Search

Rationale: Acute pain states in the trigeminal region (headaches, dental pain) fall into the most prevalent painful conditions. Standard analgesics (paracetamol/NSAIDs) represent the cornerstone of their treatment, whereas triptans are primarily used in migraine attacks. Due to limited efficacy and/or side effects of current treatments, identifying favorable combinations of available drugs is justified. Objectives: Eslicarbazepine acetate (ESL) is a novel antiepileptic drug whose effectiveness against trigeminal pain was recently demonstrated. Here, we examined the interactions between ESL and several standard/alternative analgesics (paracetamol, propyphenazone, naproxen, zolmitriptan, and metoclopramide) in a model of trigeminal pain. Methods: The antinociceptive effects of orally administered ESL, standard/alternative analgesics, and two-drug ESL-analgesic combinations were examined in the orofacial formalin test in mice. The type of interaction between drugs was determined by isobolographic analysis. Results: ESL, analgesics, and two-drug ESL-analgesic combinations significantly and dose-dependently reduced nociceptive behaviour in the second, inflammatory phase of the test. Isobolographic analysis revealed that ESL interacted additively with paracetamol/propyphenazone/zolmitriptan and synergistically with naproxen/metoclopramide (with about a 4-fold and 3-fold reduction of doses in the ESL-naproxen and ESL-metoclopramide combination, respectively). Conclusions: ESL interacted in a beneficial manner with several analgesics that are used for trigeminal pain treatment, producing synergistic interactions with naproxen/metoclopramide and additive interactions with paracetamol/propyphenazone/zolmitriptan. Our results suggest that combining ESL with analgesics could theoretically enable the use of lower doses of individual drugs for achieving pain relief.

Rationale: Acute pain states in the trigeminal region (headaches, dental pain) fall into the most prevalent painful conditions. Standard analgesics (paracetamol/NSAIDs) represent the cornerstone of their treatment, whereas triptans are primarily used in migraine attacks. Due to limited efficacy and/or side effects of current treatments, identifying favorable combinations of available drugs is justified. Objectives: Eslicarbazepine acetate (ESL) is a novel antiepileptic drug whose effectiveness against trigeminal pain was recently demonstrated. Here, we examined the interactions between ESL and several standard/alternative analgesics (paracetamol, propyphenazone, naproxen, zolmitriptan, and metoclopramide) in a model of trigeminal pain. Methods: The antinociceptive effects of orally administered ESL, standard/alternative analgesics, and two-drug ESL-analgesic combinations were examined in the orofacial formalin test in mice. The type of interaction between drugs was determined by isobolographic analysis. Results: ESL, analgesics, and two-drug ESL-analgesic combinations significantly and dose-dependently reduced nociceptive behaviour in the second, inflammatory phase of the test. Isobolographic analysis revealed that ESL interacted additively with paracetamol/propyphenazone/zolmitriptan and synergistically with naproxen/metoclopramide (with about a 4-fold and 3-fold reduction of doses in the ESL-naproxen and ESL-metoclopramide combination, respectively). Conclusions: ESL interacted in a beneficial manner with several analgesics that are used for trigeminal pain treatment, producing synergistic interactions with naproxen/metoclopramide and additive interactions with paracetamol/propyphenazone/zolmitriptan. Our results suggest that combining ESL with analgesics could theoretically enable the use of lower doses of individual drugs for achieving pain relief.

