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.     

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

The aim of this study was to determine the analgesic effects of pregabalin (a third-generation antiepileptic drug) using the acute thermal pain model (hot-plate test) in mice. Linear regression analysis was used to evaluate a dose-response relationship between logarithms of pregabalin doses and their resultant maximum possible antinociceptive effects (MPAE) using the hot-plate test in mice. From the linear equation of the dose-response relationship, doses of pregabalin that increased antinociceptive effects by 20%, 30%, 40%, and 50% were calculated and amounted to 9.33, 24.80, 65.93, and 175.26 mg/kg, respectively. In conclusion, pregabalin produces analgesic effects in a dose-dependent manner, as demonstrated using the hot-plate test in mice.     

Tramadol interaction with fluoxetine: An isobolographic analysis

Tramadol, a weak opioid agonist with effects on adrenergic and serotonergic neurotransmission, is used to treat conditions varying from postoperative to chronic malignant pain. Additionally, selective serotonin reuptake inhibitors (SSRIs) are used as adjuvants or prophylactics for the associated residual pain component. The present work evaluates, by isobolographic analysis, the interaction between a combination of racemic (±) tramadol, an opioid agonist, and fluoxetine, an SSRI, using a chemical analgesiometric test (abdominal writhing). Intraperitoneal administration of both tramadol (0.5–20 mg/kg) and fluoxetine (5–40 mg/kg) produced dose‐dependent antinociception. Co‐administration of fixed ratios of ED₅₀ fractions of fluoxetine and tramadol resulted in an additive effect. However, the least dose of fluoxetine (2.1 mg/kg) and tramadol (0.21 mg/kg) used in fixed ratios for antinociceptive effect individually showed antidepressant activity in a modified Porsolt forced swim test. The interaction studies in the writhing test suggested that such combinations might be devoid of any additional advantage over the individual drug regimen in acute cases of pain with co‐morbidity of depression. Further, the nature of interaction for such combinations in chronic pain models needs further assessment. Drug Dev. Res. 61:79‐85, 2004. © 2004 Wiley‐Liss, Inc.     

Interactions of tiagabine with ethosuximide in the mouse pentylenetetrazole-induced seizure model: an isobolographic analysis for non-parallel dose-response relationship curves

The aim of this study was to characterize the interaction between tiagabine (TGB) and ethosuximide (ETS), two antiepileptic drugs, in pentylenetetrazole (PTZ)-induced clonic seizures in mice using isobolographic analysis. The nature of the interaction between the drugs administered in combination was ascertained by estimating plasma and brain concentrations of ETS and TGB using fluorescence polarization immunoassay (FPIA) and high-performance liquid chromatography (HPLC). The results indicated that both drugs produced clear anticonvulsant effects against PTZ-induced clonic seizures in mice, but that their dose-response relationship curves (DRRCs) were not parallel, consequently necessitating the isobolographic analysis for non-parallel DRRCs. The isobolographic analysis revealed that the combination of TGB with ETS at the fixed-ratio of 1:1 exerted an additive interaction against PTZ-induced clonic seizures in mice. FPIA documented that TGB significantly elevated brain ETS concentrations (by 64%), while having no effect on plasma ETS concentrations in experimental animals. In contrast, ETS had no significant impact on plasma and brain concentrations of TGB in mice, as measured by HPLC. It can be concluded that the additive interaction between TGB and ETS at the fixed-ratio of 1:1 in the PTZ test was complicated by a significant pharmacokinetic increase in total brain ETS concentrations. At present, there are no recommendations to use this drug combination in epileptic patients.     

