Skip to main content
Download PDF

Adverse effects of metamizole on heart, lung, liver, kidney, and stomach in rats

BMC Pharmacology and Toxicology volume 25, Article number: 55 (2024) Cite this article

Abstract

Background

Metamizole is banned in some countries because of its toxicity, although it is widely used in some European countries. In addition, there is limited information on its safety profile, and it is still debated whether it is toxic to the heart, lungs, liver, kidneys, and stomach.

Aims

Our study investigated the effects of metamizole on the heart, lung, liver, kidney, and stomach tissues of rats.

Methods

Eighteen rats were divided into three groups, wassix healthy (HG), 500 mg/kg metamizole (MT-500), and 1000 mg/kg metamizole (MT-1000). Metamizole was administered orally twice daily for 14 days. Meanwhile, the HG group received pure water orally. Biochemical, histopathologic, and macroscopic examinations were performed on blood samples and tissues.

Results

Malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD), and catalase (CAT) in the lung and gastric tissues of MT-500 and MT-1000 groups were almost the same as those of the HG (p > 0.05). However, MDA levels in the heart and liver tissues of MT-500 and MT-1000 groups were higher (p < 0.05) compared to the HG, while tGSH levels and SOD, and CAT activities were lower (p < 0.05). MDA levels of MT-500 and MT-1000 groups in the kidney tissue increased the most (p < 0.001), and tGSH levels and SOD and CAT activities decreased the most (p < 0.001) compared to HG. Metamizole did not cause oxidative damage in the lung and gastric tissue. While metamizole did not change troponin levels, it significantly increased alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and creatinine levels compared to HG. Histopathologically, mild damage was detected in heart tissue, moderate damage in liver tissue, and severe damage in renal tissue. However, no histopathologic damage was found in any groups’ lung and gastric tissues.

Conclusion

Metamizole should be used under strict control in patients with cardiac and liver diseases and it would be more appropriate not to use it in patients with renal disease.

Peer Review reports

Introduction

Metamizole (MT) is known to be a non-narcotic pyrazolone derivative analgesic drug [1]. In addition, metamizole is included in the group of nonsteroidal anti-inflammatory drugs (NSAIDs) with analgesic and antipyretic effects with spasmolytic properties [2]. The mechanism of analgesic action of MT is complex, but there is a view that it may be related to suppression of a central cyclooxygenase-3 (COX-3) and stimulation of cannabinoid and opioidergic systems [3]. It has been suggested that its antipyretic effect is associated with cyclooxygenase-2 (COX-2) inhibition [4]. The critical feature of its antipyretic effect is that it reduces fever by inhibiting both prostaglandin-E2 (PGE2)-dependent and independent pathways [5]. The spasmolytic effect of MT is connected with a decrease in intracellular Ca2+ release through the inhibition of inositol phosphate synthesis [3]. Due to its excellent analgesic, antipyretic, and spasmolytic properties and good gastrointestinal tolerability, MT has been widely used worldwide [5]. It is mainly preferred in migraine, cancer-related, postoperative, and colic pain treatment [4].

However, conflicting data on the toxic effects of metamizole in different tissues are encountered in literature reviews, and information on its safety profile is also limited. For instance, the Dutch Drug Evaluation Board recently approved the oral formulation of metamizole [6]. On the contrary, metamizole is banned in some countries due to its severe side effects, such as agranulocytosis [7]. However, studies have suggested that the metamizole-related agranulocytosis risk is exaggerated [3]. In addition, studies have shown no tangible relationship between metamizole and aplastic anemia [8]. According to another report, metamizole is not administered to pregnant women despite evidence indicating no risk of teratogenic and embryotoxic effects [3]. Conflicting information on different organs regarding the toxicity of metamizole persists as well. A recent study reported very low cardiovascular side effects of metamizole [8]. Retrospective studies have suggested that metamizole is more hepatotoxic than paracetamol [9]. However, Drobnik reported that the liver toxicity of metamizole was low [3]. Studies conducted to investigate the toxic effects of metamizole argued that metamizole leads to tubular necrosis and acute tubulointerstitial nephritis in the kidneys [10]. Conversely, a recent study claimed that metamizole is suitable for patients with impaired renal function, emphasizing that it has few renal side effects [8]. Studies postulated that metamizole is safer for the gastrointestinal (GI) system and kidneys than other NSAIDs and can be used alternatively in patients at high risk of gastric or renal disorders [11]. In a case-control study, it was stated that the risk of GI bleeding was higher in metamizole users compared to aspirin and other NSAIDs [1]. No information on the pulmonary toxicity of metamizole was found in the literature. Although metamizole is frequently used for therapeutic purposes, toxicity data in many organs seem contradictory or insufficient. Therefore, we purposed to analyze metamizole’s toxic and oxidative impact on heart, lung, liver, kidney, and gastric tissues at medium and high doses in rats.

