Antipyretic effect of oral dipyrone (Metamizole) compared to oral ibuprofen in febrile children: a systematic review and meta-analysis.

BACKGROUND: Dipyrone (Metamizole) is a potent pain reliever and fever reducer with muscle relaxant properties, most commonly used as an analgesic and antipyretic agent. Despite the fact that it has been banned in many high-income countries following confirmed studies of fatal agranulocytosis and adverse drug reactions, it is still widely used in various countries of the world. However, the antipyretic therapeutic indications of dipyrone in febrile children are currently unknown, and there is little information on the advantages and disadvantages of using dipyrone in febrile children. In febrile children, we expected that dipyrone's antipyretic effectiveness wouldn't be any more effective than ibuprofen. Therefore, the purpose of this research is to evaluate the effectiveness of oral dipyrone and oral ibuprofen as antipyretics in febrile children. METHODS: Several databases, including PubMed, Scopus, Web of Science, and Cochrane Library, were searched thoroughly using a pre-established search strategy for potential research. The studies included in this analysis comprised randomized controlled trials that compared the antipyretic effects of oral ibuprofen and oral dipyrone in febrile children. Data analysis was carried out using RevMan 5.4 software. RESULTS: Three studies were selected among the 27 publications we discovered to be applicable, and they underwent qualitative and quantitative analysis. The pooled analysis revealed no discernible difference between oral dipyrone and oral ibuprofen in terms of their antipyretic effects (Mean difference (MD) = 0.06; 95% confidence interval (CI): -0.08, 0.20). CONCLUSION: Both oral dipyrone and ibuprofen are effective in reducing high-temperature levels in febrile children without any significant difference.

Metamizole outperforms meloxicam in sepsis: insights on analgesics, survival and immunomodulation in the peritoneal contamination and infection sepsis model.

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-1ß 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.

Individual use of self-medication and other remedies in COVID-19 outpatients in Western-Pomerania.

We analyzed data from positively tested COVID-19 outpatients to describe self-medication with OTC drugs and use of other remedies against symptoms of SARS-CoV-2 infection. We specifically considered their type and frequency, as well as associations with patient characteristics, and reasons for use. Data were collected between May 1, 2020 and February 22, 2021 with two questionnaires in an observational cohort study with PCR-confirmed SARS-CoV-2-positive adult outpatients in the district of Western Pomerania in Germany. 523 out of 710 outpatients (74%; 340 women and 183 men) reported using drugs and other remedies to relieve COVID-19-symptoms. Overall, participants reported utilization of 1282 finished dosage products or remedies, including 213 different ingredients. In the population of 710 outpatients, utilization of ibuprofen (26%), acetaminophen (21%), metamizole (14%), and acetylsalicylic acid (10%) was most commonly reported. Phytopharmaceuticals, herbal and animal products as well as vitamins and minerals were also frequently reported. Among the 523 participants who used drugs and other remedies, most commonly mentioned reasons for use were headache (40%), other kinds of pain (e.g. myalgia; 37%), fever (24%) and cough (16%). Our analysis showed that a majority of the participants tried to alleviate COVID-19-symptoms using drugs and other remedies. Especially analgesic and antipyretic agents, followed by herbal medicines, were used very frequently.Trial registration: German Register for Clinical Studies DRKS00021672, first registration on December 1st, 2020.

Preparation of monoclonal antibodies recognizing pharmacologically active metabolites of metamizole based on rational hapten design and their application in the detection of animal-derived food.

Metamizole (MET) is an antipyretic and analgesic drug, the illegal use of which can result in residues of MET metabolites in edible tissues of animals. In this study, a computational chemistry-assisted hapten screening strategy was used to screen for the optimal immunogenic hapten-A and the optimal coating antigen hapten-G-OVA. A monoclonal antibody capable of recognizing two pharmacologically active metabolites of MET, 4-methylamidinoantipyrine (MAA) and 4-aminoantipyrine (AA), was prepared from the hapten-A. The antibody showed excellent specificity for MAA and AA and almost no cross-reactivity with the pharmacologically inactive metabolites 4-formamidinoantipyrine (FAA) and 4-acetamidinoantipyrine (AAA). An ic-ELISA was developed for the simultaneous detection of MAA and AA in animal-derived food, the limits of detection for MAA ranged from 0.93 to 1.18 µg/kg, while those for AA ranged from 1.74 to 4.61 µg/kg. The recovery rate fell within the range of 82 %-110 %, with a coefficient of variation less than 16.39 %.