Synergistic interaction of gabapentin and oxcarbazepine in the mouse maximal electroshock seizure model--an isobolographic analysis

The anticonvulsant effects produced by mixtures of oxcarbazepine and gabapentin (two second-generation antiepileptic drugs) in numerous fixed-ratio combinations of 1:1, 1:2, 1:5, 1:10, 1:15, and 1:20 were examined isobolographically in the mouse maximal electroshock seizure model. Results displayed that mixtures of both drugs at the fixed-ratios of 1:2, 1:5, 1:10, 1:15, and 1:20 exerted supra-additive (synergistic) interactions against electroconvulsions. Only a fixed-ratio of 1:1 was indifferent with isobolography, although the combination displayed the trend towards supra-additivity. Furthermore, the combinations of oxcarbazepine with gabapentin, administered at their median effective doses (ED(50 mix)s), did not alter motor performance of animals challenged with the chimney test. Additionally, neither gabapentin nor oxcarbazepine affected total brain concentrations of co-administered drug, indicating a pharmacodynamic nature of interaction between these antiepileptics. Finally, based on preclinical data presented here the combination of oxcarbazepine and gabapentin is of particular importance for further therapy in patients with refractory partial seizures.     

Three-dimensional isobolographic analysis of interactions between lamotrigine and clonazepam in maximal electroshock-induced seizures in mice

The anticonvulsant effects of lamotrigine (LTG) and clonazepam (CZP) and combinations thereof against maximal electroshock (MES)-induced seizures in mice were investigated using three-dimensional (3D) isobolographic analysis. With this method, the doses of fixed-ratio combinations of the drugs (1:3, 1:1 and 3:1) that elicited 16, 50 and 84% of the maximum anticonvulsant effect were determined. Additionally, to evaluate the characteristics of interactions observed with 3D isobolography, the brain concentrations of both drugs were verified pharmacokinetically. The 3D isobolographic analysis showed that LTG and CZP combined at the fixed ratios of 3:1 and 1:1 interacted synergistically in the MES test for all anticonvulsant effects between 16% and 84% of maximum. In contrast, the combination of LTG and CZP at the fixed ratio of 1:3 showed only pure additivity for all estimated effects in 3D isobolography. Moreover, none of the examined antiepileptic drugs altered the brain concentrations of the coadministered drug, so the observed interactions in the MES test are of a pharmacodynamic nature. The 3D isobolographic findings suggest that in epilepsy therapy, increased efficacy of seizure control (synergistic interaction) might be achieved by using LTG and CZP in combination. In this study, some important problems and assumptions related to statistical analysis of data in 3D isobolography are discussed.     

Biphasic characteristic of interactions between stiripentol and carbamazepine in the mouse maximal electroshock-induced seizure model: a three-dimensional isobolographic analysis

The anticonvulsant effects produced by stiripentol (STP), carbamazepine (CBZ), and their combination in the maximal electroshock (MES)-induced seizures in mice were investigated using three-dimensional (3D) isobolographic analysis. With 3D isobolography, the combinations of both drugs at the fixed-ratios of 1:3, 1:1, and 3:1 for 16%, 50% and 84% antiseizure effects, respectively, were examined in order to evaluate the preclinical characteristics of the interactions between STP and CBZ. Additionally, to characterize precisely the types of interactions observed in the MES test, free plasma and total brain CBZ concentrations were estimated for all fixed-ratios tested. The 3D isobolographic analysis showed that STP and CBZ combined at the fixed-ratio of 1:3 produced supra-additive (synergistic) interactions in the MES test for the anticonvulsant effects ranging between 16% and 84%. In contrast, the combination of STP with CBZ at the fixed-ratio of 3:1 exerted sub-additive (antagonistic) interactions in 3D isobolography for all antiseizure effects examined in the MES test. Only the combination of STP and CBZ at the fixed-ratio of 1:1 was additive for the investigated effects (16%, 50% and 84%) in 3D isobolography. Pharmacokinetic evaluation of CBZ concentrations revealed that STP increased both free plasma and total brain CBZ concentrations for all fixed-ratio combinations tested (1:3, 1:1 and 3:1). In conclusion, the 3D isobolographic findings suggest that the combination of STP with CBZ exerted biphasic characteristics of interactions in the MES test, despite the pharmacokinetic increase in CBZ content in plasma and brains of experimental animals.     