Bol je kompleksno senzorno iskustvo koje ima jasnu zaštitnu ulogu, ali pod određenim uslovima može da postane hronično stanje koje značajno narušava kvalitet života. Postojeći analgetici, iako nesumnjivo korisni u terapiji različitih bolnih stanja, neretko su nedovoljno efikasni ili bezbedni. Zato postoji potreba za razvojem novih ili otkrivanjem efikasnih kombinacija postojećih analgetika kako bi se poboljšala terapija bola. Ciljevi ovog rada su bili ispitivanje efekata, mehanizama dejstva i interakcija dva potencijalna alternativna analgetika, antiepileptika eslikarbazepin acetata (ESL) i antidijabetika metformina u modelima inflamatornog i neuropatskog bola. Efekti ESL i metformina su ispitani u modelima inflamatornog trigeminalnog, visceralnog i somatskog bola, kao i modelu bolne dijabetesne neuropatije. Mehanizmi dejstva ESL u modelu trigeminalnog bola su ispitani farmakološkim pristupom, korišćenjem antagonista receptora značajnih za modulaciju bola. Vrsta interakcije između ESL/metformina i analgetika u modelima inflamatornog i neuropatskog bola je utvrđena izobolografskom analizom. ESL i metformin su pokazali efikasnost u svim korišćenim modelima inflamatornog bola i u modelu bolne dijabetesne neuropatije. Utvrđeno je da ESL ublažava trigeminalni bol posredstvom serotoninskih 5-HT1B/1D, α2/β1-adrenergičkih, muskarinskih, CB1/CB2 kanabinoidnih i opioidnih receptora. ESL i metformin stupaju u aditivne ili sinergističke interakcije sa različitim analgeticima u modelima inflamatornog i neuropatskog bola. Efikasnost ESL i metformina u modelima bola bi mogla da ukaže na njihovu potencijalnu kliničku primenu kao analgetika. Dodatno, poznavanje mehanizama dejstva ESL može doprineti uspešnoj primeni ovog leka u terapiji bola. Na kraju, oba leka stupaju u povoljne interakcije sa postojećim analgeticima. Ovaj nalaz ukazuje na potencijalno bolju efikasnost i/ili bezbednost kombinovane u odnosu na monoterapiju, kao i koji analgetici bi mogli biti povoljan izbor za lečenj, Pain is a complex sensory experience, which has a clear protective role, but under certain circumstances pain can become a chronic condition that significantly impairs the quality of life. Existing analgesics, although undoubtedly useful in the treatment of various painful conditions, are often insufficiently effective or safe. Therefore, there is a need to develop new drugs or to discover effective combinations of existing drugs in order to improve pain therapy. The objectives of this study were to investigate the effects, mechanisms of action, and interactions of two potential alternative analgesics, the antiepileptic eslicarbazepine acetate (ESL) and the antidiabetic metformin in models of inflammatory and neuropathic pain. The effects of ESL and metformin were examined in models of inflammatory trigeminal, visceral and somatic pain, as well as in a model of painful diabetic neuropathy. The mechanisms of action of ESL in the model of trigeminal pain were examined by a pharmacological approach, using antagonists of different receptors important for pain modulation. The type of interaction between ESL/metformin and analgesics in models of inflammatory and neuropathic pain was determined using isobolographic analysis. ESL and metformin were effective in all models of inflammatory pain that were used, as well as in the model of painful diabetic neuropathy. ESL was found to relieve trigeminal pain by activating serotonin 5-HT1B/1D, α2/β1-adrenergic, muscarinic, CB1/CB2 cannabinoid and opioid receptors. ESL and metformin interacted in an additive or synergistic manner with different analgesics in models of inflammatory and neuropathic pain. The efficacy of ESL and metformin in pain models may indicate their potential clinical application as analgesics. In addition, knowledge of the mechanisms of action of ESL may contribute to the successful use of this drug in the treatment of pain. Finally, both drugs interact favorably with existing analgesics. This finding indicate

