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Purpose: Some evidence that non-steroidal anti-inflammatory drugs have neuroprotective effects indicates their potential for use in a new field. However, their effects on hormone secretion have yet to be adequately discovered. Therefore, we aimed to evaluate the effects of metamizole and indomethacin on neuronal markers as well as the GnRH expression in the GT1-7 cell line., Methods: The effects of these drugs on proliferation were evaluated by MTT analysis. The effect of 10-50-250 µM concentrations of the drugs also on the expression of neuronal factors and markers, including NGF, nestin and βIII Tubulin, and additionally GnRH, was determined by the RT-qPCR method., Results: NGF and nestin mRNA expressions were increased in all concentrations of both metamizole and indomethacin. No changes were detected in βIII Tubulin. While metamizole showed an increase in GnRH mRNA expression, there was no change at 10 and 50 µM concentrations of indomethacin, but a remarkable decrease was observed at 250 µM concentrations., Conclusions: The results of our study showing an increase in the expression of neuronal factors reveal that metamizole and indomethacin may have possible neuroprotective effects. Moreover, the effects on the GnRH expression appear to be different. Animal models are required to confirm these effects of NSAIDs on neurons., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Limited availability and side effects of opioids have led to an increased use of non-opioid analgesia in animal disease models. However, by affecting the immune-inflammatory reactions, analgesia may disrupt the resolution of the host inflammation and modulate the survival in septic animals. This study used a clinically relevant sepsis mouse model of peritoneal contamination and infection (PCI) to investigate the antinociceptive and anti-inflammatory properties of two non-opioid analgesics., Methods: Adult C57BL/6J mice were intraperitoneally injected with a human feces suspension and received either no analgesics (Non-A), Meloxicam, or Metamizole orally. The mice were monitored for pain and illness. Mortality was assessed at 7 days post-PCI. A separate group of mice was sacrificed 24 hours after infection. Blood, peritoneal lavage fluid (PLF), liver, and spleen were harvested for pathogen load quantification via qPCR, macrophage phenotyping, neutrophil infiltration/activation, and systemic/tissue cytokine release by flow cytometry., Results: Meloxicam but not Metamizole reduced the mortality of septic mice by 31% on day 7 compared to the Non-A group. Both analgesics effectively alleviated pain but did not affect illness severity, body weight, and temperature. Meloxicam quadrupled the bacterial burden in the blood and PLF. In high IL-6 responders, Meloxicam treatment was associated with reduced circulating IL-10 and IL-1β compared to the Non-A septic group. In low IL-6 responders, Meloxicam increased circulating MCP-1 levels and decreased PGE2 levels compared to Non-A septic mice. Notably, Meloxicam reduced spleen neutrophil infiltration by 20% compared to two other sepsis groups., Conclusion: Metamizole and Meloxicam effectively relieved pain and increased the animals' basal activity in the PCI sepsis model. Meloxicam prolonged survival yet triggered maladaptive responses due to its immunosuppressive features that decreased tissue bacterial clearance during sepsis. In contrast, Metamizole constitutes a safe and effective non-opioid alternative for analgesic control in the non-surgical PCI sepsis model., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Liu, Sonawane, Sommerfeld, Svensson, Figge, Bauer, Bischoff, Bauer, Osuchowski and Press.)

Objective: To determine the effect of levomethadone/fenpipramide and metamizole alone and in combination on acute nociception., Methods: 8 healthy, adult Beagles were used in 2 separate randomized, complete crossover, experimental trials (threshold testing and determination of minimal alveolar concentration [MAC]) with masked observers. In both trials, treatments were 0.2 mg·kg-1 levomethadone/fenpipramide (L), 75 mg·kg-1 metamizole (M), or their combination (LM). In conscious dogs, mechanical thresholds were determined using constantly rising force. Thermal thresholds were measured via ramped contact heat. The MAC of sevoflurane was determined using the bracketing method with electrical stimulus (50 V, 50 Hz, 10 ms) before and 1 and 4 hours after treatment., Results: Mechanical thresholds in L and LM were significantly increased above baseline (BL) for 165 minutes and above M for 135 minutes. Percent thermal threshold excursion significantly increased above BL in L for 75 minutes and in LM for 135 minutes. In L and LM, the percent thermal threshold excursion was significantly higher than in M from 15 to 75 or 135 minutes, respectively. In L and LM, the MAC of sevoflurane was significantly reduced at 1 hour compared to BL and M., Conclusion: Duration but not the magnitude of thermal antinociception of levomethadone/fenpipramide was increased by metamizole. Mechanical antinociception in awake dogs and anesthetic-sparing effects of levomethadone/fenpipramide were not altered., Clinical Relevance: Coadministration of levomethadone/fenpipramide and metamizole to increase antinociception is not justified.

Background: Treatment with phenylbutazone (nonselective COX inhibitor) decreases the diuretic and natriuretic effects of furosemide by nearly 30% but the effects of COX-2 specific inhibitors (firocoxib) and atypical NSAIDs (dipyrone) are unknown., Hypothesis: Furosemide-induced diuresis after pretreatment with firocoxib or dipyrone is diminished to a lesser extent than after pretreatment with phenylbutazone., Animals: Eight healthy mares., Methods: Each mare received 4 treatments in a prospective experimental crossover study using a replicated 4 × 4 Latin Square design: furosemide alone (FU), furosemide and phenylbutazone (PB), furosemide and firocoxib (FX), and furosemide and dipyrone (DP). After 24 hours of NSAID treatment at recommended dosages, ureteral catheters were placed for continual urine collection. After a 30-minute baseline collection period, furosemide (1.0 mg/kg, IV) was administered, and urine and blood samples were collected for 4 hours. Data were assessed by repeated measures ANOVA., Results: Four-hour urine volume was (mean ± SD) ~25% less (P < .001) after pretreatment with all NSAIDs (PB 19.1 ± 2.1 mL/kg, FX 17.7 ± 3.5 mL/kg, DP 19.1 ± 3.9 mL/kg), as compared to FU (23.4 ± 5.1 mL/kg) (P < .001), but there were no differences between PB, FX, or DP. Interindividual variability in furosemide diuresis after pretreatment with different NSAIDs was observed., Conclusions and Clinical Importance: Though COX-2 selective NSAIDs and dipyrone might have less severe or fever gastrointestinal adverse effects in horses, our data suggest minimal differences in effects on furosemide-induced diuresis, and possibly, risk of nephrotoxicosis., (© 2023 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Application of dextran sodium sulfate (DSS) is often used to induce experimental colitis. Current state of the art is to refrain from the use of analgesics due to their possible interaction with the model. However, the use of analgesics would be beneficial to reduce the overall constraint imposed on the animals. Here, we analyzed the effect of the analgesics Dafalgan (paracetamol), Tramal (tramadol) and Novalgin (metamizole) on DSS-induced colitis. To study the effect of those analgesics in colitis mouse models, acute and chronic colitis was induced in female C57BL6 mice by DSS administration in the drinking water. Analgesics were added to the drinking water on days four to seven (acute colitis) or on days six to nine of each DSS cycle (chronic colitis). Tramadol and paracetamol had minor effects on colitis severity. Tramadol reduced water uptake and activity levels slightly, while mice receiving paracetamol presented with a better overall appearance. Metamizole, however, significantly reduced water uptake, resulting in pronounced weight loss. In conclusion, our experiments show that tramadol and paracetamol are viable options for the use in DSS-induced colitis models. However, paracetamol seems to be slightly more favorable since it promoted the overall wellbeing of the animals upon DSS administration without interfering with typical readouts of colitis severity.