Materials and methods

Animals

Eighteen male albino Wistar rats (277–286 g, 6–7 weeks old) were employed in the experiment. Animals were purchased from the Experimental Animals Research and Application Center at Erzincan Binali Yıldırım University. The rats were housed in an appropriate laboratory environment at a room temperature of 22 °C, 12 h in darkness, and 12 h in light; humidity levels were 30–70%. Experimental animals were fed pellet chow, tap water, and ad libitum. All experiments were performed according to the guidelines from Directive 2010/63/EU of the European Parliament (Approval Number 2016-24-199) and the ARRIVE guidelines [12].

Chemicals

Thiopental sodium (500 mg vial) was provided by Ibrahim Etem Ulagay (Türkiye). Metamizole (500 mg tablet) from Sanofi Aventis (Türkiye).

Experimental groups

The rats were randomly divided into three groups (N = 6) [13, 14]: healthy (HG), metamizole 500 mg/kg (MT-500), and metamizole 1000 mg/kg (MT-1000) administered group.

Experimental procedure

Metamizole was given in MT-500 and MT-1000 groups orally by gavage. The HG group was similarly given pure water. These processes were continued for 14 days [15], twice daily [15, 16]. At the end of the 14th day, blood was collected from the hearts of all rats and then euthanized with 50 mg/kg thiopental sodium (intraperitoneal). The heart, lung, liver, renal, and gastric tissues were removed to measure malondialdehyde (MDA), total glutathione (tGSH), superoxide dismutase (SOD) and catalase (CAT) levels biochemically. Gastric tissue was examined macroscopically, and other tissues were examined histopathologically. The levels of troponin I (TpI), alanine aminotransferase (ALT), aspartate aminotransferase (AST), Blood Urea Nitrogen (BUN), and creatinine were analyzed in blood samples.

Biochemical analyzes

Measurement of MDA, tGSH, SOD, CAT, and protein

MDA, tGSH, and SOD were determined in the supernatants prepared from tissue samples through the utilization of enzyme-linked immunosorbent assay (ELISA) rat kits (Cat no:10009055; 703002; 706002, respectively, Cayman Chemical Company). Analyses were performed according to the steps in the application procedure included in the kits. Goth method was used for CAT [17] and the Bradford method for protein [18].

Measurement of blood serum TpI

TpI levels were measured using the ELFA (Enzyme-Linked Fluorescent Assay) technique in the VIDAS Troponin I Ultra kit.

Measurement of blood serum ALT and AST

Serum ALT and AST activities were measured spectrophotometrically, and Cobas 8000 autoanalyzer (Roche Diagnostics GmBH, Germany) and ALT and AST kits (Roche Diagnostics) were used for this purpose.

Measurement of blood serum BUN and creatinine

Serum BUN and creatinine levels were measured spectrophotometrically using the Roche Cobas 8000 autoanalyzer (Roche Diagnostics GmBH, Germany). BUN was reckoned by the following formula. BUN = Serum Urea Level x 0.48. The creatinine analysis was based on the Jaffe method [19].

Histopathological analysis

Tissue samples were kept in 10% formalin to ensure tissue stability. They were then dehydrated in graded alcohol (70–99%). Tissues were made transparent using xylol and then embedded in paraffin. Sections were obtained from these paraffin blocks and stained with hematoxylin and eosin. Tissue samples were analyzed by light microscopy (DP2-SAL firmware program, Olympus Inc., Japan). Findings in six randomly selected microscopic fields were evaluated as as (+) mild, (++) moderate and (+++) severe according to Table 1 [20].

Table 1 Analysis of biochemical parameters of all rat groups
Full size table

Statistical analysis

All analyses were carried out by IBM SPSS 22.0 Statistics Program for Windows (IBM Corp., released in 2013, Armonk, NY, USA). All results were shown as mean value ± standard error of the mean (SEM). The normality of distribution for the data was assessed using the Shapiro-Wilk test. Normally distributed data were tested with one-way ANOVA, and then post hoc Tukey HSD or Games-Howell tests were used. Kruskal-Wallis test,, followed by Mann-Whitney U-test, was used to analyze non-normally distributed data. p < 0.05 was used for statistical significance.

