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1.
Naproxen is an anti‐inflammatory drug used in a variety of anti‐inflammatory syndromes. There is evidence showing that tizanidine enhances the anti‐inflammatory effect in rats. This study examines the pharmacokinetics of naproxen when it is combined with tizanidine. Combining these two drugs is an attractive modality for inflammation complaints. Oral coadministration of naproxen/tizanidine produced a synergistic anti‐inflammatory effect in rats. The swelling of the rat paw was measured by a plethysmometer using carrageenan as an inflammatory agent. In this study, rats received oral doses of naproxen (1, 3, and 4.2 mg/kg), and these doses were combined with a fixed dose of tizanidine (0.01 mg/kg). To evaluate the pharmacokinetic interaction between naproxen/tizanidine, blood samples were obtained at selected times in the 24 h after oral administration and were analyzed using a validated high‐performance liquid chromatography method. Systemic administration of naproxen alone or in combination with tizanidine produced a dose‐dependent anti‐inflammatory effect. In the pharmacokinetic interaction study, no statistically significant difference was observed for the naproxen concentration‐time profiles in the presence of tizanidine. The experimental findings suggest that systemic tizanidine is able to increase the naproxen‐induced anti‐inflammatory effect in rats. This effect was not due to a modification of the bioavailability of naproxen. 相似文献
2.
The aim of the present study was to evaluate the antinoceptive interaction between the opioid analgesic, tapentadol, and the NSAID, ketorolac, in the mouse orofacial formalin test. Tapentadol or ketorolac were administered ip 15 min before orofacial formalin injection. The effect of the individual drugs was used to calculate their ED 50 values and different proportions (tapentadol‐ketorolac in 1:1, 3:1, and 1:3) were assayed in the orofacial test using isobolographic analysis and interaction index to evaluate the interaction between the drugs. The combination showed antinociceptive synergistic and additive effects in the first and second phase of the orofacial formalin test. Naloxone and glibenclamide were used to evaluate the possible mechanisms of action and both partially reversed the antinociception produced by the tapentadol‐ketorolac combination. These data suggest that the mixture of tapentadol and ketorolac produces additive or synergistic interactions via opioid receptors and ATP‐sensitive K + channels in the orofacial formalin‐induced nociception model in mice. Drug Dev Res 78 : 63–70, 2017. © 2016 Wiley Periodicals, Inc. 相似文献
3.
The use of drug combinations to achieve a desired effect is a common practice in pharmacological reaserch and in clinical practice. The present study was designed to evaluate the potential synergistic antinociceptive interactions between tizanidine, an α‐2‐adrenoceptor agonist and tramadol on formalin‐induced nociception in rat using isobolographic analyses. Tramadol (0.1–100 μg/paw) and tizanidine (0.01–10 μg/paw) were injected into the paw prior to formalin injection (1%). Both drugs produced a dose‐dependent antinociceptive effect. The EC 50 values were estimated for individual drugs, and isobolograms were constructed. Tizanidine (EC 50 = 0.125 ± 0.026 μg) was more potent than tramadol (EC 50 = 16.45 ± 6.4 μg). The combination of tramadol‐tizanidine at fixed ratios of 1:1 (EC 50exp = 67.43 ± 11 μg; EC 50teo = 8.28 ± 3.2 μg) and 3:1 (EC 50exp = 31.25 ± 9.49 μg; CE 50teo = 12.36 ± 4.8 μg) generated subadditivity (antagonism). On the basis of the current preclinical data, the pharmacological profile of the combination of tramadol‐tizanidine produced antagonism. Thus, the utmost caution is required during the use of this combination in clinical practice, due to their antagonistic interaction. 相似文献
4.
The aim of this experimental assay was to assess the antinociceptive interaction between tapentadol and ketorolac in the acetic acid‐induced writhing model in mice. Tapentadol (5.62–31.6 mg/kg ip) or ketorolac (5.62–31.6 mg/kg ip) were administered 15 min before the acetic acid administration. The ED 50 values of the individual drugs were determined and different proportions (tapentadol–ketorolac in 1:1, 3:1, and 1:3) were assayed in combination in the writhing test. Isobolographic analysis and the interaction index demonstrated an antinociceptive synergistic interaction between tapentadol and ketorolac in all combination. Thus, the experimental ED 50 values were lower when compared with their theoretical ED 50 values. These data suggest that the tapentadol–ketorolac combination produces an antinociceptive synergistic interaction in the mouse acetic acid‐induced writhing model. Drug Dev Res 77 : 187–191, 2016. © 2016 Wiley Periodicals, Inc. 相似文献
5.
