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Paediatric Drugs Jan 2021Metamizole, which has antipyretic and pain-relieving properties, is generally used to treat fever in children who do not respond to paracetamol treatment. The most...
PURPOSE
Metamizole, which has antipyretic and pain-relieving properties, is generally used to treat fever in children who do not respond to paracetamol treatment. The most remarkable side effect of metamizole is that it causes myelotoxicity independently of dose. In this study, we aimed to present the clinical features of paediatric patients who developed agranulocytosis after the use of metamizole and draw attention to this side effect.
METHODS
The patients who were admitted to Eskişehir Osmangazi University Faculty of Medicine Hospital, Pediatric Infectious Diseases and Pediatric Hematology Service, between January 1, 2015, and December 31, 2018, with a diagnosis of secondary agranulocytosis to metamizole use were examined retrospectively.
RESULTS
In all, 12 patients were included in the study; oral metamizole was used in these patients for fever reduction. The mean absolute neutrophil count was 225/mm ± 226 (0-600/mm) at admission, and the neutrophil value of 11 patients was < 500/mm. The mean length of hospitalisation of the patients was 9.92 ± 8 (3-28) days. Eight patients received intravenous antibiotic therapy and four patients received at least one of the following treatments: intravenous immunoglobulin, granulocyte colony-stimulating factor and methylprednisolone. Bone marrow aspiration examination showed neutrophil/band maturation delaying in the myeloid series with normocellular bone marrow in three patients. Hypocellularity in the bone marrow and decrease in myeloid precursors were observed in three patients. There were no fatal cases.
CONCLUSION
The development of agranulocytosis after the use of metamizole causes long-term hospitalisation and may require the use of medications in treatment management. Considering the availability of alternative options to treat fever and pain, and given the side-effect profile of metamizole, it should not be the preferred, first-line antipyretic treatment in children.
Topics: Adolescent; Agranulocytosis; Anti-Inflammatory Agents, Non-Steroidal; Antipyretics; Child; Child, Preschool; Dipyrone; Female; Humans; Infant; Male; Pain; Retrospective Studies
PubMed: 33247375
DOI: 10.1007/s40272-020-00431-1 -
Supportive Care in Cancer : Official... Feb 2021
Topics: Febrile Neutropenia; Humans; Neoplasms
PubMed: 33215315
DOI: 10.1007/s00520-020-05894-z -
Journal of Clinical PsychopharmacologyClozapine is a very effective therapeutic option for schizophrenic disorders that have been refractory to most other therapies. This extremely positive aspect clashes...
BACKGROUND
Clozapine is a very effective therapeutic option for schizophrenic disorders that have been refractory to most other therapies. This extremely positive aspect clashes easily with an adverse effect of the drug that is deemed to be a very dangerous one: agranulocytosis. We asked whether the mandatory strict hematological follow-up prescribed in the black box warning of clozapine's label is proportioned to the actual incidence of agranulocytosis, considering that is the main reason that such a drug is often used only late in the treatment course.
METHODS
We carried out a systematic review of reports examining clozapine administration and agranulocytosis incidence. We specifically selected those where mild and moderate neutropenia was not used as a trigger to stop administration of clozapine, to better estimate the sheer incidence of agranulocytosis when clozapine was continued even with mild hematological effect, where detected. We used PubMed, MEDLINE, EMBASE, Cochrane, and ScienceDirect databases to identify clinical studies conducted between January 1975 and April 2023.
RESULTS
We included 14 studies, mostly retrospective ones, that examined the incidence of hematological adverse effects in patients using clozapine. A total of 2354 subjects were included. The mean age of the subjects was 33.5 years. The mean duration of observation of subjects who took clozapine was 800 days, with a mean daily dose of 319.5 mg per day. Of the 2354 subjects examined, we found that 11 of them experienced agranulocytosis (0.47%).
CONCLUSIONS
These results suggest the evidence of a lower incidence of agranulocytosis than previously estimated and are in line with more recent meta-analyses. We may therefore think that clinical practice may demand a revision of the approach that both psychiatrists and supervising organizations often take when talking about clozapine.
Topics: Humans; Adult; Clozapine; Antipsychotic Agents; Retrospective Studies; Agranulocytosis; Neutropenia; Schizophrenia
PubMed: 37930206
DOI: 10.1097/JCP.0000000000001765 -
Naunyn-Schmiedeberg's Archives of... Apr 2020The non-opioid analgesic metamizole (dipyrone) is used for the treatment of acute and chronic pain and fever. Agranulocytosis is known as a serious adverse drug reaction...