Results

Biochemical results

MDA, tGSH, SOD, and CAT analysis results of the heart tissue

In Fig. 1, the heart tissue MDA levels of the rats in the MT-500 and MT-1000 were slightly increased than in the healthy rats (p < 0.05). tGSH levels and SOD, and CAT activities were slightly decreased compared to HG (p < 0.05). The difference between MDA and tGSH levels and SOD, and CAT activities in the heart tissue of MT-500 and MT-1000 was insignificant (p > 0.05) (Table 1).

Fig. 1
figure 1

MDA, tGSH, SOD, and CAT levels in the heart tissue of experimental groups. * means p < 0.05 according to the HG. ** means p < 0.001 according to the HG. n = 6. MDA malondialdehyde, tGSH total glutathione, SOD superoxide dismutase, CAT catalase, HG healthy group, MT-500 500 mg/kg metamizole administered group, MT-1000 1000 mg/kg metamizole administered group

Full size image

MDA, tGSH, SOD, and CAT analysis results of the lung tissue

MDA and tGSH levels and SOD and CAT activities in the lung tissue of MT-500 and MT-1000 group animals were almost the same as those of the HG group (p > 0.05) (Fig. 2; Table 1).

Fig. 2
figure 2

MDA, tGSH, SOD, and CAT levels in the lung tissue of experimental groups. * means p < 0.05 according to the HG. ns: no significant, n = 6. MDA malondialdehyde, tGSH total glutathione, SOD superoxide dismutase, CAT catalase, HG healthy group, MT-500 500 mg/kg metamizole administered group, MT-1000 1000 mg/kg metamizole administered group

Full size image

MDA, tGSH, SOD, and CAT analysis results of the liver tissue

In Fig. 3, the MDA levels of MT-500 and MT-1000 group animals were increased compared to the healthy rats (p < 0.05). In addition, tGSH levels and SOD, and CAT activities were decreased (p < 0.05). Similarity was found between metamizole groups in terms of antioxidant data (p > 0.05) (Table 1).

Fig. 3
figure 3

MDA, tGSH, SOD, and CAT levels in the liver tissue of experimental groups. * means p < 0.05 according to the HG. ** means p < 0.001 according to the HG. n = 6. MDA malondialdehyde, tGSH total glutathione, SOD superoxide dismutase, CAT catalase, HG healthy group, MT-500 500 mg/kg metamizole administered group, MT-1000 1000 mg/kg metamizole administered group

Full size image

MDA, tGSH, SOD, and CAT analysis results of the renal tissue

The kidney tissue MDA levels of MT-500 and MT-1000 group animals were increased according to the healthy rats (p < 0.001). Likewise, tGSH levels and SOD, and CAT activities were decreased (p < 0.001). The difference between MDA and tGSH levels and SOD and CAT activities of MT-500 and MT-1000 was found to be insignificant (p > 0.05) (Fig. 4; Table 1).

Fig. 4
figure 4

MDA, tGSH, SOD, and CAT levels in the renal tissue of experimental groups. * means p < 0.05 according to the HG. ** means p < 0.001 according to the HG. n = 6. MDA malondialdehyde, tGSH total glutathione, SOD superoxide dismutase, CAT catalase, HG healthy group, MT-500 500 mg/kg metamizole administered group, MT-1000 1000 mg/kg metamizole administered group

Full size image

MDA, tGSH, SOD, and CAT analysis results of the gastric tissue

MDA and tGSH levels and SOD, and CAT activities in the gastric tissue of MT-500 and MT-1000 group animals, were almost the same as the HG group (p > 0.05) (Fig. 5; Table 1).

Fig. 5
figure 5

MDA, tGSH, SOD, and CAT levels in the and gastric tissue of experimental groups. * means p < 0.05 according to the HG. ns no significant, n = 6. MDA malondialdehyde, tGSH total glutathione, SOD superoxide dismutase, CAT catalase, HG healthy group, MT-500 500 mg/kg metamizole administered group, MT-1000 1000 mg/kg metamizole administered group

Full size image

Blood serum TpI analysis results

In Fig. 6A, the blood serum TpI levels in the MT-500 and MT-1000 were insignificant according to the control rats (p > 0.05). Similarly, the difference between the TpI levels of the MT-500 and MT-1000 was also insignificant (p = 1.000) (Table 2).