"Eco-friendly HPLC method for analysis of dipyrone and hyoscine in different matrices with biomonitoring".

A selective, precise, and accurate reversed HPLC method has been developed and validated for simultaneous separation and determination of two veterinary drugs, dipyrone and hyoscine, in their combined dosage form in the presence of their official impurities, namely 4-aminoantipyrine and tropic acid, in addition to the formulated preservative: phenol. The linearity range was found to be (1.00-35.00 µg/mL) for dipyrone and (2.50-50.00 µg/mL) for hyoscine. It exhibited a satisfactory linearity regression R (0.9999) for both drugs with LOD 0.22 µg/mL and 0.72 µg/mL and LOQ 0.65 µg/mL and 2.19 µg/mL for dipyrone and hyoscine, respectively. Additionally, the two cited drugs were also determined in the presence of dipyrone active metabolite 4-aminoantipyrine using diclofenac as an internal standard in bovine urine. The linearity range was found to be (15-75 µg/mL) for dipyrone, (2.5-60 µg/mL) for hyoscine, and (2.5-60 µg/mL) for 4-aminoantipyrine with linearity regression R (0.9999-0.9998). The LLOQ (15, 2.5, 2.5 µg/mL), LQC (45, 7.5, 7.5 µg/mL), MQC (55, 25, 25 µg/mL), and HQC (60, 50 50 µg/mL) were determined for dipyrone, hyoscine and 4-aminoantipyrine, respectively. UV detection was carried out at 220 nm. The method was validated according to the ICH guidelines, as well as according to FDA guidelines for determining both drugs in bioanalytical matrices and both proved accuracy and precision. A statistical comparison was made between the results obtained and those obtained by the reported method, showing no significant difference in accuracy and precision at p = 0.05. The suggested method was proved eco-friendly through a greenness assessment using two different tools (The analytical eco-scale scored 83, and the AGREE-Analytical Greenness Metric approach scored 0.83). The suggested method can be used in the routine work of quality control labs, screening for drug abuse, and ensuring clean sport for horse racing.

The embryotoxic and teratogenic effects of metamizole sodium.

Drug use during pregnancy is an important issue that must be investigated due to its adverse effects on maternal and foetal health. This study aimed to determine the embryotoxic and teratogenic effects of in-ovo administered metamizole (dipyrone), which can be used when needed during pregnancy and has potent analgesic, antipyretic, anti-inflammatory, and long bone (tibia and femur) effects. This study used 240 fertile eggs from Atak S breed chickens, divided into eight equal groups: control, vehicle control, and 15.62, 31.25, 62.5, 125, 250 and 500 mg/kg metamizole. The eggs were hatched on the 21st day of incubation, and the chicks' body weights and mortality rates were determined. The right and left femur and tibia bones were resected from the chicks. Anatomical reference points were determined after removing the soft tissues of the bones, and necessary morphometric measures were taken from these points with a 0.01 mm precision using digital callipers. The 100% lethal dose (LD100) was identified in the highest examined dose (500 mg/kg) in the Chicken Embryotoxicity Screening Test (CHEST)-I stage. The CHEST-II stage determined the 50% lethal dose (LD50). High-dose metamizole affected skeletal development, significantly decreasing tibia and femur lengths and corpus thicknesses and increasing mortality.

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

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.

Real-time and video-recorded pain assessment in beef cattle: clinical application and reliability in young, adult bulls undergoing surgical castration.

Bovine pain assessment relies on validated behavioral scales related to normal and pain-related behaviors. This study investigated the reliability and applicability of real-time and video-recorded pain assessment, and their agreement, in young, adult bulls undergoing surgical castration. Ten Nelore and nine Angus bulls underwent general anesthesia and surgical castration. Three-minute real-time observations and simultaneous videos were recorded at - 48 h (M0), before sedation, under fasting (M1), after surgery, 3 h after sternal recumbency (M2), after rescue analgesia (M3) and at 24 h (M4). Animals received morphine (after M2), dipyrone (after M3), and flunixin meglumine after surgical castration (M4). Two trained evaluators assessed real-time (n = 95) and video-recorded time-points (n = 95) using the Unesp-Botucatu Cattle Pain Scale (UCAPS). Both assessment methods inferred 'very good' reliability (≥ 0.81) with minimal bias, however, video-recorded assessment (4.33 ± 2.84) demonstrated slightly higher scores compared to real-time (3.08 ± 2.84). The results from this study suggest that UCAPS can be used in real-time or video-recorded to assess pain and guide analgesic therapy in cattle.

