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      Bioequivalence study of two formulations of flupirtine maleate capsules in healthy male Chinese volunteers under fasting and fed conditions

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          Abstract

          Aim

          This study developed a high-performance liquid chromatography–tandem mass spectrometry method to simultaneously determine the concentrations of flupirtine and its major active metabolite D-13223 in human plasma in order to assess the bioequivalence (BE) of two flupirtine maleate capsules among healthy male Chinese volunteers under fasting and fed conditions.

          Materials and methods

          There were two single-center, randomized, single-dose, open-label, laboratory-blinded, two-period, cross-over studies which included 24 healthy male Chinese volunteers under fasting and fed conditions, respectively. Plasma samples were collected prior to and up to 48 h after dosing. The concentrations of flupirtine and its major active metabolite D-13223 in plasma samples were determined by a validated method, that is, high-performance liquid chromatography coupled with a tandem mass spectrometry detector. Pharmacokinetic metrics of area from time zero to the last measurable concentration (AUC 0−t), area under the plasma concentration–time curve from administration to infinite time (AUC 0−∞), and C max were used for BE assessment.

          Results

          Forty-eight healthy volunteers who met the criteria were enrolled and completed the study. According to the observation of vital signs and laboratory measurement, no volunteers had any adverse reactions. Under fasting condition, the geometric mean ratios (90% CI) of the test/reference drug for flupirtine were 103.0% (98.1%–108.2%) for AUC 0−t, 102.9% (98.2%–107.9%) for AUC 0−∞, and 97.0% (85.9%–109.5%) for C max. Under fed condition, the geometric mean ratios (90% CI) of the test/reference drug for flupirtine were 101.7% (98.4%–105.1%) for AUC 0−t, 101.6% (98.5%–104.8%) for AUC 0−∞, and 103.5% (94.7%–113.0%) for C max. The difference between test and reference formulations, T max, was not statistically significant. The 90% CIs of the test/reference AUC ratio and C max ratio of D-13223 were also within the acceptance range for BE both under fasting and fed conditions.

          Conclusion

          The two formulations of flupirtine maleate capsule were bioequivalent (the test and the reference products) under fasting and fed conditions, and thus both can be used interchangeably in the clinical setting.

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          Most cited references 27

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          Efficacy of flupirtine on cognitive function in patients with CJD: A double-blind study.

          In cell culture experiments, flupirtine maleate (FLU), a triaminopyridine compound, was able to protect neuronal cells from apoptotic cell death induced by prion protein fragments and beta-amyloid peptides. As FLU is a clinically safe drug, the authors started a double-blind placebo-controlled study in patients with Creutzfeldt-Jakob disease (CJD). Twenty-eight patients with CJD were randomized to an oral treatment with either FLU (n = 13) or matching placebo (PLA; n = 15). For inclusion and continuing the study, the patients had to achieve at least 50% in two of the subscales of the dementia tests employed. A battery of standardized questionnaires was employed to monitor the progression of the disease. The main outcome variable was the cognitive part of the Alzheimer's Disease Assessment Scale (ADAS-Cog); the difference between baseline and the best score under treatment was defined as the primary efficacy variable for hypothesis testing. CJD types were homogeneously distributed among the treatment groups. Patients treated with FLU showed significantly less deterioration in the dementia tests than patients treated with PLA. The mean change in ADAS-Cog (baseline to best) was +8.4 (+/-15.3) in the FLU group and +20.6 (+/-15.1) in the PLA group (p = 0.02, one-sided t-test). FLU has beneficial effects on cognitive function in patients with CJD. These positive results also may suggest a treatment potential of FLU in other neurodegenerative disorders. However, further studies are necessary.
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            Flupirtine in pain management: pharmacological properties and clinical use.