Fig. 6
figure 6

TpI (A), ALT (B), AST (C), BUN (D), and creatinine (E) levels in the blood serum of experimental groups. * means p < 0.001 according to the HG. n = 6. TpI troponin I, ALT alanine aminotransferase, AST aspartate aminotransferase, BUN blood urea nitrogen, HG healthy group, MT-500 500 mg/kg metamizole administered group, MT-1000 1000 mg/kg metamizole administered group

Full size image
Table 2 Effects of metamizole on blood serum biochemical parameters in rats
Full size table

Blood serum ALT and AST analysis results

Blood serum ALT activity of MT-500 and MT-1000 group animals was increased according to the control rats (p < 0.001). However, the difference between ALT levels of MT-500 and MT-1000 groups was insignificant (p = 1.000) (Fig. 6B; Table 2).

Similarly, according to the HG group, blood serum AST activity was increased in the MT-500 and MT-1000. The difference between AST levels of MT-500 and MT-1000 was insignificant (p = 0.617) (Fig. 6C; Table 2).

Blood serum BUN and creatinine analysis results

As shown in Fig. 6D-E, the blood serum BUN and creatinine levels of MT-500 and MT-1000 group animals were significantly raised according to the control rats (p < 0.001). Insignificant difference between the BUN and creatinine levels of MT-500 and MT-1000 groups was found (p > 0.05) (Table 2).

Histopathological analysis results

Figure 7A shows that no damage sign was found in the heart tissue of the HG group. However, mild degeneration in cardiac myocytes and mild mononuclear cell infiltration in interstitial areas were found in animals treated with 500 mg/kg and 1000 mg/kg of metamizole (Fig. 7B-C-D-E). As seen in Fig. 8A-B-C, no histopathologic damage was observed in the HG, MT-500, and MT-1000 lung sections. The normal histologic appearance was found in the liver tissue of the HG group (Fig. 9A). Moderate necrosis was found in the liver section of MT-500 and MT-1000 (Fig. 9B-C). No histopathologic damage was found in the renal tissue of the HG group (Fig. 10A). However, severe interstitial nephritis in intertubular areas, moderate hemorrhage in intertubular areas, and degeneration of tubular epithelial cells were found in the renal tissues of MT-500, and MT-1000 groups (Fig. 10B-C-D-E).

Fig. 7
figure 7

(A) Normal histologic appearance of the heart tissue belonging to the HG group, (HxE); (B) Mild degeneration (arrowhead) appearance in cardiac myocytes belonging to the MT-500 group, (HxE); (C) Mild mononuclear cell infiltration (arrow) appearance in interstitial areas in the heart tissue belonging to the MT-500 group, (HxE); (D) Mild degeneration (arrowhead) appearance in cardiac myocytes belonging to the MT-1000 group, (HxE); (E) Mild mononuclear cell infiltrations (arrow) appearance in interstitial areas in the heart tissue belonging to the MT-1000 group, (HxE)

Full size image
Fig. 8
figure 8

(A) Normal histological appearance of the alveolus (a) and vessels (v) in the lung tissue of the HG group, (HxE); (B) Normal histological appearance of the alveolus (a) in the lung tissue of the MT-500 group, (HxE); (C) Normal histological appearance of the alveolus (a) in the lung tissue of the MT-1000 group, (HxE)

Full size image
Fig. 9
figure 9

(A) Normal histological appearance in liver tissue of the HG group, (HxE); (B) Moderate necrosis (arrow) appearance in the liver tissue of the MT-500 group, (HxE); (C) Moderate necrosis (arrow) appearance in the liver tissue of the MT-1000 group, (HxE)

Full size image
Fig. 10
figure 10

(A) Normal histological appearance of kidney tissue belonging to the HG group, (HxE); (B) Severe interstitial nephritis (*) appearance in intertubular areas in the kidney tissue of the MT-500 group, (HxE); (C) Moderate hemorrhage (arrow) in intertubular areas and degeneration of tubulous epithelial cells (arrowhead) in kidney tissue of the MT-500 group, (HxE); (D) Severe interstitial nephritis (*) appearance in intertubular areas in the kidney tissue of the MT-1000 group, (HxE); (E) Moderate hemorrhage (arrow) in intertubular areas and degeneration of tubulous epithelial cells (arrowhead) in kidney tissue of the MT-1000 group, (HxE)

Full size image

Macroscopic appearance of gastric tissue

No macroscopic damage was detected in the gastric tissue in HG, MT-500, and MT-1000 groups as seen in Fig. 11A-B-C.