Aims: In patients of all ages, metamizole is a frequently used analgesic. Recently, metamizole has been identified as an inducer of, among others, cytochrome P450 (CYP) 3A activity, but the time course of this interaction has not been evaluated., Methods: Using repeated oral microdoses (30 μg) of the CYP3A index substrate midazolam, we assessed changes in midazolam pharmacokinetics (area under the concentration-time curve from 2-4 h: AUC 2-4 and estimated partial metabolic clearance: eCl met ) before, at steady-state, and after discontinuation of 3 × 1000 mg metamizole/day orally for 8 days., Results: Significant changes in pharmacokinetic parameters were detected already 3 days after start of metamizole treatment. At the steady-state of enzyme induction, the geometric mean ratio of midazolam AUC 2-4 was substantially reduced to 0.18 (90% confidence interval: 0.14-0.24) with a corresponding 5.43-fold (4.15-7.10) increase of eCl met . After discontinuation of metamizole, the changes slowly recovered, but were still significant at the end of the observation period on the fifth day after discontinuation of metamizole therapy (AUC 2-4 reduced to 0.50 [0.41-0.63] and eCl met 1.99-fold increased [1.60-2.47, P < 0.05])., Conclusion: Metamizole acts as a strong inducer of CYP3A already few days after start of metamizole administration and, thus, should be avoided in patients using drugs with narrow therapeutic index and major clearance via CYP3A. If their administration is essential, close monitoring and dose adjustment of comedication should be performed as early as the first week after the initiation and after discontinuation of metamizole therapy., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

To avoid false-positive results in immunoassays due to cross-reactivity of antibodies with structural analogues, especially metabolites of target compounds, the preparation of highly specific antibodies is crucial. Preserving the characteristic structure of a target compound when designing a hapten is important when preparing highly specific antibodies. Here, we designed a novel hapten, 4-(((1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1 H -pyrazol-4yl)amino)methyl)benzoic acid, named AA-BA, to improve the specificity of antibodies for detection of 4-methylaminoantipyrine (MAA), a residual marker of dipyrone, an important antipyretic-analgesic and anti-inflammatory drug. The structural features of the hapten remained almost the same as those of MAA. After experimental validation, monoclonal antibody 6A4 (mAb 6A4) was prepared with the half maximal inhibitory concentration (IC 50 ) value of 4.03 ng/mL and negligible cross-reactivity with dipyrone metabolites and other antibiotics. In addition, a specific lateral flow immunoassay (LFA) strip based on colloidal gold was developed for screening MAA with a cutoff value of 25 ng/mL in milk. The developed LFA is a useful tool for rapid and accurate detection of MAA.

Backgraund: There is evidence that the adverse effects of metamizole occur due to the effect of the drug on the hematopoietic stem/progenitor cells, and therefore, the disruption of hematopoiesis. Therefore, our study aimed to evaluate the effects of metamizole on hematopoietic stem/progenitor cells using cell culture techniques., Material and Methods: In our study, samples were taken from stem cell products of healthy allogeneic stem cell transplant donors. The colony-forming unit (CFU) assay was used for the cells obtained from these samples. In addition, the drug effects on cell proliferation were evaluated with the MTT. Furthermore, the cell colonies were labelled with immunofluorescent antibodies and the effects of metamizole on cell types formed in culture were evaluated., Results: We determined that metamizole negatively affects the proliferation of cells, especially starting from 10 µM. As a result of the evaluation of colonization, we saw that the number of colonies decreased with increasing concentrations. Granulocyte-macrophage colonies were more affected at increasing concentrations than other colonies. As a result of the evaluations of our in vitro study, it was also shown as an important finding that the individual effects of the drug were highly variable., Conclusion: CFU method can be used as a suitable method to investigate the effects of drugs and toxic substances on hematopoiesis. We also think it may be suitable for pre-analysing hematopoietic side effects in new drug research. In addition, using stem cell samples in studies may contribute more easily to the in vitro simulation of hematopoietic differentiations (Fig. 7, Ref. 29). Text in PDF www.elis.sk Keywords: metamizole, hematopoietic progenitor cells, hematopoiesis, CFU assay, adverse effect.

Introduction: Dipyrone (metamizol) is regularly used in critical care for pain and fever treatment, especially in Germany and Spain. However, indication for antipyretic therapy in critically ill patients is currently unclear and data for both the risk and benefit of dipyrone treatment in the intensive care environment are scarce. We hypothesized that antipyretic efficiency of dipyrone would not exceed antipyretic efficiency of acetaminophen. We therefore aimed to compare temperature courses in critically ill patients receiving either intravenous dipyrone, acetaminophen or no antipyretic medication., Material and Methods: We included 937 intensive care unit (ICU) patients with body temperature recordings of at least 37.5°C. We investigated temperature decrease associated with dipyrone or acetaminophen and additionally compared it to an untreated control group., Results: Within the eight-hour study interval, maximum body temperature decrease in patients without antipyretic medication was -0.6°C (IQR: -1.0 to -0.4°C; n = 315). Maximal decrease in body temperature was higher both with dipyrone (-0.8°C (IQR: -1.2 to -0.4°C); p = 0.016; n = 341) and acetaminophen (-0.9°C (IQR: -1.6 to -0.6°C); p<0.001; n = 71), but did not differ between dipyrone and acetaminophen (p = 0.066). As compared to untreated patients, dipyrone only led to a marginal additional decrease in body temperature of only -0.1°C. Maximum of antipyretic effectiveness was reached four hours after administration., Conclusion: Antipyretic effectiveness of dipyrone in ICU patients may be overestimated. Given the lack of prospective data, clinical evidence for antipyretic dipyrone therapy in the ICU is insufficient and warrants further critical evaluation., Competing Interests: The authors have declared that no competing interests exist.

Although dipyrone is a widely used analgesic and antipyretic, its mechanism of action is not fully clarified. Recent studies have drawn attention to its central effects and its relationship with the endocannabinoid system. The endocannabinoid system plays important roles in processes such as anxiety, depression, fear, and learning-memory. In this study, we aimed to investigate whether endocannabinoid levels change in the amygdala in chronic unpredictable mild stress model in mice and whether cannabinoid and TRPV1 receptors mediate antidepressant and anxiolytic effects of dipyrone. Mice were submitted to chronic unpredictable mild stress protocol of 6-weeks, then behavioral test were performed. In the first part of the study, dipyrone was injected at doses of 150, 300, and 600 mg/kg (i.p.) during behavioral tests. In the second part, the CB1 antagonist AM 251 (1 mg/kg, i.p.), the CB2 antagonist AM630 (1 mg/kg, i.p.), and the TRPV1 antagonist capsazepine (3 mg/kg, i.p.) were administered alone or in combination with 300 mg/kg dipyrone to observe if these receptors mediate dipyrone effects. Endocannabinoid and N-acylethanolamines levels were measured by LC-MS/MS in amygdala. Our results showed that there were no changes in AEA, 2-AG, PEA, OAE levels in the amygdala in mice exposed to chronic unpredictable mild stress model; dipyrone exerted antidepressant and anxiolytic effects at doses of 300 and 600 mg/kg; its anxiolytic effect appears to be mediated via CB1 receptors, whereas TRPV1 receptors seems to mediate its antidepressant action., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Metamizole is an analgesic and antipyretic drug used intensively in certain countries. Previous studies have shown that metamizole induces cytochrome (CYP) 2B6 and possibly CYP3A4. So far, it is unknown whether metamizole induces additional CYPs and by which mechanism. Therefore, we assessed the activity of 6 different CYPs in 12 healthy male subjects before and after treatment with 3 g of metamizole per day for 1 week using a phenotyping cocktail approach. In addition, we investigated whether metamizole induces CYPs by an interaction with the constitutive androstane receptor (CAR) or the pregnane X receptor (PXR) in HepaRG cells. In the clinical study, we confirmed a moderate induction of CYP2B6 (decrease in the efavirenz area under the plasma concentration time curve (AUC) by 79%) and 3A4 (decrease in the midazolam AUC by 68%) by metamizole. In addition, metamizole weakly induced CYP2C9 (decrease in the flurbiprofen AUC by 22%) and moderately CYP2C19 (decrease in the omeprazole AUC by 66%) but did not alter CYP2D6 activity. In addition, metamizole weakly inhibited CYP1A2 activity (1.79-fold increase in the caffeine AUC). We confirmed these results in HepaRG cells, where 4-MAA, the principal metabolite of metamizole, induced the mRNA expression of CYP2B6, 2C9, 2C19, and 3A4. In HepaRG cells with a stable knockout of PXR or CAR, we could demonstrate that CYP induction by 4-MAA depends on CAR and not on PXR. In conclusion, metamizole is a broad CYP inducer by an interaction with CAR and an inhibitor of CYP1A2. Regarding the widespread use of metamizole, these findings are of substantial clinical relevance., (© 2020 The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Metamizole is used to relieve the visceral pain but its adverse effects limit its use. An alternative to improve its efficacy with lower doses is to combine it with a natural product as hesperidin., Aim of the Study: The aim of this study was to evaluate the antinociceptive interaction between metamizole and hesperidin in a visceral pain model using an isobolographic analysis., Methods: Antinociception was evaluated in the writhing model using acetic acid (1%) to induce writhes in mice. Metamizole (1-316 mg/kg), hesperidin (3-300 mg/kg), or combinations with a fixed-dose ratio of 1:1 were administered intraperitoneally 30 min before the acetic acid and the number of writhes was counted for 30 min. Isobolographic analysis was employed to define the nature of the compound interaction., Results: Metamizole and hesperidin in individual administration induced dose-dependent antinociceptive effects, reached an efficacy of 84.2 ± 5.9% and 66.3 ± 7.4%, respectively. The ED 50 values calculated from their dose-response curves were 84.5 ± 22.7 and 108.9 ± 17.9 mg/kg, respectively. The analysis of DRC for the metamizole + hesperidin combination, in a ratio 1:1 showed a ED 50 COMB value lower than the ED 50 ADD estimated from the additivity line from the isobologram (46.7 ± 6.3 vs. 96.7 ± 11.9 mg/kg, respectively). In addition, the pharmacological interaction calculated was of 0.48. These results suggest a synergistic interaction for the antinociceptive activity of metamizole + hesperidin combination., Conclusion: These data suggest that metamizole + hesperidin combination could be useful in treating visceral pain as it can interact synergistically using low dose of both drugs with the possibility of reducing the risk of adverse effects., (Copyright © 2021. Published by Elsevier Inc.)