Risk of agranulocytosis with metamizole in comparison with alternative medications based on health records in Spain.

PURPOSE: We aimed to estimate the absolute (incidence) and relative (hazard ratio; HR) risk of agranulocytosis associated with metamizole in comparison with non-steroidal antiinflammatory drugs (NSAIDs). METHODS: A cohort study of new users of metamizole versus NSAIDs was performed with BIFAP (Pharmacoepidemiologic Research Database in Public Health Systems; Spain). Patients aged ≥ 2 years in 2005-2022 were followed up from the day after their first metamizole or NSAID dispensation till the end of the treatment period to identify patients hospitalized due to idiosyncratic agranulocytosis. Incidence rate (IR) and adjusted HR of agranulocytosis with metamizole versus NSAID were estimated assuming the onset date of agranulocytosis was the date of hospitalization sensitivity analysis or 7 days before (main analysis). In secondary analyses, we used (1) opioids-paracetamol as negative control and (2) any hospitalized neutropenia as outcome (assuming the onset was 7 days before). RESULTS: The cohorts included 444,972 new users of metamizole, 3,814,367 NSAID, and 3,129,221 opioids-paracetamol on continuous treatment during a median of 37-40 days. Overall, 26 hospitalized agranulocytosis occurred, 5 in the first week (and so removed in main analysis) and 21 thereafter. IR of agranulocytosis was 14.20 (N = 5 cases) and 8.52 (N = 3), 1.95 (N = 6) and 1.62 (N = 5), and 4.29 (N = 15) and 3.72 (N = 13)/107 person-weeks of continuous treatment using the date of hospitalization or 7 days before, respectively. Two, 0 and 2 of cases identified in both analyses had neoplasia in every cohort, respectively. HR of agranulocytosis associated with metamizole was 7.20 [95% CI: 1.92-26.99] and 4.40 [0.90-21.57] versus NSAID, and 3.31 [1.17-9.34] and 2.45 [0.68-8.83] versus opioid-paracetamol, respectively. HR of neutropenia with metamizole was 2.98 [1.57-5.65] versus NSAID. CONCLUSIONS: Agranulocytosis was very rare but more common (above 4 times more) with metamizole than other analgesics. The impact of the drug-induced agranulocytosis was less precise with metamizole than the comparators due to its lower use, which precluded to find statistical differences in main analysis. The increased risk of hospitalized neutropenias with metamizole supports the link with its severity although triggers unavailable during the follow-up (ex. cytotoxic medication) can not be discarded.

[New manifestation of a type 2-inflammation in the upper respiratory tract with nasal polyposis under treatment with an asthma biologic]. / Neumanifestation einer Typ-2-Inflammation im Bereich der oberen Atemwege mit Polyposis nasi unter einem Asthmabiologikum.

INTRODUCTION: For 7 years we gained experience of how asthma and chronic rhinosinusitis with nasal polyposis respond to biologics. In contrast, it is much less known, how ASA/NSAID intolerance (Widal's disease) behaves under biologicals. We therefore describe the case of a patient with both clinical conditions who reacted with a severe intolerance reaction under perioperative metamizole administration.

Neuroendocrine modulation by metamizole and indomethacin: investigating the impact on neuronal markers and GnRH release.

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 ßIII 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 ßIII 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.

Use of metamizole and other non-opioid analgesics in Switzerland between 2014 and 2019: an observational study using a large health insurance claims database.

OBJECTIVE: To investigate claims patterns for metamizole and other non-opioid analgesics in Switzerland. To characterise users of these non-opioid analgesics regarding sex, age, comedications and canton of residence. METHODS: We conducted a retrospective descriptive study using administrative claims data of outpatient prescribed non-opioid analgesics of the Swiss health insurance company Helsana between January 2014 and December 2019. First, we evaluated the number of claims and defined daily doses  per year of metamizole, ibuprofen, diclofenac and paracetamol in adults aged 18 years or over. Second, we characterised new users of these non-opioid analgesics in terms of sex, age, claimed comedications and canton of residence. RESULTS: From 2014 to 2019, among the investigated non-opioid analgesics, metamizole showed the highest increase in claims (+9545 claims, +50%) and defined daily doses (+86,869 defined daily doses, +84%) per 100,000 adults. Metamizole users had the highest median age (62 years [IQR: 44-77]) compared to ibuprofen (47 years [IQR: 33-62]), diclofenac (57 years [IQR: 43-71]) and paracetamol (58 years [IQR: 39-75]) users. Metamizole users also more frequently claimed proton pump inhibitors, anticoagulants, platelet aggregation inhibitors and antihypertensive drugs than users of other non-opioid analgesics. While metamizole was most frequently claimed in German-speaking regions of Switzerland, ibuprofen and paracetamol were most frequently claimed in the French-speaking regions and diclofenac in German- and Italian-speaking regions. CONCLUSION: In Switzerland, metamizole was increasingly claimed between 2014 and 2019. Metamizole was most frequently claimed by older adults and patients with comedications suggestive of underlying conditions, which can be worsened or caused by use of nonsteroidal anti-inflammatory drugs. The lack of studies regarding the effectiveness and safety of metamizole in this population warrants further investigation.