Synergistic interaction between 4-allyl-1-hydroxy-2-methoxybenzene (eugenol) and diclofenac: An isobolograpic analysis in Wistar rats

Clinical and preclinical research that contributes pain palliation has suggested that drugs favor the expected effects and minimize the adverse effects. Among the most widely used strategies is the combination of analgesic drugs among those in the same group, with those in another group of analgesics or with co-adjuvants (nonanalgesic drugs or elements of traditional medicine). This work aims to evaluate the interaction between eugenol (EUG) and diclofenac (DFC) on nociception in the presence of a noxious stimulus through the formalin test and isobolographic analysis. The results indicate that EUG, DFC, or the combination of both produce an antinociceptive effect in rodents (p ≤ 0.05). Local co-administration of EUG and DFC gave a theoretical effective dose (Z_add) 2,936.27 ± 155.33 μg/kg (p ≤ 0.05) significantly higher as compared to the effective experimental doses (Z_mix) of 866.89 ± 0.02 μg/kg in phase 1 and 292.88 ± 0.05 μg/kg in phase 2, with an interaction index of 0.29 and 0.09, respectively. These data allow concluding that the interaction derived from the joint administration of EUG and DFC, in the rodent at a local level, is synergistic.     

Ellagic acid enhances the antinociceptive action of carbamazepine in the acetic acid writhing test with mice

Context: Ellagic acid (EA) produced antinociceptive and anti-inflammatory effects through the central and peripheral sites of action.

Objective: The objective of the current study was to examine the functional interaction between ellagic acid and carbamazepine (CBZ) on pain.

Materials and methods: Fourteen groups of mice (8–10 each) were used in this study. Pain was induced by intraperitoneal acetic acid in mice (writhing test) and the functional interaction was analyzed using the isobolographic method. EA at doses 0.3, 1, 3, and 10?mg/kg and carbamazepine at doses 3, 10, 20, and 30?mg/kg, alone and also in combination (1/2, 1/4, and 1/8 of the drug’s ED₅₀) were intraperitoneally administered 30?min before acetic acid (0.6% v/v). Then, the abdominal writhes were counted during a 25-min period.

Results: EA (0.3–10?mg/kg, i.p.) and CBZ (3–30?mg/kg, i.p.) inhibited the writhing response evoked by acetic acid. Fifty percent effective dose (ED₅₀) values against this tonic pain were 1.02?mg/kg and 6.40?mg/kg for EA and CBZ, respectively. The antinociception induced by EA showed higher potency than that of carbamazepine. Co-administration of increasing fractional increments of ED₅₀ values of EA and CBZ produced additive interaction against writhing responses, as revealed by isobolographic analysis.

Discussion and conclusion: These results suggest that a combination of carbamazepine and ellagic acid may be a new strategy for the management of neuropathic pain such as what occurs in trigeminal neuralgia, since the use of carbamazepine is often limited by its adverse effects and by reduction of its analgesic effect through microsomal enzyme induction.     

Synergistic interaction between fentanyl and a tramadol: paracetamol combination on the inhibition of nociception in mice

Multimodal analgesic approaches to manage acute and chronic pain are commonly used in humans. Here, we attempted to characterize a synergistic interaction between fentanyl, tramadol, and paracetamol on the inhibition of nociception in a model of visceral pain in mice. The three-drug combined treatment displayed a potent synergistic antinociceptive effect, together with a significant reduction of gastrointestinal transit inhibition. Furthermore, selective μ- and κ-opioid receptor antagonists reversed these synergistic antinociceptive effects, thus suggesting a pivotal role of the opioid system. Overall, this study presents accurate pre-clinical data that might be useful to improve the clinical management of opioid-mediated analgesia.     

