Metformin Synergizes With Conventional and Adjuvant Analgesic Drugs to Reduce Inflammatory Hyperalgesia in Rats.

BACKGROUND: Metformin is a widely used and safe antidiabetic drug that has recently been shown to possess analgesic properties in models of inflammatory pain. Because various arthritic inflammatory disorders are highly prevalent in diabetic patients, we aimed to examine the type of interaction between metformin and several conventional and adjuvant analgesic drugs (ibuprofen, aspirin, tramadol, and pregabalin) in a rat model of somatic inflammatory hyperalgesia. METHODS: Inflammation of the rat hind paw was induced by an intraplantar injection of carrageenan (0.1 mL, 1%). The antihyperalgesic effects of metformin (intraperitoneally), analgesics (orally or intraperitoneally), and 2-drug metformin-analgesic combinations were assessed with an electronic Von Frey anesthesiometer, by measuring the change in paw withdrawal thresholds induced by carrageenan (n = 6 rats in drug/drug combination-treated groups). First, we determined the doses of individual drugs needed to produce an antihyperalgesic effect of 50% (ED50 values). In combination experiments, drugs were coadministered in fixed-dose fractions (1/16, 1/8, 1/4, and 1/2) of their individual ED50 values and the type of interaction between components was determined by isobolographic analysis. RESULTS: Metformin (50-200 mg/kg) significantly and dose-dependently reduced carrageenan-induced hyperalgesia with a maximal antihyperalgesic effect (mean ± SEM) of 62 ± 6% (all P ≤ .024). Ibuprofen (25-150 mg/kg), aspirin (100-400 mg/kg), tramadol (0.5-5 mg/kg), and pregabalin (2.5-20 mg/kg) also produced significant and dose-dependent antihyperalgesic effects (all P ≤ .042) of similar magnitude to metformin (the maximal antihyperalgesic effects were 73 ± 4% for ibuprofen, 62 ± 4.2% for aspirin, 69 ± 5.9% for tramadol, and 56 ± 3.9% for pregabalin). In combination experiments, administration of 2-drug metformin-analgesic combinations led to a significant and dose-dependent reduction of carrageenan-induced hyperalgesia (all P ≤ .027). The isobolographic analysis revealed that metformin interacted synergistically with the examined analgesics (experimental ED50 values of 2-drug combinations were significantly lower than theoretical additive ED50 values; all P < .05) and that there was a similar, approximately 5-fold, reduction of doses of both drugs in all tested combinations. CONCLUSIONS: Our results suggest that in patients who are already receiving metformin therapy, lower doses of ibuprofen/aspirin/tramadol/pregabalin might be sufficient for achieving satisfactory pain relief. Metformin-aspirin combination might be particularly useful because it may achieve multiple therapeutic goals (glucoregulation, pain relief, and cardioprotection).

Laserpitium zernyi Hayek Flower and Herb Extracts: Phenolic Compounds, and Anti-edematous, Antioxidant, and Antimicrobial Activities.

Phenolic compounds and different biological activities of the dry MeOH extracts of the flowers and the herb (aerial parts without flowers) of Laserpitium zernyi Hayek (Apiaceae) were investigated. The total phenolic contents in the extracts were determined spectrophotometrically using Folin-Ciocalteu reagent. In both extracts, apigenin, luteolin, their 7-O-glucosides, and chlorogenic acid were detected by HPLC. Identified phenolics were quantified in both extracts, except luteolin in L. zernyi herb extract. The extracts (p.o.) were tested for anti-edematous activity in a model of carrageenan (i.pl.) induced rat paw edema. Antioxidant activity of the extracts was assessed by FRAP assay and DPPH and • OH radicals scavenging tests. Antimicrobial activity was investigated using broth microdilution test against five Gram-positive and three Gram-negative bacteria, as well as against two strains of Candida albicans. The polyphenol-richer flower extract exerted higher anti-edematous and antioxidant activities. The herb extract exhibited better antimicrobial effect against Micrococcus luteus, Enterococcus faecalis, Bacillus subtilis, and Pseudomonas aeruginosa, while against other tested microorganisms, the activity of both extracts was identical. Demonstrated biological activities of L. zernyi flower and herb extracts represent a good basis for their further investigation as potential new herbal medicinal raw materials.

The Efficacy of Eslicarbazepine Acetate in Models of Trigeminal, Neuropathic, and Visceral Pain: The Involvement of 5-HT1B/1D Serotonergic and CB1/CB2 Cannabinoid Receptors.