Prospective evaluation of the emetogenic profile and analgesic efficacy of intravenous ibuprofen and metamizole in the immediate postoperative period of pediatric acute appendicitis. / Evaluación prospectiva del perfil emético y la eficacia analgésica del ibuprofeno y el metamizol intravenosos en el postoperatorio inmediato de la apendicitis aguda pediátrica.

BACKGROUND: Literature comparing different alternatives for pain control in the immediate postoperative period of pediatric acute appendicitis (PAA) is scarce. MATERIALS AND METHODS: We prospectively compared the analgesic and emetogenic profile of intravenous ibuprofen and metamizole in the immediate postoperative period of PAA. For this purpose, we used a sample of patients operated on in 2021 in our center. Participants were recruited on arrival at the Emergency Department and histopathological confirmation of the diagnosis was obtained in all of them. Pain was evaluated every 8 hours after the surgery with validated visual analog scales ranging from 0 to 10 points. Repeated measures ANOVA was used to compare the evolution of pain in the 48 hours after surgery between the two groups. RESULTS: The sample included 95 patients (65% males) with a mean age of 9.7 years (sd: 3.14). 41 patients were treated with Ibuprofen (group 1) and 54 with metamizole (group 2). No significant differences were found in the level of pain either in the comparisons of point measurements or in its evolution in the 48 hours after surgery (p= 0.58). After adjusting for the received fluid therapy, children in the metamizole group had significantly more emetic episodes and needed significantly more doses of ondansetron. CONCLUSIONS: In our cohort, ibuprofen had a similar analgesic efficacy and a better emetogenic profile than metamizole in the immediate postoperative period of PAA. Future prospective, adequately controlled studies with larger sample sizes are needed to validate these findings.

INTRODUCCION: En la literatura existen pocas referencias que comparen las distintas alternativas disponibles para controlar el dolor en el postoperatorio inmediato de la apendicitis aguda pediátrica (AAP). MATERIAL Y METODOS: Comparación prospectiva del perfil analgésico y emético del ibuprofeno y el metamizol intravenosos en el postoperatorio inmediato de la AAP, para lo cual se recurre a una muestra de pacientes operados en 2021 en nuestro centro. Los participantes fueron reclutados a su llegada a Urgencias, obteniéndose confirmación histopatológica del diagnóstico en todos ellos. La evaluación del dolor se llevó a cabo cada 8 horas tras la cirugía mediante escalas analógicas visuales validadas, con valoraciones entre los 0 y los 10 puntos. Se realizó un ANOVA de las medidas repetidas entre los dos grupos para comparar la evolución del dolor en las 48 horas posteriores a la cirugía. RESULTADOS: La muestra estaba compuesta por un total de 95 pacientes (65% de ellos varones) con una edad media de 9,7 años (DT: 3,14). 41 pacientes fueron tratados con ibuprofeno (grupo 1) y 54 con metamizol (grupo 2). No se hallaron diferencias significativas en lo que respecta al dolor, ni en las comparaciones de las mediciones puntuales, ni en su evolución en las 48 horas posteriores a la cirugía (p= 0,58). Una vez realizado el ajuste correspondiente a la terapia de fluidos recibida, los niños del grupo metamizol tuvieron significativamente más episodios eméticos y necesitaron significativamente más dosis de ondansetrón. CONCLUSIONES: En nuestra cohorte, el ibuprofeno tuvo una eficacia analgésica similar y un mejor perfil emético que el metamizol en el postoperatorio inmediato de la AAP. Se hacen necesarios nuevos estudios prospectivos, adecuadamente controlados y con mayor tamaño muestral que validen estos hallazgos.