Dipyrone (DIP), also known as metamizole, is an over-the-counter analgesic used in Europe and Latin America. Evidence suggesting that inflammatory pain attenuation by DIP is associated with a direct impact on peripheral primary nociceptive neurons through the stimulation of nitric oxide signaling pathway. However, the molecular mechanism by which DIP activates this pathway remains unknown. The PI3Kγ/AKT signaling cascade activation is one of the well-known molecular mechanisms that promote nitric oxide production in sensory neurons. Herein, we investigated the role of the PI3Kγ/AKT signaling cascade in the context of peripheral analgesic effect of DIP. DIP was administered into PGE2 pre-sensitized paws of rats and mechanical hyperalgesia was determined using electronic von Frey test after 1 h. Nonselective or selective pharmacological inhibitors of PI3Kγ and AKT were also administered in DIP-treated rats under paws sensitized with PGE2. Intraplantar injection of DIP attenuated PGE2-induced hyperalgesia in a dose-dependent manner. Treatment with nonselective (wortmannin or LY294002) or selective (AS605240) pharmacological inhibitors of PI3Kγ reduced the peripheral antihypernociceptive effect of DIP. Consistently, AKT selective inhibitor also reversed analgesic DIP effects. Corroborating these data, we found that DIP induced AKT phosphorylation in cultured dorsal root ganglion neurons, which was prevented in the presence of PI3Kγ selective inhibitor. Taken together, these findings provide evidence that peripheral analgesic effect of DIP is dependent on the activation of PI3Kγ/AKT signaling pathway., (© 2020 Société Française de Pharmacologie et de Thérapeutique.)

Objective: Use of injectable metamizole in the outpatient setting is controversial due to safety concerns. We aimed to compare injectable metamizole prescribing patterns for children and adults with further evaluation of nationwide metamizole consumption trend., Materials and Methods: In this retrospective cross-sectional study, 100 injectable drug-containing prescriptions written in each month of 2010 in 32 provinces of Turkey were selected. Drug utilization patterns on injectable metamizole-containing prescriptions (n = 1,270) were analyzed and compared by "pediatric" and "adult" groups. Additionally, nationwide outpatient consumption data from 2010 to 2018 were obtained, and the utilization trend was examined., Results: Children received 12.4% of injectable metamizole-containing prescriptions. Male predominance was observed in children (62.7%), as opposed to female predominance in adults (55.2%, p < 0.05). The most frequent diagnoses were "acute tonsillopharyngitis" and "acute bronchitis" in both groups. Single-diagnosis prescriptions constituted 79.1% of the pediatric group and 53.1% of the adult group (p < 0.05). Diagnoses, drugs, and injectable analgesics per prescription were significantly higher in adults (1.68 ± 0.86, 3.45 ± 0.90, and 1.06 ± 0.23, respectively) than in children (1.22 ± 0.43, 3.25 ± 0.88, and 1.00, respectively) (p < 0.05). The percentage of prescriptions containing injectable antibiotics was higher in children (83.6%) than in adults (64.9%). Outpatient injectable metamizole consumption showed a decreasing trend in 2010 - 2018., Conclusion: Despite recent downward trend, prescribing of injectable metamizole in primary care was considerably prevalent. This study, which highlights fundamental differences among metamizole utilization patterns in children and adults, addresses the inadequacy of rational use of the drug in terms of preferred indications and accompanying drugs.

Agranulocytosis is a rare yet severe idiosyncratic adverse drug reaction to metamizole, an analgesic widely used in countries such as Switzerland and Germany. Notably, an underlying mechanism has not yet been fully elucidated and no predictive factors are known to identify at-risk patients. With the aim to identify genetic susceptibility variants to metamizole-induced agranulocytosis (MIA) and neutropenia (MIN), we conducted a retrospective multi-center collaboration including cases and controls from three European populations. Association analyses were performed using genome-wide genotyping data from a Swiss cohort (45 cases, 191 controls) followed by replication in two independent European cohorts (41 cases, 273 controls) and a joint discovery meta-analysis. No genome-wide significant associations ( p < 1 × 10 -7 ) were observed in the Swiss cohort or in the joint meta-analysis, and no candidate genes suggesting an immune-mediated mechanism were identified. In the joint meta-analysis of MIA cases across all cohorts, two candidate loci on chromosome 9 were identified, rs55898176 (OR = 4.01, 95%CI: 2.41-6.68, p = 1.01 × 10 -7 ) and rs4427239 (OR = 5.47, 95%CI: 2.81-10.65, p = 5.75 × 10 -7 ), of which the latter is located in the SVEP1 gene previously implicated in hematopoiesis. This first genome-wide association study for MIA identified suggestive associations with biological plausibility that may be used as a stepping-stone for post-GWAS analyses to gain further insight into the mechanism underlying MIA.

Non-steroidal anti-inflammatory drugs produce antinociceptive effects mainly through peripheral cyclooxygenase inhibition. In opposition to the classical non-steroidal anti-inflammatory drugs, paracetamol and dipyrone exert weak anti-inflammatory activity, their antinociceptive effects appearing to be mostly due to mechanisms other than peripheral cyclooxygenase inhibition. In this review, we classify classical non-steroidal anti-inflammatory drugs, paracetamol and dipyrone as “non-opioid analgesics” and discuss the mechanisms mediating participation of the endocannabinoid system in their antinociceptive effects. Non-opioid analgesics and their metabolites may activate cannabinoid receptors, as well as elevate endocannabinoid levels through different mechanisms: reduction of endocannabinoid degradation via fatty acid amide hydrolase and/or cyclooxygenase-2 inhibition, mobilization of arachidonic acid for the biosynthesis of endocannabinoids due to cyclooxygenase inhibition, inhibition of endocannabinoid cellular uptake directly or through the inhibition of nitric oxide synthase production, and induction of endocannabinoid release.

Background: Treatment of neuropathic pain is still challenging. Recent studies have suggested that dorsal root ganglia (DRG), which carry sensory neural signals from the peripheral nervous system to the central nervous system, are important for pathological nociception. A proper understanding of the significance and function of DRG and their role in pharmacotherapy can help to improve the treatment of neuropathic pain. Metamizole, also known as sulpyrine or dipyrone, is a non-opioid analgesic commonly used in clinical practice, but it is not used for neuropathic pain treatment., Methods: Chronic constriction injury (CCI) of the sciatic nerve was induced in Wistar rats. Metamizole was administered intraperitoneally (ip) preemptively at 16 and 1 h before CCI and then twice a day for 7 days. To evaluate tactile and thermal hypersensitivity, von Frey and cold plate tests were conducted, respectively., Results: Our behavioral results provide evidence that repeated intraperitoneal administration of metamizole diminishes the development of neuropathic pain symptoms in rats. Simultaneously, our findings provide evidence that metamizole diminishes the expression of pronociceptive interleukins (IL-1beta, IL-6, and IL-18) and chemokines (CCL2, CCL4, and CCL7) in DRG measured 7 days after sciatic nerve injury. These assays indicate, for the first time, that metamizole exerts antinociceptive effects on nerve injury-induced neuropathic pain at the DRG level., Conclusions: Finally, we indicate that metamizole-induced analgesia in neuropathy is associated with silencing of a broad spectrum of cytokines in DRG. Our results also suggest that metamizole is likely to be an effective medication for neuropathic pain.

