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Fu J, Li Q, Sun R, Gu C, Yu M, Liu W, Yang Y, Cui X. Guizhi Fuling capsules can alleviate bortezomib-induced peripheral neuropathy by decreasing Interleukin-6 levels to regulate mTOR pathway-induced autophagy. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2025; 139:156494. [PMID: 39978280 DOI: 10.1016/j.phymed.2025.156494] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Revised: 02/06/2025] [Accepted: 02/09/2025] [Indexed: 02/22/2025]
Abstract
OBJECTIVE To investigate the therapeutic effect and underlying mechanism of Guizhi Fuling capsule (GZFL) on bortezomib-induced peripheral neuropathy (BiPN). MATERIALS AND METHODS Interleukin-6 (IL-6) levels in the plasma of Multiple myeloma (MM) patients were measured by ELISA, and correlation analysis between IL-6 and clinical features of BiPNs was performed. Then, we assess the clinical therapeutic effects of GZFL on MM patients by detecting IL-6 level, PN grade, FACT score, VAS score, MVC and SCV before and after the treatment. A combination of LC/MS and network pharmacology analysis was used to investigate the components and targets of GZFL. Then, bioinformatics was carried out. After PC12 cells were treated with GZFL, a BiPN cell model was constructed to evaluate cell autophagy function by cell viability, IL-6 levels, ROS levels, immunofluorescence staining of LC3 puncta, electron transmission electron microscopy (TEM), and Western blotting (WB). C57BL/6 mice were administered bortezomib by intraperitoneal injection to establish a model of BiPN. Nerve injury in BiPN mice was observed by measuring ethology, motor nerve conduction velocity, and IL-6. ROS, HE staining. TEM, western blotting and IHC were used to detect the expression of autophagy-related indexes. RESULTS In BiPN patients, IL-6 levels were positively correlated with the PN and FACT, VAS scores. Collectively, GZFL can alleviate BiPN by reducing the level of IL-6, which is mainly manifested in the decline of PN grade, FACT, VAS score and the improvement of MVC and SCV. Thirty-four components and 107 targets of GZFL for BiPN were obtained. IL-6, mTOR, and AKT1 showed high degree values, and the significantly enriched signaling pathways were closely related to inflammatory factors and autophagy pathways, such as TNF and the mTOR signaling pathway. GZFL significantly decreased IL-6 levels in cell and animal models of BiPN. For the autophagy test, GZFL increased PC12 cell ability and the numbers of LC3 puncta and autophagic vesicles after bortezomib treatment. In vivo experiments showed that GZFL effectively improved the behavior of mice with BiPN and alleviated sciatic nerve injury. WB and IHC showed that GZFL enhanced autophagy, as indicated by the alteration of autophagy-related protein levels in PC12 cells and sciatic nerve tissue. CONCLUSION The present study confirmed that GZFL significantly ameliorates peripheral neuropathy by regulating autophagy levels via alleviating high levels of IL-6 . TRIAL REGISTRATION The link to the registration: Chinese Clinical Trial Registry (https://www.chictr.org.cn/bin/project/edit?pid=214832). The name of the trial register is "The role of mitochondrial autophagy in multiple myeloma peripheral neuropathy and the application of traditional Chinese medicine for warming Yang and removing blood stasis". The clinical trial registration number is ChiCTR2400088065.
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Affiliation(s)
- Jiaqi Fu
- The First School of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250014, China
| | - Qian Li
- Department of Surgery, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine/Shandong Hospital of Integrated Traditional Chinese and Western Medicine, Jinan, China
| | - Runjie Sun
- Center of Oncology and Hematology, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine/Shandong Hospital of Integrated Traditional Chinese and Western Medicine, Jinan, China
| | - Chunyan Gu
- Nanjing Hospital of Chinese Medicine affiliated to Nanjing University of Chinese Medicine, Nanjing, China; School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Manya Yu
- The First School of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250014, China
| | - Wei Liu
- Department of Science and Technology, Shandong University of Traditional Chinese Medicine, Jinan, China.
| | - Ye Yang
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China.
| | - Xing Cui
- Center of Oncology and Hematology, The Second Affiliated Hospital of Shandong University of Traditional Chinese Medicine/Shandong Hospital of Integrated Traditional Chinese and Western Medicine, Jinan, China.
