Andreea Farcas, Teodora Balcescu, Laura Anghel, Camelia Bucsa, Cristina Mogoșan
Introduction : Important drug safety issues are evaluated through a referral procedure in the EU by the Pharmacovigilance Risk Assessment Committee (PRAC) within the European Medicines Agency. We aim to describe all safety-related referrals assessed by the PRAC by June 2019. Methods : Publicly available data on safety issues assessed through referral procedures that reached a final decision during July 2012-June 2019 were identified, analyzed and classified according to predefined criteria. Results : Fifty-one safety issues were assessed by PRAC for 45 medicines/combinations/therapeutic classes during this timeframe...
March 18, 2020: Expert Opinion on Drug Safety
Fan Zhang, Shuna Liu, Lu Jin, LiangQinDaoErJi Tang, Xu Zhao, Tianshuo Yang, Yiyue Wang, Binghui Huo, Ruiyu Liu, Han Li
INTRODUCTION: Gout arthritis is an inflammatory disease characterized by severe acute pain. The goal of pharmacological gout arthritis treatments is to reduce pain, and thereby increase the patient's quality of life. The Kv7/M channel activators retigabine and flupirtine show analgesic efficacy in animal models of osteoarthritic pain. We hypothesized that these drugs may also alleviate gout arthritis pain. OBJECTIVE: To determine the effects of retigabine and flupirtine on pain behavior associated with monosodium urate (MSU)-induced gout arthritis...
February 14, 2020: Pharmacology
Dayalan Sampath, Philip M Lam, Maddy Laoprasert, Michael J Diaz, Nicolas Busquet, Andrew M White, Marco I Gonzalez, Yogendra H Raol
BACKGROUND: Hypoxia-ischemia (HI) is the most common cause of brain injury in newborns and the survivors often develop cognitive and sensorimotor disabilities that undermine the quality of life. In the current study, we examined the effectiveness of flupirtine, a potassium channel opener, shown previously in an animal model to have strong anti-neonatal-seizure efficacy, to provide neuroprotection and alleviate later-life disabilities caused by neonatal hypoxic-ischemic injury. METHODS: The rats were treated with a single dose of flupirtine for 4 days following HI induction in 7-day-old rats...
January 2, 2020: Pediatric Research
Ming-Chi Lai, Ray-Chang Tzeng, Chin-Wei Huang, Sheng-Nan Wu
Perampanel (PER) is a selective blocker of AMPA receptors showing efficacy in treating various epileptic disorders including brain tumor-related epilepsy and also potential in treating motor neuron disease. However, besides its inhibition of AMPA-induced currents, whether PER has any other direct ionic effects in different types of neurons remains largely unknown. We investigated the effects of PER and related compounds on ionic currents in different types of cells, including hippocampal mHippoE-14 neurons, motor neuron-like NSC-34 cells and U87 glioma cells...
October 22, 2019: Biomolecules
John Williamson, Tanveer Singh, Jaideep Kapur
This review summarizes the efforts of our laboratories to develop a mechanism-based therapy for the treatment of organophosphate (OP) nerve agent-induced seizures. Organophosphate poisoning can occur during warfare and terrorist attacks and in the civilian sphere because of intentional or unintentional poisoning. Persons exposed to OPs experience seizures. We developed animal models of OP poisoning and then evaluated the effects of OP on excitatory α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated glutamatergic neurotransmission in the hippocampus using patch-clamp electrophysiology...
August 6, 2019: Epilepsy & Behavior: E&B
Abhijit S Nair
No abstract text is available yet for this article.
May 10, 2019: Current Medical Research and Opinion
Robert K Hofstetter, Mahmoud Hasan, Georg M Fassauer, Christian Bock, Abdrrahman S Surur, Steven Behnisch, Christoph W Grathwol, Felix Potlitz, Tobias Oergel, Werner Siegmund, Andreas Link
Supercritical fluid chromatography (SFC) holds the potential to become an orthogonal method to HPLC/UHPLC in xenobiotic metabolism studies, due to its outstanding capacity to simultaneously separate highly similar (as HPLC) and physicochemically different analytes (problematic using HPLC). Paucity of guideline-conform validation, however, has been a major obstacle to clinical application of SFC, even in cases where biotransformation yields chemically dissimilar metabolites that require more than one HPLC method for comprehensive analysis...
April 25, 2019: Journal of Chromatography. A
Abdrrahman S Surur, Christian Bock, Kristin Beirow, Konrad Wurm, Lukas Schulig, Markus K Kindermann, Werner Siegmund, Patrick J Bednarski, Andreas Link
Drug induced liver injury (DILI) and tissue discoloration led to the recent discontinuation of the therapeutic use of the closely related drugs flupirtine and retigabine, respectively. Experience gained with these drugs strongly suggests that heterotetramer, voltage-gated potassium channels 2 and 3 (KV7.2/3) are valid targets for effective treatment of pain and epilepsy. Because the adverse effects are not related to the mechanism of action, it appears promising to investigate chemical modifications of these clinically validated, drug-like leads...