The non-opioid analgesic metamizole (dipyrone) is used for the treatment of acute and chronic pain and fever. Agranulocytosis is known as a serious adverse drug reaction of metamizole with potentially fatal outcome. However, its frequency is controversially discussed. The aim of our study was to determine the risk of metamizole-associated agranulocytosis and neutropenia using statutory health insurance data. We analyzed data from a large German health insurance fund in the period from 2010 to 2013. Metamizole-exposed subjects were identified and compared to a propensity score-matched control cohort. A total of 630,285 metamizole-treated subjects and 390,830 matched control subjects were included. In the metamizole cohort, ICD codes for agranulocytosis and neutropenia appeared more often than in non-users. The relative risk for drug-induced agranulocytosis and neutropenia (D70.1) was 3.03 (95% confidence interval, 2.49 to 3.69). The risk for developing drug-induced agranulocytosis and neutropenia after metamizole prescription was 1: 1602 (CI 95%, 1:1926 to 1:1371). Our results confirm the risk estimation of previous studies. However, the outcome of our study may be confounded by an association of metamizole treatment and chemotherapy. Therefore, consequences for treatment have to be drawn with care.
Topics: Adult; Aged; Anti-Inflammatory Agents, Non-Steroidal; Antipyretics; Dipyrone; Female; Humans; Insurance, Health; Male; Middle Aged; Neutropenia; Risk
PubMed: 31811328
DOI: 10.1007/s00210-019-01774-4 -
The Pharmacogenomics Journal Feb 2021Antithyroid drug (ATD) is a mainstay of Graves' disease (GD). About 0.1-0.5% of patients with GD treated with ATD exhibit ATD-induced agranulocytosis, which is... (Meta-Analysis)
Meta-Analysis
Antithyroid drug (ATD) is a mainstay of Graves' disease (GD). About 0.1-0.5% of patients with GD treated with ATD exhibit ATD-induced agranulocytosis, which is characterized by severe reduction of circulating neutrophils. Immune-mediated responses have been proposed as a possible mechanism for the pathogenesis of ATD-induced agranulocytosis. Although it has been reported that the HLA class II allele (HLA-DRB1*08:03) was associated with ATD-induced agranulocytosis in multiple populations, the entire HLA region have not been explored in Japanese. Therefore, we performed HLA sequencing for 10 class I and 11 class II genes in 87 patients with ATD-induced agranulocytosis and 384 patients with GD who did not show ATD-induced agranulocytosis. By conducting case-control association studies at the HLA allele and haplotype levels, we replicated the association between HLA-DRB1*08:03:02 and ATD-induced agranulocytosis (P = 5.2 × 10, odds ratio = 2.80), and identified HLA-B*39:01:01 as an independent risk factor (P = 1.4 × 10, odds ratio = 3.35). To verify reproducibility of the novel association of HLA-B*39:01:01, we reanalyzed allele frequency data for HLA-B*39:01:01 from previous case-control association studies. The association of HLA-B*39:01:01 was significantly replicated in Chinese (P = 9.0 × 10), Taiwanese (P = 1.1 × 10), and European populations (P = 5.2 × 10). A meta-analysis combining results from the previous and current studies reinforced evidence of the association between HLA-B*39:01:01 and ATD-induced agranulocytosis (P = 1.2 × 10, pooled OR = 3.66, 95% CI; 2.41-5.57). The results of this study will provide a better understanding of the pathogenesis of ATD-induced agranulocytosis in the context of HLA-mediated hypersensitivity reactions.
Topics: Agranulocytosis; Alleles; Antithyroid Agents; Female; Gene Frequency; Genetic Association Studies; Graves Disease; HLA-DRB1 Chains; Haplotypes; Humans; Japan; Male; Neutrophils; Risk Factors
PubMed: 32963330
DOI: 10.1038/s41397-020-00187-4 -
Epidemiology and Psychiatric Sciences Nov 2022Clozapine is licensed for treatment-resistant psychosis and remains underutilised. This may berelated to the stringent haematological monitoring requirements that are... (Review)
Review
AIMS
Clozapine is licensed for treatment-resistant psychosis and remains underutilised. This may berelated to the stringent haematological monitoring requirements that are mandatory in most countries. We aimed to compare guidelines internationally and develop a novel Stringency Index. We hypothesised that the most stringent countries would have increased healthcare costs and reduced prescription rates.