Background and Purpose: While dipyrone is a widely used analgesic, its mechanism of action is not completely understood. Recently, we have reported that the dipyrone metabolite 4-aminoantipyrine (4-AA) reduces PGE 2 -induced pain-related behaviour through cannabinoid CB 1 receptors. Here, we ascertained, in naive and PGE 2 -induced "inflamed" conditions, both in vivo and in vitro, the molecular mechanisms involved in the 4-AA-induced analgesic effects., Experimental Approach: The effect of local administration of 4-AA (160 μg per paw) on capsaicin (0.12 μg per paw) injection-induced pain-related behaviour and 4-AA's effect on 500-nM capsaicin-induced changes in intracellular calcium concentration ([Ca 2+ ] i ) in cultured primary sensory neurons were assessed in vivo and in vitro, respectively., Key Results: 4-AA reduced capsaicin-induced nociceptive behaviour in naive and inflamed conditions through CB 1 receptors. 4-AA (100 μM) reduced capsaicin-induced increase in [Ca 2+ ] i in a CB 1 receptor-dependent manner, when PGE 2 was not present. Following PGE 2 application, 4-AA (1-50 μM) increased the [Ca 2+ ] i . Although 4-AA activated both TRPV1 and TRPA1 channels, increased [Ca 2+ ] i was mediated through TRPV1 channels. Activation of TRPV1 channels resulted in their desensitisation. Blocking CB 1 receptors reduced both the excitatory and desensitising effects of 4-AA., Conclusion and Implications: CB 1 receptor-mediated inhibition of TRPV1 channels and TRPV1-mediated Ca 2+ -influx- and CB 1 receptor-dependent desensitisation of TRPV1 channels contribute to the anti-nociceptive effect of 4-AA in naive and inflamed conditions respectively. Agonists active at both CB 1 receptors and TRPV1 channels might be useful as analgesics, particularly in inflammatory conditions., (© 2020 The British Pharmacological Society.)

Background: Normothermic ex vivo liver perfusion (NEVLP) is a promising strategy to increase the donor pool in liver transplantation. Small animal models are essential to further investigate questions regarding organ preservation and reconditioning by NEVLP. A dual vessel small animal NEVLP (dNEVLP) model was developed using metamizole as a vasodilator and compared to conventional portovenous single vessel NEVLP (sNEVLP)., Methods: Livers of male Wistar rats were perfused with erythrocyte-supplemented culture medium for six hours by either dNEVLP via hepatic artery and portal vein or portovenous sNEVLP. dNEVLP was performed either with or without metamizole treatment. Perfusion pressure and flow rates were constantly monitored. Transaminase levels were determined in the perfusate at the start and after three and six hours of perfusion. Bile secretion was monitored and bile LDH and GGT levels were measured hourly. Histopathological analysis was performed using liver and bile duct tissue samples after perfusion., Results: Hepatic artery pressure was significantly lower in dNEVLP with metamizole administration. Compared to sNEVLP, dNEVLP with metamizole treatment showed higher bile production, lower levels of transaminases during and after perfusion as well as significantly lower necrosis in liver and bile duct tissue. Biochemical markers of bile duct injury showed the same trend., Conclusion: Our miniaturized dNEVLP system enables normothermic dual vessel rat liver perfusion. The administration of metamizole effectively ameliorates arterial vasospasm allowing for six hours of dNEVLP, with superior outcome compared to sNEVLP., Competing Interests: The authors have declared that no competing interests exist.

Pain is a classical sign of inflammation, and sensitization of primary sensory neurons (PSN) is the most important mediating mechanism. This mechanism involves direct action of inflammatory mediators such as prostaglandins and sympathetic amines. Pharmacologic control of inflammatory pain is based on two principal strategies: (i) non-steroidal anti-inflammatory drugs targeting inhibition of prostaglandin production by cyclooxygenases and preventing nociceptor sensitization in humans and animals; (ii) opioids and dipyrone that directly block nociceptor sensitization via activation of the NO signaling pathway. This review summarizes basic concepts of inflammatory pain that are necessary to understand the mechanisms of peripheral NO signaling that promote peripheral analgesia; we also discuss therapeutic perspectives based on the modulation of the NO pathway., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Dipyrone is an analgesic pro-drug used clinically to control moderate pain with a high analgesic efficacy and low toxicity. Dipyrone is hydrolyzed to 4-methylaminoantipyrine (4-MAA), which is metabolized to 4-aminoantipyrine (4-AA). Here, were investigate the involvement of peripheral cannabinoid CB 2 and opioid receptor activation in the local antihyperalgesic effect of dipyrone and 4-MAA. The inflammatory agent, carrageenan was administered to the hindpaw of male Wistar rats, and the mechanical nociceptive threshold was quantified by electronic von Frey test. Dipyrone or 4-MAA were locally administered 2.5 h after carrageenan. Following dipyrone injection, hindpaw tissue was harvested and its hydrolysis to 4-MAA was analyzed by mass spectrometry (MS). The selective CB 2 receptor antagonist (AM630), naloxone (a non-selective opioid receptor antagonist), nor-BNI (a selective kappa-opioid receptor), CTOP (a selective mu-opioid receptor), or naltrindole (a selective delta-opioid receptor) was administered 30 min prior to 4-MAA. The results demonstrate that carrageenan-induced mechanical hyperalgesia was inhibited by dipyrone or 4-MAA in a dose-dependent manner. Dipyrone administered to the hindpaw was completely hydrolyzed to 4-MAA. The antihyperalgesic effect of 4-MAA was completely reversed by AM630, naloxone and nor-BNI, but not by CTOP or naltrindole. These data suggest that the local analgesic effect of dipyrone is mediated by its hydrolyzed bioactive form, 4-MAA and, at least in part, depends on CB 2 receptor and kappa-opioid receptor activation. In conclusion, the analgesic effect of dipyrone may involve a possible interaction between the cannabinoid and opioid system in peripheral tissue., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Central neuropathic pain is a common untreated symptom in progressive multiple sclerosis (PMS) and is associated with poor quality of life and interference with patients' daily activities. The neuroinflammation process and mitochondrial dysfunction in the PMS lesions generate reactive species. The transient potential receptor ankyrin 1 (TRPA1) has been identified as one of the major mechanisms that contribute to neuropathic pain signaling and can be activated by reactive compounds. Thus, the goal of our study was to evaluate the role of spinal TRPA1 in the central neuropathic pain observed in a PMS model in mice. We used C57BL/6 female mice (20-30 g), and the PMS model was induced by the experimental autoimmune encephalomyelitis (EAE) using mouse myelin oligodendrocyte glycoprotein (MOG 35-55 ) antigen and CFA (complete Freund's adjuvant). Mice developed progressive clinical score, with motor impairment observed after 15 days of induction. This model induced mechanical and cold allodynia and heat hyperalgesia which were measured up to 14 days after induction. The hypersensitivity observed was reduced by the administration of selective TRPA1 antagonists (HC-030031 and A-967079, via intrathecal and intragastric), antioxidants (α-lipoic acid and apocynin, via intrathecal and intragastric), and TRPA1 antisense oligonucleotide (via intrathecal). We also observed an increase in TRPA1 mRNA levels, NADPH oxidase activity, and 4-hydroxinonenal (a TRPA1 agonist) levels in spinal cord samples of PMS-EAE induced animals. In conclusion, these results support the hypothesis of the TRPA1 receptor involvement in nociception observed in a PMS-EAE model in mice.

