Synergistic interaction of pregabalin with the synthetic cannabinoid WIN 55,212-2 mesylate in the hot-plate test in mice: an isobolographic analysis

BackgroundThe aim of the study was to determine the type of interaction between pregabalin (a 3^rd-generation antiepileptic drug) and WIN 55,212-2 mesylate (WIN – a highly potent non-selective cannabinoid CB1 and CB2 receptor agonist) administered in combination at a fixed ratio of 1:1, in the acute thermal pain model (hot-plate test) in mice.MethodsLinear regression analysis was used to evaluate the dose-response relationships between logarithms of drug doses and their resultant maximum possible antinociceptive effects in the mouse hot-plate test. From linear equations, doses were calculated that increased the antinociceptive effect by 30% (ED₃₀ values) for pregabalin, WIN, and their combination. The type of interaction between pregabalin and WIN was assessed using the isobolographic analysis.ResultsResults indicated that both compounds produced a definite antinociceptive effect, and the experimentally-derived ED₃₀ values for pregabalin and WIN, when applied alone, were 29.4 mg/kg and 10.5 mg/kg, respectively. With isobolography, the experimentally derived ED_{30 mix} value for the fixed ratio combination of 1:1 was 5.7 mg/kg, and differed significantly from the theoretically calculated ED_{30 add} value of 19.95 mg/kg (p < 0.01), indicating synergistic interaction between pregabalin and WIN in the hot-plate test in mice.ConclusionsIsobolographic analysis demonstrated that the combination of WIN with pregabalin at a fixed ratio of 1:1 exerted synergistic interaction in the mouse model of acute thermal pain. If the results from this study could be adapted to clinical settings, the combination of WIN with pregabalin might be beneficial for pain relief in humans.     

Synergistic interaction of gabapentin with tiagabine in the hot-plate test in mice: an isobolographic analysis

This study was aimed at determining the analgesic effect of gabapentin and tiagabine, two antiepileptic drugs that were administered alone and in combination at a fixed ratio of 1:1, in the acute thermal pain model (hot-plate test) in mice.Linear regression analysis was used to evaluate the dose-response relationships between logarithms of antiepileptic drug doses and their resultant maximum possible antinociceptive effects in the mouse hot-plate test. From linear equations, we calculated doses that increased the antinociceptive effect by 50% (ED₅₀ values) for gabapentin, tiagabine and their combination. The type of interaction between gabapentin and tiagabine was assessed using the isobolographic analysis.Results indicated that both antiepileptic drugs produced the definite antinociceptive effect, and the experimentally derived ED₅₀ values for gabapentin and tiagabine, when applied alone, were 504.4 mg/kg and 5.67 mg/kg, respectively.With isobolography, the experimentally derived ED_{50 mix} value for the fixed ratio combination of 1:1 was 139.31 mg/kg and significantly differed from the theoretically calculated ED_{50 add} value, which was 255.04 mg/kg (p < 0.05), indicating the synergistic interaction between gabapentin and tiagabine in the hot-plate test in mice.In conclusion, the combination of tiagabine with gabapentin at a fixed ratio of 1:1 exerted a synergistic interaction in the mouse model of nociceptive pain. If the results from this study could be extrapolated to clinical settings, the combination of tiagabine with gabapentin might be beneficial for pain relief in humans.     

Dose-response relationship analysis of vigabatrin doses and their antinociceptive effects in the hot-plate test in mice

This study was aimed at determining the analgesic effects of vigabatrin (VGB, a newer antiepileptic drug) in the acute thermal pain model (hot-plate test) in mice. Linear regression analysis was used to evaluate a dose-response relationship between logarithms of VGB doses and their resultant maximum possible antinociceptive effects (MPAE) in the hot-plate test in mice. From the linear equation of dose-response relationship, doses of VGB that increased the antinociceptive effect by 15%, 20% and 25% were calculated and amounted in this study to 144, 383 and 1,016 mg/kg, respectively. In conclusion, VGB in a dose-dependent manner produces the analgesic effects in mice in the hot-plate test. The method allowing for the calculation of doses of VGB increasing the antinociceptive effects by 15%, 20% and 25% can be readily adapted to preclinical studies because these values perfectly characterize the potency of antiepileptic drugs with respect to suppression of acute thermal pain in mice.     