BACKGROUND: Many clinical pain states that are difficult to treat share a common feature of sensitization of nociceptive pathways. Drugs that could normalize hyperexcitable neural activity (e.g., antiepileptic drugs) may be useful in relieving these pain states. Eslicarbazepine acetate (ESL) is a novel antiepileptic drug derived from carbamazepine/oxcarbazepine with a more favorable metabolic profile and potentially better tolerability. We examined the efficacy of ESL in models of inflammatory and neuropathic pain and the potential mechanism involved in its action. METHODS: The antinociceptive effects of ESL were assessed in mice models of trigeminal (orofacial formalin test), neuropathic (streptozotocin-induced diabetic neuropathy model), and visceral pain (writhing test). The influence of 5-HT1B/1D serotonin receptor (GR 127935) and CB1 (AM251) and CB2 cannabinoid receptor (AM630) antagonists on the antinociceptive effect of ESL was tested in the model of trigeminal pain. RESULTS: ESL exhibited significant and dose-dependent antinociceptive effects in the second phase of the orofacial formalin test (P ≤ 0.011), in the tail-flick test in diabetic mice (P ≤ 0.013), and in the writhing test (P ≤ 0.003). GR 127935 (P ≤ 0.038) and AM251 and AM630 (P ≤ 0.013 for both antagonists) significantly inhibited the antinociceptive effect of ESL in a dose-related manner. CONCLUSIONS: ESL exhibited efficacy in models of trigeminal, neuropathic, and visceral pain. In the trigeminal pain model, the antinociceptive effect of ESL is, at least in part, mediated by 5-HT1B/1D serotonin and CB1/CB2 cannabinoid receptors. This study indicates that ESL could be useful in the clinical treatment of inflammatory and neuropathic pain.

The effects of levetiracetam, sumatriptan, and caffeine in a rat model of trigeminal pain: interactions in 2-component combinations.

BACKGROUND: Levetiracetam is an antiepileptic drug with analgesic efficacy shown in pain models and small clinical trials. Sumatriptan is used in acute migraine treatment. Caffeine is widely consumed in some beverages/foods and is also an adjuvant in analgesic formulations. We examined the effects of systemic levetiracetam, sumatriptan, and caffeine and their interactions in 2-component combinations in the rat orofacial formalin test, a model of trigeminal pain. METHODS: Rats received a subcutaneous injection of formalin solution into the perinasal area, and the total time spent in nociceptive behavior (face rubbing) was quantified. The antinociceptive effect of drugs/drug combinations was assessed 1 hour after per os administration. The type of interaction between levetiracetam/sumatriptan and caffeine was examined by comparing the effects of a fixed, effective dose of levetiracetam/sumatriptan alone with the effects of the same dose applied with increasing, subeffective doses of caffeine. The type of interaction between levetiracetam and sumatriptan was determined by isobolographic analysis. RESULTS: Levetiracetam (1-50 mg/kg) and sumatriptan (0.5-5 mg/kg) produced significant and dose-dependent antinociceptive effects in both phases of the orofacial formalin test (P ≤ 0.001). Caffeine (7.5-100 mg/kg) produced significant antinociception in the second phase of the test (P = 0.04). Caffeine (1-7.5 mg/kg) significantly reduced the antinociceptive effects of levetiracetam (25 mg/kg) (first phase P = 0.002, second phase P < 0.001) and sumatriptan (2.5 mg/kg) (first phase P = 0.014, second phase P = 0.027); dose-dependent inhibition was observed in the second phase. Levetiracetam and sumatriptan exerted an additive interaction in the second phase of the orofacial formalin test. CONCLUSIONS: Results indicate that levetiracetam may be useful for treatment of pain in the trigeminal region. Dietary caffeine might decrease the effects of levetiracetam and sumatriptan; this needs to be considered in clinical settings. A levetiracetam-sumatriptan combination could also be useful in trigeminal pain treatment. Its efficacy and adverse effects should be examined clinically.

Antihyperalgesic/antinociceptive effects of ceftriaxone and its synergistic interactions with different analgesics in inflammatory pain in rodents.