Metformin‐dependent mechanisms have been implicated in the antinociceptive effect of some non‐steroidal anti‐inflammatory drugs (NSAIDs). In this study, the effect of local peripheral or systemic administration of metformin on the local peripheral or systemic antinociception induced by indomethacin, ketorolac and metamizole was assessed in the rat carrageenan‐induced thermal hyperalgesia model. Rats were injected with carrageenan (1%, 50 µl) into the right hindpaw which reduced paw withdrawal latency, a measure of thermal hyperalgesia. Local peripheral or systemic administration of indomethacin, ketorolac or metamizole dose‐dependently reduced carrageenan‐induced thermal hyperalgesia. Local peripheral pre‐treatment with metformin (800 µg/paw) partially inhibited the anti‐hyperalgesic effect of indomethacin (200 µg/paw) and metamizole (200 µg/paw), but not that of ketorolac (200 µg/paw). In contrast, systemic pre‐treatment with metformin (200 mg/kg) attenuated the antihyperalgesic effect of metamizole (10 mg/kg), but not that observed with either indomethacin (10 mg/kg) or ketorolac (10 mg/kg). These findings suggest that some but not all NSAIDs have effects mediated by metformin‐dependent mechanisms. Drug Dev Res 78 : 98–104, 2017. ©2017 Wiley Periodicals, Inc. 相似文献
6.
Treatment of neuropathic pain is an area of largely unmet medical need. Pregabalin and gabapentin are anticonvulsants widely used for the treatment of neuropathic pain. Unfortunately, these drugs are only effective in 50–60% of the treated patients. In addition, both drugs have substantial side effects. Several studies have reported that ultralow doses of opioid receptor antagonists can induce analgesia and enhance the analgesic effect of opioids in rodents and humans. The objective of the present study was to assess the antiallodynic synergistic interaction between gabapentinoids and naltrexone in rats. Oral administration of pregabalin (ED 50 = 2.79 ± 0.16 mg/kg) or gabapentin (ED 50 = 21.04 ± 2.87 mg/kg) as well as intrathecal naltrexone (ED 50 = 0.11 ± 0.02 ng) reduced in a dose‐dependent manner tactile allodynia in rats. Maximal antiallodynic effects (∼100%) were reached with 30 mg/kg of pregabalin, 300 mg/kg of gabapentin or 0.5 ng of naltrexone. Co‐administration of pregabalin or gabapentin and naltrexone in a fixed‐dose ratio (1:1) remarkably reduced spinal nerve ligation‐induced tactile allodynia showing a synergistic interaction. The data indicate that combinations of pregabalin or gabapentin and ultra‐low doses of naltrexone are able to reduce tactile allodynia in neuropathic rats with lower doses that those used when drugs are given individually and with an improved side effects profile. Drug Dev Res 78 : 371‐380, 2017. © 2017 Wiley Periodicals, Inc. 相似文献
7.
The coadministration of non‐steroidal anti‐inflammatory drugs (NSAIDs) with medicinal plant extracts may increase anti‐inflammatory activity, thus permitting the use of lower NSAID doses and limiting the side effects. The aim of this study was to explore the interactions between an ethanolic extract of M. chamomilla extract (MCE) with two NSAIDs, diclofenac and indomethacin on carrageenan‐induced paw inflammation and gastric injury in rats. Diclofenac, indomethacin and MCE, or combinations with MCE produced an anti‐inflammatory effect. Effective dose (ED) values were estimated for the individual drugs, and isobolograms were constructed. The final experimental ED values were 483.7 mg/kg for diclofenac + MCE combination, and 212.6 mg/kg for indomethacin + MCE. These values were lower (p < 0.05) than the theoretical ED values (1186.9 mg/kg for diclofenac + MCE combination, and 1183.8 mg/kg for indomethacin + MCE). These data suggest that the interactions between NSAIDs and MCE that mediate the anti‐inflammatory effects at the systemic level are synergistic and may have therapeutic advantages for the clinical treatment of inflammatory processes. Drug Dev Res 78 : 360‐367, 2017. © 2017 Wiley Periodicals, Inc. 相似文献
8.