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Doña I, Torres MJ, Celik G, Phillips E, Tanno LK, Castells M. Changing patterns in the epidemiology of drug allergy. Allergy 2024; 79:613-628. [PMID: 38084822 DOI: 10.1111/all.15970] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 11/23/2023] [Accepted: 11/26/2023] [Indexed: 03/01/2024]
Abstract
Drug allergy (DA) remains a complex and unaddressed problem worldwide that often deprives patients of optimal medication choices and places them at risk for life-threatening reactions. Underdiagnosis and overdiagnosis are common and due to the lack of standardized definitions and biomarkers. The true burden of DA is unknown, and recent efforts in data gathering through electronic medical records are starting to provide emerging patterns around the world. Ten percent of the general population engaged in health care claim to have a DA, and the most common label is penicillin allergy. Up to 20% of emergency room visits for anaphylaxis are due to DA and 15%-20% of hospitalized patients report DA. It is estimated that DA will increase based on the availability and use of new and targeted antibiotics, vaccines, chemotherapies, biologicals, and small molecules, which are aimed at improving patient's options and quality of life. Global and regional variations in the prevalence of diseases such as human immunodeficiency virus and mycobacterial diseases, and the drugs used to treat these infections have an impact on DA. The aim of this review is to provide an update on the global impact of DA by presenting emerging data on drug epidemiology in adult and pediatric populations.
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Affiliation(s)
- Immaculada Doña
- Allergy Research Group, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Malaga, Spain
- Allergy Unit, Hospital Regional Universitario de Málaga, Malaga, Spain
| | - Maria Jose Torres
- Allergy Research Group, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Malaga, Spain
- Allergy Unit, Hospital Regional Universitario de Málaga, Malaga, Spain
- Departamento de Medicina, Universidad de Málaga, Malaga, Spain
| | - Gulfem Celik
- Division of Immunology and Allergy, Department of Chest Diseases, Ankara University School of Medicine, Ankara, Turkey
| | - Elizabeth Phillips
- Department of Medicine, Center for Drug Safety and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
- Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia
| | - Luciana Kase Tanno
- Division of Allergy, Department of Pulmonology, Allergy and Thoracic Oncology, University Hospital of Montpellier, Montpellier, France
- Desbrest Institute of Epidemiology and Public Health, UMR UA11 University of Montpellier-INSERM, Montpellier, France
- WHO Collaborating Centre on Scientific Classification Support, Montpellier, France
| | - Mariana Castells
- Division of Allergy and Immunology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA
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Picard M, Filion CA, Auclair MH, Noujaim J, de Guerké L, Dionne JL, Beaudet J, Amireault C, Fortin S. Cytokine profiling, pretreatment with anakinra, and tolerance development in platinum-induced mixed hypersensitivity reactions. Ann Allergy Asthma Immunol 2023; 131:501-512.e9. [PMID: 37321446 DOI: 10.1016/j.anai.2023.06.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Revised: 05/23/2023] [Accepted: 06/05/2023] [Indexed: 06/17/2023]
Abstract
BACKGROUND Cytokine-release reactions (CRR) induced by platinum-based chemotherapy, manifesting with fever, chills, and rigors, are poorly understood and not easily prevented by usual premedication or desensitization. OBJECTIVE To gain a better understanding of platinum-induced CRR and to explore the use of anakinra as a tool to prevent its clinical manifestations. METHODS A cytokine and chemokine panel was obtained before and after platinum infusion in 3 cases with a mixed (immunoglobulin E-mediated and CRR) platinum-induced hypersensitivity reaction and in 5 controls either tolerant or with an immunoglobulin E-mediated platinum-induced hypersensitivity reaction. Anakinra was given as premedication in the 3 CRR cases. RESULTS Cytokine-release reaction was associated with a marked release of interleukin (IL)-2, IL-5, IL-6, IL-10, and tumor necrosis factor-ɑ in all cases whereas only IL-2 and IL-10 increased in some controls after platinum infusion, and to a lesser extent than in cases. Anakinra seemed to block CRR symptoms in 2 cases. In the third case, who initially had CRR symptoms despite anakinra, tolerance to oxaliplatin appeared to develop after repeated re-exposures, as suggested by the decreasing levels of cytokines after oxaliplatin, except IL-10, and the capacity to progressively shorten the desensitization protocol and taper the premedication, in addition to the negativization of the oxaliplatin skin test result. CONCLUSION In patients with platinum-induced CRR, anakinra could be a useful premedication to block its clinical manifestations, and monitoring of IL-2, IL-5, IL-6, IL-10, and tumor necrosis factor-ɑ could help predict tolerance development, thereby allowing safe adjustments to the desensitization protocol and premedication.
