorder caused mainly by lack of dopamine in the brain. Dopamine is a neurotransmitter involved in movement, motivation, memory, and other...
Parkinson's disease (PD) is a progressive neurodegenerative disorder caused mainly by lack of dopamine in the brain. Dopamine is a neurotransmitter involved in movement, motivation, memory, and other functions; its level is decreased in PD brain as a result of dopaminergic cell death. Dopamine loss in PD brain is a cause of motor deficiency and, possibly, a reason of the cognitive deficit observed in some PD patients. PD is mostly not recognized in its early stage because of a long latency between the first damage to dopaminergic cells and the onset of clinical symptoms. Therefore, it is very important to find reliable molecular biomarkers that can distinguish PD from other conditions, monitor its progression, or give an indication of a positive response to a therapeutic intervention. PD biomarkers can be subdivided into four main types: clinical, imaging, biochemical, and genetic. For a long time protein biomarkers, dopamine metabolites, amino acids, etc. in blood, serum, cerebrospinal liquid (CSF) were considered the most promising. Among the candidate biomarkers that have been tested, various forms of α-synuclein (α-syn), i.e., soluble, aggregated, post-translationally modified, etc. were considered potentially the most efficient. However, the encouraging recent results suggest that microRNA-based analysis may bring considerable progress, especially if it is combined with α-syn data. Another promising analysis is the advanced metabolite profiling of body fluids, called "metabolomics" which may uncover metabolic fingerprints specific for various stages of PD. Conventional pharmacological treatment of PD is based on the replacement of dopamine using dopamine precursors (levodopa, L-DOPA, L-3,4 dihydroxyphenylalanine), dopamine agonists (amantadine, apomorphine) and MAO-B inhibitors (selegiline, rasagiline), which can be used alone or in combination with each other. Potential risk factors include environmental toxins, drugs, pesticides, brain microtrauma, focal cerebrovascular damage, and genomic defects. This review covers molecules that might act as the biomarkers of PD. Then, PD risk factors (including genetics and non-genetic factors) and PD treatment options are discussed.
- Adverse reaction and rational use of paracetamol tablets and its drug content detection based on spectral test. [Journal Article]
- PJPak J Pharm Sci 2018; 31(4(Special)):1743-1749
- Paracetamol and amantadine hydrochloride tablet is a commonly used drug to relieve the common cold. Its main ingredient is 4-Acetamidophenol. The safety of acetaminophen containing cold drugs has att...
Paracetamol and amantadine hydrochloride tablet is a commonly used drug to relieve the common cold. Its main ingredient is 4-Acetamidophenol. The safety of acetaminophen containing cold drugs has attracted more and more attention in recent years. In order to promote the clinical safety of drugs, the adverse reaction and clinical application of acetaminophen drugs are analyzed in this paper. The adverse reactions induced by acetaminophen mainly include: allergic reaction (46.1%), liver and kidney injury (25%), blood system (15.7%) and digestive system (5.2%). At the same time, we tested the content of acetaminophen by using spectral test. It can be seen that the method can be extended to the quantitative analysis and quality control of the effective components of other compound drugs.
- Computational Study of HCV p7 Channel: Insight into a New Strategy for HCV Inhibitor Design. [Journal Article]
- ISInterdiscip Sci 2018 Sep 07
- HCV p7 protein is a cation-selective ion channel, playing an essential role during the life cycle of HCV viruses. To understand the cation-selective mechanism, we constructed a hexameric model in lip...
HCV p7 protein is a cation-selective ion channel, playing an essential role during the life cycle of HCV viruses. To understand the cation-selective mechanism, we constructed a hexameric model in lipid bilayers of HCV p7 protein for HCB JFH-1 strain, genotype 2a. In this structural model, His9 and Val6 were key factors for the HCV cation-selective ion channel. The histidine residues at position 9 in the hexameric model formed a first gate for HCV p7 channel, acting as a selectivity filter for cations. The valines mentioned above formed a second gate for HCV p7 channel, serving as a hydrophobic filter for the dehydrated cations. The binding pocket for the channel blockers, e.g., amantadine and rimantadine, was composed of residues 20-26 in H2 helix and 52-60 in H3 helix in i + 2 monomer. However, the molecular volumes for both amantadine and rimantadine were too small for the binding pocket of HCV p7 channel. Thus, designing a compound similar with rimantadine and having much larger volume would be an effective strategy for discovering inhibitors against HCV p7 channel. To achieve this point, we used rimantadine as a structural template to search ChEMBL database for the candidates employing favorable binding affinities to HCV p7 channel. As a result, six candidates were identified to have potential to be novel inhibitors against HCV p7 channel.