Aims: Eslicarbazepine acetate (ESL) is a novel dibenzazepine antiepileptic, that has demonstrated efficacy against trigeminal pain, both in preclinical and clinical studies. However, ESL's mechanism of antinociceptive action remains uncertain. Here, we aimed to examine the contribution of adrenergic/cholinergic/opioid receptors to the antinociceptive effects of ESL in a trigeminal pain model, as these neurotransmitter systems are known to have an important role in the modulation of trigeminal nociception. Main methods: ESL's effects in the orofacial formalin test were examined following peroral and local peripheral administration (subcutaneous, into the perinasal region). The involvement of adrenergic/cholinergic/opioid receptors was evaluated by intraperitoneally pretreating mice with an appropriate antagonist immediately after peroral application of ESL. We used antagonists of alpha(1)-adrenergic (prazosin), alpha(2)-adrenergic (yohimbine), beta(3)-adrenergic (non-selective, propranolol and beta(1)-selective, metoprolol), muscarinic (atropine), nicotinic (mecamylamine) and opioid receptors (naloxone). Additionally, the role of peripheral alpha(2)-adrenergic, beta(1)-adrenergic, muscarinic and opioid receptors was evaluated by co-injecting ESL with an antagonist into the perinasal area. Key findings: ESL dose-dependently reduced formalin-induced nociceptive behavior after systemic and local peripheral application. Systemic administration of yohimbine, propranolol, metoprolol, atropine and naloxone inhibited ESL's antinociceptive effects in a dose-related manner. Prazosin and mecamylamine did not produce inhibitory effects. Local application of yohimbine, atropine and naloxone into the perinasal area also produced a dose-related inhibition of ESL's efficacy, whereas metoprolol failed to inhibit the local antinociceptive effects of ESL. Significance: This study suggests that ESL's efficacy against trigeminal nociception is mediated by peripheral (and possibly central

Present study investigated triterpene profile, antihyperalgesic and antiedematous activities of Hieracium scheppigianum flowering aerial parts dichloromethane extract (SCH), and antihyperalgesic and antiedematous activities of previously chemically characterised polyphenol-rich H. glabratum and H. calophyllum flowering aerial parts methanol extracts (GLA and CAL, respectively). α- and β-Amyrin and their acetates, and lupeol acetate were identified and quantified in SCH by GC-FID and GC-MS. In carrageenan-induced localised inflammation model in rats, SCH and GLA (50–200 mg/kg, p.o.) produced significant and dose-dependent antihyperalgesic effect of 26.9%–56.2% (ED50=163.0 ± 26.5 mg/kg) and 25.3%–51.6% (ED50=211.6 ± 70.6 mg/kg), respectively, and CAL (200 mg/kg, p.o.) exhibited effect of 38.1%. Extracts did not significantly reduce paw edema. SCH and GLA, which demonstrated higher (over 50%) antihyperalgesic efficacy, were tested in a rotarod test (200 mg/kg, p.o.) and no alteration of motor coordination was observed. Also, acute administration of SCH and GLA in mice (2000 mg/kg, p.o.) caused neither mortality nor toxicity.

The study focused on formulation of carmellose sodium hydrogels and nonionic microemulsions with 5% and 10% of levetiracetam and investigation of drug concentration influence on their physicochemical characteristics and in-use stability as well as influence of drug concentration and carrier type on in vitro drug release and in vivo antihyperalgesic/antiedematous activity in a rat model of localized (intraplantar) carrageenan-induced inflammation. Hydrogels were pseudoplastic semisolids with thixotropy and pH 7.37–7.58. Microemulsions were low viscous Newtonian nanodispersions of oil droplets (13.11–15.11 nm) in water, with pH 4.01–4.64. Physical stability of the investigated systems was preserved over the 3-month storage under ambient conditions. Levetiracetam release followed zero order and Korsmeyer-Peppas models (R2 ≥ 0.99) reflecting the combined effects of drug concentration and carrier viscosity. All levetiracetam-loaded formulations produced significant reduction of hyperalgesia and paw swelling induced by carrageenan (p < 0.001). Their efficacy in exerting antihyperalgesic activity was significantly higher than that observed with the reference 5% ibuprofen hydrogel preparation (up to 6 h) (p < 0.001), while antiedematous activity was comparable with the reference product. No erythema and visible blood vessels were observed in a rat ear test. The study demonstrated percutaneous delivery of levetiracetam as useful and safe therapeutic option for localized inflammatory pain with potential to overcome the insufficient efficacy of topically applied nonsteroidal anti-inflammatory drugs in the form of a hydrogel. [Figure not available: see fulltext.]. © 2020, Controlled Release Society.