             J. Devulder (2010)
            Flupirtine is a centrally acting, non-opioid analgesic that is available in a number of European countries for the treatment of a variety of pain states. The therapeutic benefits seen with flupirtine relate to its unique pharmacological properties. Flupirtine displays indirect NDMA receptor antagonism via activation of potassium channels and is the first representative of a pharmacological class denoted the 'selective neuronal potassium channel openers'. The generation of the M-current is facilitated by flupirtine via the opening of neuronal Kv7 potassium channels. The opening of these channels inhibits exaggerated neuronal action potential generation and controls neuronal excitability. Neuronal hyperexcitability is a physiological component of many pain states such as chronic pain, migraine and neurogenic pain. Although large-scale clinical trials are lacking, the clinical trial database available to date from smaller-scale studies, together with extensive clinical experience, indicate that flupirtine effectively reduces chronic musculoskeletal pain, migraine and neuralgias, amongst other types of pain. In addition, flupirtine produces, at recommended clinical doses, muscle-relaxing effects in the presence of abnormally increased muscle tension. Its analgesic and muscle-relaxant properties were comparable to tramadol and chlormezanone, respectively, in two prospective trials in patients with lower back pain. Cytoprotective, anti-apoptotic and antioxidant properties have also been associated with flupirtine use in a small number of studies to date. When provided as combination therapy with morphine, flupirtine increases the antinociceptive activity of morphine 4-fold. Flupirtine displays superior tolerability when compared with tramadol and pentazocine. The most common adverse effects associated with flupirtine use are drowsiness, dizziness, heartburn, dry mouth, fatigue and nausea. With respect to its molecular structure, mechanism of action and adverse event profile, flupirtine is a unique drug. Flupirtine is an analgesic with many potential therapeutic benefits that may prove useful in the treatment of many disease states.
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              Concomitant facilitation of GABAA receptors and KV7 channels by the non-opioid analgesic flupirtine.

              Flupirtine is a non-opioid analgesic that has been in clinical use for more than 20 years. It is characterized as a selective neuronal potassium channel opener (SNEPCO). Nevertheless, its mechanisms of action remain controversial and are the purpose of this study. Effects of flupirtine on native and recombinant voltage- and ligand-gated ion channels were explored in patch-clamp experiments using the following experimental systems: recombinant K(IR)3 and K(V)7 channels and α3β4 nicotinic acetylcholine receptors expressed in tsA 201 cells; native voltage-gated Na(+), Ca(2+), inward rectifier K(+), K(V)7 K(+), and TRPV1 channels, as well as GABA(A), glycine, and ionotropic glutamate receptors expressed in rat dorsal root ganglion, dorsal horn and hippocampal neurons. Therapeutic flupirtine concentrations (≤10 µM) did not affect voltage-gated Na(+) or Ca(2+) channels, inward rectifier K(+) channels, nicotinic acetylcholine receptors, glycine or ionotropic glutamate receptors. Flupirtine shifted the gating of K(V)7 K(+) channels to more negative potentials and the gating of GABA(A) receptors to lower GABA concentrations. These latter effects were more pronounced in dorsal root ganglion and dorsal horn neurons than in hippocampal neurons. In dorsal root ganglion and dorsal horn neurons, the facilitatory effect of therapeutic flupirtine concentrations on K(V)7 channels and GABA(A) receptors was comparable, whereas in hippocampal neurons the effects on K(V)7 channels were more pronounced. These results indicate that flupirtine exerts its analgesic action by acting on both GABA(A) receptors and K(V)7 channels. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2017
                01 December 2017
                : 11
                : 3441-3448
                Affiliations
                Technical Center for Clinical Pharmacy, Department of Drug Clinical Trail Management Agency, General Hospital of Shenyang Military Area Command, Shenyang, China
                Author notes
                Correspondence: Yunbiao Tang, Technical Center for Clinical Pharmacy, Department of Drug Clinical Trail Management Agency, General Hospital of Shenyang Military Area Command, No 83 Wenhua Road, Shenyang 110840, China, Tel +86 1 337 282 8008, Email tangyb99@ 123456163.com
                Article
                dddt-11-3441
                10.2147/DDDT.S149913
                5716300
                © 2017 Liu et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Original Research

                Pharmacology & Pharmaceutical medicine

                flupirtine, d-13223, lc-ms/ms

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