April 16, 2019: Organic & Biomolecular Chemistry
Te-Ling Lu, Wei-Ting Chang, Chee-Hong Chan, Sheng-Nan Wu
Tolvaptan (TLV), an oral non-peptide antagonist of vasopressin V2 receptor, has been increasingly used for managements in patients with hyponatremia and/or syndrome of inappropriate antidiuretic hormone secretion. However, none of the studies have thus far been investigated with regard to its possible perturbations on membrane ion currents in endocrine or neuroendocrine cells. In our electrophysiological study, the whole-cell current recordings showed that the presence of TLV effectively and differentially suppressed the amplitude of delayed rectifier K+ ( I K(DR) ) and M-type K+ current ( I K(M) ) in pituitary GH3 cells with an IC50 value of 6...
2019: Frontiers in Pharmacology
Sigal Kaplan, Birgit Ehlken, Xenia Hamann
OBJECTIVES: This report characterizes flupirtine prescribing patterns before and after the implementation of risk minimization measures (RMM) in Germany as a complementary analysis to support previous study findings. METHODS: A retrospective analysis was conducted using a patient-level longitudinal prescription database (IMS® LRx) in Germany. The study population included patients who were prescribed flupirtine-containing products. One-year periods before (2012) and after (April 2015 - March 2016) RMM implementation were assessed for the following measures: flupirtine use of up to two weeks, flupirtine use when other analgesics are contraindicated, and concomitant use of drugs with a known potential to induce liver injury...
March 13, 2019: Current Medical Research and Opinion
Andreas Link, Christian Bock, Abdrrahman S Surur, Kristin Beirow, Markus K Kindermann, Lukas Schulig, Anja Bodtke, Patrick J Bednarski
The potassium channel openers flupirtine and retigabine have proven to be valuable analgesics or antiepileptics. Their recent withdrawal due to occasional hepatotoxicity and tissue discoloration, respectively, leaves a therapeutic niche unfilled. Metabolic oxidation of both drugs gives rise to formation of electrophilic quinones. These elusive, highly reactive metabolites may induce liver injury in the case of flupirtine and blue tissue discoloration after prolonged intake of retigabine. We examined which structural features can be altered to avoid the detrimental oxidation of the aromatic ring and shift oxidation towards the formation of more benign metabolites...
March 12, 2019: ChemMedChem
Christian Bock, Andreas Link
The highly structurally similar drugs flupirtine and retigabine have been regarded as safe and effective for many years but lately they turned out to exert intolerable side effects. While the twin molecules share the mode of action, both stabilize the open state of voltage-gated potassium channels, the form and severity of adverse effects is different. The analgesic flupirtine caused drug-induced liver injury in rare but fatal cases, whereas prolonged use of the antiepileptic retigabine led to blue tissue discoloration...
February 25, 2019: Future Medicinal Chemistry
Fan Zhang, Yani Liu, Dandan Zhang, Xizhenzi Fan, Decheng Shao, Han Li
Osteoarthritic pain has a strong impact on patients' quality of life. Understanding the pathogenic mechanisms underlying osteoarthritic pain will likely lead to the development of more effective treatments. In the present study of osteoarthritic model rats, we observed a reduction of M-current density and a remarkable decrease in the levels of KCNQ2 and KCNQ3 proteins and mRNAs in dorsal root ganglia (DRG) neurons, which were associated with hyperalgesic behaviors. The activation of KCNQ/M channels with flupirtine significantly increased the mechanical threshold and prolonged the withdrawal latency of osteoarthritic model rats at 3-14 days after model induction, and all effects of flupirtine were blocked by KCNQ/M-channel antagonist, XE-991...
February 13, 2019: Pharmacology
Edmund Cheung So, Ning-Ping Foo, Shun Yao Ko, Sheng-Nan Wu
Bisoprolol (BIS) is a selective antagonist of β₁ adrenergic receptors. We examined the effects of BIS on M-type K⁺ currents (IK(M) ) or erg -mediated K⁺ currents (IK(erg) ) in pituitary GH3, R1220 cells, and hippocampal mHippoE-14 cells. As GH₃ cells were exposed to BIS, amplitude of IK(M) was suppressed with an IC50 value of 1.21 μM. The BIS-induced suppression of IK(M) amplitude was not affected by addition of isoproterenol or ractopamine, but attenuated by flupirtine or ivabradine. In cell-attached current, BIS decreased the open probability of M-type K⁺ (KM ) channels, along with decreased mean opening time of the channel...