- Computational screening of known broad-spectrum antiviral small organic molecules for potential influenza HA stem inhibitors. [Journal Article]
- PlosPLoS One 2018; 13(9):e0203148
- CONCLUSIONS: Using in silico docking analysis, we identified 18 bioactive flavonoids with potential strong binding cababilities to influenza HA-stems of various subtypes, which are the target for bNAb. The virtual screened bioassay hit compounds depicted a high number of Hbonds but low interaction and docking values compared to antiviral flavonoids. Using structure-based design and nanotechnology-based approaches, identified molecules could be modified to generate next generation anti-influenza drugs.
- Validated HPLC-MS/MS method for quantification of ethylmethylhydroxypyridine succinate in rat brain and its application to a pharmacokinetic study. [Journal Article]
- JCJ Chromatogr B Analyt Technol Biomed Life Sci 2018 Oct 01; 1096:180-186
- 2-ethyl-6-methyl-3-hydroxypyridine (EMHP) succinate is the original antioxidant and antihypoxic drug commonly prescribed in Russia. The objective of this study was to develop a rapid, simple and sens...
2-ethyl-6-methyl-3-hydroxypyridine (EMHP) succinate is the original antioxidant and antihypoxic drug commonly prescribed in Russia. The objective of this study was to develop a rapid, simple and sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for EMHP quantitation in rat brain tissue with the use of a bead beating homogenizer. The comparison between two approaches to brain tissue preparation was performed, when spiking the blank brain tissue with EMHP reference standard and internal standard (IS) before and after homogenization step. Chromatographic separation was achieved using Zorbax Eclipse Plus C18 column (1.8 μm, 2.1 × 50 mm) and elution was performed with the mobile phase, consisting of 10 mM of ammonium formate aqueous solution with 0.1% formic acid as solvent A and 0.1% formic acid in methanol as solvent B [44%(А):56%(В), v/v]. Flow rate was 0.4 mL/min and the total run time for each sample analysis was 2.0 min. EMHP and amantadine, IS of this study, were analyzed in positive ionization mode. Ion transitions of m/z 138.0 → 123.0 for EMHP and m/z 152.0 → 135.0 for amantadine were selected in multiple reaction monitoring mode. The developed method for EMHP determination in rat brain samples was validated for selectivity, linearity, accuracy, precision, matrix effects, and stability. The lower and upper limits of quantification were determined to be 1 and 1500 ng/g, respectively. The developed and validated HPLC-MS/MS method was successfully applied to determine EMHP concentrations in rat brain tissue following the intraperitoneal administration at a dose of 3.4 mg/kg.
- Inhibitors of the M2 Proton Channel Engage and Disrupt Transmembrane Networks of Hydrogen-Bonded Waters. [Journal Article]
- JAJ Am Chem Soc 2018 Sep 12
- Water-mediated interactions play key roles in drug binding. In protein sites with sparse polar functionality, a small-molecule approach is often viewed as insufficient to achieve high affinity and sp...
Water-mediated interactions play key roles in drug binding. In protein sites with sparse polar functionality, a small-molecule approach is often viewed as insufficient to achieve high affinity and specificity. Here we show that small molecules can enable potent inhibition by targeting key waters. The M2 proton channel of influenza A is the target of the antiviral drugs amantadine and rimantadine. Structural studies of drug binding to the channel using X-ray crystallography have been limited because of the challenging nature of the target, with the one previously solved crystal structure limited to 3.5 Å resolution. Here we describe crystal structures of amantadine bound to M2 in the Inwardclosed conformation (2.00 Å), rimantadine bound to M2 in both the Inwardclosed (2.00 Å) and Inwardopen (2.25 Å) conformations, and a spiro-adamantyl amine inhibitor bound to M2 in the Inwardclosed conformation (2.63 Å). These X-ray crystal structures of the M2 proton channel with bound inhibitors reveal that ammonium groups bind to water-lined sites that are hypothesized to stabilize transient hydronium ions formed in the proton-conduction mechanism. Furthermore, the ammonium and adamantyl groups of the adamantyl-amine class of drugs are free to rotate in the channel, minimizing the entropic cost of binding. These drug-bound complexes provide the first high-resolution structures of drugs that interact with and disrupt networks of hydrogen-bonded waters that are widely utilized throughout nature to facilitate proton diffusion within proteins.