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Affiliation(s)
- Matthieu Picard
- Division of Clinical Immunology and Allergy, Department of Medicine, Hôpital Maisonneuve-Rosemont, Université de Montreal, Montreal, Quebec, Canada.
| | - Charles Alexandre Filion
- Division of Clinical Immunology and Allergy, Department of Medicine, Hôpital Maisonneuve-Rosemont, Université de Montreal, Montreal, Quebec, Canada
| | - Marie-Hélène Auclair
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Hôpital Maisonneuve-Rosemont, Université de Montréal, Montreal, Quebec, Canada
| | - Jonathan Noujaim
- Division of Hematology, Oncology and Cellular Therapy, Department of Medicine, Hôpital Maisonneuve-Rosemont, Université de Montréal, Montreal, Quebec, Canada
| | - Lara de Guerké
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Hôpital Maisonneuve-Rosemont, Université de Montréal, Montreal, Quebec, Canada
| | - Jean-Luc Dionne
- Division of Hematology, Oncology and Cellular Therapy, Department of Medicine, Hôpital Maisonneuve-Rosemont, Université de Montréal, Montreal, Quebec, Canada
| | - Julie Beaudet
- Division of Hematology, Oncology and Cellular Therapy, Department of Medicine, Hôpital Maisonneuve-Rosemont, Université de Montréal, Montreal, Quebec, Canada
| | - Carl Amireault
- Division of Hematology and Oncology, Department of Medicine, Hôpital Pierre-Boucher, Longueuil, Quebec, Canada
| | - Suzanne Fortin
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Hôpital Maisonneuve-Rosemont, Université de Montréal, Montreal, Quebec, Canada
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Drug fever induced by carboplatin-based regimens: Higher incidence in a women's hospital. Taiwan J Obstet Gynecol 2021; 60:882-887. [PMID: 34507666 DOI: 10.1016/j.tjog.2021.07.018] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/14/2021] [Indexed: 11/22/2022] Open
Abstract
OBJECTIVE Previous studies have reported low incidence of carboplatin-related drug fever in early cancer treatment cycles. This study describes and analyzes relatively higher incidence rate of carboplatin-related drug fever associated with gynecologic cancer chemotherapy in order to allay anxiety in patients and avoid unnecessary interventions. MATERIALS AND METHODS All gynecologic cancer cases treated with carboplatin in a women's hospital in 2017 and 2018 were retrospectively reviewed and analyzed. Data for patients who experienced carboplatin-induced drug fever and those who received the same treatment but did not experience drug fever were compared for statistical significance. Risk factors for drug fever were identified by logistic regression analysis. RESULTS In total, 318 females with a mean age of 52 years were included in the analysis. Drug fever was observed in 25 patients (7.86%) in 45 cycles of total 1605 carboplatin-containing infusions. Fever occurred at a median of the third (range: 1-7) cycle, starting at 10.62 h (range: 1.18-50.35 h) after carboplatin infusion, and was generally controlled within 3 days. After chemotherapy rechallenge, the mean frequency of drug fever was 2 times per patient (range: 1-4 times). There were 35/45 drug fever incidents (77.78%) that were classified as grade II; in 15/45 cases (33.33%), antibiotic treatment was immediately initiated to prevent infection. Younger age was found to be a risk factor for drug fever following carboplatin treatment (odds ratio = 0.126, 95% confidence interval: 0.025-0.628; p < 0.05). CONCLUSIONS The retrospective analysis demonstrated that carboplatin-induced drug fever, which occurred on post treatment 3 days, was a type of delayed hypersensitivity reaction with an incidence rate of 7.86% in gynecologic cancer. Younger age was identified as a risk factor. Drug fever is generally tolerated by patients, who insist on chemotherapy. Knowledge of carboplatin-induced drug fever may help physicians reach timely recognition for appropriate interventions.
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Ghazanfar H, Nawaz I, Ali N. Oxaliplatin-Induced Thrombocytopenia: A Case Report and Review of Pathophysiology of Various Speculative Mechanisms. Cureus 2020; 12:e9929. [PMID: 32968590 PMCID: PMC7505612 DOI: 10.7759/cureus.9929] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Oxaliplatin is one of the most common anti-neoplastic agents used in the treatment of small bowel adenocarcinoma. Peripheral neuropathy is one of the most common side effects of oxaliplatin. Oxaliplatin-induced thrombocytopenia is an extremely rare side effect and can result from various mechanisms. We present a case of a 66-year-old female who presented to the hospital for the ninth cycle of FOLFOX chemotherapy for her small bowel adenocarcinoma. The patient developed severe thrombocytopenia within 24 hours of administration of oxaliplatin. Physicians need to be aware of the sudden onset of severe thrombocytopenia associated with oxaliplatin use as early diagnosis and prompt treatment can prove lifesaving for these patients.
