A Multi-center, Randomized, Controlled, Partially Blinded Study to Assess the Pharmacokinetics and Comparative Bioavailability of Nicotine From Two Variants of Nicotine Pouch 2.0 (NP2), 4mg and 6mg, Compared to Nicotine Lozenge 4mg and Nicotine Gum 4mg in Adult Cigarette Smokers

This is a multi-center, randomized, controlled, partially blinded study to assess the pharmacokinetics and comparative bioavailability of nicotine from two variants of NP2 (4 and 6 mg) in comparison with Loz-4mg and Gum-4mg in adult cigarette smokers. The subjects will be blinded to the randomized sequence and will be blinded to the variants of NP2 they will receive. The study will be conducted with 4 periods and 4 sequences in a Williams design (crossover).

开始日期2023-10-20

申办/合作机构-

ACTRN12609000975291 / Completed临床2期IIT

In post stroke patients, treatment with nefiracetam decreases the severity of apathy

开始日期2010-07-27

申办/合作机构

Fremantle Hospital & Health Service (Australia)

NCT00001933 / Completed临床2期IIT

Nefiracetam Therapy of Alzheimer's Type Dementia

Some of the thinking difficulties of Alzheimer's patients may be due to a deficiency in a brain chemical called acetylcholine, which helps transmit messages between nerve cells. Nefiracetam is a new drug that stimulates acetylcholine. This study will test whether Nefiracetam can safely improve memory, thinking and activities of daily living in patients with mild to moderate intellectual impairment due to Alzheimer's disease.
Patients in the study must have a caregiver and designated representative. Candidates will be given a medical history and physical examination that includes a complete neurologic and neuropsychologic evaluation, blood tests, and an electrocardiogram. A chest X ray and magnetic resonance imaging (MRI) test will be done on patients who have not had these tests within the previous two years. During the 20-week study, each patient will take three pills twice a day for twenty weeks of either Nefiracetame or placebo (sugar pill). Neither the patients nor the doctors will know which patients are getting the drug and which are getting the placebo. Blood and urine tests will be done frequently throughout the study. Patients will be asked to have a spinal tap (on a voluntary basis) to measure the levels of drug in the spinal fluid, and a PET scan (a brain imaging test).
At the end of the study, patients who feel they are doing well with no side effects from the drug (or placebo) may be given the option of continuing treatment for another seven months.
Animal studies showed that Nefiracetam improved learning impairment and memory in rats with dementia. In a small study of humans, about one-fourth of patients who were given a low dose of the drug had improved intellectual function, and about one-half who received a higher dose improved.

开始日期1999-07-01

申办/合作机构

National Institute of Neurological Disorders & Stroke

100 项与 VDCCs x NMDA receptor 相关的临床结果

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100 项与 VDCCs x NMDA receptor 相关的转化医学

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0 项与 VDCCs x NMDA receptor 相关的专利（医药）

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项与 VDCCs x NMDA receptor 相关的文献（医药）

2024-09-01·Journal of Biological Chemistry

Nerve injury augments Cacna2d1 transcription via CK2-mediated phosphorylation of the histone deacetylase HDAC2 in dorsal root ganglia

Article

作者: Pan, Hui-Lin ; Chen, Shao-Rui ; Huang, Yuying ; Ghosh, Krishna

Development of chronic neuropathic pain involves complex synaptic and epigenetic mechanisms. Nerve injury causes sustained upregulation of α2δ-1 (encoded by the Cacna2d1 gene) in the dorsal root ganglion (DRG), contributing to pain hypersensitivity by directly interacting with and augmenting presynaptic NMDA receptor activity in the spinal dorsal horn. Under normal conditions, histone deacetylase 2 (HDAC2) is highly enriched at the Cacna2d1 gene promoter in the DRG, which constitutively suppresses Cacna2d1 transcription. However, nerve injury leads to HDAC2 dissociation from the Cacna2d1 promoter, promoting the enrichment of active histone marks and Cacna2d1 transcription in primary sensory neurons. In this study, we determined the mechanism by which nerve injury diminishes HDAC2 occupancy at the Cacna2d1 promoter in the DRG. Spinal nerve injury in rats increased serine-394 phosphorylation of HDAC2 in the DRG. Coimmunoprecipitation showed that nerve injury enhanced the physical interaction between HDAC2 and casein kinase II (CK2) in the DRG. Furthermore, repeated intrathecal treatment with CX-4945, a potent and specific CK2 inhibitor, markedly reversed nerve injury-induced pain hypersensitivity, HDAC2 phosphorylation, and α2δ-1 expression levels in the DRG. In addition, treatment with CX-4945 largely restored HDAC2 enrichment at the Cacna2d1 promoter and reduced the elevated levels of acetylated H3 and H4 histones, particularly H3K9ac and H4K5ac, at the Cacna2d1 promoter in the injured DRG. These findings suggest that nerve injury increases CK2 activity and CK2-HDAC2 interactions, which enhance HDAC2 phosphorylation in the DRG. This, in turn, diminishes HDAC2 enrichment at the Cacna2d1 promoter, thereby promoting Cacna2d1 transcription.