Characterization of acute adverse-effect profiles of selected antiepileptic drugs in the grip-strength test in mice

The aim of this study was to assess the acute adverse effects (neurotoxic) of several antiepileptic drugs (clonazepam, lamotrigine, oxcarbazepine, phenytoin, phenobarbital and topiramate) by measuring skeletal muscular strength in mice using the grip-strength test. Linear regression analysis of grip-strength in relation to drug dose-response allowed us to determine D₅₀ values, the dosages of antiepileptic drugs that reduced grip-strength in mice by 50% compared to control animals. Each of the antiepileptic drugs studied reduced skeletal muscular strength in mice in a dose-dependent manner. The D₅₀ for clonazepam was 31.7 mg/kg, lamotrigine – 47.7 mg/kg, oxcarbazepine – 87.3 mg/kg, phenobarbital – 128.7 mg/kg, phenytoin – 69.7 mg/kg, and topiramate – 509.5 mg/kg. In conclusion, the grip-strength test can aid in evaluating acute adverse effects of drugs with respect to their influence on muscular strength in experimental animals.     

Medical conditions in fibromyalgia patients and their relationship to pregabalin efficacy: pooled analysis of Phase III clinical trials

Objective: Patients with fibromyalgia demonstrate high rates of comorbid somatic and psychiatric disorders. The current post hoc study analyzed the prevalence of comorbid conditions and their relationship to pregabalin efficacy in patients with fibromyalgia pooled from four Phase III clinical trials.

Methods: Patients diagnosed with fibromyalgia according to the American College of Rheumatology criteria, randomized to placebo or 300, 450, or 600 mg/day pregabalin, and with ≥ 1 postbaseline pain score were included. The frequency of comorbid conditions was obtained from patient-reported, voluntary medical histories. Patients were categorized based on the presence of a medical condition (e.g., irritable bowel syndrome) or a group of medical conditions (e.g., neurological disorders). Two efficacy variables were examined within each comorbid category: endpoint changes from baseline in weekly mean pain diary scores (11-point numeric rating scale) and Patient Global Impression of Change.

Results: A large proportion of patients exhibited concomitant headache, immunological (allergy), gastroesophageal, and/or psychiatric disorders. The efficacy analyses performed on these subgroups of patients, amongst others, showed – with few exceptions – consistent pain reductions of similar magnitude with pregabalin.

Conclusion: Comorbid conditions are common among patients with fibromyalgia and their presence is not associated with altered pregabalin efficacy.     

Centrally mediated antinociceptive effects of cannabinoid receptor ligands in rat models of nociception

The endogenous nonapeptide hemopressin (HE) demonstrates potent block of the cannabinoid subtype-1 (CB1) receptor in vitro and robust antinociception in vivo. The current study evaluated the effects of centrally administered HE in mechanistically distinct pre-clinical rat models of pain—the hot plate test and the hind paw formalin test. The non-subtype selective CB receptor agonist WIN 55,212-2 was tested concurrently as a positive control. In the hot plate test, neither intrathecal (i.t.) HE nor WIN 55,212-2 significantly altered the latency to respond to noxious heat. By contrast, i.t. HE and WIN 55,212-2 significantly reduced pain-related behaviors in the formalin test. Possible HE functionality as a CB1 receptor antagonist at the spinal level was evaluated in the formalin test. Intrathecal pretreatment with HE did not attenuate the antinociceptive effect of i.t. WIN 55,212-2. However, pretreatment with the CB1 receptor antagonist rimonabant did; i.t. rimonabant pretreatment was not antinociceptive. Potential supraspinal antinociceptive activity of HE was also evaluated. Whereas intracerebroventricular (i.c.v.) injection of WIN 55,212-2 reduced pain-related behaviors in the formalin test, interestingly, i.c.v. HE increased behaviors. In the current study, an antinociceptive effect with the CB receptor ligand HE was obtained under the specific condition of tissue injury and not in the uninjured state. Thus, HE could be a useful analgesic peptide with a novel spinal mechanism of action.     

Antinociceptive activitiy of narcotic agonist and partial agonist analgesics and other agents in the tail-immersion test in mice and rats.

The antinociceptive activity of a series of narcotic agonist (morphine-like) and partial agonist (pentazocine-like) agents was assessed in both mice and rats using a tail-immersion nociceptive test. Narcotic agonist agents (diamorphine, etorphine, morphine and pethidine) displayed characteristically steep and parallel log dose-response lines in both species, whether administered peripherally or centrally. The partial agonists examined (cyclazocine, nalorphine and pentazocine) also produced parallel but much shallower log dose-response lines of essentially different slope to the agonists. The claimed pure antagonist naloxone also exhibited low-order antinociceptive activity, with a dose-response line parallel to that of the partial agonists. The tail-immersion test in mice showed specific sensitivity to narcotic agonists and partial agonists, while peripherally acting analgesics (e.g. aspirin, indomethacin, paracetamol and sodium salicylate) were generally inactive. It is therefore suggested that this test would be of particular value in assessing antinociceptive activity of the partial agonist type in small laboratory animals.     