February 2, 2019: International Journal of Molecular Sciences
Abdrrahman S Surur, Kristin Beirow, Christian Bock, Lukas Schulig, Markus K Kindermann, Anja Bodtke, Werner Siegmund, Patrick J Bednarski, Andreas Link
Neuronal voltage-gated potassium channels KV 7.2/KV 7.3 are sensitive to small-molecule drugs such as flupirtine, even though physiological response occurs in the absence of ligands. Clinically, prolonged use of flupirtine as a pain medication is associated with rare cases of drug-induced liver injury. Thus, safety concerns prevent a broader use of this non-opioid and non-steroidal analgesic in therapeutic areas with unmet medical needs such as hyperactive bladder or neonatal seizures. With the goal of studying influences of chemical structure on activity and toxicity of flupirtine, we explored modifications of the benzylamino bridge and the substitution pattern in both rings of flupirtine...
January 2019: ChemistryOpen
Madhoosudan A Patil, Brock A Matter, Yogendra H Raol, David W A Bourne, Ryan A Kelley, Uday B Kompella
Flupirtine, a nonopioid analgesic drug, is effective in treating neonatal seizures. However, its brain delivery and pharmacokinetics are unknown in neonatal mammals. The purpose of this study was to determine the pharmacokinetics of flupirtine and the formation of its active metabolite D-13223 in various tissues such as brain in neonate animals. On postnatal day 7, rat pups received 25 mg/kg of flupirtine intraperitoneally. Liver; heart; kidney; lung; spleen; retina; serum; and brain regions hippocampus, cortex, and the remaining brain (devoid of cerebellum) were harvested up to 24-h postdosing...
December 16, 2018: Pharmaceutics
Udo Bonnet, Johanna Cristina Strasser, Norbert Scherbaum
OBJECTIVE: To provide further evidence of dependence on non-opioid analgesics (NOAs). METHODS: Post-hoc-analysis of a cross-sectional study of a ≥ -65-year-old non-demented German general hospital population. Four hundred in-patients (75 ± 6.4 years; 63% females) were included and screened for current and past dependence on NOAs using a structured interview (SKID-I) based on DSM-IV-TR. The addiction section of SKID-I was expanded to the following NOAs: gabapentinoids, acetaminophen, metamizole, flupirtine, and non-steroidal anti-inflammatory drugs (NSAIDs)...
November 11, 2018: Addictive Behaviors
Christian Bock, Kristin Beirow, Abdrrahman S Surur, Lukas Schulig, Anja Bodtke, Patrick J Bednarski, Andreas Link
Flupirtine, an opener of neuronal voltage gated potassium channels (KV7.2/3), has been used as a therapeutic alternative for pain treatment in patients refractory to NSAIDs and opioids. Because flupirtine is associated with rare but fatal drug-induced liver injury that may result from the formation of toxic metabolites upon metabolic oxidation, we synthesized novel derivatives with the goal of identifying equally active and ultimately safer KV7.2/3 channel openers. Four thioether analogues were designed to lack a nitrogen atom that would be a prerequisite for the formation of toxic para-quinone diimines, and form sulfoxide and sulfone metabolites instead...
November 21, 2018: Organic & Biomolecular Chemistry
Robert H Schüchen, Martin Mücke, Milka Marinova, Dmitrij Kravchenko, Winfried Häuser, Lukas Radbruch, Rupert Conrad
Non-opioid analgesics are widely used for pain relief in palliative medicine. However, there is a lack of evidence-based recommendations addressing the efficacy, tolerability, and safety of non-opioids in this field. A comprehensive systematic review and meta-analysis on current evidence can provide a basis for sound recommendations in clinical practice. A database search for controlled trials on the use of non-opioids in adult palliative patients was performed in Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PsycINFO, and EMBASE from inception to 18 February 2018...
December 2018: Journal of Cachexia, Sarcopenia and Muscle
Nadine Theofel, Philipp Möller, Elke Vejmelka, Kerstin Kastner, Sonja Roscher, Stefan Scholtis, Michael Tsokos
Methoxetamine, 3-methoxyphencyclidine or 3-methoxyeticyclidine are arylcyclohexylamines which have been abused in the past. However, the market for new psychoactive substances, in particular for research chemicals, is rapidly growing and new compounds are being regularly explored by users. Abuse can lead to clinical case and in the worst-case scenario to fatalities. We present the fatal case of a 52-year-old man, who was found dead in the bedroom by his fiancé. He had abused N-ethyldeschloroketamine and venlafaxine prior to his death...
October 26, 2018: Journal of Analytical Toxicology
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