METHOD
We conducted a literature review and survey of guidelines internationally. Guideline identification involved a literature review and consultation with clinical academics. We focused on the haematological monitoring parameters, frequency and thresholds for discontinuation and rechallenge after suspected clozapine-induced neutropenia. In addition, indicators reflecting monitoring guideline stringency were scored and visualised using a choropleth map. We developed a Stringency Index with an international panel of clozapine experts, through a modified-Delphi-survey. The Stringency Index was compared to health expenditure per-capita and clozapine prescription per 100 000 persons.
RESULTS
One hundred twocountries were included, from Europe ( = 35), Asia ( = 24), Africa ( = 20), South America ( = 11), North America ( = 7) and Oceania and Australia ( = 5). Guidelines differed in frequency of haematological monitoring and discontinuation thresholds. Overall, 5% of included countries had explicit guidelines for clozapine-rechallenge and 40% explicitly prohibited clozapine-rechallenge. Furthermore, 7% of included countries had modified discontinuation thresholds for benign ethnic neutropenia. None of the guidelines specified how long haematological monitoring should continue. The most stringent guidelines were in Europe, and the least stringent were in Africa and South America. There was a positive association ( = 0.43, < 0.001) between a country's Stringency Index and healthcare expenditure per capita.
CONCLUSIONS
Recommendations on how haematological function should be monitored in patients treated with clozapine vary considerably between countries. It would be useful to standardise guidelines on haematological monitoring worldwide.
Topics: Humans; Clozapine; Antipsychotic Agents; Neutropenia; Psychotic Disorders; Australia
PubMed: 36426600
DOI: 10.1017/S204579602200066X -
Journal For Immunotherapy of Cancer Jun 2023Recombinant granulocyte colony-stimulating factor (G-CSF) is routinely administered for prophylaxis or treatment of chemotherapy-induced neutropenia. Chronic...
BACKGROUND
Recombinant granulocyte colony-stimulating factor (G-CSF) is routinely administered for prophylaxis or treatment of chemotherapy-induced neutropenia. Chronic myelopoiesis and granulopoiesis in patients with cancer has been shown to induce immature monocytes and neutrophils that contribute to both systemic and local immunosuppression in the tumor microenvironment. The effect of recombinant G-CSF (pegfilgrastim or filgrastim) on the production of myeloid-derived suppressive cells is unknown. Here we examined patients with pancreatic cancer, a disease known to induce myeloid-derived suppressor cells (MDSCs), and for which pegfilgrastim is routinely administered concurrently with FOLFIRINOX but not with gemcitabine-based chemotherapy regimens.
METHODS
Serial blood was collected from patients with pancreatic ductal adenocarcinoma newly starting on FOLFIRINOX or gemcitabine/n(ab)paclitaxel combination chemotherapy regimens. Neutrophil and monocyte frequencies were determined by flow cytometry from whole blood and peripheral blood mononuclear cell fractions. Serum cytokines were evaluated pretreatment and on-treatment. Patient serum was used in vitro to differentiate healthy donor monocytes to MDSCs as measured by downregulation of major histocompatibility complex II (HLA-DR) and the ability to suppress T-cell proliferation in vitro. C57BL/6 female mice with pancreatic tumors were treated with FOLFIRINOX with or without recombinant G-CSF to directly assess the role of G-CSF on induction of immunosuppressive neutrophils.
RESULTS
Patients receiving FOLFIRINOX with pegfilgrastim had increased serum G-CSF that correlated with an induction of granulocytic MDSCs. This increase was not observed in patients receiving gemcitabine/n(ab)paclitaxel without pegfilgrastim. Interleukin-18 also significantly increased in serum on FOLFIRINOX treatment. Patient serum could induce MDSCs as determined by in vitro functional assays, and this suppressive effect increased with on-treatment serum. Induction of MDSCs in vitro could be recapitulated by addition of recombinant G-CSF to healthy serum, indicating that G-CSF is sufficient for MDSC differentiation. In mice, neutrophils isolated from spleen of G-CSF-treated mice were significantly more capable of suppressing T-cell proliferation.
CONCLUSIONS
Pegfilgrastim use contributes to immune suppression in both humans and mice with pancreatic cancer. These results suggest that use of recombinant G-CSF as supportive care, while critically important for mitigating neutropenia, may complicate efforts to induce antitumor immunity.