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.

Alzheimer’s disease (AD), the most common cause of dementia, is growing health, social and economic issue because of the increasing number of sufferers, limited efficacy of available treatment options, and high total healthcare costs. It is clinically characterized by cognitive and behavioral impairments, both of which need to be treated appropriately to improve patients’ quality of life and their caregivers as well. Currently, available anti-dementia medications provide only modest and transient cognitive benefits. Donepezil, rivastigmine and galantamine (cholinesterase inhibitors) are indicated for the symptomatic management of mild to moderately severe AD, while memantine (NMDA glutamate receptors antagonist) is recommended for moderate-to-severe AD. A special focus on behavioral symptoms (e.g. anxiety, depression, aggression) management is required as they cause great suffering in patients/caregivers. The use of medications that can impair cognitive function, such as drugs with anticholinergic activity, should be avoided in patients with dementia. Additionally, interventions that could delay or prevent dementia onset in some subjects are focused on minimizing modifiable risk factors (hypertension, diabetes, depression) and maximizing protective factors (physical activity, healthy diet, leisure, and social activities). The treatment of AD remains a challenge., Alzheimer-ova bolest (AB), najčešći oblik demencije, rastući je zdravstveni, socijalni i ekonomski problem zbog sve većeg broja obolelih, nedovoljne efikasnosti postojećih terapijskih mera, kao i velikih ukupnih troškova nege. Klinički se manifestuje smanjenjem kognitivnih funkcija i poremećajima ponašanja, koje treba adekvatno lečiti kako bi se popravio kvalitet života obolelih i njihovih negovatelja. Raspoloživi lekovi za lečenje demencija ostvaruju umereno i prolazno poboljšanje kognitivnih funkcija. Donepezil, rivastigmin i galantamin (inhibitori holinesteraza) su indikovani kao simptomatska terapija blage do umereno teške forme AB, dok se memantin (antagonist glutamatergičkih NMDA receptora) preporučuje za lečenje umerene do teške AB. Poseban aspekt lečenja predstavlja terapija bihejvioralnih simptoma (anksioznost, depresija, agresivnost), koji su veliki problem za pacijente i negovatelje. Trebalo bi izbegavati primenu lekova koji nepovoljno utiču na kogniciju, kao što su lekovi sa antiholinegičkim dejstvom, kod pacijenata sa demencijom. Dodatno, kontrola promenljivih faktora rizika (hipertenzija, dijabetes, depresija) i usvajanje protektivnih faktora (fizička aktivnost, zdrava ishrana, socijalne aktivnosti i aktivnosti u slobodno vreme) možda može da spreči ili odloži pojavu demencije kod izvesnih ljudi. Lečenje AB i dalje je veliki izazov.

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)sign ificantlyand dose-dependently reduced carrageenan-induced hyperalgesia with a maximal antihyperalgesic effect (mean SEM) of 62 6% (all P lt = .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 lt = .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 (