加巴喷丁联合西酞普兰滴定治疗慢性偏头痛伴广泛性焦虑障碍临床疗效分析

目的:探讨加巴喷丁联合西酞普兰对慢性偏头痛(CM)伴广泛性焦虑障碍患者的临床疗效、安全性及两药的有效剂量.方法:按照随机数字表法将210例慢性偏头痛患者纳入加巴喷丁联合西酞普兰组(治疗组)105例和托吡酯联合西酞普兰组(对照组)105例,均治疗6个月.分别记录2组患者治疗前及治疗3,6个月后每月发作天数、偏头痛严重程度...     

药物相互作用动力学分析方法及其CoDrug软件

在药物治疗学领域，复方新药的组方筛选和优化，临床联合用药方案的设计与评价，以及中药方剂配伍规律的定量研究，均需要药物相互作用的动力学分析。本结合其专用软件CoDrug，简介了多药物联合应用时优选最佳组份，剂量和比例的权重配方法；分析药物相互作用动态规律的参数法和映射法，以及多指标综合分析法，列出了系统研究药物相互作用动力学的完整方案。     

Pharmacogenetics‐based population pharmacokinetic analysis of gabapentin in patients with chronic pain: Effect of OCT2 and OCTN1 gene polymorphisms

Gabapentin (GAB) is eliminated unchanged in urine, and organic cation transporters (OCT2 and OCTN1) have been shown to play a role in GAB renal excretion. This prospective clinical study aimed to evaluate the genetic polymorphisms effect on GAB pharmacokinetic (PK) variability using a population pharmacokinetic approach. Data were collected from 53 patients with chronic pain receiving multiple doses of GAB. Patients were genotyped for SLC22A2 c.808G>T and SLC22A4 c.1507C>T polymorphisms. Both polymorphisms' distribution followed the Hardy‐Weinberg equilibrium. An one‐compartment model with first‐order absorption and linear elimination best described the data. The absorption rate constant, volume of distribution, and clearance estimated were 0.44 h^?1, 86 L, and 17.3 × (estimated glomerular filtration ratio/89.58)^1.04 L/h, respectively. The genetic polymorphism SLC22A4 c.1507C>T did not have a significant influence on GAB absorption, distribution or elimination. Due to the low minor allelic frequency of SLC22A2 c.808G>T, further studies require higher number of participants to confirm its effect on GAB renal elimination. In conclusion, GAB clinical pharmacokinetics are strongly influenced by renal function and absorption process, but not by the OCTN1 (SLC22A4 c.1507C>T) polymorphism.     

利用PASS软件分析心内科门诊处方药物相互作用

目的 了解门诊处方中出现的药物相互作用情况，评估PASS系统的性能。方法 随机抽取心内科门诊处方2152份，利用PASS系统药物相互作用审查功能对其进行回顾性分析。结果 共有637份处方出现1258次药物相互作用。其中严重者有136次。中度有930次，轻微有192次；发生相互作用的比例与处方药物品种数呈正相关。结论 门诊合理用药水平有待提高，PASS能有效监测药物不良相互作用。     

药物安全性评价研究中供试品的检测与分析

供试品的检测与分析是保证药物非临床安全性评价结果可靠性的关键性因素。本文从药物安全性评价中供试品的含量检测方法验证、取样分析、含量准确性分析、稳定性分析、均匀性分析、分析结果和超标准结果的处理、剩余样品的处理等方面进行了讨论,并提出作者的看法。     

Study of the clomipramine-morphine interaction in the forced swimming test in mice

Tricyclic antidepressant-morphine interactions have been extensively studied on pain tests but less often on tests predictive of antidepressant activity. The effects of clomipramine (CMI) and morphine were tested on the forced swimming test in mice after pretreatment with CMI, morphine or saline. Like CMI, though less so, morphine was significantly active. Morphine pretreatment partially inhibited the effect of CMI irrespective of the morphine pretreatment dose, but reduction of morphine activity by CMI was non-significant. Acquired tolerance to morphine occurred, but not to CMI. The mechanisms at work were discussed. CMI and desmethylclomipramine (DCMI) plasma levels remained the same after morphine pretreatment, ruling out a pharmacokinetic mechanism. The interaction implied involvement of opiate systems. CMI might have been acting on two different opiate receptor populations, one sensitive to morphine pretreatment, the other not. The mechanism of this action seems to be different from that of morphine.     