BACKGROUND: The ß-lactam antibiotic ceftriaxone stimulates glutamate transporter GLT-1 expression and is effective in neuropathic and visceral pain models. This study examined the effects of ceftriaxone and its interactions with different analgesics (ibuprofen, celecoxib, paracetamol, and levetiracetam) in somatic and visceral pain models in rodents. METHODS: The effects of ceftriaxone (intraperitoneally/intraplantarly), analgesics (orally), and their combinations were examined in the carrageenan-induced paw inflammatory hyperalgesia model in rats (n = 6-12) and in the acetic acid-induced writhing test in mice (n = 6-10). The type of interaction between ceftriaxone and analgesics was determined by isobolographic analysis. RESULTS: Pretreatment with intraperitoneally administered ceftriaxone (10-200 mg/kg per day) for 7 days produced a significant dose-dependent antihyperalgesia in the somatic inflammatory model. Acute administration of ceftriaxone, via either intraperitoneal (10-200 mg/kg) or intraplantar (0.05-0.2 mg per paw) routes, produced a significant and dose-dependent but less efficacious antihyperalgesia. In the visceral pain model, significant dose-dependent antinociception of ceftriaxone (25-200 mg/kg per day) was observed only after the 7-day pretreatment. Isobolographic analysis in the inflammatory hyperalgesia model revealed approximately 10-fold reduction of doses of both drugs in all examined combinations. In the visceral nociception model, more than 7- and 17-fold reduction of doses of both drugs was observed in combinations of ceftriaxone with ibuprofen/paracetamol and celecoxib/levetiracetam, respectively. CONCLUSIONS: Ceftriaxone exerts antihyperalgesia/antinociception in both somatic and visceral inflammatory pain. Its efficacy is higher after a 7-day pretreatment than after acute administration. The two-drug combinations of ceftriaxone and the nonsteroidal analgesics/levetiracetam have synergistic interactions in both pain models. These results suggest that ceftriaxone, particularly in combinations with ibuprofen, celecoxib, paracetamol, or levetiracetam, may provide useful approach to the clinical treatment of inflammation-related pain.

The local peripheral antihyperalgesic effect of levetiracetam and its mechanism of action in an inflammatory pain model.

BACKGROUND: We have recently shown that levetiracetam, administered systemically, exerts an antihyperalgesic effect in a rat inflammatory pain model. In this study, we examined whether levetiracetam has local peripheral antihyperalgesic/anti-edematous effects in the same model of localized inflammation and whether opioidergic, adrenergic, purinergic, 5-HTergic, and GABAergic receptors are involved in its antihyperalgesic action. METHODS: Rats were intraplantarly (IPL) injected with carrageenan. A paw pressure test was used to determine the effect/s of (a) levetiracetam when applied IPL, on carrageenan-induced hyperalgesia, and (b) naloxone (a nonselective opioid receptor antagonist), CTAP (a selective µ-opioid receptor antagonist); yohimbine (a selective α(2)-adrenoceptor antagonist), BRL 44408 (a selective α(2A)-adrenoceptor antagonist), MK-912 (a selective α(2C)-adrenoceptor antagonist); caffeine (a nonselective adenosine receptor antagonist), DPCPX (a selective adenosine A(1) receptor antagonist); methysergide (a nonselective 5-HT receptor antagonist), GR 127935 (a selective 5-HT(1B/1D) receptor antagonist); and bicuculline (a selective GABA(A) receptor antagonist), all applied IPL, on the levetiracetam-induced antihyperalgesia. Moreover, levetiracetam's influence on paw inflammatory edema was measured by plethysmometry. RESULTS: Levetiracetam (200-1000 nmol/paw) produced a significant dose-dependent reduction of the paw inflammatory hyperalgesia and edema induced by carrageenan. Naloxone (75-300 nmol/paw), CTAP (1-5 nmol/paw); yohimbine (130-520 nmol/paw), BRL 44408 (50-200 nmol/paw), MK-912 (5-20 nmol/paw); caffeine (500-1500 nmol/paw), DPCPX (3-30 nmol/paw); methysergide (10-100 nmol/paw) and GR 127935 (50-200 nmol/paw); but not bicuculline (400 nmol/paw), significantly depressed the antihyperalgesic effects of levetiracetam (1000 nmol/paw). The effects of levetiracetam and antagonists were attributed to local peripheral effects because they were not observed after administration into the contralateral hind-paw. CONCLUSIONS: Our results show that levetiracetam produces local peripheral antihyperalgesic and anti-edematous effects in a rat model of localized inflammation. Antihyperalgesia is at least in part mediated by peripheral µ-opioid, α2A,C-adrenergic, A1 adenosine, and 5-HT1B/1D receptors, but not by GABAA receptors. These findings could contribute toward a better understanding of the analgesic effects of levetiracetam, and improved treatments of inflammatory pain with a lower incidence of systemic side effects and drug interactions of levetiracetam.

Synergistic interactions between paracetamol and oxcarbazepine in somatic and visceral pain models in rodents.