Fig. 11
figure 11

(A) Macroscopic appearance of stomach tissue belonging to the HG group; (B) Macroscopic appearance of stomach tissue belonging to the MT-500 group; (C) Macroscopic appearance of stomach tissue belonging to the MT-1000 group

Full size image

Discussion

Metamizole is widely used for pain relief due to its potent analgesic, antipyretic, and spasmolytic properties [21]. However, the debate regarding the benefits and risks of this analgesic drug is still an ongoing concern. The articles highlight the need for high-quality and adequately sized studies evaluating the medium and long-term safety of metamizole [22]. Our study investigated the effects of metamizole on heart, lung, liver, renal, and gastric tissues at medium and high doses biochemically and histopathologically in rats. The heart tissue MDA levels of the metamizole-treated animals were slightly higher, and antioxidants were slightly lower than the HG, biochemically. MDA is a toxic oxidant product formed by reactive oxygen species (ROS) oxidizing cell membrane lipids (LPO) [23]. tGSH is an endogenous non-enzymatic antioxidant, while SOD and CAT are enzymatic antioxidants [24]. Literature reviews report that the cardiovascular side effects of metamizole are very low [8]. In our current study, both medium and high doses of metamizole were able to show a slight but significant reduction in tGSH levels and SOD, and CAT activities as well as a slight but significant increase in MDA levels, which have altered the oxidant/antioxidant balance of metamizole in against antioxidants in some extend. The reason for the decrease in tGSH levels and SOD and CAT activities in damaged tissues is the excessive consumption of antioxidants while neutralizing ROS [25, 26]. Although oxidative stress was observed in the heart tissue of the metamizole group, no significant change was found in TpI levels in blood serum. As is known, an increase in serum TpI is an important indicator of myocardial damage [27]. Interestingly, the metamizole group’s serum TpI levels were almost the same as those in the HG, suggesting no severe damage to the cardiac muscles.

Histopathologically, no structural abnormality was observed except mild degeneration in the myocytes of the metamizole 500 and 1000 mg/kg dose groups and mild mononuclear cell infiltration in the interstitial areas.

The current study’s biochemical and histopathological findings showed that metamizole administered at medium and high doses did not cause damage to the lung tissue. Correspondingly, previous studies stated that metamizole might be used safely in patients with chronic obstructive pulmonary disease when required since it does not impair lung function [28]. Alpaslan et al. also demonstrated by microscopic examination that metamizole is not toxic to the lungs [29]. Metamizole has a favorable effect leading to improved airway function in asthmatic patients with moderate airway obstruction [30].

The biochemical findings of the present study reveal that medium and high doses of metamizole cause significant oxidative stress in the liver tissues. In addition, the substantial increase in MDA and the decrease in tGSH levels and SOD, and CAT activities in the MT-500 and MT-1000 groups show that oxidative stress was markedly induced in liver tissue compared to the heart tissue-treated groups. However, some studies have emphasized that the risk of liver impairment during MT treatment is relatively low [3]. A recent study showed that 500 and 1000 mg/kg metamizole doses caused moderate liver damage [15]. Yapar et al. found that the administration of high doses of metamizole to mice resulted in an increase in liver oxidant levels and a decrease in GSH levels [31]. Bedir et al. reported that in animals treated with metamizole, liver damage markers ALT and AST activities increased in blood serum simultaneously with oxidant parameters in the liver tissue [15]. Similarly, in a present study, ALT and AST activities of metamizole groups increased parallelly to liver tissue oxidant parameters. In the histopathological examination, we observed moderate tissue damage in the liver tissue in the MT 500 and 1000 groups, supporting the changes in biochemical parameters. Consistently, a previous study histopathologically observed that moderate necrosis developed in the liver tissue of 500 and 1000 mg/kg MT groups in response to oxidative stress [15].

Metamizole substantially increased MDA and decreased tGSH levels and SOD, and CAT activities in renal tissue. A recently published study emphasized that metamizole has few renal side effects and is particularly suitable for patients with impaired renal function [8]. In contrast, another study showed that metamizole can cause tubular necrosis and acute tubulointerstitial nephritis. However, these pathological findings have not been associated with oxidant tissue damage [10]. Moreover, no information was found showing metamizole-induced oxidative damage to the kidneys. Alongside the significant increase in tissue MDA levels, histopathologically severe interstitial nephritis, hemorrhage, and degeneration of tubular epithelial cells were observed in metamizole groups. A recent study, consistent with our results, showed that oxidative stress is closely associated with renal tissue damage [32].