2024-03-01·Brain Communications

Hippocampal hyperphosphorylated tau-induced deficiency is rescued by L-type calcium channel blockade

Article

作者: Rajani, Vishaal ; Omoluabi, Tamunotonye ; Torraville, Sarah E ; Maziar, Aida ; Ando, Kanae ; Hasan, Zia ; Duraid, Sarah ; Yuan, Qi ; Crossley, Chelsea A ; Hell, Johannes W

AbstractAging and Alzheimer’s disease are associated with chronic elevations in neuronal calcium influx via L-type calcium channels. The hippocampus, a primary memory encoding structure in the brain, is more vulnerable to calcium dysregulation in Alzheimer’s disease. Recent research has suggested a link between L-type calcium channels and tau hyperphosphorylation. However, the precise mechanism of L-type calcium channel-mediated tau toxicity is not understood. In this study, we seeded a human tau pseudophosphorylated at 14 amino acid sites in rat hippocampal cornu ammonis 1 region to mimic soluble pretangle tau. Impaired spatial learning was observed in human tau pseudophosphorylated at 14 amino acid sites-infused rats as early as 1–3 months and worsened at 9–10 months post-infusion. Rats infused with wild-type human tau exhibited milder behavioural deficiency only at 9–10 months post-infusion. No tangles or plaques were observed in all time points examined in both human tau pseudophosphorylated at 14 amino acid sites and human tau-infused brains. However, human tau pseudophosphorylated at 14 amino acid sites-infused hippocampus exhibited a higher amount of tau phosphorylation at S262 and S356 than the human tau-infused rats at 3 months post-infusion, paralleling the behavioural deficiency observed in human tau pseudophosphorylated at 14 amino acid sites-infused rats. Neuroinflammation indexed by increased Iba1 in the cornu ammonis 1 was observed in human tau pseudophosphorylated at 14 amino acid sites-infused rats at 1–3 but not 9 months post-infusion. Spatial learning deficiency in human tau pseudophosphorylated at 14 amino acid sites-infused rats at 1–3 months post-infusion was paralleled by decreased neuronal excitability, impaired NMDA receptor-dependent long-term potentiation and augmented L-type calcium channel-dependent long-term potentiation at the cornu ammonis 1 synapses. L-type calcium channel expression was elevated in the soma of the cornu ammonis 1 neurons in human tau pseudophosphorylated at 14 amino acid sites-infused rats. Chronic L-type calcium channel blockade with nimodipine injections for 6 weeks normalized neuronal excitability and synaptic plasticity and rescued spatial learning deficiency in human tau pseudophosphorylated at 14 amino acid sites-infused rats. The early onset of L-type calcium channel-mediated pretangle tau pathology and rectification by nimodipine in our model have significant implications for preclinical Alzheimer’s disease prevention and intervention.

2023-05-01·Brain Research

A model of zinc dynamics evoked by intense stimulation at the cleft of hippocampal mossy fiber synapses

Article

作者: Sousa, Marta S ; Rosário, Luís M ; Quinta-Ferreira, Rosa M ; Quinta-Ferreira, M Emília ; Sampaio Dos Aidos, Fernando D S ; Miraldo, João N ; Santos, Rosa M ; Matias, Carlos M ; Alves, João L ; Freitas, Johnattan C S

Zinc is a transition metal that is particularly abundant in the mossy fibers of the hippocampal CA3 area. Despite the large number of studies about the zinc role in mossy fibers, the action of zinc in synaptic mechanisms is only partly known. The use of computational models can be a useful tool for this study. In a previous work, a model was developed to evaluate zinc dynamics at the mossy fiber synaptic cleft, following weak stimulation, insufficient to evoke zinc entry into postsynaptic neurons. For intense stimulation, cleft zinc effluxes must be considered. Therefore, the initial model was extended to include postsynaptic zinc effluxes based on the Goldman-Hodgkin-Katz current equation combined with Hodgkin and Huxley conductance changes. These effluxes occur through different postsynaptic escape routes, namely L- and N-types voltage-dependent calcium channels and NMDA receptors. For that purpose, various stimulations were assumed to induce high concentrations of cleft free zinc, named as intense (10 μM), very intense (100 μM) and extreme (500 μM). It was observed that the main postsynaptic escape routes of cleft zinc are the L-type calcium channels, followed by the NMDA receptor channels and by N-type calcium channels. However, their relative contribution for cleft zinc clearance was relatively small and decreased for higher amounts of zinc, most likely due to the blockade action of zinc in postsynaptic receptors and channels. Therefore, it can be concluded that the larger the zinc release, the more predominant the zinc uptake process will be in the cleft zinc clearance.