BACKGROUND: Combination therapy is a valid approach in pain treatment, in which a reduction of doses could reduce side effects and still achieve optimal analgesia. We examined the effects of coadministered paracetamol, a widely used non-opioid analgesic, and oxcarbazepine, a relatively novel anticonvulsant with analgesic properties, in a rat model of paw inflammatory hyperalgesia and in a mice model of visceral pain and determined the type of interaction between components. METHODS: The effects of paracetamol, oxcarbazepine, and their combinations were examined in carrageenan-induced (0.1 mL, 1%) paw inflammatory hyperalgesia in rats and in an acetic acid-induced (10 mg/kg, 0.75%) writhing test in mice. In both models, drugs were coadministered in fixed-dose fractions of the 50% effective dose (ED(50)), and type of interaction was determined by isobolographic analysis. RESULTS: Paracetamol (50-200 mg/kg peroral), oxcarbazepine (40-160 mg/kg peroral), and their combination (1/8, 1/4, 1/3, and 1/2 of a single drug ED(50)) produced a significant, dose-dependent antihyperalgesia in carrageenan-injected rats. In the writhing test in mice, paracetamol (60-180 mg/kg peroral), oxcarbazepine (20-80 mg/kg peroral), and their combination (1/16, 1/8, 1/4, and 1/2 of a single drug ED(50)) significantly and dose dependently reduced the number of writhes. In both models, isobolographic analysis revealed a significant synergistic interaction between paracetamol and oxcarbazepine, with a >4-fold reduction of doses of both drugs in combination, compared with single drugs ED(50). CONCLUSIONS: The synergistic interaction between paracetamol and oxcarbazepine provides new information about combination pain treatment and should be explored further in patients, especially with somatic and/or visceral pain.

Vortioxetine reduces pain hypersensitivity and associated depression-like behavior in mice with oxaliplatin-induced neuropathy.

Chronic pain and depression commonly occur together so dual-acting agents might be particularly useful. The population of patients with chemotherapy-induced neuropathy is increasing in parallel with the increase of population of cancer survivors and there is a compelling need for satisfactory treatment of symptoms of neuropathy and concomitant depression. We examined the effects of vortioxetine, a novel antidepressant with unique mechanism of action, on pain hypersensitivity and depression-like behavior in oxaliplatin-induced neuropathy model in mice (OIPN). Vortioxetine (1-10 mg/kg, p.o.) significantly and dose-dependently reduced mechanical allodynia in von Frey test and cold allodynia in acetone test in OIPN mice, in both repeated prophylactic and acute therapeutic treatment regimens. It also reduced depression-like behavior in the forced swimming test in OIPN mice, in both treatment paradigms. Its antiallodynic and antidepressive-like effects were comparable to those exerted by duloxetine (1-15 mg/kg, p.o.). The antiallodynic and antidepressive-like effects of repeatedly administered vortioxetine might be related to the increased content of 5-hydroxytryptamine (5-HT) and noradrenaline (NA), detected in the brainstem of treated OIPN mice. These results indicate that vortioxetine could be potentially useful in prevention and treatment of chemotherapy-induced neuropathy, for the relief of pain and concomitant depressive symptoms. It should be further tested to this regard in clinical settings.

The antinociceptive effects of anticonvulsants in a mouse visceral pain model.

BACKGROUND: There is evidence supporting the antinociceptive effects of carbamazepine, oxcarbazepine, gabapentin, and topiramate in various models of neuropathic pain as well as inflammatory somatic pain. Data are lacking on the antinociceptive potential of these drugs against visceral pain. In this study, we examined and compared the effects of carbamazepine, oxcarbazepine, gabapentin, and topiramate in the writhing test as a visceral pain model in the mouse. In addition, the influence of these anticonvulsants on motor performance was examined to compare the tolerability of these anticonvulsants when used against acute visceral pain. METHODS: The antinociceptive effects of these anticonvulsants were examined in the acetic acid writhing test in mice. The side effect propensity of these drugs was examined using the rotarod test. RESULTS: Carbamazepine (25-60 mg/kg; p.o.), oxcarbazepine (10-40 mg/kg; p.o.), gabapentin (10-70 mg/kg; p.o.), and topiramate (5-30 mg/kg; p.o.) caused a significant dose-dependent reduction the number of writhes in the writhing test. In the rotarod test, carbamazepine (60-140 mg/kg; p.o.) and oxcarbazepine (120-450 mg/kg; p.o.) significantly reduced the time spent on the rotarod in a dose- and time-dependent manner. Gabapentin (1000-2000 mg/kg; p.o.) and topiramate (400-1500 mg/kg; p.o.) did not produce significant impairment of motor performance at the highest doses used. The therapeutic index (motor impairing dose TD(50)/writhing ED(50)) values were topiramate (>148.5) > gabapentin (>60.2) > oxcarbazepine (15.2) > carbamazepine (2.3). CONCLUSIONS: These results indicate that oxcarbazepine, gabapentin, and topiramate are effective in the writhing model in mice, in a dose range, which is not related to motor impairment; topiramate is the most potent and the most tolerable drug.

GABAergic mechanisms are involved in the antihyperalgesic effects of carbamazepine and oxcarbazepine in a rat model of inflammatory hyperalgesia.