Low levels of brain-derived neurotrophic factor (BDNF), a key regulator of synaptic plasticity, are associated with neurological diseases, including depression and Alzheimer's disease. Therefore, BDNF is a drug target for these diseases. Here we screened for inducers of neuronal Bdnf expression from a pharmacologically validated compound library using our recently developed screening assay based on luciferase activity in cultured cortical neurons. We identified 18 pharmacologically validated compounds, most of which were inferred to induce Bdnf expression by their validated pharmacological actions, such as G s -coupled receptor activation or neuronal excitation. Unexpectedly, the screening assay identified the antipyretic drug, dipyrone, to increase Bdnf expression. Dipyrone induced endogenous Bdnf expression by Ca 2+ influx evoked via L-type voltage-dependent Ca 2+ channels and the N-methyl-d-aspartate receptor, indicating that dipyrone induced activity-regulated Bdnf expression in neurons. However, dipyrone-induced Bdnf expression is independent of validated pharmacological effects. Although our screening assay is difficult to reveal how active compounds induce Bdnf expression, this method is convenient to identify inducers of Bdnf expression in primary neurons. Our screening assay evaluated neuronal BDNF induction and can be used to screen for drug re-positioning, as well as novel candidate drugs, for neurological diseases that have low levels of BDNF in the brain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The clinical relevance of the drug interaction between valproic acid and dipyrone is presented in the context of a gerontopsychiatric case. It is assumed that dipyrone at a dose of 4 g/d has a relevant influence on the valproate level and the associated clinical outcome. This may be due to a possible induction of CYP2B6 and increased valproate metabolism. In the case of a treatment of valproate combined with dipyrone, a close monitoring of the valproate level is recommended., Competing Interests: Die Autoren geben an, dass kein Interessenkonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)

Tagetes lucida Cav. (Asteraceae) is an ancient medicinal plant commonly used to alleviate pain. Nevertheless, scientific studies validating this property are lacking in the literature. Animal models of pain were used to evaluate the antinociceptive and anti-inflammatory activities of T. lucida essential oil (TLEO) and a bioactive metabolite. The chemical constitution and possible toxicity of the extract and the mechanism of action of β-caryophyllene were also explored. Temporal course curves and dose-response graphics were generated using TLEO (0.1-10 mg/kg or 3.16-31.62 mg/kg) and β-caryophyllene (3.16-10 mg/kg). Metamizole (80 mg/kg) and indomethacin (20 mg/kg) were used as reference drugs in the formalin assay and writhing test in rats and mice, respectively. The β-caryophyllene mechanism of action was explored in the presence of naloxone (1 mg/kg), flumazenil (10 mg/kg), WAY100635 (0.16 mg/kg), or nitro-l-arginine methyl ester (L-NAME) (20 mg/kg) in the formalin test in rats. GC/MS analysis demonstrated the presence of geranyl acetate (49.89%), geraniol (7.92%), and β-caryophyllene (6.27%). Significant and dose-dependent antinociceptive response was produced by TLEO and β-caryophyllene without the presence of gastric damage. In conclusion, β-caryophyllene was confirmed as a bioactive compound in the T. lucida analgesic properties by involving the participation of receptors like opioids, benzodiazepines, and Serotonin 1A receptor (5-HT 1A ), as well as nitric oxide.

Aim: Metamizole is a frequently used antipyretic and analgesic prodrug, yet its pharmacokinetics has not been thoroughly studied in infants and with coadministered medications. Thus, an LC-MS/MS method was developed to quantify the four major metamizole metabolites in human plasma. Methodology: Pre- and postcolumn infusion was installed to enable robust analyte retention and electrospray ionization following deproteinization of plasma samples. Results: The method was linear (R > 0.996), accurate (93.1-106.0%) and precise (≤12.7%). Mean recovery was more than 91.8% and ion suppression less than 13.1% for all analytes. Pharmacokinetic profiles were reproducible after 4 years at -80°C except for the formylated metabolite (-22.2%). Conclusion: The method fulfilled pertinent criteria of validation guidelines and required only little sample volume. The method therefore qualifies for metamizole analyses in children.

Background: Leakage following colorectal anastomosis surgery causes various complications associated with high morbidity and mortality, especially in pediatric patients. It might be caused by the use of non-steroidal anti-inflammatory drugs (NSAIDs) as postoperative analgesics. This study aimed to compare the effect of metamizole and paracetamol on colonic anastomosis and fibroblast activities, including proliferation, migration, and collagen synthesis, in Wistar rats., Methods: Rats were divided into control, paracetamol and metamizole groups. The colonic anastomosis was evaluated by determining the integrity of the muscle layers, the formation of granulation tissue, and mucosal anastomosis. Fibroblast activities were analyzed by measuring the proliferation, migration, and collagen synthesis., Results: Metamizole caused more damage to muscle layer integrity, more inhibition of granulation tissue formation in the anastomosis area and lower mucosal anastomosis compared with paracetamol and control groups. Metamizole had a higher cytotoxic effect than paracetamol, which suppressed the proliferation and migration of fibroblasts. Furthermore, both drugs did not affect the synthesis of collagen., Conclusion: Metamizole shows worse effects on the integrity of muscle layers, inhibition of granulation tissue formation, mucosal anastomosis, fibroblast proliferation, and migration, but not collagen synthesis, than paracetamol in Wistar rat intestines following colonic anastomosis. These findings might indicate that paracetamol is safer than metamizole as analgesic following colonic anastomosis.

Postoperative ileus (POI) is a common complication after abdominal surgery characterized by motility disturbances leading to increased morbidity and mortality in surgical patients. Intestinal manipulation of the murine small bowel is an established animal model resulting in an increased postsurgical inflammation within the intestinal muscular externa and a delayed gastrointestinal transit. Some analgesics have been shown to affect inflammation. In this study, we compared the immunomodulatory effects of two different analgesics. Mice were treated with tramadol, metamizole or saline as a control in our established POI model. The postoperative inflammatory response was assessed by gene expression of pro-inflammatory cytokines at different time points and immunocytes extravasation into the muscularis externa. Functional motility analyses were performed by a gastrointestinal transit measurement. Metamizole application reduced the pro-inflammatory response after surgery and improved gastrointestinal motility, while tramadol showed no alteration in cytokine gene expression, influx of immunocytes and gastrointestinal transit compared with the controls. In conclusion. we suggest tramadol as analgesia in immunological studies on POI in mice as it does not affect the underlying inflammation of POI.

Objective: Evaluation the development of perioperative body temperature while administrating a combination of acepromazine and metamizol (AM) versus anesthesia with acepromazine (A) alone., Material and Methods: In this prospective, quasi-randomized controlled study 20 dogs undergoing standardized tibial plateau leveling osteotomy were alternatingly assigned to group A or group AM (n = 10 each). The patients' body temperature values were recorded from the time of premedication up to its post-surgical return to reference values., Results: Body temperature decreases during anesthesia in both groups were comparable (p = 0.12). Postoperatively on the other hand, temperature development differed significantly between the two groups (p = 0.0455). In 6 dogs of the group AM, body temperature continued to decrease following extubation prior to returning to normothermic values., Conclusion: Intraoperatively, all patients developed hypothermia, regardless of the investigated anesthetic medication administered. Postoperatively, patients not receiving metamizol reached normothermia more rapidly., Competing Interests: Die Autoren bestätigen, dass kein Interessenkonflikt besteht., (© Georg Thieme Verlag KG Stuttgart · New York.)

The cannabinoid system has been suspected to play a role in the mechanisms of action of dipyrone and paracetamol. Our purpose was to measure the local endocannabinoid and N-acylethanolamide levels in the brain and spinal cord of rats following dipyrone and paracetamol administration. Nociception was assessed 1, 5, and 12 h following drug injections in Wistar rats, using tail-flick and hot-plate tests. The antinociceptive effects of dipyrone (150, 300, and 600 mg/kg, i.p.) and paracetamol (30, 100, and 300 mg/kg, i.p.) were observed. After administration of the highest doses of dipyrone and paracetamol, endocannabinoid (N-arachidonoylethanolamide (AEA), 2-arachidonoylglycerol (2-AG)) and N-acylethanolamide (palmitoylethanolamide (PEA), oleoylethanolamide (OEA)) levels were measured in the periaqueductal gray (PAG), rostral ventromedial medulla (RVM), and spinal cords of rats using tandem mass spectrometry with liquid chromatography. Increased 2-AG levels were observed in the PAG and the RVM 12 h after paracetamol injection; dipyrone exerted no action on 2-AG levels. Analgesic administrations led to a reduction in AEA levels in the RVM and spinal cord; similar decreases in PEA and OEA levels were observed in the RVM and the spinal cord. Dipyrone and paracetamol administrations appear to exert complicated effects on endocannabinoid and N-acylethanolamide levels in rats.