The current work evaluates the interaction between two commonly used drugs, tramadol (Tra) and gabapentin (Gbp). Dose‐response curves (DRC) and isobolographic analysis were used to confirm their synergistic antihyperalgesic and anti‐allodynic responses in a rat neuropathic pain model involving chronic constriction injury of the sciatic nerve and in von Frey and acetone tests. Tra and Gbp produced dose‐dependent antihyperalgesic and anti‐allodynic effects. Dose‐response studies of combinations of Tra and Gbp in combination showed the DRC was leftward‐shifted compared to the DRCs for each compound alone. One combination demonstrated both antihyperalgesic and anti‐allodynic effects greater than those observed after individual administration. The remaining combinations demonstrated an additive effect. The Tra+Gbp combination demonstrated a potentiative effect with smaller doses of Tra. Additionally, it was determined lethal dose 50 (LD 50) of Tra alone and tramadol + Gbp 10 using mice to 48 h post administration. The DRC (death) were similar for Tra alone and in Tra in combination, despite the improved effectiveness of Tra in the presence of GBP, 10 mg/kg. A combination of these drugs could be effective in neuropathic pain therapy because they can produce potentiative (at a low dose) or additive effects. Drug Dev Res 77 : 217–226, 2016. © 2016 Wiley Periodicals, Inc. 相似文献
9.
| Preclinical Research & Development | The combination of nonsteroidal anti‐inflammatory drugs (NSAIDs) with herbal products having analgesic and anti‐inflammatory effects may increase their beneficial effects and limit their side effects. In this study, the effects of an interaction between α‐bisabolol and the NSAID, diclofenac on nociception (formalin test), inflammation (paw inflammation produced by carrageenan) and gastric injury in rat was assessed. Diclofenac, α‐bisabolol, or diclofenac–α‐bisabolol combinations produced antinociceptive and anti‐inflammatory effects in rat ( p < .05). The systemic administration of diclofenac, but not α‐bisabolol, produced gastric damage while the diclofenac–α‐bisabolol combinations produced limited gastric damage. Effective dose (ED 40) values were determined for each individual drug and analyzed isobolographically. The theoretical ED 40 values for the antinociceptive (98.89 mg/kg) and the anti‐inflammatory (41.2 mg/kg) effects differed from the experimental ED 40 values (antinociception: 38.7 mg/kg and anti‐inflammation: 13.4 mg/kg). We concluded that the interactions between diclofenac and α‐bisabolol are synergistic. These data suggest that the diclofenac–α‐bisabolol combinations can interact to produce minor gastric damage, thereby offering a safer therapeutic alternative for the clinical management of inflammation and/or inflammatory pain. 相似文献
10.
Gabapentin is an anticonvulsant used to treat neuropathic pain. Mangiferin is an antioxidant that has antinociceptive and antiallodynic effects in inflammatory and neuropathic pain models. The purpose of this study was to determine the interaction between mangiferin and gabapentin in the development and maintenance of formalin‐induced secondary allodynia and hyperalgesia in rats. Gabapentin, mangiferin, or their fixed‐dose ratio combination were administrated peripherally. Isobolographic analyses was used to define the nature of the interaction of antiallodynic and/or antihyperalgesic effects of the two compounds. Theoretical ED 50 values for the combination were 74.31 µg/paw and 95.20 µg/paw for pre‐ and post‐treatment, respectively. These values were higher than the experimental ED 50 values, 29.45 µg/paw and 37.73 µg/paw respectively, indicating a synergistic interaction in formalin‐induced secondary allodynia and hyperalgesia. The antiallodynic and antihyperalgesic effect induced by the gabapentin/mangiferin combination was blocked by administration of L‐NAME, the soluble guanylyl cyclase inhibitor, ODQ and glibenclamide. These data suggest that the gabapentin‐ mangiferin combination produces a synergistic interaction at the peripheral level. Moreover, the antiallodynic and hyperalgesic effect induced by the combination is mediated via the activation of an NO‐cyclic GMP‐ATP‐sensitive K + channel pathway. Drug Dev Res 78 : 390‐402, 2017. © 2017 Wiley Periodicals, Inc. 相似文献
11.