BACKGROUND/AIMS: The purpose of this study was to investigate the involvement of GABAergic mechanisms in the antihyperalgesic effect of carbamazepine and oxcarbazepine by examining the effect of bicuculline (GABA(A) receptor antagonist) on these effects of antiepileptic drugs. METHODS: Rats were intraplantarly (i.pl.) injected with the proinflammatory compound concanavalin A (Con A). A paw-pressure test was used to determine: (1) the development of hyperalgesia induced by Con A; (2) the effects of carbamazepine/oxcarbazepine on Con A-induced hyperalgesia, and (3) the effects of bicuculline on the carbamazepine/oxcarbazepine antihyperalgesia. RESULTS: Intraperitoneally injected bicuculline (0.5-1 mg/kg, i.p.) exhibited significant suppression of the systemic antihyperalgesic effects of carbamazepine (27 mg/kg, i.p.) and oxcarbazepine (80 mg/kg, i.p.). When applied intraplantarly, bicuculline (0.14 mg/paw, i.pl.) did not produce any change in the peripheral antihyperalgesic effects of carbamazepine (0.14 mg/paw, i.pl.) and oxcarbazepine (0.5 mg/paw, i.pl.). Bicuculline alone did not produce an intrinsic effect in the paw-pressure test. CONCLUSION: These results indicate that the antihyperalgesic effects of carbamazepine and oxcarbazepine against inflammatory hyperalgesia involve in part the GABAergic inhibitory modulation of pain transmission at central, but not at peripheral sites, which is mediated via GABA(A) receptor activation.

The involvement of peripheral alpha 2-adrenoceptors in the antihyperalgesic effect of oxcarbazepine in a rat model of inflammatory pain.

BACKGROUND: We studied whether peripheral alpha2-adrenergic receptors are involved in the antihyperalgesic effects of oxcarbazepine by examining the effects of yohimbine (selective alpha2-adrenoceptor antagonist), BRL 44408 (selective alpha(2A)-adrenoceptor antagonist), MK-912 (selective alpha2C-adrenoceptor antagonist), and clonidine (alpha2-adrenoceptor agonist) on the antihyperalgesic effect of oxcarbazepine in the rat model of inflammatory pain. METHODS: Rats were intraplantarly (i.pl.) injected with the proinflammatory compound concanavalin A (Con A). A paw-pressure test was used to determine: 1) the development of hyperalgesia induced by Con A; 2) the effects of oxcarbazepine (i.pl.) on Con A-induced hyperalgesia; and 3) the effects of i.pl. yohimbine, BRL 44408, MK-912 and clonidine on the oxcarbazepine antihyperalgesia. RESULTS: Both oxcarbazepine (1000-3000 nmol/paw; i.pl.) and clonidine (1.9-7.5 nmol/paw; i.pl.) produced a significant dose-dependent reduction of the paw inflammatory hyperalgesia induced by Con A. Yohimbine (260 and 520 nmol/paw; i.pl.), BRL 44408 (100 and 200 nmol/paw; i.pl.) and MK-912 (10 and 20 nmol/paw; i.pl.) significantly depressed the antihyperalgesic effects of oxcarbazepine (2000 nmol/paw; i.pl.) in a dose-dependent manner. The effects of antagonists were due to local effects since they were not observed after administration into the contralateral hindpaw. Oxcarbazepine and clonidine administered jointly in fixed-dose fractions of the ED(50) (1/4, 1/2, and 3/4) caused significant and dose-dependent reduction of hyperalgesia induced by Con A. Isobolographic analysis revealed an additive antihyperalgesic effect. CONCLUSIONS: Our results indicate that the peripheral alpha2A and alpha2C adrenoceptors could be involved in the antihyperalgesic effects of oxcarbazepine in a rat model of inflammatory hyperalgesia.

Opioidergic mechanisms are not involved in the antihyperalgesic effects of carbamazepine and oxcarbazepine.

The mechanisms of the analgesic action of carbamazepine and oxcarbazepine, in particular the role of opioid receptors, have not been established precisely. The systemic effects of naloxone, an opioid receptor antagonist, on the antihyperalgesic effects of carbamazepine and oxcarbazepine were examined in the model of inflammatory hyperalgesia induced by the intraplantar (i.pl.) administration of concanavaline A (Con A, 0.8 mg/paw) into the rat hind paw. Naloxone (3 mg/kg; i.p.) did not alter the antihyperalgesic effects of either carbamazepine or oxcarbazepine. These results indicate that the opioid system of pain modulation does not play a significant role in the antihyperalgesic effects of carbamazepine and oxcarbazepine.

The anti-hyperalgesic effects of carbamazepine and oxcarbazepine are attenuated by treatment with adenosine receptor antagonists.