In accordance with the 'refinement' component of the 3Rs, the primary aim of this study was to investigate and compare ketamine + medetomidine (KM) and s-ketamine + medetomidine (SKM) anaesthetic protocols in C57BL/6J mice (both sexes). We sought to determine whether s-ketamine could provide adequate surgical tolerance at a 50% dose relative to that of ketamine racemate and whether antagonism of medetomidine could be initiated 15 min earlier. The second aim was to investigate the potential improvement in analgesia for both anaesthetic protocols by adding butorphanol or metamizole. Analgesia was tested via the pedal withdrawal reaction (PWR) to a painful stimulus. During anaesthesia, respiratory frequency, pulse oximetry, body temperature and PWR were monitored. Among the 16 mice in each group, the PWR was lost in all the KM + metamizole (35:56 ± 6:07 min), KM + butorphanol (43:45 ± 2:14 min) and SKM + butorphanol (24:03 ± 5:50 min) mice, 15 of the non-premedicated KM (37:00 ± 8:11 min) mice, and 9 of the pure SKM (20:00 ± 4:19 min) mice; the latter group increased to 11 mice (17:16 ± 5:10 min) with premedication of metamizole. In contrast to the racemic combination, s-ketamine at the dose used here did not lead to sufficient loss of the PWR. However, earlier partial antagonism of SKM resulted in a slightly shorter and qualitatively better recovery than later partial antagonism of SKM. The addition of metamizole or butorphanol to KM or SKM anaesthesia positively influences the analgesic quality. However, when butorphanol is added, controlled ventilation may be necessary, especially for male mice.

Dipyrone (metamizole), acting through its main metabolites 4-methyl-amino-antipyrine and 4-amino-antipyrine, has established analgesic, antipyretic, and spasmolytic pharmacological effects, which are mediated by poorly known mechanisms. In rats, intravenously administered dipyrone delays gastric emptying (GE) of liquids with the participation of capsaicin-sensitive afferent fibers. This effect seems to be mediated by norepinephrine originating from the sympathetic nervous system but not from the superior celiac-mesenteric ganglion complex, which activates β2-adrenoceptors. In rats, in contrast to nonselective non-hormonal anti-inflammatory drugs, dipyrone protects the gastric mucosa attenuating the development of gastric ulcers induced by a number of agents. Clinically, it has been demonstrated that dipyrone is effective in the control of colic-like abdominal pain originating from the biliary and intestinal tracts. Since studies in humans and animals have demonstrated the presence of β2-adrenoceptors in biliary tract smooth muscle and β2-adrenoceptor activation has been shown to occur in dipyrone-induced delayed GE, it is likely that this kind of receptors may participate in the reduction of smooth muscle spasm of the sphincter of Oddi induced by dipyrone. There is no evidence that dipyrone may interfere with small bowel and colon motility, and the clinical results of its therapeutic use in intestinal colic appear to be due to its analgesic effect.

This experiment was carried out aiming to assess walking manner and speed of broiler chickens with different gait scores (GS), with or without sound stimulus, and with or without administration of analgesic. To that end, 1,000 birds were evaluated by the GS test and 74 were selected for walking speed analyses. Weight at slaughter and breast yield values were obtained for comparisons. Walking speed analyses, both with and without analgesic and with and without stimulus were performed. Non-parametric statistics was applied to the GS data that did not meet the assumptions of the statistical model (normality and homogenicity) using Fisher's exact test according to the data behavior (P<0.05). The analyses of data on speed, weight at slaughter, and breast yield were evaluated by ANOVA and compared by Tukey's test (P<0.05). Walking speed differed after acoustic stimulus with or without administration of metamizole sodium. Body weight was also different in each GS. It is thus concluded that the birds may feel discomfort when their GS is higher than 0, but that such discomfort may be suppressed when they are stimulated to walk., Competing Interests: The authors have declared that no competing interests exist.

Background: Dipyrone comedication in aspirin-treated patients is associated with impaired pharmacodynamic response to aspirin (high on-treatment platelet reactivity [HTPR]). Additionally, in small observational studies, an association with impaired outcome has been described. In this uncontrolled, hypothesis-generating study, we aimed to investigate strategies to prevent this drug-drug interaction in patients with coronary artery disease (CAD)., Methods: We analyzed pharmacodynamic response to aspirin in 80 dipyrone co-medicated CAD patients. Aspirin antiplatelet effects were measured using arachidonic acid (AA)-induced light-transmission aggregometry (LTA). Platelet reactivity was associated with daily dose, administration form, and frequency. Additionally, we conducted a time-series analysis in patients with HTPR to aspirin with re-evaluation of pharmacodynamic response to aspirin after 5 days., Results: Patients' mean age was 75.5 ± 9.8 years. Forty-three (54%) were male, 22 (27.5%) obese, and 38 (47.5%) diabetics. Baseline characteristics, cardiovascular risk factors, comorbidities, comedication, or laboratory parameters did not differ between patients with or without HTPR. HTPR to aspirin occurred in 34 out of 80 patients (42.5%). The incidence of HTPR was associated with dipyrone daily dose (< 1 g/day: HTPR 20% vs. > 3 g/day: HTPR 50%, p > 0.0001) and form of administration (i.v. 87.5% vs. oral 37.5%; p < 0.0001). A strict order of intake (aspirin 30 min prior to dipyrone) restored aspirin antiplatelet effects in all patients (HTPR before 100% vs. HTPR after 0%, p = 0.0002)., Conclusion: This study shows that dipyrone should be used with caution in aspirin-treated patients. If dipyrone seems indispensable, the lowest effective dose and a strict order of intake seem favorable.

Metamizol (also known as dipyrone or sulpyrine) is one of the non-opioid analgesics commonly used in clinical practice in the treatment of somatic and visceral pain. Here, our results give evidence that repeated twice daily intraperitoneal metamizol administration during 7 days diminished development of neuropathic pain symptoms in a mouse model of neuropathic pain. We observed that metamizol inhibited the activation of spinal microglia in neuropathic mice. Moreover, our findings provide evidence that pronociceptive (IL-1β, XCL1, and CCL2), but not antinociceptive (IL-1α, IL-1RA, and IL-18BP), factors play an important role in metamizol-induced antinociception. We observed that metamizol influences the spinal levels of the nociceptin receptor (NOP) but does not alter the expression of other members of the opioid receptor family (mu (MOP), delta (DOP) and kappa (KOP)), or other important nociception receptors (transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1)). Metamizol administration did not affect the levels of the opioid prohormones (proopiomelanocortin (POMC), proenkephalin (PENK), prodynorphin (PDYN), and pronociceptin (PNOC)). However, we observed an enhanced antinociceptive effect of oxycodone, but not buprenorphine, after metamizol treatment. In conclusion, we found that metamizol-induced analgesia in neuropathy is associated with silencing microglia activation and, consequently, with a reduction in pronociceptive cytokines. These results provide evidence that metamizol may join the modest arsenal of effective remedies for neuropathic pain and may constitute part of a multimodal pain therapy., (Copyright © 2018. Published by Elsevier Inc.)