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Affiliation(s)
| | - Iqra Nawaz
- Internal Medicine, BronxCare Health System, Bronx, USA
| | - Nisha Ali
- Internal Medicine, BronxCare Health System, Bronx, USA
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6
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Jakubovic BD, Vecillas LDL, Jimenez-Rodriguez TW, Sanchez-Sanchez S, Castells M. Drug hypersensitivity in the fast lane: What clinicians should know about phenotypes, endotypes, and biomarkers. Ann Allergy Asthma Immunol 2020; 124:566-572. [PMID: 32302769 DOI: 10.1016/j.anai.2020.04.005] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 04/01/2020] [Accepted: 04/06/2020] [Indexed: 12/18/2022]
Abstract
OBJECTIVE To review novel concepts in drug hypersensitivity and the management of immediate hypersensitivity reactions. DATA SOURCES English language literature on MEDLINE and Embase surrounding drug hypersensitivity and desensitization. STUDY SELECTIONS References were selected based on relevance, date of publication, and originality. RESULTS There are numerous citations looking at categorizing drug reactions, pathogenesis, biomarkers, and desensitization. Current understanding supports the use of a phenotype-endotype-biomarker model for categorizing immediate hypersensitivity reactions. Drug desensitization is a powerful therapeutic strategy that enables temporary induction of tolerance to medications that triggered immediate reactions. CONCLUSION Immediate hypersensitivity reactions are diverse in presentation and pathogenesis. Drug desensitization is an effective intervention with sufficient evidence to support its more widespread availability.
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Affiliation(s)
- Baruch D Jakubovic
- Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
| | - Leticia de Las Vecillas
- Divison of Allergy, Marqués de Valdecilla University Hospital-Instituto de Investigacion Marques de Valdecilla (IDIVAL), Santander, Spain
| | | | - Soledad Sanchez-Sanchez
- Division of Allergy & Clinical Immunology, Department of Medicine, University Hospital Complex of A Coruna, A Coruna, Spain
| | - Mariana Castells
- Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, Massachusetts
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8
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Miyamoto S, Okada R, Ando K. Platinum hypersensitivity and desensitization. Jpn J Clin Oncol 2015; 45:795-804. [DOI: 10.1093/jjco/hyv081] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2015] [Accepted: 05/03/2015] [Indexed: 01/28/2023] Open
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9
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Schreck I, Grico N, Hansjosten I, Marquardt C, Bormann S, Seidel A, Kvietkova DL, Pieniazek D, Segerbäck D, Diabaté S, van der Horst GTJ, Oesch-Bartlomowicz B, Oesch F, Weiss C. The nucleotide excision repair protein XPC is essential for bulky DNA adducts to promote interleukin-6 expression via the activation of p38-SAPK. Oncogene 2015; 35:908-18. [PMID: 25982271 DOI: 10.1038/onc.2015.145] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2014] [Revised: 02/20/2015] [Accepted: 03/20/2015] [Indexed: 12/17/2022]
Abstract
Polycyclic aromatic hydrocarbons (PAHs) are environmental pollutants, and many are potent carcinogens. Benzo[a]pyrene (B[a]P), one of the best-studied PAHs, is metabolized ultimately to the genotoxin anti-B[a]P-7,8-dihydrodiol-9,10-epoxide (BPDE). BPDE triggers stress responses linked to gene expression, cell death and survival. So far, the underlying mechanisms that initiate these signal transduction cascades are unknown. Here we show that BPDE-induced DNA damage is recognized by DNA damage sensor proteins to induce activation of the stress-activated protein kinase (SAPK) p38. Surprisingly, the classical DNA damage response, which involves the kinases ATM and ATR, is not involved in p38-SAPK activation by BPDE. Moreover, the induction of p38-SAPK phosphorylation also occurs in the absence of DNA strand breaks. Instead, increased phosphorylation of p38-SAPK requires the nucleotide excision repair (NER) and DNA damage sensor proteins XPC and mHR23B. Interestingly, other genotoxins such as cisplatin (CDDP), hydrogen peroxide and ultraviolet radiation also enhance XPC-dependent p38-SAPK phosphorylation. In contrast, anti-benzo[c]phenanthrene-3,4-dihydrodiol-1,2-epoxide, the DNA adducts of which are not properly recognized by NER, does not trigger p38-SAPK activation. As a downstream consequence, expression and secretion of the pro-inflammatory cytokine interleukin-6 is induced by BPDE and CDDP in vitro and by CDDP in the murine lung, and depends on XPC. In conclusion, we describe a novel pathway in which DNA damage recognition by NER proteins specifically leads to activation of p38-SAPK to promote inflammatory gene expression.
