200 research outputs found
Evaluation of cebranopadol, a dually acting nociceptin/orphanin FQ and opioid receptor agonist in mouse models of acute, tonic, and chemotherapy-induced neuropathic pain
Background Cebranopadol (a.k.a. GRT-6005) is a dually
acting nociceptin/orphanin FQ and opioid receptor agonist
that has been recently developed in Phase 2 clinical trials
for painful diabetic neuropathy or cancer pain. It also
showed analgesic properties in various rat models of pain
and had a better safety profile as compared to equi-analgesic
doses of morphine. Since antinociceptive properties
of cebranopadol have been studied mainly in rat models, in
the present study, we assessed analgesic activity of subcutaneous
cebranopadol (10 mg/kg) in various mouse pain
models.
Methods We used models of acute, tonic, and chronic pain
induced by thermal and chemical stimuli, with a particular
emphasis on pharmacoresistant chronic neuropathic pain
evoked by oxaliplatin in which cebranopadol was used
alone or in combination with simvastatin.
Key results As shown in the hot plate test, the analgesic
activity of cebranopadol developed more slowly as compared
to morphine (90-120 min vs. 60 min). Cebranopadol
displayed a significant antinociceptive activity in acute
pain models, i.e., the hot plate, writhing, and capsaicin
tests. It attenuated nocifensive responses in both phases of
the formalin test and reduced cold allodynia in oxaliplatininduced
neuropathic pain model. Its efficacy was similar to that of morphine. Used in combination and administered
simultaneously, 4 or 6 h after simvastatin, cebranopadol
did not potentiate antiallodynic activity of this cholesterollowering
drug. Cebranopadol did not induce any motor
deficits in the rotarod test.
Conclusion Cebranopadol may have significant potential
for the treatment of various pain types, including inflammatory
and chemotherapy-induced neuropathic pain
Impact of feature selection on system identification by means of NARX-SVM
Support Vector Machines (SVM) are widely used in many fields of science, including system identification. The selection of feature vector plays a crucial role in SVM-based model building process. In this paper, we investigate the influence of the selection of feature vector on modelâs quality. We have built an SVM model with a non-linear ARX (NARX) structure. The modelled system had a SISO structure, i.e. one input signal and one output signal. The output signal was temperature, which was controlled by a Peltier module. The supply voltage of the Peltier module was the input signal. The system had a non-linear characteristic. We have evaluated the modelâs quality by the fit index. The classical feature selection of SVM with NARX structure comes down to a choice of the length of the regressor vector. For SISO models, this vector is determined by two parameters: nu and ny. These parameters determine the number of past samples of input and output signals of the system used to form the vector of regressors. In the present research we have tested two methods of building the vector of regressors, one classic and one using custom regressors. The results show that the vector of regressors obtained by the classical method can be shortened while maintaining the acceptable quality of the model. By using custom regressors, the feature vector of SVM can be reduced, which means also the reduction in calculation time
Chemotherapy-induced peripheral neuropathy : part 1 - current state of knowledge and perspectives for pharmacotherapy
Background Despite the increasing knowledge of the etiology of neuropathic pain, this type of chronic pain is resistant to available analgesics in approximately 50% of patients and therefore is continuously a subject of considerable interest for physiologists, neurologists, medicinal chemists, pharmacologists and others searching for more effective treatment options for this debilitating condition. Materials and methods The present review article is the first of the two articles focused on chemotherapy-induced peripheral neuropathy (CIPN). Results CIPN is regarded as one of the most common drug-induced neuropathies and is highly pharmacoresistant. The lack of efficacious pharmacological methods for treating CIPN and preventing its development makes CIPN-related neuropathic pain a serious therapeutic gap in current medicine and pharmacotherapy. In this paper, the most recent advances in the field of studies on
CIPN caused by platinum compounds (namely oxaliplatin and cisplatin), taxanes, vinca alkaloids and bortezomib are summarized. Conclusions The prevalence of CIPN, potential causes, risk factors, symptoms and molecular mechanisms underlying this
pharmacoresistant condition are discussed
Chemotherapy-induced peripheral neuropathy-part 2 : focus on the prevention of oxaliplatin-induced neurotoxicity
Background Chemotherapy-induced peripheral neuropathy (CIPN) is regarded as one of the most common dose-limiting adverse effects of several chemotherapeutic agents, such as platinum derivatives (oxaliplatin and cisplatin), taxanes, vinca alkaloids and bortezomib. CIPN affects more than 60% of patients receiving anticancer therapy and although it is a nonfatal condition, it significantly worsens patientsâ quality of life. The number of analgesic drugs used to relieve pain symptoms in CIPN is very limited and their efficacy in CIPN is significantly lower than that observed in other neuropathic pain types. Importantly, there are currently no recommended options for effective prevention of CIPN, and strong evidence for the utility and clinical efficacy of some previously tested preventive therapies is still limited. Methods The present article is the second one in the two-part series of review articles focused on CIPN. It summarizes the most recent advances in the field of studies on CIPN caused by oxaliplatin, the third-generation platinum-based antitumor drug used to treat colorectal cancer. Pharmacological properties of oxaliplatin, genetic, molecular and clinical features of oxaliplatin-induced neuropathy are discussed. Results Available therapies, as well as results from clinical trials assessing drug candidates for the prevention of oxaliplatininduced neuropathy are summarized. Conclusion Emerging novel chemical structures-potential future preventative pharmacotherapies for CIPN caused by oxaliplatin are reported
Wide-range measurement of thermal preference : a novel method for detecting analgesics reducing thermally-evoked pain in mice
Background: Wide use of oxaliplatin as an antitumor drug is limited by severe neuropathy with pharmacoresistant cold hypersensitivity as the main symptom. Novel analgesics to attenuate cold hyperalgesia and new methods to detect drug candidates are needed. Methods: We developed a method to study thermal preference of oxaliplatin-treated mice and assessed analgesic activity of intraperitoneal duloxetine and pregabalin used at 30 mg/kg. A prototype analgesiameter and a broad range of temperatures (0-45 °C) were used. Advanced methods of image analysis (deep learning and machine learning) enabled us to determine the effectiveness of analgesics. The loss or reversal of thermal preference of oxaliplatin-treated mice was a measure of analgesia. Results: Duloxetine selectively attenuated cold-induced pain at temperatures between 0 and 10 °C. Pregabalintreated mice showed preference towards a colder plate of the two used at temperatures between 0 and 45 °C. Conclusion: Unlike duloxetine, pregabalin was not selective for temperatures below thermal preferendum. It influenced pain sensation at a much wider range of temperatures applied. Therefore, for the attenuation of cold hypersensitivity duloxetine seems to be a better than pregabalin therapeutic option. We propose wide-range measurements of thermal preference as a novel method for the assessment of analgesic activity in mice
Studies on the Activity of Selected Highly Lipophilic Compounds toward hGAT1 Inhibition. Part II
In this paper, we describe the latest results involving molecular modeling and pharmacodynamic studies of the
selected highly lipophilic compounds acting by human GABA transporter 1 (hGAT1) inhibition. The chemical interaction of 17
GABA analogues with a model of hGAT1 is described using the molecular docking method. The biological role of GAT1 is
related to the regulation of GABA level in the central nervous system and GAT1 inhibition plays an important role in the
control of seizure threshold. To confirm that GAT1 can be also a molecular target for drugs used to treat other neurological and
psychiatric diseases (e.g., pain and anxiety), in the in vivo part of this study, potential antinociceptive and anxiolytic-like
properties of tiagabine, a selective GAT1 inhibitor, are described
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