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James Mooney, Scott M Rawls
The efficacy of KCNQ2/3 channel agonists against drug reward has not been defined despite their ability to reduce locomotor-stimulant and dopamine-activating effects of psychostimulants. We tested the hypothesis that flupirtine (FLU) (2.5, 10, 20 mg/kg), a KCNQ2/3 agonist, reduces cocaine (15 mg/kg) conditioned place preference. FLU (20 mg/kg), injected concurrently with cocaine during conditioning, reduced the development of cocaine conditioned place preference. FLU (20 mg/kg) also reduced cocaine locomotor activation without affecting baseline activity...
January 25, 2017: Behavioural Pharmacology
Kenta Teruya, Katsumi Doh-Ura
Although an effective therapy for prion disease has not yet been established, many advances have been made toward understanding its pathogenesis, which has facilitated research into therapeutics for the disease. Several compounds, including flupirtine, quinacrine, pentosan polysulfate, and doxycycline, have recently been used on a trial basis for patients with prion disease. Concomitantly, several lead antiprion compounds, including compound B (compB), IND series, and anle138b, have been discovered. However, clinical trials are still far from yielding significantly beneficial results, and the findings of lead compound studies in animals have highlighted new challenges...
November 11, 2016: Cold Spring Harbor Perspectives in Medicine
Sadanandavalli Retnaswami Chandra, Thomas Gregor Issac, Mariamma Philip, Veeranna Gadad
INTRODUCTION: Prion diseases are protein conformation disorders and neither caused by viroid or virus but is a transmissible particle labeled a prion by Pruisner. Normal prion protein becomes infectious by a different folding, but the triggers are not known. Based on the characteristic brain pathology, they are grouped under spongiform encephalopathy affecting both man and animals. Estimated prevalence is one per million. Creutzfeldt-Jakob disease (CJD) registry from National Institute and Neurosciences (NIMHANS), Bengaluru, reported 69 cases in 30 years...
September 2016: Indian Journal of Psychological Medicine
Riccardo Bientinesi, Cesare Mancuso, Maria Martire, Pier Francesco Bassi, Emilio Sacco, Diego Currò
Voltage-gated type 7 K(+) (KV7 or KCNQ) channels regulate the contractility of various smooth muscles. With this study, we aimed to assess the role of KV7 channels in the regulation of human detrusor contractility, as well as the gene and protein expression of KV7 channels in this tissue. For these purposes, the isolated organ technique, RT-qPCR, and Western blot were used, respectively. XE-991, a selective KV7 channel blocker, concentration-dependently contracted the human detrusor; mean EC50 and Emax of XE-991-induced concentration-response curve were 14...
February 2017: Naunyn-Schmiedeberg's Archives of Pharmacology
Michal Bencze, Michal Behuliak, Anna Vavřínová, Josef Zicha
AIMS: The goal of our study was to reveal the important mechanism(s) responsible for the enhanced contractility of isolated arteries from animals suffering genetic hypertension. MAIN METHODS: Contractile force of endothelium-denuded arteries, modulated by various interventions, was measured by wire myography. KEY FINDINGS: Spontaneously hypertensive rat (SHR) and Wistar-Kyoto rat (WKY) arteries were stimulated by norepinephrine, increased extracellular K(+) or tyramine...
December 1, 2016: Life Sciences
Hiroaki Takagi, Hikaru Hashitani
The modulation of spontaneous excitability in detrusor smooth muscle (DSM) upon the pharmacological activation of different populations of K(+) channels was investigated. Effects of distinct K(+) channel openers on spontaneous action potentials in DSM of the guinea-pig bladder were examined using intracellular microelectrode techniques. NS1619 (10μM), a large conductance Ca(2+)-activated K(+) (BK) channel opener, transiently increased action potential frequency and then prevented their generation without hyperpolarizing the membrane in a manner sensitive to iberiotoxin (IbTX, 100nM)...
October 15, 2016: European Journal of Pharmacology
Ji Eun Yang, Min Seok Song, Yiming Shen, Pan Dong Ryu, So Yeong Lee
KCNQ (KV7) channels are voltage-gated potassium (KV) channels, and the function of KV7 channels in muscles, neurons, and sensory cells is well established. We confirmed that overall blockade of KV channels with tetraethylammonium augmented the mineralization of bone-marrow-derived human mesenchymal stem cells during osteogenic differentiation, and we determined that KV7.3 was expressed in MG-63 and Saos-2 cells at the mRNA and protein levels. In addition, functional KV7 currents were detected in MG-63 cells...