Pain is a symptom of most diseases that can significantly impair the patient's quality of life. In many diseases it is impossible to eliminate the cause of pain therefore the real goal of treatment is the removal of pain as a symptom, by application of analgesics. Contemporary pharmacotherapy employs conventional (opioid and non-opioid analgesics - NSAIDs and paracetamol) and adjuvant analgesics (antiepileptics, antidepressants and others). Analgesic effect of non-opioid analgesics is mainly the consequence of prostaglandin synthesis inhibition. They are effective for pain of mild/moderate intensity. In acute pain there is no difference in efficiency between NSAIDs and paracetamol, so the choice of the drug is individual. In chronic pain, when inflammation is present, NSAIDs are more effective than paracetamol. Long-term use of high doses of NSAIDs is often accompanied by side effects. In order to reduce their frequency, a careful assessment of risk for each patient should be made, a drug with a low risk of certain side effects should be chosen, the dose and duration of treatment should be limited and the possibility of topical application should be considered. The need for long-term use of NSAIDs should be reviewed periodically., Bol je simptom većine oboljenja koji može značajno narušiti kvalitet života pacijenta. Kod mnogih oboljenja nemoguće je otkloniti uzrok bola, stoga je realni cilj lečenja uklanjanje bola kao simptoma, primenom analgetika. Savremena farmakoterapija raspolaže klasičnim (opioidni i ne-opiodini analgetici: NSAIL i paracetamol) i adjuvantnim analgeticima (antiepileptici, antidepresivi i drugi). Analgetičko dejstvo ne-opioidnih analgetika uglavnom je posledica inhibicije sinteze prostaglandina. Efikasni su kod bola blagog/umerenog intenziteta. Kod akutnog bola nema razlike u efikasnosti između NSAIL i paracetamola pa je izbor leka individualan. NSAIL su efikasniji kod hroničnih bolnih stanja u kojima je prisutna inflamacija, ali njihovu dugotrajnu primenu često prate neželjena dejstva. Kako bi se smanjila učestalost neželjenih efekata NSAIL, treba izvršiti pažljivu procenu rizika za svakog pacijenta, odabrati lek sa niskim rizikom za određeno neželjeno dejstvo, ograničiti dozu i trajanje tretmana i razmotriti mogućnost topikalne primene. Potrebu za dugotrajnom primenom NSAIL treba povremeno preispitivati.

The aim of this study was to test the potential of high molecular weight exopolysaccharide (EPS) produced by the putative probiotic strain Lactobacillus paraplantarum BGCG11 (EPS CG11) to alleviate inflammatory pain in Wistar rats. The EPS CG11 was isolated from bacterial surface and was subjected to Fourier-transform infrared spectroscopy (FTIR) and thermal analysis. FTIR spectra confirmed the polysaccharide structure of isolated sample, while the thermal methods revealed good thermal properties of the polymer. The antihyperalgesic and antiedematous effects of the EPS CG11 were examined in the rat model of inflammation induced by carrageenan injection in hind paw. The results showed that the intraperitoneal administration of EPS CG11 produced a significant decrease in pain sensations (mechanical hyperalgesia) and a paw swelling in a dose-dependent manner as it was measured using Von Frey anesthesiometer and plethysmometer, respectively. These effects were followed by a decreased expression of IL-1 beta and iNOS mRNAs in rat's paw tissue suggesting that the antihyperalgesic and antiedematous effects of the EPS CG11 are related to the suppression of inflammatory response. Additionally, we demonstrated that EPS CG11 exhibits immunosuppressive properties in the peritonitis model induced by carrageenan. Expression levels of pro-inflammatory mediators IL-1 beta, TNF-alpha and iNOS were decreased, together with the enhanced secretion of anti-inflammatory IL-10 and IL-6 cytokines, while neutrophil infiltration was not changed. To the best of our knowledge, this is the first study which reports an antihyperalgesic effect as the novel property of bacterial EPSs. Given the high demands of pharmaceutical industry for the replacement of commonly used analgesics due to numerous side effects, this study describes a promising natural compound for the future pharmacological testing in the area.