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Affiliation(s)
- I Schreck
- Institute of Toxicology and Genetics, KIT Campus North, Eggenstein-Leopoldshafen, Germany
| | - N Grico
- Institute of Toxicology and Genetics, KIT Campus North, Eggenstein-Leopoldshafen, Germany.,Institute of Toxicology, University of Mainz, Mainz, Germany
| | - I Hansjosten
- Institute of Toxicology and Genetics, KIT Campus North, Eggenstein-Leopoldshafen, Germany
| | - C Marquardt
- Institute of Toxicology and Genetics, KIT Campus North, Eggenstein-Leopoldshafen, Germany
| | - S Bormann
- Institute of Toxicology and Genetics, KIT Campus North, Eggenstein-Leopoldshafen, Germany
| | - A Seidel
- Biochemical Institute for Environmental Carcinogens, Lurup 4, Grosshansdorf, Germany
| | - D L Kvietkova
- Department of Biosciences and Nutrition, Karolinska Institutet, Novum, S-14183 Huddinge, Sweden
| | - D Pieniazek
- Department of Biosciences and Nutrition, Karolinska Institutet, Novum, S-14183 Huddinge, Sweden
| | - D Segerbäck
- Department of Biosciences and Nutrition, Karolinska Institutet, Novum, S-14183 Huddinge, Sweden
| | - S Diabaté
- Institute of Toxicology and Genetics, KIT Campus North, Eggenstein-Leopoldshafen, Germany
| | - G T J van der Horst
- MGC, Department of Genetics, Erasmus University Medical Center, Rotterdam, The Netherlands
| | | | - F Oesch
- Institute of Toxicology, University of Mainz, Mainz, Germany
| | - C Weiss
- Institute of Toxicology and Genetics, KIT Campus North, Eggenstein-Leopoldshafen, Germany
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Khurana A, Mitsis D, Kowlgi GN, Holle LM, Clement JM. Atypical presentation of fever as hypersensitivity reaction to oxaliplatin. J Oncol Pharm Pract 2014; 22:319-24. [DOI: 10.1177/1078155214558350] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Oxaliplatin, a third-generation, platinum-based agent is widely used, most commonly in the FOLFOX (5-fluorouracil, leucovorin and oxaliplatin) regimen, which is the first-line therapy in metastatic colorectal adenocarcinoma and adjuvant chemotherapy in stage III colorectal cancer. Platinum-based products are well known for causing hypersensitivity reactions. Fever associated with oxaliplatin-hypersensitivity reactions typically follows a specific pattern. It usually starts during the oxaliplatin infusion or immediately after (within hours instead of days) and happens after several administrations (mean 2–25) with unpredictable clinical presentations. We report a case of oxaliplatin-induced hypersensitivity reaction manifesting as fever but with unusual presentation than the aforementioned features.
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Affiliation(s)
- Arushi Khurana
- Internal Medicine Residency Program, School of Medicine, University of Connecticut, Farmington, USA
| | - Demytra Mitsis
- Department of Medical Oncology, Roswell Park Cancer Institute, Buffalo, USA
| | - Gurukripa N Kowlgi
- Internal Medicine Residency Program, School of Medicine, University of Connecticut, Farmington, USA
| | - Lisa M Holle
- School of Pharmacy, University of Connecticut, Farmington, USA
| | - Jessica M Clement
- Neag Comprehensive Cancer Center, University of Connecticut Health Center, Farmington, USA
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Toki MI, Saif MW, Syrigos KN. Hypersensitivity reactions associated with oxaliplatin and their clinical management. Expert Opin Drug Saf 2014; 13:1545-54. [PMID: 25307143 DOI: 10.1517/14740338.2014.963551] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Oxaliplatin , has become an integral part of the medical treatment of colorectal cancer and other malignancies. Increased use of the drug during the last decade, has led to increased occurrence of oxaliplatin-induced hypersensitivity reactions (HSRs), posing a significant challenge for clinicians. This article aims to review the existing literature regarding the incidence, clinical presentation, pathophysiology, risk factors and current management of oxaliplatin-induced HSRs. AREAS COVERED A systematic review of the English literature published in PubMed and Medline was undertaken. The clinical manifestations of HSRs were found to be variable and unpredictable. These reactions should be an important concern, as their potential life-threatening risks can force doctors to stop treatment and seek alternatives, which may be less effective, not as well tolerated and/or more expensive. There are a few strategies to prevent these reactions so that patients can still benefit from oxaliplatin. Such strategies include the use of premedication (steroid and antagonists of type I and II histamine receptors), prolonged infusion time and desensitization. EXPERT OPINION The presented management strategies as well as novel diagnostic tools including skin/intradermal tests and specific IgE have shown promising results. However, future research and validation are warranted in bigger clinical trials.
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Affiliation(s)
- Maria I Toki
- National and Kapodistrian University of Athens, Sotiria General Hospital, Medical School, Third Department of Medicine, Oncology Unit , 152 Mesogeion Ave, 11527, Athens , Greece +30 210 770 0220 ; +30 210 778 1035 ;
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Caiado J, Picard M. Diagnostic Tools for Hypersensitivity to Platinum Drugs and Taxanes: Skin Testing, Specific IgE, and Mast Cell/Basophil Mediators. Curr Allergy Asthma Rep 2014; 14:451. [DOI: 10.1007/s11882-014-0451-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Cortijo-Cascajares S, Nacle-López I, García-Escobar I, Aguilella-Vizcaíno MJ, Herreros-de-Tejada A, Cortés-Funes Castro H, Calleja-Hernández MÁ. Effectiveness of oxaliplatin desensitization protocols. Clin Transl Oncol 2012; 15:219-25. [DOI: 10.1007/s12094-012-0909-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2012] [Accepted: 05/28/2012] [Indexed: 10/28/2022]
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Kurian S, Macintyre J, Mushtaq M, Rocha-Lima CM, Ahn Y. Oxaliplatin induced disseminated intravascular coagulation: A case report and review of literature. World J Gastrointest Oncol 2012; 4:181-3. [PMID: 22844549 PMCID: PMC3406283 DOI: 10.4251/wjgo.v4.i7.181] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2011] [Revised: 11/01/2011] [Accepted: 11/15/2011] [Indexed: 02/05/2023] Open
Abstract
Oxaliplatin in combination with a fluoropyrimide is a treatment option for colorectal cancer patients in the adjuvant and metastatic settings. Very few hematological emergencies have been reported associated with Oxaliplatin. These include autoimmune hemolytic anemia, thrombocytopenia and pancytopenia. We present a case report of a patient who developed hematuria and disseminated intravascular coagulation while receiving the second cycle of FOLFOX and bevacizumab for metastatic colon cancer.