Pharmacokinetics-Based Pediatric Dose Evaluation and Optimization Using Saliva - A Case Study.

Understanding pharmacokinetics (PK) in children is a prerequisite to determine optimal pediatric dosing. As plasma sampling in children is challenging, alternative PK sampling strategies are needed. In this case study we evaluated the suitability of saliva as alternative PK matrix to simplify studies in infants, investigating metamizole, an analgesic used off-label in infants. Six plasma and 6 saliva PK sample collections were scheduled after a single intravenous dose of 10 mg/kg metamizole. Plasma/saliva pharmacometric (PMX) modeling of the active metabolites 4-methylaminoantipyrine (4-MAA) and 4-aminoantipyrine (4-AA) was performed. Various reduced plasma sampling scenarios were evaluated by PMX simulations. Saliva and plasma samples from 25 children were included (age range, 5-70 months; weight range, 8.7-24.8 kg). Distribution of metamizole metabolites between plasma and saliva was without delay. Estimated mean (individual range) saliva/plasma fractions of 4-MAA and 4-AA were 0.32 (0.05-0.57) and 0.57 (0.25-0.70), respectively. Residual variability of 4-MAA (4-AA) in saliva was 47% (28%) versus 17% (11%) in plasma. A simplified sampling scenario with up to 6 saliva samples combined with 1 plasma sample was associated with similar PK parameter estimates as the full plasma sampling scenario. This case study with metamizole shows increased PK variability in saliva compared to plasma, compromising its suitability as single matrix for PK studies in infants. Nonetheless, rich saliva sampling can reduce the number of plasma samples required for PK characterization, thereby facilitating the conduct of PK studies to optimize dosing in pediatric patients.

Effects of major analgesics on male fertility: A systematic literature review.

OBJECTIVE: To verify, based on a systematic literature review, the effects of the main analgesics on male fertility. DATA SOURCES: The studies were analyzed from the PubMed, SciELO and LILACS databases. STUDY SELECTION: The articles selected for the present review included: cohort studies; cross-sectional studies, clinical trials; complete studies; studies with animal models that addressed the proposed theme and that were published within the stipulated period from March 1, 2013, to March 31, 2023, in English, Portuguese and Spanish. These would later have to go through inclusion stages such as framing the type of study and exclusion criteria. DATA COLLECTION: Author's name, year of publication, study population, number of patients, analgesic, administration time, dose, and effect. CONCLUSIONS: There are in vitro and in vivo studies that link paracetamol and ibuprofen to endocrine and seminal changes that are harmful to male fertility. However, more clinical research is needed to determine the doses and timing of administration that affect fertility. The effects of aspirin on male fertility are still unclear due to the lack of studies and consistent methodologies. There is not enough research on dipyrone and its relationship with male fertility, requiring more studies in this area.

Increased Use and Large Variation in Strong Opioids and Metamizole (Dipyrone) for Minor and Major Musculoskeletal Injuries Between 2008 and 2018: An Analysis of a Representative Sample of Swiss Workers.

PURPOSE: Musculoskeletal (MSK) injuries are a major contributing factor for chronic pain. To date, little is known how pain medication use in MSK injuries has changed over time. We assessed pain medication prescription for MSK injuries in a representative sample of Swiss workers between 2008 and 2018. METHODS: Retrospective analysis of the Swiss Accident Insurance Fund (Suva) data. We calculated annual pain medication use, treatment days, and costs associated with pain medication use in minor and major MSK injuries. RESULTS: In total, 1,921,382 cases with MSK injuries with ≥ 1 pain medication were analyzed. Whereas MSK injuries with ≥ 1 pain medication increased by 9.4%, we observed a larger increase in metamizole (+ 254%), strong opioids (+ 88.4%), coxibs (+ 85.8%), and paracetamol (+ 28.1%). Strong opioids were increasingly used in minor (+ 91.4%) and major (+ 88.3%) injuries. The increase in metamizole (+ 390.6%) and coxibs (+ 115.5%) was larger in minor injuries compared to major injuries (+ 238.7% and + 80.6%, respectively). Medical expenses decreased in all medications except for strong opioids where a substantial increase was observed (+ 192.4% in minor; + 34% in major injuries). CONCLUSIONS: We observed a disproportionate increase in metamizole, strong opioids, coxibs, and paracetamol prescriptions even in minor MSK injuries between 2008 and 2018. Whereas treatment costs decreased for all pain medications, there was a substantial increase in strong opioids. A more liberal prescription practice of opioids conflict with current evidence-based practice recommendations and need to be addressed by physicians and policy makers.