The effect of metamizole on the GI tract is confusing in the literature. Some studies suggest that metamizole is safer for the GI tract than other NSAIDs [11]. Some emphasize that the risk of GI bleeding is higher in metamizole users compared to aspirin and other NSAIDs [1]. Gastrotoxic drugs are known to cause damage to the gastric mucosa in the form of marked hyperemia, round oval, and irregular mucosal defects of different numbers and diameters [33]. It has also been documented that the severity of this macroscopic damage in gastric tissue is directly related to the increase in oxidants and decrease in antioxidants [34]. However, our experimental results showed that metamizole did not alter the balance between oxidant and antioxidant parameters in the gastric tissue of the animals. Macroscopically, the gastric mucosal surface was not different from that of the healthy group.

Conclusions

The effects of medium and high doses of metamizole on the heart, lung, liver, kidney, and stomach were investigated biochemically and histopathologically and evaluated by comparison. Both our biochemical and histopathological findings showed that metamizole did not cause damage to the lung and stomach tissue. However, metamizole caused mild oxidative damage in heart tissue, moderate oxidative damage in liver tissue, and severe oxidative damage in renal tissue. Metamizole had similar toxicity at both 500 and 1000 mg/kg doses. The findings of this study indicate that metamizole can be used in patients with lung and stomach diseases. Strict control is required in patients with liver and heart diseases, and it would be more appropriate not to use in patients with renaldisease.

Limitations

At the same time, it is essential to investigate the effects of metamizole on all organs and tissues on a larger scale and to measure more parameters to clarify the mechanism of its toxic effect.

Data availability

No datasets were generated or analysed during the current study.

References

  1. Andrade S, Bartels DB, Lange R, Sandford L, Gurwitz J. Safety of metamizole: a systematic review of the literature. J Clin Pharm Ther. 2016;41(5):459–77.

    Article  CAS  PubMed  Google Scholar 

  2. Lutz M. Metamizole (Dipyrone) and the liver: a review of the literature. J Clin Pharmacol. 2019;59(11):1433–42.

    Article  CAS  PubMed  Google Scholar 

  3. Jasiecka A, Maslanka T, Jaroszewski JJ. Pharmacological characteristics of metamizole. Pol J Vet Sci. 2014;17(1):207–14.

    Article  CAS  PubMed  Google Scholar 

  4. de Leeuw TG, Dirckx M, Gonzalez Candel A, Scoones GP, Huygen F, de Wildt SN. The use of dipyrone (metamizol) as an analgesic in children: what is the evidence? A review. Paediatr Anaesth. 2018;28(3):309.

    Article  PubMed  Google Scholar 

  5. Liu J, Dai XL, Zhou XJ, Gu BH, Yang ZH, Lai J. Metamizole-induced acute liver failure in a boy. Clin Res Hepatol Gastroenterol. 2021;45(4):101570.

    Article  CAS  PubMed  Google Scholar 

  6. van Diepen ATN, Simons P, Bos JM, Kramers C. [Metamizol: current status in Dutch practice]. Ned Tijdschr Geneeskd. 2022;166.

  7. Collares EF, Troncon LEA. Effects of dipyrone on the digestive tract. Brazilian J Med Biol Res = Revista brasileira de pesquisas medicas e Biologicas. 2019;52(2):e8103.

    Article  CAS  Google Scholar 

  8. Stromer W, Palladini M, Metamizole. A comprehensive approach to its benefit-risk profile. Evid Self-Medication. 2022;2(2).

  9. Hedenmalm K, Pacurariu A, Slattery J, Kurz X, Candore G, Flynn R. Is there an increased risk of Hepatotoxicity with Metamizole? A comparative cohort study in incident users. Drug Saf. 2021;44(9):973–85.

    Article  CAS  PubMed  Google Scholar 

  10. Redondo-Pachon MD, Enriquez R, Sirvent AE, Millan I, Romero A, Amoros F. Acute renal failure and severe thrombocytopenia associated with metamizole. Saudi journal of kidney diseases and transplantation: an official publication of the Saudi Center for Organ Transplantation. Saudi Arabia. 2014;25(1):121–5.

    Google Scholar 

  11. Konijnenbelt-Peters J, van der Heijden C, Ekhart C, Bos J, Bruhn J, Kramers C. Metamizole (Dipyrone) as an alternative Agent in Postoperative Analgesia in patients with contraindications for nonsteroidal anti-inflammatory drugs. Pain Practice: Official J World Inst Pain. 2017;17(3):402–8.