| Preclinical Research & Development | The objective of the present study was to evaluate the tapentadol–diclofenac combination in three dose‐ratios in the mouse acetic acid‐induced visceral pain and their ulcerogenic activity on the stomachal mucous. Dose‐response curves were generated for tapentadol, diclofenac, and their combination in the acetic acid‐induced writhing test in mice. Moreover, the stomachs of animals were surgically removal and gastrointestinal ulcerogenic action of the combination was assessed. The isobolographic analysis, interaction index, and ANOVA were used to analyze the data. The isobolographic analysis and interaction index showed a similar antinociceptive activity for the three combinations of the analgesic mixture. Moreover, tapentadol and the proportions 1:1 or 3:1 of the analgesic combination caused a mild gastrointestinal damage. These data indicate that the systemic co‐administration of tapentadol and diclofenac produced a synergistic interaction in the acetic acid‐induced visceral pain test with an acceptable gastric damage profile in mice. 相似文献
12.
Diclofenac and tramadol are drugs widely used for the treatment of pain. However, side effects may limit their use. As both drugs produce side effects that are dose‐dependent, it seems appropriate to combine them in order to reduce the requirements for efficacy and, consequently, side effects. The purpose of this study was to evaluate the possible synergistic effect of these drugs in three experimental models of nociception in the rat. Dose‐response curves for diclofenac and tramadol were constructed in three models, thermal hyperalgesia, formalin, and hot plate. From these curves, ED 40 or ED 30 (according to the model employed) values were obtained and isobolographic analyses were carried out based on 0.5:0.5 proportions. Synergistic interactions were observed in the thermal hyperalgesia and hot plate models and an additive interaction was obtained in the formalin test. These results suggest a good therapeutic potential of this combination in the treatment of pain. Drug Dev Res 72: 391–396, 2011. © 2011 Wiley‐Liss, Inc. 相似文献
13.
The present study was designed to evaluate the possible antinociceptive interaction between diacerhein and some antiepileptic drugs (carbamazepine, topiramate and gabapentin) on formalin‐induced nociception. Diacerhein, each of the antiepileptics or a fixed dose‐ratio combination of these drugs was assessed after local peripheral and oral administration in rats. lsobolographic analyses were used to define the interaction between drugs. Diacerhein, antiepileptic drugs (carbamazepine, topiramate and gabapentin) or their combinations yielded a dose‐dependent antinociceptive effect when administered by both routes. Theoretical ED 30 values for the combination estimated from the isobolograms were obtained as follows: diacerhein‐carbamazepine (85.99 ± 7.07 μg/paw; 56.53 ± 4.56 mg/kg po), diacerhein‐topiramate (197.97 ± 22.90 μg/paw; 13.06 ± 2.44 mg/kg po) and diacerhein‐gabapentin (96.87 ± 17.73 μg/paw; 17.90 ± 4.70 mg/kg p.o.) for the local peripheral and oral administration routes, respectively. These values were significantly higher than the experimentally obtained ED 30 values: diacerhein‐carbamazepine (49.33 ± 3.37 μg/paw; 35.49 ± 7.91 mg/kg po), diacerhein‐topiramate (133.00 ± 39.10 μg/paw; 8.87 ± 1.46 mg/kg po) and diacerhein‐gabapentin (70.98 ± 14.73 μg/paw; 10.95 ± 3.23 mg/kg po). The combinations produced their antinociceptive effects without motor impairment in the rotarod test indicating synergistic interactions with a good side effect profile. 相似文献
14.