Rationale We have reported that levetiracetam, a novel anticonvulsant with analgesic properties, synergizes with ibuprofen/aspirin/paracetamol in a model of diabetic painful neuropathy (DPN). Most guidelines recommend gabapentin, pregabalin, and duloxetine as first-or second-line agents for DPN. Objective We examined the effects of combination treatment of first-/second-line analgesics with levetiracetam in a model of DPN. Additionally, the levetiracetam's combinations with antioxidants, low dose of aspirin, coenzyme Q10, or alpha-lipoic acid were evaluated. Methods Diabetes was induced in C57BL/6 mice with a single high dose of streptozotocin. The antinociceptive effects of orally administered levetiracetam, gabapentin, pregabalin, duloxetine (acute treatment) and aspirin, coenzyme Q10, and alpha-lipoic acid (preventive 7-day treatment), as well as combinations of levetiracetam with individual drugs were examined in the tail-flick test. In combination experiments, the drugs were coadministered in fixed-dose fractions of single-drug ED50; the type of interaction was determined by isobolographic analysis. Results About 60-, 32-, 30-, 26-, 18-, and 6-fold reductions of doses of both drugs in levetiracetam combinations with pregabalin, gabapentin, coenzyme Q10, aspirin, duloxetine, and alpha-lipoic acid, respectively, were detected. Conclusions Combinations of levetiracetam with gabapentin/pregabalin/duloxetine that target different mechanisms/sites of action involved in DPN, as well as combinations of levetiracetam and low-dose aspirin/coenzyme Q10/alpha-lipoic acid that target underlying causes of DPN, produce marked synergistic interactions in reducing nociception in diabetic mice. This suggests that these combination treatments might be of great benefit for diabetic patients and should be explored further in clinical trials.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used medications in the world. They act via inhibition of cyclooxygenase (COX) isoenzymes. The combined analgesic, anti-inflammatory, and antipyretic effects make NSAIDs especially useful for symptomatic relief of painful inflammatory conditions and fever. They are used for treating musculoskeletal disorders (chronic, like osteoarthritis and rheumatoid arthritis, and acute, like acute gout and injuries), headaches, dental and postoperative pain, and dysmenorrhea, and aspirin also for prevention of cardiovascular events. NSAIDs may cause serious gastrointestinal, cardiovascular, and renal adverse effects, which may be prevented by performing risk assessments for each patient, choosing a NSAID with low risk for the particular side effect, and limiting its dosage and treatment duration. Gastroprotective agents are recommended for gastroduodenal ulcers prevention. Topical NSAIDs application offers a possibility for minimization of all systemic NSAIDs side effects, as well as drug-drug interactions. Evidence supports topical NSAIDs use in hands and knees osteoarthritis, and probably also in acute musculoskeletal pain. They can cause local skin irritation. Modified-release oral preparations improve patient compliance, and are especially important for short-acting NSAIDs. Topical modified-release preparations could improve efficacy and tolerability of NSAIDs topical treatment, and patient compliance.

Ethnopharmacological relevance: Meadowsweet (Filipendula ulmaria (L.) Maxim.), and dropwort (Filipendula vulgaris Moench) flowers are traditionally used to treat various ailments, including inflammatory conditions. The aim of the present study was to validate the aforementioned ethnomedicinal claim by assessing antihyperalgesic and antiedematous activities and toxicity of orally administered lyophilized flower infusions (LFIs) of F. ulmaria and F. vulgaris in experimental animals. Materials and methods: The phytochemical analysis of LFIs was performed by HPLC-DAD. Antihyperalgesic and antiedematous activities were estimated in a rat model of inflammation induced by intraplantar injection of carrageenan using Von Frey anesthesiometer and plethysmometer, respectively. Moreover, acute oral toxicity of LFIs in mice was evaluated by observing changes in animal behavior and mortality for a period of 14 days following the treatment. Results: HPLC-DAD analysis revealed the presence of phenolic acids and flavonoids in LFIs, among which spiraeoside was identified as the principal component (56.27 +/- 1.03 and 55.67 +/- 1.82 mg/g of LFI in F. ulmaria and F. vulgaris, respectively). The LFIs of F. ulmaria and F. vulgaris (100-300 mg/kg; p.o.) produced significant and dose-dependent antihyperalgesic effects: ED50 +/- SEM values were 164.8 +/- 15.4 mg/kg (110.3-246.3 mg/kg) and 172.2 +/- 6.2 mg/kg (147.4-201.3 mg/kg) for F. ulmaria and F. vulgaris, respectively. On the other hand, LFIs of both species (100-300 mg/kg; p.o.) did not significantly reduce edema. Good safety profiles were evidenced in the toxicological study. The median lethal dose (LD50) of the tested extracts is likely to be greater than 2000 mg/kg. Conclusion: The results of the present study support the use of F. ulmaria and F. vulgaris flowers in folk medicine for relieving pain in diseases with an inflammatory component.