Abdominal pain is a common health problem that requires efficacious and safe therapy. Broccoli is a rich source of health-promoting bioactive compounds with potential for pain therapy. However, there is a lack of scientific pharmacological evidence to support this. Our aim was to investigate the antinociceptive and spasmolytic activities of broccoli aqueous extracts from seeds, sprouts, and inflorescence, as well as some metabolites. Experiments were done using enteral and parenteral administration in an in vivo model of pain accompanied with an in vitro assay. Data established that sprouts (100 mg/kg, i.p. and 1000 mg/kg, p.o.) produced significant and major antinociceptive effect at similar or even lower doses in comparison to the seeds (125 mg/kg, i.p. and 1000 mg/kg, p.o.) and broccoli heads (250 mg/kg, i.p. and 1000 mg/kg, p.o.). These results resembled the analgesic response observed with the reference drug metamizole (80 mg/kg, i.p.). Chlorogenic acid (CA, 3, 10, 30, and 100 mg/kg, i.p.) and SFN (0.1, 1 and 10 mg/kg, i.p.) were partial responsible antinociceptive metabolites of broccoli. SFN effects involved participation of endogenous opioids, since they were inhibited in the presence of naltrexone (5 mg/kg, s.c.). In the in vitro assay, a significant 80% spasmolytic-like response was reached with SFN alone in comparison to 20% obtained with aqueous extracts of sprouts and seeds. Participation of calcium channels was a mechanism involved in the in vitro response of SFN. In conclusion, broccoli sprouts, SFN and CA are potential nutraceuticals for abdominal pain therapy., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background: Antidepressants have been found to possess antinociceptive and analgesic properties and are prescribed in the treatment of chronic pain., Aim: To evaluate the antinociceptive properties of escitalopram after a single administration., Materials and Methods: Forty Wistar rats were used in the study. They were divided into 5 groups (n=8) treated with saline solution (control group), metamizole (150 mg/kg b.w.), escitalopram (5, 10 and 20 mg/kg b.w.) intraperitoneally. The nociceptive tests we used employed thermal (hot plate and plantar test), mechanical (analgesimeter) and chemical (formalin test) stimuli. Criteria for analgesic effect were increased latency in hot plate, plantar test, analgesimeter and decreased paw licking time in formalin test., Results: The reference analgesic metamizole showed significant analgesic effect in all tests excluding the first phase with formalin. Escitalopram in doses of 5 and 20 mg/kg b.w. increased paw withdrawal latency in analgesimeter at 2 hours compared to control. Escitalopram in a dose of 5 mg/kg b.w. increased the duration of the stay on the hot plate at 1 hour, while doses of 10 and 20 mg/kg b.w. significantly increased this indicator at 1 and 3 hours in comparison to the saline treated group. In the plantar test, escitalopram in all used doses significantly increased the nociceptive response latency compared to control. A dose of 5 mg/kg b.w. decreased hind paw licking time during phase 1 of the formalin test, whereas doses of 10 and 20 mg/kg b.w. decreased phase 2 licking time compared to the control group., Conclusion: The antidepressant escitalopram has analgesic properties but they are not dose- or time-dependent.

Background: The antifungal activity of some popular analgesic drugs was postulated by several authors., Objectives: The aim of this study was to verify the antifungal effectiveness of acetylsalicylic acid, ibuprofen, metamizole, meloxicam and paracetamol against triazole-susceptible and triazole-resistant Candida spp isolates., Methods: The minimal inhibitory concentration as well as fractional inhibitory concentration of selected analgesics and triazole on eighteen Candida spp isolates were determined by the standard microdilution method according to EUCAST., Results: Among five tested compounds, only ibuprofen showed an antifungal effect against all tested isolates. In combination tests of analgesics with triazole, three types of interaction have been observed: indifference, synergism and antagonism. An azole-resistant strain of C. albicans demonstrated synergism with IBU and each of the 5 tested azole. Posaconazole also demonstrated synergism with IBU in two other cases, namely a C. albicans strain and with C. glabrata, which were both azole-resistant. Combination of FLU and IBU in two cases resulted in antagonism: in experiments with C. glabrata and C. tropicalis. This interaction was also observed when metamizole and fluconazole were used in combination on C. krusei., Conclusions: The results obtained by us confirmed antifungal activity of ibuprofen, what support purposefulness to continue the study on antimicrobial activity of this group of drugs., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Background/aim: The perioperative phase is supposed to be a period with high vulnerability for cancer dissemination. Acetaminophen and metamizole are common analgesics administered during this phase. We investigated the effect of acetaminophen, metamizole and 4-methylaminoantipyrine (MAA) on proliferation and apoptosis of colon carcinoma cell lines (SW 480 and HT 29)., Materials and Methods: Proliferation was detected by cell proliferation ELISA BrdU, and apoptosis by Annexin V staining. Cytochrome c and caspase 3, 8 and 9 expression levels were detected by western blot., Results: Acetaminophen, metamizole or MAA caused slight changes in proliferation. Acetaminophen, metamizole or the combination increased apoptosis in both cell lines. All agents decreased caspase 3 and 8 expression in SW480. Acetaminophen decreased caspase 9 expression in both cell lines., Conclusion: In clinically relevant doses, acetaminophen and/or metamizole induce apoptosis in both colon cancer cell lines. Both mitochondrial and death receptor pathways might be involved in acetaminophen-induced apoptosis., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: To evaluate the effects of dipyrone on sensitivity to aspirin (acetylsalicylic acid [ASA]) in patients who underwent peripheral artery vascular reconstruction., Subjects and Methods: Impedance aggregometry and light transmission aggregometry were used to determine the effects of dipyrone on ASA treatment in 21 patients. Blood samples were drawn in a 7-day period after the surgery. The cut-off value for high on-treatment platelet reactivity (HTPR) was set at < 65% of aggregation inhibition for impedance aggregometry. For light transmission aggregometry the cut-off value for arachidonic acid-induced aggregation was set at > 20% of aggregating platelets, and the cut-off value for epinephrine-induced aggregation was > 44% of aggregating platelets. The cut-off value for each method was derived from a large number of patients treated with a daily dose of 100 mg of ASA., Results: We found HTPR in 14 (67%) of the 21 patients. None had primary resistance to ASA, i.e., after the addition of ASA in vitro all samples showed antiplatelet efficacy. Regression analysis showed a possible correlation between lower efficacy of ASA treatment and higher daily doses of dipyrone (p = 0.005 for impedance aggregometry, p = 0.04 for light transmission aggregometry), higher platelet count (p = 0.005 for impedance aggregometry), and shorter time from surgery (p = 0.03 for impedance aggregometry)., Conclusion: HTPR occurs in 67% of ASA-treated patients after lower limb vascular surgery. The occurrence of HTPR correlates with the daily dose of dipyrone. Therefore, dipyrone should not be used as a postoperative analgesic in ASA-treated patients after peripheral artery revascularisation due to its influence on the effectiveness of ASA., (© 2018 The Author(s) Published by S. Karger AG, Basel.)

Background: Adenocarcinoma of the pancreas is one of the most aggressive cancer diseases affecting the human body. Recent research has shown the importance of the perioperative phase in disease progression. Particularly during this vulnerable phase, substances such as metamizole and paracetamol are given as general anesthetics and postoperative analgesics. Therefore, the effects of metamizole and paracetamol on tumor progression should be investigated in more detail because the extent to which these substances influence the carcinogenesis of pancreatic carcinoma is still unclear. This study analyzed the influence of metamizole and its active metabolites MAA (4-N-methyl-aminoantipyrine) and paracetamol on the proliferation, apoptosis, and necrosis of the pancreatic cancer cell lines PaTu 8988t and Panc-1 in vitro., Methods: Cell proliferation was measured by means of the ELISA BrdU assay and the rate of apoptosis by flow cytometry using the Annexin V assay., Results: Metamizole and paracetamol significantly inhibited cell proliferation in pancreatic cancer cells. After the addition of metamizole to PaTu 8988t cells, the rate of apoptosis was reduced after 3 h of incubation but significantly increased after 9 h of incubation., Conclusion: The oncogenic potential of pancreatic adenocarcinoma is mainly characterized by its extreme growth rate. Non-opioid analgesics such as metamizole and paracetamol are given as general anesthetics and postoperative analgesics. The combination of metamizole or paracetamol with cytotoxic therapeutic approaches may achieve synergistic effects. Further studies are necessary to identify the underlying mechanisms so that new therapeutic options may be developed for the treatment of this aggressive tumor.