The antinociceptive effects of carbamazepine and oxcarbazepine, and the influence of caffeine, were examined in a paw pressure test in rats. Carbamazepine (10-40 mg/kg; intraperitoneal, i.p.) and oxcarbazepine (40-160 mg/kg; i.p.) caused a significant dose-dependent reduction of the paw inflammatory hyperalgesia induced by concanavalin A (Con A), intraplantarly (i.p1.). A comparable pattern of antinociceptive effect of carbamazepine and oxcarbazepine was observed; the only difference is their potency, in that carbamazepine was about three times more potent than oxcarbazepine. Caffeine (5-20mg/kg; i.p.), a non-selective adenosine receptor antagonist, significantly depressed the antinociceptive effects of carbamazepine and oxcarbazepine, in a dose- and time-dependent manner. Also, a significant depression of the antinociceptive effects of carbamazepine and oxcarbazepine was observed by pretreatment with 1,3-dipropyl-8-cyclopentylxantine (DPCPX, 0.4 and 0.8 mg/kg; i.p.), an adenosine A(1) receptor antagonist. These findings indicate that, in a paw inflammatory hyperalgesia in rats, the antinociceptive effects of both drugs are, at least partially, mediated by adenosine A(1) receptors. In conclusion, the present study suggests the potential clinical importance of carbamazepine and oxcarbazepine in the treatment of inflammatory pain. In addition, caffeine consumption could possibly depress the analgesic effects of both anticonvulsive drugs.

Levetiracetam interacts synergistically with nonsteroidal analgesics and caffeine to produce antihyperalgesia in rats.

UNLABELLED: Levetiracetam is a novel anticonvulsant with antihyperalgesic efficacy in inflammatory pain. Nonsteroidal analgesics and caffeine, as analgesic adjuvant, are widely used against inflammatory pain. This study characterized the manner in which levetiracetam interacts with analgesics (ibuprofen, celecoxib, and paracetamol) and caffeine to suppress hyperalgesia in a model of localized inflammation. Rat paw inflammation was induced by intraplantar carrageenan (.1 mL, 1%). Hyperalgesia and antihyperalgesic effects of levetiracetam (orally), analgesics (orally), and caffeine (intraperitoneally) alone and 2-drug combinations of levetiracetam with analgesics or caffeine were examined by a modified paw pressure test. The type of interaction between components was determined by isobolographic analysis or by analysis of the log dose-response curves for drug combination and drugs alone. Levetiracetam (10-200 mg/kg), ibuprofen (12.5-100 mg/kg), celecoxib (3.75-30 mg/kg), paracetamol (50-200 mg/kg), caffeine (15-100 mg/kg), and 2-drug combinations of levetiracetam with analgesics/caffeine produced a significant, dose-dependent reduction of inflammatory hyperalgesia. Isobolographic analysis revealed that levetiracetam exerts a synergistic interaction with analgesics, with approximately 7-, 9-, and 11-fold reduction of doses of both drugs in combination of levetiracetam with paracetamol, celecoxib, and ibuprofen, respectively. Analysis of the log dose-response curves for levetiracetam (1-50 mg/kg) in the presence of caffeine (10 mg/kg) and levetiracetam applied alone also revealed a synergistic interaction. Levetiracetam's ED50 in the presence of caffeine was reduced approximately 11-fold. PERSPECTIVE: The presented data suggest that 2-drug combinations of levetiracetam and nonsteroidal analgesics or caffeine could be useful in treatment of inflammatory pain. The efficacy and the adverse effects of those mixtures should be explored further in clinical settings.

The mechanisms of antihyperalgesic effect of topiramate in a rat model of inflammatory hyperalgesia.

Recent studies have shown that topiramate, a structurally novel anticonvulsant, exerts antinociceptive activity in animal models of neuropathic, acute somatic, and visceral pain. This study was aimed to examine: (i) the effects of systemically and locally peripherally administered topiramate in the rat inflammatory pain model and (ii) the potential role and site(s) of gamma-aminobutyric acid (GABA), opioid, and adrenergic receptors in topiramate's antihyperalgesia. Rats received intraplantar (i.pl.) injections of the pro-inflammatory compound carrageenan. A paw pressure test was used to determine: (i) the effect of systemic and local peripheral topiramate on carrageenan-induced hyperalgesia and (ii) the effects of systemic and local peripheral bicuculline (selective GABAA receptor antagonist), naloxone (nonselective opioid receptor antagonist), and yohimbine (selective α2-adrenergic receptor antagonist) on topiramate-induced antihyperalgesia. Systemic topiramate (40-160 mg/kg; p.o.) produced a significant dose-dependent reduction in the paw inflammatory hyperalgesia induced by carrageenan. The antihyperalgesic effect of systemic topiramate was significantly decreased by systemic bicuculline (0.5-1 mg/kg; i.p.), naloxone (2-5 mg/kg; i.p.), and yohimbine (1-3 mg/kg; i.p.). Local peripheral topiramate (0.03-0.34 mg/paw; i.pl.) also produced significant dose-dependent antihyperalgesia, which was significantly depressed by local peripheral yohimbine (0.05-0.2 mg/paw; i.pl.) but not by local peripheral bicuculline (0.15 mg/paw; i.pl.) or naloxone (0.1 mg/paw; i.pl.). The results suggest that topiramate produces systemic and local peripheral antihyperalgesia in an inflammatory pain model, which is, at least partially, mediated by central GABAA and opioid receptors and by peripheral and most probably central α2-adrenergic receptors. These findings contribute to better understanding of topiramate's action in pain states involving inflammation.