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Affiliation(s)
- Shweta Kurian
- Shweta Kurian, Jessica Macintyre, Muzammil Mushtaq, Caio Max Rocha-Lima, Yeon Ahn, Division of Hematology Oncology, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, United States
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Proteomic approaches in understanding action mechanisms of metal-based anticancer drugs. Met Based Drugs 2011; 2008:716329. [PMID: 18670610 PMCID: PMC2486358 DOI: 10.1155/2008/716329] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2007] [Revised: 04/20/2008] [Accepted: 06/17/2008] [Indexed: 12/13/2022] Open
Abstract
Medicinal inorganic chemistry has been stimulating largely by the success of the anticancer drug, cisplatin. Various metal complexes are currently used as therapeutic agents (e.g., Pt, Au, and Ru) in the treatment of malignant diseases, including several types of cancers. Understanding the mechanism of action of these metal-based drugs is for the design of more effective drugs. Proteomic approaches combined with other biochemical methods can provide comprehensive understanding of responses that are involved in metal-based anticancer drugs-induced cell death, including insights into cytotoxic effects of metal-based anticancer drugs, correlation of protein alterations to drug targets, and prediction of drug resistance and toxicity. This information, when coupled with clinical data, can provide rational basses for the future design and modification of present used metal-based anticancer drugs.
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Petković M, Kamčeva T. FAB, ESI and MALDI Mass Spectrometric methods in the study of metallo-drugs and their biomolecular interactions. Metallomics 2011; 3:550-65. [DOI: 10.1039/c0mt00096e] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
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Santodirocco M, Lombardi V, Fesce C, Palumbo G, Capalbo S, Landriscina M. Life-threatening oxaliplatin-induced acute thrombocytopenia, hemolysis and bleeding: a case report. Acta Oncol 2009; 47:1602-4. [PMID: 18607839 DOI: 10.1080/02841860801978913] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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18
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Chen JS, Changchien CR, Tang R. Postoperative fever and survival in patients after open resection for colorectal cancer: a long-term follow-up study of 2,311 prospectively enrolled patients. Dis Colon Rectum 2008; 51:1649-55. [PMID: 18709505 DOI: 10.1007/s10350-008-9397-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2007] [Revised: 03/27/2008] [Accepted: 04/14/2008] [Indexed: 02/08/2023]
Abstract
PURPOSE Two reports on the impact of postoperative fever on survival after surgery in patients with colorectal cancer yielded contradictory results. Our study examined possible associations between postoperative fever and long-term survival of patients who underwent resection of colorectal cancer. METHODS We investigated 2,311 consecutive patients who underwent elective open colorectal resection for primary colorectal cancer at a single institution between 1995 and 1998. The primary end points were cancer-specific and overall survival. Multiple covariate impact of risk factors on survival rates was assessed by Cox regression analysis. RESULTS A total of 252 patients (12.2 percent) developed postoperative fever. The most important independent risk factor for postoperative fever was postoperative morbidity (odds ratio, 4.9; 95 percent confidence interval, 3.7-6.6) followed by blood transfusion (1.7; 1.2-2.2), Stage IV disease (1.6; 1.1-2.2), male gender (1.4; 1.0-1.9), and rectal cancer (1.4; 1.0-1.8). Cox regression modeling indicated that stage, histology, tumor location, and blood transfusion were statistically significant covariate predictors for cancer-specific survival. Postoperative fever was not independently associated with cancer-specific or overall survival. CONCLUSIONS This study did not support the hypothesis that postoperative fever is an independent prognostic factor after colorectal resection for primary colorectal cancer.