March 18, 2016: International Journal of Molecular Sciences
Paola Nicoletti, Anneke N Werk, Ashley Sawle, Yufeng Shen, Thomas J Urban, Sally A Coulthard, Einar S Bjornsson, Ingolf Cascorbi, Aris Floratos, Thomas Stammschulte, Ursula Gundert-Remy, Matthew R Nelson, Guruprasad P Aithal, Ann K Daly
OBJECTIVE: Flupirtine is a nonopioid analgesic with regulatory approval in a number of European countries. Because of the risk of serious liver injury, its use is now limited to short-term pain management. We aimed to identify genetic risk factors for flupirtine-related drug-induced liver injury (DILI) as these are unknown. MATERIALS AND METHODS: Six flupirtine-related DILI patients from Germany were included in a genome-wide association study (GWAS) involving a further 614 European cases of DILI because of other drugs and 10,588 population controls...
May 2016: Pharmacogenetics and Genomics
D Thapa, V Ahuja, C Dass, S Gombar, A Huria
BACKGROUND: Flupirtine is a unique non-opioid, centrally acting analgesic with muscle relaxant properties. So far no study has evaluated, use of preoperative flupirtine on postoperative morphine sparing effect in patients undergoing total abdominal hysterectomy (TAH). MATERIALS AND METHODS: We performed a prospective, controlled, and randomized study in 50 female patients of American Society of Anesthesiologists physical status I-II, aged between 30 and 60 years scheduled for TAH under general anesthesia (GA)...
January 2016: Saudi Journal of Anaesthesia
Patrick Roberts, Athan Spiros, Hugo Geerts
The current treatment of Parkinson's disease with dopamine-centric approaches such as L-DOPA and dopamine agonists, although very successful, is in need of alternative treatment strategies, both in terms of disease modification and symptom management. Various non-dopaminergic treatment approaches did not result in a clear clinical benefit, despite showing a clear effect in preclinical animal models. In addition, polypharmacy is common, sometimes leading to unintended effects on non-motor cognitive and psychiatric symptoms...
2016: Frontiers in Pharmacology
Elise R Hedegaard, Jacob Johnsen, Jonas A Povlsen, Nichlas R Jespersen, Jeffrey A Shanmuganathan, Mia R Laursen, Steen B Kristiansen, Ulf Simonsen, Hans Erik Bøtker
The voltage-gated KV7 (KCNQ) potassium channels are activated by ischemia and involved in hypoxic vasodilatation. We investigated the effect of KV7 channel modulation on cardiac ischemia and reperfusion injury and its interaction with cardioprotection by ischemic preconditioning (IPC). Reverse-transcription polymerase chain reaction revealed expression of KV7.1, KV7.4, and KV7.5 in the left anterior descending rat coronary artery and all KV7 subtypes (KV7.1-KV7.5) in the left and right ventricles of the heart...
April 2016: Journal of Pharmacology and Experimental Therapeutics
M Giorgi, V De Vito, A Poapolathep, R Rychshanova, M Sgorbini, H Owen
Flupirtine (FLU) is a non-opioid analgesic drug, with no antipyretic or anti-inflammatory effects, used in the treatment of a wide range of pain states in human beings. It does not induce the side effects associated with the classical drugs used as pain relievers. The aim of this study was to evaluate the pharmacokinetic profiles of FLU after IV and PO administration in healthy horses. Six mixed breed adult mares were randomly assigned to two treatment groups using an open, single-dose, two-treatment, two-phase, paired, cross-over design (2 × 2 Latin-square)...
February 2016: Veterinary Journal
Atul Maheshwari, Rachel L Marks, Katherine M Yu, Jeffrey L Noebels
OBJECTIVE: Two monogenic mouse models of childhood absence epilepsy, stargazer and tottering, differ strikingly in their response to N-methyl-d-aspartate (NMDA) receptor blockade. We sought to evaluate the change in interictal relative gamma power as a reliable biomarker for this gene-linked antiepileptic drug (AED) response. METHODS: The effects of AEDs on absolute and relative (to the total) power of frequencies between 2 and 300 Hz were analyzed within the interictal electroencephalogram (EEG) and correlated with antiseizure efficacy in awake behaving stargazer, tottering, and wild-type (WT) littermate control mice...