Pharmacological interaction between oxcarbazepine and two COX inhibitors in a rat model of inflammatory hyperalgesia.

Oxcarbazepine, ibuprofen and etodolac have efficacy in inflammatory pain. The combination of different drugs activates both central and peripheral pain inhibitory pathways to induce additive or synergistic antinociception, and this interaction may allow lower doses of each drug combined and improve the safety profile, with lower side-effects. This study aimed to examine the effects of oxcarbazepine-ibuprofen and oxcarbazepine-etodolac combinations, in a rat model of inflammatory hyperalgesia, and determine the type of interaction between drugs. Rats were intraplantarly injected with carrageenan (0.1 ml, 1%) and the hyperalgesia was assessed by modified paw pressure test. The anti-hyperalgesic effects of oxcarbazepine, ibuprofen and etodolac and oxcarbazepine-ibuprofen and oxcarbazepine-etodolac combinations were examined. Drugs were co-administered in a fixed-dose fractions of the ED50 and the type of interaction was determined by isobolographic analysis. Oxcarbazepine (40-160 mg/kg; p.o.), ibuprofen (10-120 mg/kg; p.o.) and etodolac (5-20 mg/kg; p.o.) produced a significant, dose-dependent anti-hyperalgesia in carrageenan-injected rats. ED50 values (mean±SEM) for oxcarbazepine, ibuprofen and etodolac were 88.17±3.65, 47.07±10.27 and 13.05±1.42 mg/kg, respectively. Oxcarbazepine-ibuprofen and oxcarbazepine-etodolac combinations induced significant and dose-dependent anti-hyperalgesia. Isobolographic analysis revealed that oxcarbazepine exerts a synergistic interaction with ibuprofen, with almost 4-fold reduction of doses of both drugs in combination. In contrast, there was an additive interaction with etodolac. Synergistic interaction of oxcarbazepine with ibuprofen and its additive interaction with etodolac provide new information about the combination pain treatment and could be explored further in patients with inflammatory pain. Adverse effect analysis of the combinations is necessary to verify possible clinical use of the mixtures.

Analysis of the antinociceptive interactions in two-drug combinations of gabapentin, oxcarbazepine and amitriptyline in streptozotocin-induced diabetic mice.

Antiepileptic and antidepressant drugs are the primary treatments for pain relief in diabetic neuropathy. Combination therapy is a valid approach in pain treatment, where a reduction of doses could reduce side effects and still achieve optimal analgesia. We examined the effects of two-drug combinations of gabapentin, oxcarbazepine, and amitriptyline on nociception in diabetic mice and aimed to determine the type of interaction between components. The nociceptive responses in normal and diabetic mice were assessed by the tail-flick test. The testing was performed before and three weeks after the diabetes induction with streptozotocin (150mg/kg; i.p.), when the antinociceptive effects of gabapentin, oxcarbazepine, amitriptyline and their two-drug combinations were examined. Gabapentin (10-40mg/kg; p.o.) and oxcarbazepine (20-80mg/kg; p.o.) produced a significant, dose-dependent antinociception in diabetic mice while amitriptyline (5-60mg/kg; p.o.) produced weak antinociceptive effect. In normal mice, neither of the drugs produced antinociception. Gabapentin and oxcarbazepine, co-administered in fixed-dose fractions of the ED(50) to diabetic mice, induced significant, dose-dependent antinociception. Isobolographic analysis revealed synergistic interaction. Oxcarbazepine (10-60mg/kg; p.o.)+amitriptyline (5mg/kg; p.o.) and gabapentin (10-30mg/kg; p.o.)+amitriptyline (5mg/kg; p.o.) combinations significantly and dose-dependently reduced nociception in diabetic mice. Analysis of the log dose-response curves for oxcarbazepine or gabapentin in a presence of amitriptyline and oxcarbazepine or gabapentin applied alone, revealed a synergism in oxcarbazepine-amitriptyline and additivity in gabapentin-amitriptyline combination. These findings provide new information about the combination therapy of painful diabetic neuropathy and should be explored further in patients with diabetic neuropathy.

Comparison of vasorelaxant effect and tolerance profile of a novel isosorbide-5-mononitrate derivative with its stereoisomer and parent drug on rat mesenteric artery.