    Article  Google Scholar 

  12. Percie du Sert N, Hurst V, Ahluwalia A, Alam S, Avey MT, Baker M, et al. The ARRIVE guidelines 2.0: updated guidelines for reporting animal research. PLoS Biol. 2020;18(7):e3000410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Emir A, Kalkan Y, Bostan H. Histopathological effects of intramuscular metamizole sodium on rat sciatic nerve. Iran J Basic Med Sci. 2016;19(8):829–36.

    PubMed  PubMed Central  Google Scholar 

  14. Kumbasar S, Salman S, Al RA, Ozturk C, Yarali O, Alp HH, et al. The effect of metamizole on ischemia/reperfusion injury in the rat ovary: an analysis of biochemistry, molecular gene expression, and histopathology. Indian J Pharmacol. 2016;48(1):32–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bedir Z, Ozkaloglu K, Can A, Cicek B, Gulaboglu M, Suleyman Z, et al. Effect of Thiamine Pyrophosphate upon possible Metamizole-Induced Liver Injury in rats. Int J Pharmacol. 2023;19(1):139–46.

    Article  CAS  Google Scholar 

  16. Zajaczkowska R, Kwiatkowski K, Pawlik K, Piotrowska A, Rojewska E, Makuch W, et al. Metamizole relieves pain by influencing cytokine levels in dorsal root ganglia in a rat model of neuropathic pain. Pharmacol Rep. 2020;72(5):1310–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Goth L. A simple method for determination of serum catalase activity and revision of reference range. Clin Chim Acta. 1991;196(2–3):143–51.

    Article  CAS  PubMed  Google Scholar 

  18. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248–54.

    Article  CAS  PubMed  Google Scholar 

  19. Ou M, Song Y, Li S, Liu G, Jia J, Zhang M, et al. LC-MS/MS Method for Serum Creatinine: comparison with enzymatic method and Jaffe Method. PLoS ONE. 2015;10(7):e0133912.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Kocaturk H, Bedir F, Turangezli Ö, Arslan R, Çoban TA, Altuner D, et al. Effect of adenosine triphosphate, benidipine and their combinations on bevacizumab-induced kidney damage in rats. Adv Clin Exp Med. 2021;30(11):1175–83.

    Article  PubMed  Google Scholar 

  21. Cascorbi I. The uncertainties of Metamizole Use. Clin Pharmacol Ther. 2021;109(6):1373–5.

    Article  PubMed  Google Scholar 

  22. Kotter T, da Costa BR, Fassler M, Blozik E, Linde K, Juni P, et al. Metamizole-associated adverse events: a systematic review and meta-analysis. PLoS ONE. 2015;10(4):e0122918.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Suleyman H, Ozcicek A. Molecular mechanism of Ischemia Reperfusion Injury. Archives Basic Clin Res. 2019;2(1):25–7.

    Article  Google Scholar 

  24. Demirci-Cekic S, Ozkan G, Avan AN, Uzunboy S, Capanoglu E, Apak R. Biomarkers of oxidative stress and antioxidant defense. J Pharm Biomed Anal. 2022;209:114477.

    Article  CAS  PubMed  Google Scholar 

  25. Urso ML, Clarkson PM. Oxidative stress, exercise, and antioxidant supplementation. Toxicology. 2003;189(1–2):41–54.

    Article  CAS  PubMed  Google Scholar 

  26. Clarkson PM, Thompson HS. Antioxidants: what role do they play in physical activity and health? Am J Clin Nutr. 2000;72(2 Suppl):S637–46.

    Article  Google Scholar 

  27. Cordwell SJ, Edwards AV, Liddy KA, Moshkanbaryans L, Solis N, Parker BL, et al. Release of tissue-specific proteins into coronary perfusate as a model for biomarker discovery in myocardial ischemia/reperfusion injury. J Proteome Res. 2012;11(4):2114–26.

    Article  CAS  PubMed  Google Scholar 

  28. Gulmez SE, Tulunay FC, Beder S, Kayacan O, Karnak D. Does dipyrone have any effect on respiratory function in COPD patients? Respiratory medicine. 2006;100(5):828–34.

  29. Gokcimen A, Özgüner M, Bayram D, Ural M, Sulak O. Effects of metamizol sodium on liver, kidney and lung tissues of the rat. SDÜ Tıp Fakültesi Dergisi. 2006;13(1):27–31.

    Google Scholar 

  30. Gulmez SE, Celik G, Misirligil Z, Tulunay FC. Dipyrone improves small airway function in asthmatic patients with moderate obstruction. J Investigat Allergol Clin Immunol. 2007;17(4):242–8.