Atropine (AT) and dipyrone (Dp) induce a delay of gastric emptying (GE) of liquids in rats by inhibiting muscarinic receptors and activating β2-adrenergic receptors, respectively. The objective of the present study was to determine the effects of pretreatment with AT and Dp, given alone or in combination, on the effect of hypoglycemia in the liquid GE in rats. Male Wistar adult rats (280-310 g) were pretreated intravenously with AT, Dp, AT plus Dp or their vehicle and then treated 30 min later with iv insulin or its vehicle (n=8-10 animals/group). Thirty min after treatment, GE was evaluated by determining, in awake rats, the percent gastric retention (%GR) of a saline meal labeled with phenol red administered by gavage. The results indicated that insulin induced hypoglycemia in a dose-dependent manner resulting in a significant reduction in %GR of liquid only at the highest dose tested (1 U/kg). Pretreatment with AT significantly increased %GR in the rats treated with 1 U/kg insulin. Surprisingly, after pretreatment with AT, the group treated with the lowest dose of insulin (0.25 U/kg) displayed significantly lower %GR compared to its control (vehicle-treated group), which was not seen in the non-pretreated animals. Pretreatment with Dp alone at the dose of 40 mg/kg induced an increase in %GR in both vehicle and 0.25 U/kg-treated rats. A higher dose of Dp alone (80 mg/kg) significantly reduced the effect of a marked hypoglycemia induced by 1 U/kg of insulin on GE while in combination with AT the effect was completely abolished. The results with AT suggest that moderate hypoglycemia may render the inhibitory mechanisms of GE ineffective while Dp alone and in combination with AT significantly overcame the effect of hypoglycemia on GE.

Unlike non-steroidal anti-inflammatory drugs (NSAIDs), metamizole has poor anti-inflammatory effects; and is suitable for models where analgesia, but not anti-inflammatory effects, is desirable. Like opioids, these drugs produce perioperative analgesia while reducing anaesthetic requirements, but it remains unclear whether they may develop tolerance or hyperalgesia, and thus decrease in analgesic efficacy. The aim was to determine whether tolerance or hyperalgesia to metamizole occurred in rats, and whether the sevoflurane minimum alveolar concentration (MAC) was affected. In a randomized, prospective, controlled study, male Wistar rats ( n = 8 per group) were administered metamizole (300 mg/kg, day 4). Previously, the following treatments were provided: daily metamizole for four days (0-3), morphine (10 mg/kg; positive control, day 0 only) or saline (negative control). The main outcome measures were mechanical (MNT) and warm thermal (WNT) nociceptive quantitative sensory thresholds. The baseline sevoflurane MAC and the reduction produced by the treatments were also determined. The mean (SD) baseline MAC [2.4(0.2)%vol] was decreased by morphine and metamizole by 45(11)% and 33(7)% ( P = 0.000, both), respectively. Baseline MNT [35.4(4.5) g] and WNT [13.2(2.4) s] were decreased by morphine and metamizole: MNT reduction of 22(6)% ( P = 0.000) and 22(7)% ( P = 0.001), respectively and WNT reduction of 34(14)% ( P = 0.000) and 24(13)% ( P = 0.001). The baseline MAC on day 4 was neither modified by treatments nor the MAC reduction produced by metamizole (days 0 and 4; P > 0.05). In conclusion, repeated metamizole administration may produce hyperalgesia, although it may not modify its anaesthetic sparing effect. The clinical relevance of this effect in painful research models requiring prolonged analgesic therapy warrants further investigation.

Background: The purpose of this study was to evaluate the effect of the systemic administration of dipyrone in a triple subarachnoid hemorrhage (SAH) model of cerebral vasospasm in rabbits., Methods: Experimental subarachnoid hemorrhage was induced in rabbits by injecting autologous arterial blood into the cisterna magna. Digital subtraction angiographies (DSA) were performed before and after the first experimental SAH, and at 30, 45, 60 minutes and 72 hours after the first drug administration to measure the diameter of basilar artery. Intracisternal blood injections were repeated 24 and 48 hours after the first injection. Dipyrone (N.=20) or 0.9% NaCl (N.=20) was administered intravenously after initial SAH induction and repeated at 8-hour intervals intramuscularly. After sacrificing by perfusion-fixation, basilar arteries were removed and sectioned for transmission electron microscopic (TEM) examination., Results: The average basilar artery diameter measured by DSA was 724±19 μm in the control, and 686±29 μm in treatment group before SAH. After SAH, mean basilar artery diameters decreased to 71% and 68% of their basal values, respectively. Dipyrone significantly attenuated the basilar artery diameter at one and 72 hours after the first drug administration, in comparison to the control group. TEM studies showed more edema in the endothelial cells of the basilar arteries of the control group when compared to the treatment group., Conclusions: Dipyrone showed a beneficial effect in autologous blood-induced basilar artery vasospasm in rabbits. These data support the idea that dipyrone can be a potential candidate drug to be tested in patients suffering from cerebral vasospasm secondary to subarachnoid hemorrhage.

Objective: To investigate the relationship between metamizol pharmacokinetics and the antinociceptive effect produced after subcutaneous administration of metamizol (177.8 mg/kg) alone or in combination with morphine (3.2 mg/kg), under acute and chronic treatments., Methods: Antinociception was assessed using the pain-induced functional impairment model in rat (PIFIR). Serial blood samples were collected from the same animals to study the pharmacokinetics of metamizol., Key Findings: The co-administration of the drugs in single dose, confirmed the potentiation of their individual antinociceptive effects. When the drugs were administered alone following the chronic schedule, a pronounced tolerance development to their antinociceptive effects was found, whereas it was significantly attenuated when they were administered together. Metamizol pharmacokinetics was unaltered by the presence of morphine. Plasma concentrations of 4-methylaminoantipyrine, an active metabolite markedly decreased under chronic administration., Conclusions: The mechanism involved in the potentiation of the antinociceptive effect produced by the combination, cannot be explained by the interaction of morphine on metamizol pharmacokinetics. Other pharmacokinetic interactions along with known pharmacodynamic interactions in which metamizol active metabolites contribute, should be considered. The frequency of administration enhances tolerance development and induces metamizol elimination process., (© 2017 Royal Pharmaceutical Society.)

Metamizole (dipyrone) is a first-line, non-opioid analgesic used for postoperative pain management. Clinical data and animal experiments indicate a possible vasodilator action of this drug. We investigated the effects of metamizole on human artery and vein tone in an ex vivo model to assess potential contributions to venous pooling. Excess segments of bypass grafts were harvested during coronary artery bypass grafting procedures. Tensions were measured in an organ bath for 120 min after adding metamizole to the preconstricted vessels. Contribution of endothelium was assessed in endothelium-denuded vessels, and indometacin was used to identify cyclooxygenase-mediated effects. Internal mammary arteries (n = 6) constricted after addition of 1, 3, and 10 μM metamizole and remained constricted at the lower doses. Transient constrictions also occurred in saphenous veins (n = 20), but veins relaxed below solvent controls after 20 min at all concentrations. Endothelium removal (n = 12) and cyclooxygenase inhibition (n = 12) suppressed the vasoconstrictor effect but not the vasodilator effect. Metamizole and its metabolites display counteracting effects on blood vessel tone ex vivo. The vasoconstrictor effect is mediated by cyclooxygenase-derived products. The net effect is site-specific, resulting in a selective venous vasodilator action. This may exacerbate unwanted venous pooling during postoperative pain therapy.

It has been established that the midbrain periaqueductal gray matter (PAG) and rostral ventro-medial medulla (RVM) are involved in the descending pain control system. The latter involves the midline nucleus raphe magnus (NRM) and adjacent reticular formation. These brain structures are is one of important parts of CNS circuit that controls nociceptive transmission at the level of spinal cord. Here we report that microinjection of commonly used non-steroidal anti-inflammatory drugs (NSAIDs), diclofenac, ketorolac, metamizol, and xefocam into the NRM produces strong antinociception which is mediated by the opioid mechanism. The experiments were carried out on experimental and control (saline) white albino male rats. Animals were implanted with a guide cannula in the NRM and tested for antinociception following microinjection of NSAIDs into the NRM in the tail flick (TF) and hot plate (HP) tests. The analysis of variance (ANOVA) with post-hoc Tukey-Kramer multiple comparison tests were used for statistical evaluation. The obtained data show that microinjection of these NSAIDs into the NRM produced antinociception as revealed by a latency increase in the tail-flick (TF) and hot plate (HP) latencies compared to the saline control microinjected into the same nucleus. Furthermore, we definitely showed that pre-treatment with opioid antagonist naloxone in the NRM diminishes NSAID-induced antinociception expressing in significant decrease in TF and HP latencies (P<0.001). The present findings support the concept that antinociceptive effects of NSAIDs are mediated via an endogenous opioid system possibly involving the descending pain modulatory circuit.