BACKGROUND/AIMS: 5-Ketoximeisosorbide-2-mononitrate (50-IS-2-MN) was synthesized and its pharmacological and toxicological characteristics were examined and compared with its parent drug, isosorbide-5-mononitrate (IS-5-MN, CAS 16051-77-7), and its diastereoisomer 2-ketoximeisosorbide-5-mononitrate. METHODS: Vasorelaxation was studied on phenylephrine-precontracted rat superior mesenteric artery rings in organ bath procedure. In some rings, the endothelium was mechanically removed. In vitro tolerance was induced by treating the precontracted rings with maximal concentrations of the parent drug and the ketoximes, and after washing out, the procedure was repeated for two times. Furthermore, rats were treated with a single oral dose (1000 mg/kg) of 50-IS-2-MN and 20-IS-5-MN. RESULTS: After a phenylephrine-induced contraction, 50-IS-2-MN (10(-8)-10(-4) mol/l) caused a concentration-dependent relaxation of the rat superior mesenteric artery that was strongly potentiated after the removal of the vascular endothelium. In preparations with or without endothelium, 50-IS-2-MN was a more potent relaxant than either the parent compound or its isomer. The mechanism of the relaxant effect of 50-IS-2-MN involves the activated soluble guanylyl cyclase-cyclic GMP pathway. Hydralazine (10(-5) mol/l), a strong antioxidant, ameliorated tolerance to IS-5-MN, but did not affect the absence of tolerance to either ketoxime. The minimum lethal dose in rat for 5O-IS-2-MN and 20-IS-5-MN was greater than 1000 mg/kg. CONCLUSION: These results suggest that the modification of the configuration at the ester carbon of IS-5-MN contributes to more potent and tolerance-devoid activity on the rat superior mesenteric artery.

The effects of alpha2-adrenoceptor agents on anti-hyperalgesic effects of carbamazepine and oxcarbazepine in a rat model of inflammatory pain.

In this study, the effects of yohimbine (alpha2-adrenoceptor antagonist) and clonidine (alpha2-adrenoceptor agonist) on anti-hyperalgesia induced by carbamazepine and oxcarbazepine in a rat model of inflammatory pain were investigated. Carbamazepine (10-40 mg/kg; i.p.) and oxcarbazepine (40-160 mg/kg; i.p.) caused a significant dose-dependent reduction of the paw inflammatory hyperalgesia induced by concanavalin A (Con A, intraplantarly) in a paw pressure test in rats. Yohimbine (1-3 mg/kg; i.p.) significantly depressed the anti-hyperalgesic effects of carbamazepine and oxcarbazepine, in a dose- and time-dependent manner. Both drug mixtures (carbamazepine-clonidine and oxcarbazepine-clonidine) administered in fixed-dose fractions of the ED50 (1/2, 1/4 and 1/8) caused significant and dose-dependent reduction of the hyperalgesia induced by Con A. Isobolographic analysis revealed a significant synergistic (supra-additive) anti-hyperalgesic effect of both combinations tested. These results indicate that anti-hyperalgesic effects of carbamazepine and oxcarbazepine are, at least partially, mediated by activation of adrenergic alpha2-receptors. In addition, synergistic interaction for anti-hyperalgesia between carbamazepine and clonidine, as well as oxcarbazepine and clonidine in a model of inflammatory hyperalgesia, was demonstrated.

Comparison of the relaxant effects of a new oxime-nitrate derived from isosorbide-5-mononitrate and the parent drug.

The transformation of isosorbide-5-mononitrate (CAS 16051-77-7, IS-5-MN) to the corresponding keto derivative and its ketoxime (oxime-nitrate derivative of isosorbide) is described. The effects of IS-5-MN and the new oxime-nitrate (ON) on the endothelial and smooth muscle cells of isolated rings of the rat superior mesenteric artery were examined. After contraction induced by phenylephrine, IS-5-MN (10(-8)-10(-4) mol/l) caused a concentration-dependent relaxation. Removal of the vascular endothelium strongly potentiated this effect. On the other hand, the new ON (10(-8)-10(-4) mol/l) was a more potent relaxant than the parent drug, but its effect was not dependent on the vascular endothelium. The inhibitory effect of the artery without endothelium to the new ON was more pronounced than that to IS-5-MN. The mechanism of the relaxant effect of the new compound consisted in the liberation of nitric-oxide (NO) which activated guanylate cyclase (GC), upon which accumulation of cyclic guanosine monophosphate (cGMP) occurred, which was the second messenger leading to relaxation. Tolerance to the frequent applications of the new compound was not observed, moreover a slight increase of the effect was detected in comparison with IS-5-MN for which tolerance was observed to a great extent. Clinically, the new ON could be favorable in all types of angina in comparison with the classical IS-5-MN.