Effect Of Flupirtine Research Articles

A Prospective Randomised Controlled Study of Pre-Emptive Oral Flupirtine on Postoperative Analgesia in Patients Undergoing Abdominal Surgeries Under General Anesthesia

BACKGROUND AND AIMS : Flupirtine is non-opioid, non- NSAID, centrally acting indirect NMDA receptor antagonist. Its analgesic effect is equivalent to NSAIDS and opioids with devoid of their side effects. Abdominal surgeries are the most painful surgeries amongst the surgical procedures. So we did a prospective randomised controlled study to evaluate the pre-emptive analgesic effect of flupirtine for postoperative pain relief in patients undergoing abdominal surgeries. MATERIALS AND METHODS : 60 patients of either sex posted for elective abdominal surgeries were included in this study. These patients were aged between 18 and 60 years with ASA physical status I and II. They were randomly divided into two groups, named group A and group B. Patients in group A received 2 oral placebo capsules and group B patients received 2 flupirtine 100mg capsules orally. Both drugs were administered two hours before the surgery. All patients underwent abdominal surgeries under general anaesthesia. In the postoperative period patients were assessed for intensity of pain using Numerical rating scale, Time to first rescue analgesia, Ramsey sedation score and side effects in the first 24 hours postoperative period. If NRS score ≥ 4, rescue analgesia tramadol 50mg iv was given at 4 hours interval. RESULTS : The mean NRS score was significantly (p = 0.00, p = 0.00) decreased in group B patients for the first 3 hours. The time to first rescue analgesia was significantly high (p=0.00) in flupirtine group patients. 60% of the patients in control group received rescue analgesia in the first hour of postoperative period. The mean RSS score was high in group B patients in the first 3 to 5 hours. Seven patients in flupirtine group were experienced side effects such as giddiness, nausea, vomiting and retrosternal discomfort. CONCLUSION : This study concludes that pre-emptive administration of oral flupirtine 200mg provides effective analgesia in the first 2 to 3 hours of postoperative period in patients undergoing abdominal surgeries with mild to moderate sedation.

Activation of axonal Kv7 channels in human peripheral nerve by flupirtine but not placebo - therapeutic potential for peripheral neuropathies: results of a randomised controlled trial

BackgroundFlupirtine is an analgesic with muscle-relaxing properties that activates Kv7 potassium channels. Kv7 channels are expressed along myelinated and unmyelinated peripheral axons where their activation is expected to reduce axonal excitability and potentially contribute to flupirtine’s clinical profile.Trial designTo investigate the electrical excitability of peripheral myelinated axons following orally administered flupirtine, in-vitro experiments on isolated peripheral nerve segments were combined with a randomised, double-blind, placebo-controlled, phase I clinical trial (RCT).MethodsThreshold tracking was used to assess the electrical excitability of myelinated axons in isolated segments of human sural nerve in vitro and motoneurones to abductor pollicis brevis (APB) in situ in healthy subjects. In addition, the effect of flupirtine on ectopic action potential generation in myelinated axons was examined using ischemia of the lower arm.ResultsFlupirtine (3-30 μM) shortened the relative refractory period and increased post-conditioned superexcitability in human myelinated axons in vitro. Similarly, in healthy subjects the relative refractory period of motoneurones to APB was reduced 2 hours after oral flupirtine but not following placebo. Whether this effect was due to a direct action of flupirtine on peripheral axons or temperature could not be resolved. Flupirtine (200 mg p.o.) also reduced ectopic axonal activity induced by 10 minutes of lower arm ischemia. In particular, high frequency (ca. 200 Hz) components of EMG were reduced in the post-ischemic period. Finally, visual analogue scale ratings of sensations perceived during the post-ischemic period were reduced following flupirtine (200 mg p.o.).ConclusionsClinical doses of flupirtine reduce the excitability of peripheral myelinated axons.Trial registrationClinicalTrials registration is NCT01450865.

Attenuation of methamphetamine induced dopaminergic neurotoxicity by flupirtine: microdialysis study on dopamine release and free radical generation.

Flupirtine is a triaminopyridine derived centrally acting analgetic, which has been found to display neuroprotective effects in models of excitotoxic cell damage, global, and focal ischemia, but no direct interaction with any component of the N-methyl-D-aspartate (NMDA) and glutamate triggered Ca(2+)-channel. Additionally flupirtine shows potent antioxidant effects in isolated mitochondria and cell culture. Work in models of monoamine depletion and neuroleptic induced catalepsy in rats suggests a interaction of flupirtine with the dopaminergic neurotransmitter system as well. This prompted us to examine the effect of flupirtine on methamphetamine toxicity in mice and to investigate the influence on dopamine release and free radical formation in the rat striatum by microdialysis that may explain methamphetamine neurotoxicity. Pretreatment of C57-BL mice with flupirtine (4 x 10 mg/kg) significantly attenuated the striatal dopamine loss after methamphetamine application (4 x 5 mg/kg). In rats, a single injection of 10 mg/kg flupirtine reduced the methamphetamine induced striatal dopamine release by almost 50%, as measured by in vivo microdialysis. Flupirtine, however, did not influence the increase of free radical formation after methamphetamine infusion, which was assayed after infusion of salicylic acid by quantification of 2,3- and 2,5-dihydroxybenzoic acid. This suggests that other mechanisms rather than dopamine metabolism and autoxidation, may contribute to methamphetamine neurotoxicity.