- Perioperative Management of Severe Traumatic Brain Injury: What Is New? [Review]
- CACurr Anesthesiol Rep 2018; 8(3):279-289
- Severe traumatic brain injury (TBI) continues to represent a global public health issue, and mortality and morbidity in TBI patients remain substantial. There are ongoing international collaborations...
Severe traumatic brain injury (TBI) continues to represent a global public health issue, and mortality and morbidity in TBI patients remain substantial. There are ongoing international collaborations to provide guidelines for perioperative care and management of severe TBI patients. In addition, new pharmacologic agents are being tested along with cognitive rehabilitation to improve functional independence and outcome in TBI patients. This review will discuss the current updates in the guidelines for the perioperative management of TBI patients and describe potential new therapies to improve functional outcomes.
- [Antipsychotic-induced motor symptoms in schizophrenic psychoses-Part 1 : Dystonia, akathisia und parkinsonism]. [Review]
- NNervenarzt 2018 Aug 20
- Acute antipsychotic-induced movement disorders (AIMD) are clinically relevant since they are frequently associated with high subjective distress, and since over the long-term they can negatively impa...
Acute antipsychotic-induced movement disorders (AIMD) are clinically relevant since they are frequently associated with high subjective distress, and since over the long-term they can negatively impact treatment adherence of patients with schizophrenic psychoses. This review article summarizes the relevant studies on the prevalence, risk factors, prevention and treatment options and instruments for early prediction of acute AIMD in schizophrenic psychoses. The current evidence and treatment recommendations are divided into three main areas: acute dystonia, akathisia, and parkinsonism. For the treatment of acute dystonia trihexyphenidyl and biperiden have shown their efficacy. Considering pharmacological treatment of akathisia, there is some preliminary evidence for medication with lipophilic beta-receptor blockers (propranolol and pindolol), clonidine, benzodiazepines, mianserin, mirtazapine und trazodone. The treatment options for drug-induced parkinsonism include reduction or switching from one antipsychotic to another with a lower affinity for dopamine D2 receptors, amantadine or in the regular administration of anticholinergic drugs. In conclusion, acute AIMD is easily to recognize but is not always effectively and durably treated. Early recognition and treatment of acute AIMD could be associated with improved treatment outcomes.
- [Antipsychotic-induced motor symptoms in schizophrenic psychoses-Part 2 : Catatonic symptoms and neuroleptic malignant syndrome]. [Review]
- NNervenarzt 2018 Aug 20
- In rare cases, pharmacotherapy in schizophrenic psychoses can be associated with life-threatening antipsychotic-induced movement disorders. The two most severe complications are antipsychotic-associa...
In rare cases, pharmacotherapy in schizophrenic psychoses can be associated with life-threatening antipsychotic-induced movement disorders. The two most severe complications are antipsychotic-associated catatonic symptoms (ACS) and neuroleptic malignant syndrome (NMS). Although both constellations necessitate rapid medical care, the diagnosis is still a clinical challenge. Although there is no established treatment of ACS (here designated as a specific subtype of catatonic symptoms), an attempt should be made with benzodiazepines and memantine can also be helpful. In severe drug-refractory cases electroconvulsive therapy (ECT) can be indicated. The NMS represents a life-threatening constellation that frequently requires intensive care unit treatment. The medicinal treatment with benzodiazepines, bromocriptine, amantadine, dantrolene and/or ECT is also advocated. Finally, this review article also summarizes the currently available literature for treatment of genuine catatonic symptoms. In conclusion, the abovementioned clinical syndromes must be rapidly recognized and treated. Early recognition and treatment of these movement disorders can under certain circumstances be lifesaving and favorably influence the later clinical outcome.
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- Clinical and genetic investigation of amantadine-associated corneal edema. [Journal Article]
- COClin Ophthalmol 2018; 12:1367-1371
- CONCLUSIONS: Amantadine-associated corneal edema is characteristically posterior and central and appears unlikely to represent early or subclinical decompensation of Fuchs dystrophy. We describe the unique outcome of continued corneal clearance after restarting amantadine concurrently with steroids, a pattern that has persisted over 32 months to date.