Ethnopharmacological relevance: Meadowsweet (Filipendula ulmaria (L.) Maxim.), and dropwort (Filipendula vulgaris Moench) flowers are traditionally used to treat various ailments, including inflammatory conditions. The aim of the present study was to validate the aforementioned ethnomedicinal claim by assessing antihyperalgesic and antiedematous activities and toxicity of orally administered lyophilized flower infusions (LFIs) of F. ulmaria and F. vulgaris in experimental animals. Materials and methods: The phytochemical analysis of LFIs was performed by HPLC-DAD. Antihyperalgesic and antiedematous activities were estimated in a rat model of inflammation induced by intraplantar injection of carrageenan using Von Frey anesthesiometer and plethysmometer, respectively. Moreover, acute oral toxicity of LFIs in mice was evaluated by observing changes in animal behavior and mortality for a period of 14 days following the treatment. Results: HPLC-DAD analysis revealed the presence of phenolic acids and flavonoids in LFIs, among which spiraeoside was identified as the principal component (56.27 +/- 1.03 and 55.67 +/- 1.82 mg/g of LFI in F. ulmaria and F. vulgaris, respectively). The LFIs of F. ulmaria and F. vulgaris (100-300 mg/kg; p.o.) produced significant and dose-dependent antihyperalgesic effects: ED50 +/- SEM values were 164.8 +/- 15.4 mg/kg (110.3-246.3 mg/kg) and 172.2 +/- 6.2 mg/kg (147.4-201.3 mg/kg) for F. ulmaria and F. vulgaris, respectively. On the other hand, LFIs of both species (100-300 mg/kg; p.o.) did not significantly reduce edema. Good safety profiles were evidenced in the toxicological study. The median lethal dose (LD50) of the tested extracts is likely to be greater than 2000 mg/kg. Conclusion: The results of the present study support the use of F. ulmaria and F. vulgaris flowers in folk medicine for relieving pain in diseases with an inflammatory component.

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 lt 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

Painful diabetic neuropathy is difficult to treat. Single analgesics often have insufficient efficacy and poor tolerability. Combination therapy may therefore be of particular benefit, because it might provide optimal analgesia with fewer adverse effects. This study aimed to examine the type of interaction between levetiracetam, a novel anticonvulsant with analgesic properties, and commonly used analgesics (ibuprofen, aspirin and paracetamol) in a mouse model of painful diabetic neuropathy. Diabetes was induced in C57BL/6 mice with a single high dose of streptozotocin, applied intraperitoneally (150 mg/kg). Thermal (tail-flick test) and mechanical (electronic von Frey test) nociceptive thresholds were measured before and three weeks after diabetes induction. The antinociceptive effects of orally administered levetiracetam, analgesics, and their combinations were examined in diabetic mice that developed thermal/mechanical hypersensitivity. In combination experiments, the drugs were co-administered in fixed-dose fractions of single drug ED50 and the type of interaction was determined by isobolographic analysis. Levetiracetam (10-100 mg/kg), ibuprofen (2-50 mg/kg), aspirin (5-75 mg/kg), paracetamol (5-100 mg/kg), and levetiracetam-analgesic combinations produced significant, dose-dependent antinociceptive effects in diabetic mice in both tests. In the tail-flick test, isobolographic analysis revealed 15-, and 19-fold reduction of doses of both drugs in the combination of levetiracetam with aspirin/ibuprofen, and paracetamol, respectively. In the von Frey test, approximately 7- and 9-fold reduction of doses of both drugs was detected in levetiracetam-ibuprofen and levetiracetam-aspirin/levetiracetam-paracetamol combinations, respectively. These results show synergism between levetiracetam and ibuprofen/aspirin/paracetamol in a model of painful diabetic neuropathy and might provide a useful approach to the treatment of patients suffering from painful diabetic neuropathy.