    CAS  Google Scholar 

  31. Atakişi O, Yapar K, Atakişi E, Uzlu E, Çitil M, Uzun M, et al. The Effect of different doses of Metamisole Sodium on serum enzyme activities and tissue oxidant levels in liver and kidney in mice. Kafkas Universitesi Veteriner Fakultesi Dergisi. 2007;13(2):121–5.

    Google Scholar 

  32. Erdem KTO, Bedir Z, Kuyrukluyildiz U, Tas HG, Suleyman Z, Bulut S, et al. Effect of tocilizumab on ischemia-reperfusion-induced oxido-inflammatory renal damage and dysfunction in rats. Exp Anim. 2022;71(4):491–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ekinci B, Suleyman B, Mammadov R, Bulut S, Ozcicek A, Ergul C, et al. Beneficial interaction of pycnogenol with indomethacin in rats. Gen Physiol Biophys. 2022;41(5):473–81.

    Article  CAS  PubMed  Google Scholar 

  34. Isik B, Suleyman B, Mammadov R, Bulut S, Yavuzer B, Altuner D, et al. Effect of Ketorolac and Nimesulide Combination on Surgical Pain, stomach and Kidneys. Lat Am J Pharm. 2023;42(1):36–45.

    CAS  Google Scholar 

Download references

Funding

The author(s) declare that they have not received any financial support for the research, the writing and/or the publication of this article.

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Erzurum City Hospital, Erzurum, 25240, Türkiye

    Sedat Ciftel

  2. Department of Pharmacology, Faculty of Medicine, Erzincan Binali Yildirim University, Erzincan, 24100, Türkiye

    Bahadir Suleyman, Renad Mammadov & Halis Suleyman

  3. Department of Cardiology, Faculty of Medicine, Erzincan Binali Yildirim University, Erzincan, 24100, Türkiye

    Resit Coskun

  4. Department of Medical Biochemistry, Faculty of Medicine, Erzincan Binali Yildirim University, Erzincan, 24100, Türkiye

    Taha A. Coban

  5. Department of Pathology, Faculty of Veterinary Medicine, Dicle University, Diyarbakır, 21280, Türkiye

    Behzad Mokhtare

  6. Division of Gastroenterology, Erzurum Regional Training and Research Hospital, Erzurum, 25240, Türkiye

    Serkan Cerrah

  7. Department of Physiology, Faculty of Medicine, Erzincan Binali Yildirim University, Erzurum, 25240, Türkiye

    Betul Cicek

  8. Department of Internal Medicine Nursing, Faculty of Health Sciences, Erzincan Binali Yildirim University, Erzincan, 24100, Türkiye

    Zeynep Suleyman

Authors
  1. Sedat Ciftel
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bahadir Suleyman
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Renad Mammadov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Resit Coskun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Taha A. Coban
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Behzad Mokhtare
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Halis Suleyman
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Serkan Cerrah
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Betul Cicek
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Zeynep Suleyman
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

S.C.: writing-original draft, writing-review and editing, funding acquisition. B.S.: Conceptualization, data curation, funding acquisition, investigation, software, supervision, validation, visualization, writing-original draft, writing-review and editing. R.M.: Investigation, methodology, project administration, resources, writing-original draft, writing-review and editing. R.C.: Validation, writing-review and editing. T.A.C.: Conceptualization, investigation, methodology, project administration, formal analysis, writing-original draft, writing-review and editing. B.M.: writing-original draft, writing-review and editing. H.S.: Conceptualization, data curation, methodology, project administration, writing-original draft, writing-review and editing. S.C.: Methodology, resources, writing-original draft, writing-review and editing. B.C.: Revision, writing-original draft, writing-review and editing. Z.S.: Investigation, methodology, writing-original draft, writing-review and editing.

Corresponding author

Correspondence to Zeynep Suleyman.

Ethics declarations

Ethical approval

This study was approved by the Erzincan Binali Yildirim University Animal Experimentation Local Ethics Committee (Date: 27.10.2022 No: 54). It was conducted in accordance with local legislation and institutional requirements.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ciftel, S., Suleyman, B., Mammadov, R. et al. Adverse effects of metamizole on heart, lung, liver, kidney, and stomach in rats. BMC Pharmacol Toxicol 25, 55 (2024). https://doi.org/10.1186/s40360-024-00780-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s40360-024-00780-4

Keywords

BMC Pharmacology and Toxicology

ISSN: 2050-6511

Contact us