The aim of this work was to evaluate the effect of docosahexaenoic acid (DHA) on the pharmacokinetics and pharmacodynamics—nociception—of naproxen in rats, as well as to determine the gastric safety resulting from this combination versus naproxen alone. Female Wistar rats were orally administered DHA, naproxen or the DHA‐naproxen mixture at fixed‐ratio combination of 1:3. The antinociceptive effect was evaluated using the formalin test. The gastric injury was determined 3 h after naproxen administration. An isobolographic analysis was performed to characterize the antinociceptive interaction between DHA and naproxen. To determine the possibility of pharmacokinetic interactions, the oral bioavailability of naproxen was evaluated in presence and absence of oral DHA. The experimental effective dose ED 30 values ( Zexp ) were decreased from theoretical additive dose values ( Zadd ; P < 0.05). The isobolographic analysis showed that the combination exhibited supra‐additive interaction. The oral administration of DHA increased the pharmacokinetic parameter AUC 0‐t of naproxen ( P < 0.05). Furthermore, the gastric damage induced by naproxen was abolished when this drug was combined with DHA. These data suggest that oral administration of DHA‐naproxen combination induces gastric safety and supra‐additive antinociceptive effect in the formalin test so that this combination could be useful to management of inflammatory pain. Drug Dev Res 78 : 332‐339, 2017. © 2017 Wiley Periodicals, Inc. 相似文献
15.
Drug combinations are routinely used in the treatment of pain. In drug associations, adjuvants such as caffeine, are employed with different non‐steroidal anti‐inflammatories drugs (NSAIDs), however, at present does not exist studies showing the effect of the combination of racemic flurbiprofen ( rac‐Flur) in association with caffeine. The objective of this work was to evaluate the combination of rac‐Flur + caffeine oral in arthritic gout‐type pain in rats. The antinociceptive effects of the rac‐Flur alone and in combination with caffeine were analyzed on a pain‐induced functional impairment model in rat. rac‐Flur induced a dose‐dependent antinociceptive effect and caffeine did not present any effect. The combination of rac‐Flur and caffeine achieve a higher percentage of antinociceptive effect compared with the individual administration of rac‐Flur. The dose‐response curve (DRCs) shows that the combination of rac‐Flur (31.6 mg/kg) + caffeine (17.8 mg/kg) exhibited the maximal antinociceptive efficacy (294.0 ± 21.2 area units), while rac‐Flur alone (31.6 mg/kg) showed 207.2 ± 35.2 au, thus indicating an increase in efficacy (potentiation). Furthermore, the DRCs of the combinations presented a displacement to the left, indicating a change in the potency. Caffeine is able to increase the effect of rac‐Flur in the arthritic gout‐type pain in rats. Drug Dev Res 77 : 192–198, 2016. © 2016 Wiley Periodicals, Inc. 相似文献
16.
The aim of the present study was to analyze the antihyperalgesic and antiallodynic interaction between the non‐selective cholecystokinin (CCK) antagonist receptor, proglumide, and the selective cyclooxygenase‐2 inhibitor, celecoxib in streptozotocin (STZ)‐induced diabetic rats. Hyperalgesia was evaluated in the formalin test and tactile allodynia using von Frey filaments. Isobolographic analyses were employed to define the nature of the compound interactions, using a fixed dose ratio (0.5:0.5). Proglumide (20–160 mg/kg) and celecoxib (0.3–30 mg/kg) in these fixed dose ratio combinations induced dose‐dependent antihyperalgesia and an antiallodynic effect in diabetic rats. ED 40 values were calculated for the treatments and an isobologram was constructed. Theoretical ED 40 values for combination proglumide–celecoxib estimated from the isobolograms for antihyperalgesic and antiallodynic activity (30.50 ± 1.90 mg/kg and 45.81 ± 4.55 mg/kg, respectively) were obtained, while experimental ED 40 values for this antihyperalgesic and antiallodynic combined effect (13.83 ± 0.65 mg/kg and 17.74 ± 3.57 mg/kg; respectively) were significantly different. Coadministration of proglumide–celecoxib showed an interaction index value of 0.45 ± 0.03 for the antihyperalgesic effect and 0.39 ± 0.08 for the antiallodynic activity, indicating a synergistic interaction. These data suggest that proglumide and celecoxib can interact synergistically to reduce hyperalgesic and allodynic behaviors in diabetic neuropathy. This combination could be useful to treat neuropathic pain in diabetic patients. Drug Dev Res 78 : 116–123, 2017. ©2017 Wiley Periodicals, Inc. 相似文献
17.