癫痫伴感染患者体内拉莫三嗪与利福平相互作用分析

目的：探究癫痫伴有细菌感染患者进行抗菌治疗时,拉莫三嗪（LTG）与利福平（RFP）在其体内相互作用对LTG血药浓度以及癫痫症状的影响。方法：通过神经科门诊收集16例伴有混合菌感染的癫痫患者,回顾性分析在LTG抗癫痫治疗方案中添加RFP进行抗菌治疗的临床资料,采用LC-MS/MS法监测拉莫三嗪血清浓度,通过自身前后对照以及多疗程间对比的方法观察在为期约2个月的RFP治疗前、治疗中以及停止治疗后LTG标准化血药浓度（CDR_LTG）、癫痫症状以及发作次数变化。结果： 16例患者的CDR_LTG在RFP抗菌治疗第3天有明显的下降。相比于RFP治疗前,6例患者的CDR_LTG在治疗第6天下降（44.23±15.78）%,9例患者在第14天下降（66.19±15.73）%,两者有显著统计学差异（P=0.020）。1例患者连续服用RFP 42 d后,CDR_LTG可由2.65 μg·mL^-1·kg·mg^-1下降至0.38 μg·mL^-1·kg·mg^-1。单一疗程中,多例患者在RFP治疗3~5 d时出现癫痫发作,7 d后却未见症状加重或发作频率升高;多疗程相互比较,患者发作症状较前一疗程减轻,次数减少。结论： RFP可重复显著地降低癫痫患者体内LTG浓度,此作用随着合用时间延长而显著加强。长期抗菌治疗有助于改善癫痫患者症状以及降低发作次数。     

Acute and chronic effects of three benzodiazepines in the social interaction anxiety test in mice

The effects on active social interaction of acute and chronic dosage with diazepam (1 mg/kg), desmethyldiazepam (2 mg/kg),and chlor-desmethyldiazepam (0.125 mg/kg) were studied in pairs of mice. The mice were tested under either high or low levels of illumination. In all cases acute drug treatment significantly reduced social interaction, but this was not seen with chronic treatment (9 days). Two of the drugs, diazepam and desmethyldiazepam, showed an anxiolytic action, i.e., these drugs resulted in significantly less variation in social interaction with the change in light levels, compared with vehicle-injected controls.     

Additive interaction between peripheral and central mechanisms involved in the antinociceptive effect of diclofenac in the formalin test in rats

It has been proposed that the antinociception of systemic diclofenac is the outcome of peripheral and central actions. Hence, our purpose was to examine if systemic diclofenac is able to achieve effective concentrations at local and spinal sites and to characterize the interaction between its local and spinal actions. Pain was produced in the rat using the formalin test. Oral diclofenac (1-10 mg/kg) reduced formalin-induced pain. The antinociceptive effect of oral diclofenac (10 mg/kg) was abolished by local or spinal administration of either L-NAME (1-100 microg and 1-50 microg) or glibenclamide (12.5-100 microg and 25-75 microg). These results suggest that oral diclofenac achieves effective concentrations producing an antinociceptive effect involving participation of the NO-potassium channel pathway at both, the local and spinal levels. In an additional experimental series, diclofenac was administered either locally (25-200 mug) or spinally (12.5-100 mug), yielding an antinociceptive effect by both routes. Then, diclofenac was given simultaneously by these two routes in a fixed-ratio, and antinociception was assayed. Isobolographic analysis revealed an additive interaction between the local and spinal effects of diclofenac. Hence, our results provide evidence that the overall antinociceptive effect induced by systemic diclofenac is the outcome of central and peripheral mechanisms.