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Affiliation(s)
- Jinn-Shiun Chen
- Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Linko, Taiwan
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19
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Syrigou E, Syrigos K, Saif MW. Hypersensitivity reactions to oxaliplatin and other antineoplastic agents. Curr Allergy Asthma Rep 2008; 8:56-62. [PMID: 18377776 DOI: 10.1007/s11882-008-0011-0] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Although the reported incidence of hypersensitivity reactions (HSR) to antineoplastic agents is considered to be uncommon, it is difficult to evaluate their exact prevalence, mainly because their definition is vast and pathogenic mechanisms are vague. HSR include facial flushing, erythema, pruritus, fever, tachycardia, dyspnea, tongue swelling, rash/hives, headache, chills, weakness, vomiting, burning sensations, dizziness, and edema. Treatment and prevention consists of slowing the infusion rate, steroids, and type 1 and 2 histamine receptor antagonists. Desensitization could allow the small number of patients who experience severe HSR to receive effective therapy for their cancer. Reintroductions have only been reported as single case studies or small cohorts. Large-scale validation on desensitization strategies is still missing. With regard to oxaliplatin, knowledge of its rare but eminent toxicity is paramount, because this drug is widely used in treating colorectal cancer, the second-highest cause of cancer mortality in the United States.
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Affiliation(s)
- Ekaterini Syrigou
- Section of Medical Oncology, Yale University School of Medicine, 333 Cedar Street, FMP:116, New Haven, CT 06520, USA
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Saif MW, Roy S, Ledbetter L, Madison J, Syrigos K. Fever as the only manifestation of hypersensitivity reactions associated with oxaliplatin in a patient with colorectal cancer Oxaliplatin-induced hypersensitivity reaction. World J Gastroenterol 2007; 13:5277-81. [PMID: 17876901 PMCID: PMC4171312 DOI: 10.3748/wjg.v13.i39.5277] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hypersensitivity reactions (HSR) to oxaliplatin in patients with colorectal cancer include facial flushing, erythema, pruritis, fever, tachycardia, dyspnea, tongue swelling, rash/hives, headache, chills, weakness, vomiting, burning sensations, dizziness, and edema. We report a patient with fever as the sole manifestation of initial HSR, review the literature and discuss the management of HSR. A 57-year-old female with T3N2M0 rectal adenocarcinoma received modified FOLFOX-6. She tolerated the first 8 cycles without any toxicities except grade 1 peripheral neuropathy and nausea. During 9th and 10th infusions, she developed fever to a maximum of 38.3°C with stable hemodynamic status despite medications. During 11th infusion, she developed grade 3 HSR consisting of symptomatic bronchospasm, hypotension, nausea, vomiting, cough, and fever. On examination, she was pale, cyanotic, with a temperature of 38.8°C, BP dropped to 95/43 mm Hg, pulse of 116/min and O2 saturation of 88%-91%. She was hospitalized for management and recovered in 24 h. Fever alone is not a usual symptom of oxaliplatin HSR. It may be indicative that the patient may develop serious reactions subsequently, as did our patient who developed hypotension with the third challenge. Treatment and prevention consists of slowing the infusion rate, use of steroids and antagonists of Type 1 and 2 histamine receptor antagonists, whereas desensitization could help to provide the small number of patients who experience severe HSR with the ability to further receive an effective therapy for their colorectal cancer.
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Affiliation(s)
- M Wasif Saif
- Section of Medical Oncology, Yale University School of Medicine, New Haven, CT 06520, USA.
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21
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Abstract
The reported incidence of hypersensitivity reactions (HSRs) associated with oxaliplatin in patients with colorectal cancer (CRC) is approximately 12%, with 1 - 2% of patients developing grade 3 or 4 in severity. However, the recent rising incidence of HSR to oxaliplatin observed is the result of increasing clinical use. HSR to oxaliplatin may manifest as facial flushing, rash/hives, tachycardia, dyspnoea, erythema, pruritus, fever, tongue swelling, headache, chills, weakness, vomiting, burning sensations, dizziness and oedema. Anaphylactic shock is rare but serious, and must be considered in the event of hypotension. No definitive approaches to prevent and treat HSR associated with oxaliplatin are available; however, few successful strategies have been reported. Such strategies include: slowing the infusion rate, use of steroids and antagonists of type 1 and 2 histamine receptors, and desensitisation. Successful implementation of oxaliplatin desensitisation protocols based on other platinum-containing compounds have been reported, which could enable a small number of patients who experience severe HSR to further receive an effective therapy for CRC. However, reintroductions have only been reported as single case studies or small cohorts. Large-scale validation on desensitisation strategies are still missing. Recently, subcutaneous adrenaline has also been utilised as an alternative approach to manage HSR to oxaliplatin. Knowledge of this rare but real toxicity of oxaliplatin is paramount because the use of this drug continues to increase not only for the treatment of patients with stage II-IV CRC, but also other solid malignancies. In this article, the author discusses the incidence, clinical presentation, pathogenesis, risk factors and current strategies of management of HSR associated with oxaliplatin.
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Affiliation(s)
- M Wasif Saif
- Yale University School of Medicine, Section of Medical Oncology, 333 Cedar Street, FMP 116, New Haven, CT 06520, USA.