The purpose of this study was to evaluate the antinociceptive interaction between acetaminophen and lysine clonixinate in the formalin test, and the possible role of opioidergic and nitric oxide pathways in the interaction. The effect of individual drugs and their combination was evaluated using the 3% formalin test in mice. Acetaminophen (31.6, 100, 178, and 316 mg/kg, i.p.) or lysine clonixinate (5.6, 10, 17.8, and 31.6 mg/kg, i.p.) were administered 10 min before formalin injection. To assess the possible mechanism(s) of action for the combination, naloxone (1 mg/kg) and N (G)‐nitro‐L‐arginine methyl ester (L‐NAME) (3 mg/kg) were used. Isobolographic analysis and the interaction index showed a synergistic effect. The experimental ED 30 was lower when compared with theoretical ED 30. Naloxone, but not L‐NAME, reduced the antinociceptive effect of the combination. Administration of antagonists alone did not modify formalin‐induced nociception. These data suggest that the acetaminophen–lysine clonixinate combination produces a synergistic effect involving opioid receptors. 相似文献
18.
| Preclinical Research & Development | Current drugs for obesity treatment have limited efficacy and considerable adverse effects. Combination of drugs with complementary mechanisms of action at lower doses may produce a greater efficacy with a better safety profile. This study was designed to assess the anorectic effect and safety of a diethylpropion + topiramate mixture in rats. The anorectic effect of drugs was measured using a sweetened milk consumption model, and the corresponding interaction was determined by isobolographic analysis, interaction index and confidence intervals. Additionally, blood pressure was measured using a sphygmomanometer in the rat tail. Diethylpropion and topiramate alone or in combination increased the anorectic effect in a dose‐dependent fashion in either nondeprived or 12 hr food‐deprived rats. All theoretical ED 30 values of diethylpropion + topiramate combinations at 1:1, 1:3, and 3:1 dose ratios were significantly higher than experimental ED 30 values. In addition, interaction indices and confidence intervals confirmed the potentiation between both drugs. Theoretical ED 30 of diethylpropion + topiramate combination did not affect the blood pressure. Data suggests that low doses of the diethylpropion + topiramate combination can potentiate the anorectic effect of individual drugs with a better safety profile, which deserves further investigation in clinical trials. 相似文献
19.
Systemic coadministration of tramadol and dexketoprofen can produce antinociceptive synergism in animals. There has been only limited evaluation of this drug combination in the peripheral nervous system in terms of the antinociceptive interaction and its mechanisms. The aim of the present study was to evaluate the peripheral antinociceptive interaction between tramadol and dexketoprofen in the formalin test and the involvement of the nitric oxide (NO)–cyclic guanosine monophosphate pathway and ATP‐sensitive K + channels. Different doses of tramadol or dexketoprofen were administered locally to the formalin‐injured mouse paw and the antinociceptive effect evaluated. ED 50 values were calculated for both drugs alone and in combination. Coadministration of tramadol and dexketoprofen produced an antinociceptive synergistic interaction during the second phase of the formalin test. Pretreatment with NO antagonists, including l ‐NG‐nitroarginine methyl ester and 1H‐[1,2,4]‐oxadiazolo‐[4,3‐a]‐quinoxalin‐1‐one, or the ATP‐sensitive K + channel antagonist glibenclamide reversed the antinociceptive synergistic effect of the tramadol–dexketoprofen combination, suggesting that NO and ATP‐sensitive K + channels were involved. 相似文献
20.
The presence of pain as part of the cancer process is variable. Glioblastoma multiform (GBM) can produce bone metastasis, a condition that involves other pathological phenotypes including neuropathic and inflammatory pain. Tramadol and gabapentin are drugs used in the treatment of neuropathic pain. However, there are no studies evaluating their analgesic effects in bone metastasis. We produced a pain model induced by the inoculation of glioma cells (10 5) into the rat femur, by perforating the intercodiloid fossa. Painful behavior was evaluated by measuring mechanical allodynia using the Von Frey test while thermal hyperalgesia was assessed in the plantar test. Histopathological features were evaluated and antinociceptive responses were compared using tramadol and gabapentin. The inoculation of cells inside the right femur produced nociceptive behaviors. Tramadol and gabapentin produced an anti‐allodynic effect in this condition, but tramadol did not produce an anti‐hyperalgesic response. The development of this model will allow us to perform tests to elucidate the pathology of bone metastasis, cancer pain, and in particular the pain produced by glioma. Drug Dev Res 78 : 173–183, 2017. © 2017 Wiley Periodicals, Inc. 相似文献
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