Management of analgesia in acute pancreatitis: Results of a national survey. / Manejo de la analgesia en la pancreatitis aguda. Resultados de una encuesta nacional.

INTRODUCTION: Acute pancreatitis is one of the main reasons for digestive admissions. Adequate pain treatment is crucial in its management. However, there are hardly any descriptions of the analgesic guidelines used in our setting. METHODS: On-line survey on analgesic management in acute pancreatitis, aimed at attending physicians and residents practising in Spain. RESULTS: Two hundred and nine physicians from 88 centres responded to the survey. Ninety percent were specialists in gastrointestinal medicine and 69% worked in a tertiary centre. The majority (64.4%) do not routinely use scales to measure pain. When choosing a drug, experience in its use was the most important factor. The most commonly prescribed initial treatments are: combination of paracetamol and metamizole (53.5%), paracetamol alone (19.1%) and metamizole alone (17.4%). As rescue: meperidine (54.8%), tramadol (17.8%), morphine chloride (17.8%) and metamizole (11.5%). Continuous perfusion is used in 8.2% of initial treatments. Physicians with >10 years of service use more metamizole as monotherapy (50%), while residents and attending physicians with <10 years of service prescribe it in combination with paracetamol (85%). If progression is needed, morphine chloride and meperidine are mainly used. The speciality of the respondent, the size of the work centre and the unit/service where the patients were admitted did not influence the analgesia prescribed. Satisfaction with pain management reached 7.8/10 (SD 0.98). CONCLUSION: In our setting, metamizole and paracetamol are the most commonly used analgesics as initial pain treatment in acute pancreatitis, and meperidine is the most commonly used rescue analgesic.

Fatal pulmonary hemorrhage, pneumothorax and skin necrosis caused by IRIS to an Aspergillus flavus infection in a young patient with metamizole associated agranulocytosis.

We report the case of a young female with steroid-dependent ulcerative colitis (UC) who developed a complex systemic infection with Aspergillus flavus. This occurred following a UC relapse while vacationing in the Middle East, leading to extended use of metamizole and subsequent agranulocytosis. On her return to Germany, she was hospitalized for neutropenic sepsis and later transferred to our hospital due to persistent cytopenia and suspected Hemophagocytic Lymphohistiocytosis (HLH). Despite initial stabilization with targeted treatment for pulmonary Aspergillus flavus infection, her condition rapidly deteriorated following the onset of an Immune Reconstitution Inflammatory Syndrome (IRIS), which manifested as skin necrosis and pneumothorax after the replenishment of neutrophil granulocytes. The patient eventually died from an unmanageable pulmonary hemorrhage. Microscopy of skin necroses showed a massive presence of Aspergillus flavus, but tissue culture remained negative, suggesting effective antifungal treatment yet delayed phagocytosis due to agranulocytosis. This case underscores the need to consider IRIS in immunosuppressed patients who worsen despite aggressive and appropriately targeted treatment, highlighting its potential beyond the commonly recognized context in HIV-positive patients.

Discovery of GPX4 inhibitors through FP-based high-throughput screening.

Ferroptosis is a form of non-apoptotic cell death, regulated by phospholipid hydroperoxide glutathione peroxidase 4 (GPX4), a selenoprotein with a selenocysteine residue (sec) in the active site. GPX4 is a promising target for cancer cells in therapy-resistant conditions via ferroptosis, which can reduce the level of lipid reactive oxygen species (ROS). So far, all existing GPX4 inhibitors covalently bind to GPX4 via a reactive alkyl chloride moiety or masked nitrile-oxide electrophiles with poor selectivity and pharmacokinetic properties and most were obtained by cell phenotype-based screening. Lacking of effective high-throughput screening methods for GPX4 protein limits the discovery of GPX4 inhibitors. Here, we report a fluorescence polarization (FP)-based high throughput screening (HTS) assay for GPX4-U46C-C10A-C66A in vitro, and found Metamizole sodium from our in-house compound library inhibits GPX4-U46C-C10A-C66A enzyme activity. Structure-activity relationships (SAR) demonstrated the importance of sulfonyl group on interaction between Metamizole sodium and GPX4-U46C-C10A-C66A. Our FP assay could be an effective tool for discovery of GPX4 inhibitors and Metamizole sodium was a potential inhibitor for GPX4 in vitro.