Flupirtine ameliorates ischaemic-like death of rat retinal ganglion cells by preventing calcium influx

The effect of flupirtine on the loss of retinal ganglion cells following transient elevation of intraocular pressure (experimental ischaemia) or NMDA-induced excitotoxicity was studied. Ischaemia (60 min) or intravitreal injection of NMDA (20 nmol) caused a decrease in Thy-1 mRNA and Thy-1 immunoreactivity which are associated with ganglion cells. Administration of flupirtine counteracted these changes. Moreover, flupirtine dose-dependently inhibited NMDA-induced 45 Ca 2+ influx into cultured cortical neurones and retinal pieces in vitro with maximal inhibition being observed at 200 μM. A similar concentration of flupirtine failed to inhibit kainate-stimulated calcium influx into cultured cortical neurones. In addition, flupirtine had no significant effect on [ 3 H ]nitrendipine or [ 3 H ]diltiazem binding to cortical membranes. The present studies are consistent with previous findings which suggested flupirtine to act as a NMDA antagonist by a mechanism that still remains to be clarified.

Effect of flupirtine on cell death of human umbilical vein endothelial cells induced by reactive oxygen species

Flupirtine (KATADOLON®), known as a nonopiate centrally acting analgesic drug, was tested as to its potential to prevent apoptosis of human endothelial cells induced by reactive oxygen species (ROS). It was found that Flupirtine displayed no effect on viability and cell proliferation of human umbilical vein endothelial cells (HUVEC) up to a concentration of 10 μg/mL. Apoptosis, induced by ROS and generated by hypoxanthine/xanthine oxidase (EC 1.1.3.22) (HX/XOD) or t-butyl hydroperoxide, was reduced after preincubation with Flupirtine for 3 hr by 35% and 41%, respectively. The maximal cytoprotective effect against apoptosis was observed at a drug concentration of 1 to 3 μg/mL. Flow cytometric studies revealed that Flupirtine was able to decrease the number of necrotic cells as well as of apoptotic cells. Neither the simultaneous administration of Flupirtine with the apoptosis-inducing agent nor the preincubation of HUVEC with Flupirtine influenced the increase in the intracellular Ca 2+ concentration [Ca 2+] i caused by the production of ROS.

Antiparkinsonian effect of flupirtine in monoamine-depleted rats.

Excitatory amino acid receptor antagonists lead to marked suppression of parkinsonian-like symptoms in rodent and primate models of Parkinson's disease and are able to potentiate the ability of L-DOPA to reverse akinesia and ameliorate muscular rigidity displayed in these animal models. Flupirtine, which is clinically used as a non-opioid analgesic agent, has some N-methyl-D-aspartate (NMDA) antagonistic properties in several in vivo and in vitro experiments. We now report that in monoamine depleted rats (pretreated with reserpine, 5 mg/kg, and alpha-methyl-para-tyrosine, 250 mg/ kg i.p.) flupirtine dose-dependently (1-20 mg/kg i.p.) suppressed rigidity, measured as tonic EMG activity in the gastrocnemius muscle, but had no effect on akinesia, measured as locomotor activity. In addition, it potentiated the antiparkinsonian effect of L-DOPA on akinesia and rigidity in this rodent model of Parkinson's disease. These effects of flupirtine are of particular clinical relevance, since flupirtine is devoid of the typical side effects of NMDA-receptor antagonists.

Influence of flupirtine, a novel nonopioid analgesic agent on somatosensory evoked potentials in rats.

The effect of flupirtine, a novel nonopioid analgesic, on somatosensory evoked potentials (SEP) was investigated in anesthetized rats. Primary somatosensory potentials were evoked in the cerebral cortex by stimulation of the skin of the whiskery part of the face. Flupirtine injected i.p. dose-dependently prolonged the latency and reduced the amplitude of SEP with ID50-values of 5.4 mg/kg (2.6-9.3 mg/kg) and 7.9 mg/kg (3.9-13.8 mg/kg), respectively. This effect of flupirtine (10 mg/kg, i.p.) on the latency and the amplitude of SEP, did not change when naloxone (1 mg/kg, i.p.) was given before flupirtine. The results indicate that the analgesic flupirtine decreases the primary somatosensory evoked potential by diminishing the excitability of cortical neurons. Opioid mechanisms are not involved.

Effects of flupirtine on the pain-related evoked potential and the spontaneous EEG.

Flupirtine is a novel and in all probability centrally acting antinociceptive drug [1]. Its analgesic action was proved in numerous clinical studies [2]. The action of flupirtine is neither mediated by opiate receptor systems nor by serotoninergic mechanisms, but seems to be effected by an activation of the descending noradrenergic pain control system [3, 4]. The aim of the present study was to investigate temporal characteristics of the analgesic effect of flupirtine when tested against placebo.