Antinociceptive effects of haloperidol and its metabolites in the formalin test in mice

Rationale Formalin-induced pain is reduced in sigma-1 (σ₁) receptor knockout mice; therefore, we hypothesized that haloperidol and its metabolites I and II, which have affinity for σ₁ receptors, may modulate formalin-induced pain. Results Intraplantar administration of formalin (2.5%) to CD-1 mice produced a biphasic period of pain. Haloperidol (0.03–1 mg/kg, s.c.) and reduced haloperidol (metabolite II, 0.25–8 mg/kg, s.c.) dose-dependently inhibited both phases of formalin-induced pain. Haloperidol metabolite I (4–128 mg/kg, s.c.) also produced dose-dependent antinociception in the second phase of the formalin test, but was less potent and effective against first-phase pain. Haloperidol metabolite III (16 and 128 mg/kg) and (−)sulpiride (200 mg/kg), which have no affinity for σ₁ receptors, did not produce significant antinociception in either phase of the formalin test. The order of potency of the drugs to produce their antinociceptive effect [haloperidol > metabolite II > metabolite I ≫ metabolite III= (−)sulpiride=inactive] correlated with their affinity for σ₁ receptors, but not with their affinity for σ₂ or dopamine D₂ receptors. Naloxone (1 mg/kg, s.c.) did not antagonize the antinociception induced by haloperidol and its metabolites. None of the antinociceptive drugs in the formalin test produced any antinociception in the tail flick test. Conclusion These results suggest that the antinociceptive effect of haloperidol and its metabolites in the formalin test is not due to unspecific/generalised inhibition of nociception or modulation of opioid receptors, and that it may be related, at least partially, to the ability of these drugs to interact with σ₁ receptors.     

天津市某三甲医院关于“取消头孢菌素皮试”的医、护问卷调查及分析

目的：调查天津医科大学总医院医护人员对"取消头孢菌素皮试"的态度和落实"取消头孢菌素皮试"的主要困难。方法：通过"问卷星"平台制作题为《是否取消头孢菌素皮试的问卷调查》的调查问卷,通过微信平台发放,"问卷星"平台回收、提取数据,调查对象为该院的医生和护士。通过对调查对象的基本资料与"取消头孢菌素皮试"态度做单因素卡方检验和二元Logistic回归分析,明确影响"取消头孢菌素皮试"态度的主要因素;对不支持取消皮试的主要顾虑做多选题问卷并做多重响应分析,明确该院对"取消头孢菌素皮试"的主要阻力。结果：收回问卷362份,有效问卷301份,问卷合格率83.15%;支持和不支持"取消头孢菌素皮试"的分别为81份（占比26.9%）和220份（占比73.1%）。单因素卡方检验显示科室和职称有显著差异（P<0.05）。二元Logistic回归分析结果显示,职称为支持"取消头孢菌素皮试"态度的主要影响因素。多重响应分析显示"头孢菌素说明书有皮试要求""既定医疗流程中需做皮试"及"目前没有国家级政策性文件支持头孢菌素不需皮试"是取消头孢菌素皮试面临的主要阻力。结论：该院医护人员对"取消头孢菌素皮试"呈消极态度。药师应积极、准确地向医护人员传递头孢菌素皮试的相关信息,国家出台并强推"取消头孢菌素皮试"的文件,可为落实该项工作提供有力的支持。     

Behavioral modulation of neuronal calcium/calmodulin-dependent protein kinase II activity: differential effects on nicotine-induced spinal and supraspinal antinociception in mice

Recent studies have implicated the involvement of Ca(2+)-dependent mechanisms, in particular calcium/calmodulin-dependent protein kinase II (CaM kinase II) in nicotine-induced antinociception using the tail-flick test. The spinal cord was suggested as a possible site of this involvement. The present study was undertaken to investigate the hypothesis that similar mechanisms exist for nicotine-induced antinociception in the hot-plate test, a response thought to be centrally mediated. In order to assess these mechanisms, i.c.v. administered CaM kinase II inhibitors were evaluated for their effects on antinociception produced by either i.c.v. or s.c. administration of nicotine in both tests. In addition, nicotine's analgesic effects were tested in mice lacking half of their CaM kinase II (CaM kinase II heterozygous) and compare it to their wild-type counterparts. Our results showed that although structurally unrelated CaM kinase II inhibitors blocked nicotine's effects in the tail-flick test in a dose-related manner, they failed to block the hot-plate responses. In addition, the antinociceptive effects of systemic nicotine in the tail-flick but not the hot-plate test were significantly reduced in CaM kinase II heterozygous mice. These observations indicate that in contrast to the tail-flick response, the mechanism of nicotine-induced antinociception in the hot-plate test is not mediated primarily via CaM kinase II-dependent mechanisms at the supraspinal level.