January 2016: Epilepsia
John M Barrett, Patrick Degenaar, Evelyne Sernagor
Retinitis pigmentosa (RP) is a progressive retinal dystrophy that causes visual impairment and eventual blindness. Retinal prostheses are the best currently available vision-restoring treatment for RP, but only restore crude vision. One possible contributing factor to the poor quality of vision achieved with prosthetic devices is the pathological retinal ganglion cell (RGC) hyperactivity that occurs in photoreceptor dystrophic disorders. Gap junction blockade with meclofenamic acid (MFA) was recently shown to diminish RGC hyperactivity and improve the signal-to-noise ratio (SNR) of RGC responses to light flashes and electrical stimulation in the rd10 mouse model of RP...
2015: Frontiers in Cellular Neuroscience
Dayalan Sampath, Doron Shmueli, Andrew M White, Yogendra H Raol
Current first-line drugs for the treatment of neonatal seizures have limited efficacy and are associated with side effects. Uncontrolled seizures may exacerbate brain injury and contribute to later-life neurological disability. Therefore, it is critical to develop a treatment for neonatal seizures that is effective and safe. In early-life, when the γ-aminobutyric acid (GABA) inhibitory system is not fully developed, potassium channels play an important role in controlling excitability. An earlier study demonstrated that flupirtine, a KCNQ potassium channel opener, is more efficacious than diazepam and phenobarbital for the treatment of chemoconvulsant-induced neonatal seizures...
October 21, 2015: Neuroscience Letters
Vanita Ahuja, Sukanya Mitra, Sunita Kazal, Anju Huria
BACKGROUND AND AIMS: Flupirtine maleate is a centrally acting, non-opioid analgesic with unique muscle relaxant properties as compared to common analgesics. The aim of this study was to compare post-operative analgesic efficacy of flupirtine maleate and ibuprofen in patients undergoing gynaecological ambulatory surgeries. METHODS: This prospective, randomised controlled study was conducted in 60 women of American Society of Anesthesiologists physical status I/II, 18-70 years of age and scheduled to undergo gynaecological ambulatory surgeries...
July 2015: Indian Journal of Anaesthesia
H Burkhardt, M Wehling
Non-opioid analgesics are frequently used to control chronic pain in elderly patients; however some of these drugs show high rates of adverse drug reactions. Among these are significant clinical problems which impede an effective and safe pain control. This review provides recent data concerning non-steroidal anti-inflammatory drugs (NSAID), acetaminophen, metamizol and flupirtin. Due to their risk profile NSAIDs are less appropriate due to high incidence rates and drug-related risk patterns. Acetaminophen, metamizol and flupirtin may be recommended instead; however a shortcoming of acetaminophen in comparison to NSAIDs is its weaker action to control pain...
August 2015: Der Schmerz
Felicia Klinger, Mirnes Bajric, Isabella Salzer, Mario M Dorostkar, Deeba Khan, Daniela D Pollak, Helmut Kubista, Stefan Boehm, Xaver Koenig
BACKGROUND AND PURPOSE: The Kv 7 channel activator flupirtine is a clinical analgesic characterized as 'selective neuronal potassium channel opener'. Flupirtine was found to exert comparable actions at GABAA receptors and Kv 7 channels in neurons of pain pathways, but not in hippocampus. EXPERIMENTAL APPROACH: Expression patterns of GABAA receptors were explored in immunoblots of rat dorsal root ganglia, dorsal horns and hippocampi using antibodies for 10 different subunits...
October 2015: British Journal of Pharmacology
Roland Wörz
BACKGROUND: After an extended series of investigations in animals, healthy volunteers and pain patients with different methods, flupirtine was introduced in 1986 into the German market. Flupirtine has a unique chemical structure and differs in its profile of effects and side effects from established NSAIDs (non-steroidal anti-inflammatory drugs) on the one hand and from opioids on the other hand. In the years after introduction, muscle relaxing effects were observed and experimentally shown...
December 15, 2014: MMW Fortschritte der Medizin
Hanna M Jaeger, Jens R Pehlke, Britta Kaltwasser, Ertugrul Kilic, Mathias Bähr, Dirk M Hermann, Thorsten R Doeppner
N-methyl-D-aspartate receptor (NMDAR) activation induces excitotoxicity, contributing to post-stroke brain injury. Hitherto, NMDAR deactivation failed in clinical trials due to insufficient pre-clinical study designs and drug toxicity. Flupirtine is an indirect NMDAR antagonist being used as analgesic in patients. Taking into account its tolerability profile, we evaluated effects of flupirtine on post-stroke tissue survival, neurological recovery and brain remodeling.Mice were exposed to stroke and intraperitoneally treated with saline (control) or flupirtine at various doses (1-10 mg/kg) and time-points (0-12 hours)...
June 10, 2015: Oncotarget
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