Topics: Animals; Female; Humans; Mice; Antineoplastic Combined Chemotherapy Protocols; Gemcitabine; Granulocyte Colony-Stimulating Factor; Immunosuppression Therapy; Leukocytes, Mononuclear; Mice, Inbred C57BL; Neutropenia; Paclitaxel; Pancreatic Neoplasms; Recombinant Proteins; Tumor Microenvironment
PubMed: 37344102
DOI: 10.1136/jitc-2022-006589 -
World Journal of Pediatrics : WJP Nov 2022
Topics: Humans; Neutropenia
PubMed: 35962272
DOI: 10.1007/s12519-022-00593-7 -
Endocrine Practice : Official Journal... Dec 2021Agranulocytosis is a rare but serious adverse drug reaction (ADR) of thionamide antithyroid drugs (ATDs). We explored the characteristics of ADRs in patients with...
OBJECTIVE
Agranulocytosis is a rare but serious adverse drug reaction (ADR) of thionamide antithyroid drugs (ATDs). We explored the characteristics of ADRs in patients with hyperthyroidism.
METHODS
This retrospective study included 3558 inpatients with Graves disease treated in a Class A Grade 3 hospital between 2015 and 2019. The clinical presentation and laboratory workup of patients with antithyroid drug (ATD)-induced agranulocytosis was analyzed.
RESULTS
Agranulocytosis was thought to be caused by ATDs in 36 patients. The hospital length of stay was 12 (10-16) days, and hospitalization costs were approximately $2810.89 ($2156.50-$4164.67). The median duration of ATD therapy prior to agranulocytosis development was 30 (20-40) days. Fever (83.33%) and sore throat (75%) were the most common symptoms as early signs of agranulocytosis. The lowest neutrophil counts were 0.01 (0.00-0.03) × 10/L and 0.14 (0.02-0.29) × 10/L in the methimazole and propylthiouracil groups, respectively (P = .037). The recovery times of agranulocytosis were 9.32 ± 2.89 days and 5.60 ± 4.10 days in the methimazole and propylthiouracil groups, respectively (P = .016). Patients with severe agranulocytosis required a longer time to recover (P < .001) and had closer to normal serum thyroxine and triiodothyronine levels. The interval between the first symptom of agranulocytosis and ATD withdrawal was 1 (0-3) day.
CONCLUSIONS
Patients with agranulocytosis needed a long hospital length of stay and incurred high costs. Methimazole was prone to causing a more serious agranulocytosis than propylthiouracil. High thyroid hormone was unlikely to play a role in adverse drug reactions. Patient education is important.
Topics: Agranulocytosis; Antithyroid Agents; Humans; Hyperthyroidism; Methimazole; Propylthiouracil; Retrospective Studies
PubMed: 34216800
DOI: 10.1016/j.eprac.2021.06.017 -
Expert Review of Anticancer Therapy Oct 2021A decrease in relative-dose intensity (RDI) of chemotherapy has been shown to be associated with poor patient outcomes in solid tumors and non-Hodgkin's lymphoma. The... (Review)
Review
INTRODUCTION
A decrease in relative-dose intensity (RDI) of chemotherapy has been shown to be associated with poor patient outcomes in solid tumors and non-Hodgkin's lymphoma. The actual delivered chemotherapy dose received by patients can be influenced by dose reductions and treatment delays, often due to toxicities, most commonly chemotherapy-induced neutropenia (CIN).
AREAS COVERED
We review seminal evidence and more recent studies that have shown an association between higher RDI and improved patient survival. A smaller number of studies has shown no association between RDI and outcomes. These differences may be due to study limitations, including low power, differences in patient and disease characteristics, or the chemotherapeutic regimen. We describe guidelines recommendations to prevent and treat CIN with granulocyte-colony stimulating factor (G-CSF) and describe novel approaches to prevent neutropenia that are being developed that may provide greater value and be associated with fewer adverse events than standard G-CSF options.
EXPERT OPINION
Maintaining RDI is important to ensure optimal patient outcomes. This can be achieved through the proper administration of G-CSF prophylaxis and treatment. Newer agents in development to treat and/or prevent CIN are entering regulatory review and may potentially change the treatment landscape for CIN in the future.
Topics: Antineoplastic Combined Chemotherapy Protocols; Granulocyte Colony-Stimulating Factor; Humans; Lymphoma, Non-Hodgkin; Neoplasms; Neutropenia
PubMed: 34114525
DOI: 10.1080/14737140.2021.1941891