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Christodoulou C, Anastasopoulos D, Visvikis A, Mellou S, Detsi I, Tsiakalos G, Pateli A, Klouvas G, Papadimitriou A, Skarlos DV. Guillain-Barré syndrome in a patient with metastatic colon cancer receiving oxaliplatin-based chemotherapy. Anticancer Drugs 2004; 15:997-9. [PMID: 15514570 DOI: 10.1097/00001813-200411000-00010] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
We report Guillain-Barre syndrome (GBS), developed in a patient with metastatic colon cancer, receiving oxaliplatin-based chemotherapy. The 53-year-old patient was treated with first-line chemotherapy consisting of oxaliplatin 45 mg/m2, 5-fluorouracil 450 mg/m2 and folinic acid 200 mg/m2, all given on the same day in a weekly schedule. After 13 weeks of treatment and a cumulative oxaliplatin dose of 585 mg/m2, the patient developed unsteadiness of gait, dysphagia, and weakness of both the upper and lower limbs, as well as impairment of all sensory modalities. Clinical examination, computed tomography and magnetic resonance imaging scans of the brain, blood tests, nerve conduction studies, and cerebrospinal fluid analysis confirmed the diagnosis of GBS. Intravenous immunoglobulin G was administered for 5 days and the patient recovered fully. Oxaliplatin can cause acute and delayed neurotoxicity, but this is the first report of GBS in a patient receiving oxaliplatin-based chemotherapy. Elevation of pro-inflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-6, induced by oxaliplatin, may represent the relevant causal links involved in the cascade of events which have led to the immune-mediated demyelination in the peripheral nervous system in this patient.
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Affiliation(s)
- C Christodoulou
- Second Oncology Department; Neurology Department, Henry Dunant Hospital, Athens, Greece.
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Koutras AK, Makatsoris T, Paliogianni F, Kopsida G, Onyenadum A, Gogos CA, Mouzaki A, Kalofonos HP. Oxaliplatin-Induced Acute-Onset Thrombocytopenia, Hemorrhage and Hemolysis. Oncology 2004; 67:179-82. [PMID: 15539924 DOI: 10.1159/000081006] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2003] [Accepted: 02/25/2004] [Indexed: 11/19/2022]
Abstract
BACKGROUND Oxaliplatin is a novel platinum derivative with established anti-tumor activity in colorectal cancer. Acute-onset hemolytic anemia and thrombocytopenia associated with this drug have rarely been reported and some of these cases have been severe or even fatal. CASE REPORT This case report describes a patient who developed fever, chills, abdominal and back pain as well as sudden-onset severe thrombocytopenia, upper gastrointestinal bleeding and hemolysis immediately after treatment with oxaliplatin for metastatic colorectal cancer. The reaction appeared during the 14th cycle of chemotherapy. Corticosteroids and antihistamines were administered together with platelet transfusions. Over the next 2 days platelet count improved and the syndrome abated. The patient was discharged 4 days later. Furthermore, the reaction was accompanied by a strongly positive Coombs test and increased TNF-alpha and IL-10 serum levels which returned to normal following anti-inflammatory drug administration. CONCLUSION Physicians should be aware of the possibility of acute hematological emergencies following oxaliplatin administration.
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Affiliation(s)
- A K Koutras
- Division of Oncology, Department of Medicine, University Hospital, Patras Medical School, Rion, Greece
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Kennedy JG, Donahue JP, Hoang B, Boland PJ. Vesicant characteristics of oxaliplatin following antecubital extravasation. Clin Oncol (R Coll Radiol) 2003; 15:237-9. [PMID: 12924452 DOI: 10.1016/s0936-6555(02)00338-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Oxaliplatin is a novel class of platinum chermotherapeutic agent used in refractory adenocarcinoma. It has previously been regarded as a non-vesicant, and as such was considered safe to administer through peripheral veins. This report documents severe muscle and subcutaneous reaction with a single dose of oxaliplatin at the site of extravasation in a patient aged 58 years. Conventional therapeutic modalities were employed to reduce the effect of the soft tissue infiltrate. Despite that, significant muscle necrosis and fibrosis occurred. Surgery was deferred secondary to patient choice, and eventual extensive physical therapy restored function to the elbow joint. This case shows that oxaliplatin may not be an appropriate cytotoxic agent to be administered through a peripheral line and consideration must be made for central access when this drug is used. In addition, when extravasation does occur, the current report indicates that non-surgical management can be successful.
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Affiliation(s)
- J G Kennedy
- Department of Orthopaedic Surgery, Memorial Sloan Kettering Cancer Center, New York 10021, USA
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Pharmacoepidemiology and drug safety. Pharmacoepidemiol Drug Saf 2001; 10:173-88. [PMID: 11499857 DOI: 10.1002/pds.547] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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