Structures already discussed alongside bone osteosarcoma in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
RCSB Protein Data Bank · entry 4AT5 · 1.71 Å · ligand 5-{3-methoxy-4-[(4-methoxybenzyl)oxy]benzyl}pyrimidine-2,4-diamine (MUJ). Experimental structure, not a prediction.
A systematic review of two studies involving 802 patients found no significant difference in event-free survival when mifamurtide was added to standard chemotherapy for either non-metastatic or metastatic osteosarcoma. There was a significant difference in progression-free survival favouring the addition of mifamurtide in patients with pulmonary metastatic or relapsed disease. Overall survival showed no significant difference in metastatic disease, but a significant difference favouring mifamurtide was seen in non-metastatic patients. Survival after relapse was also significantly better with mifamurtide in the pulmonary metastatic or relapsed group. The review authors concluded that the evidence is limited and no definitive conclusions can be made.
A retrospective analysis of 18 children with osteosarcoma who received mifamurtide reported that of 15 patients with primary non-metastatic disease, 13 showed complete remission for a median of 24 months (range 16–36) and 2 were still on treatment with complete remission. Of 3 patients with progressive disease, 2 died and 1 had progressive disease at 51 months. The median follow-up was 20 months (range 7–51). The most common side effects were chills and fever (17 of 18 patients), which were transient and often not seen in later doses. Headache, myalgia, arthralgia, and back pain were also reported. No grade 3–4 neutropenia, thrombocytopenia, or abnormal liver or kidney function were observed with mifamurtide alone after chemotherapy completion.
A prospective study of two paediatric patients treated with mifamurtide plus chemotherapy according to the SEOP-SO-2010 protocol reported both were in complete remission at 10 and 13 months after treatment. One patient had a flu-like reaction after the first dose, which resolved with premedication. The authors stated that effectiveness could not be assessed due to the small sample size.
A separate laboratory study examined osteoclasts from osteosarcoma patients and found increased pro-osteoporotic markers and decreased anti-osteoporotic markers compared to healthy donors, an effect worsened during chemotherapy. In cultures, mifamurtide reduced the pro-osteoporotic markers and increased the anti-osteoporotic marker, suggesting a possible role in countering chemotherapy-induced bone loss. This is a preclinical finding only.
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
The JBI Database of Systematic Reviews and Implementation Reports · 2017 · 39 citations · open access
Effectiveness of mifamurtide in addition to standard chemotherapy for high-grade osteosarcoma: a systematic review
AbstractBACKGROUND: Osteosarcoma mostly occurs during the period of rapid bone growth in children and adolescents as high-grade osteosarcomas. Current treatment recommended for high-grade non-metastatic and metastatic and/or relapsed osteosarcoma involves neoadjuvant multiagent conventional chemotherapy, followed by surgical resection of macroscopically detected tumor and postoperative adjuvant chemotherapy. However, residual micrometastatic deposits that develop following surgery have shown resistance to postoperative/adjuvant chemotherapy. Therefore, there is a critical need for more effective and innovative therapeutic approaches such as immune stimulatory agents. The most extensively studied immune stimulatory agent in the treatment of osteosarcoma is mifamurtide. The aim of this systematic review was to identify and synthesize the evidence on the effectiveness of mifamurtide in addition to standard chemotherapy on survival outcomes. OBJECTIVES: To present the best available evidence on the treatment of high-grade non-metastatic and metastatic osteosarcoma with mifamurtide in addition to standard chemotherapy. INCLUSION CRITERIA TYPES OF PARTICIPANTS: All populations of patients regardless of age, gender or ethnicity with high-grade, resectable, non-metastatic and metastatic osteosarcoma based on histological diagnosis. TYPES OF INTERVENTIONS AND COMPARATORS: This review focused on intravenous infusion of either of the pharmaceutical formulations of mifamurtide (MTP-PE or L-MTP-PE) in addition to standard chemotherapy, and the comparator was chemotherapy alone. TYPES OF STUDIES: This review considered any experimental study design including randomized controlled trials, non-randomized trials and quasi-experimental studies. OUTCOMES: The primary outcomes of interest were event-free survival, overall survival and recurrence of osteosarcoma. Secondary outcomes that were considered included health-related quality of life and any mifamurtide-related adverse events. SEARCH STRATEGY: A search for published and unpublished literature in English was undertaken (seven published literature databases, four unpublished literature databases, and three government agency and organizational websites were searched). Studies published between 1990 to June 2016 were considered. A three-step strategy was developed using MeSH terminology and keywords to ensure that all relevant studies were included related to this review. METHODOLOGICAL QUALITY: The methodological quality of included studies was assessed by two reviewers, who appraised each study independently, using a standardized Joanna Briggs Institute (JBI) critical appraisal tool. DATA EXTRACTION: Data was extracted from the studies that were identified as meeting the criteria for methodological quality using the standard JBI data extraction tool. DATA SYNTHESIS: Due to the heterogeneity of populations and interventions in available studies, meta-analysis was not possible and results are presented in narrative form. RESULTS: Three papers outlining two studies involving 802 patients evaluated the effectiveness of mifamurtide in addition of chemotherapy. Results indicated no significant difference in event-free survival between the addition of mifamurtide to standard chemotherapy regimen and chemotherapy alone, both in non-metastatic and metastatic osteosarcoma patients. There was a significant difference in progression-free survival favoring the addition of mifamurtide in pulmonary metastatic and/or relapsed osteosarcoma. There was no significant difference in overall survival between the addition of mifamurtide and chemotherapy alone in metastatic osteosarcoma; however there was a significant difference favoring the addition of mifamurtide in non-metastatic osteosarcoma patients. The addition of mifamurtide resulted in a significant difference in survival after relapse in pulmonary metastatic and/or relapsed osteosarcoma patients. Both studies reported on mifamurtide-related adverse events - the first was reported as toxicity which included haematological, hepatic, renal, gastrointestinal disorders, cardiac, rhythm and nervous system disorders, ear disorders and others (infection, fever; and performance status) in metastatic osteosarcoma patients. Results were similar across all combined treatment regimens. Although no statistical analysis was undertaken, the figures suggest there were no significant differences between the treatment regimens. In the other study, mifamurtide-related adverse events were reported as clinical toxic effects of mifamurtide in relapsed osteosarcoma, which included chills, fever and headache for the initial dose of mifamurtide, while for the subsequent doses of mifamurtide all patients reported toxicity as delayed fatigue. CONCLUSIONS: The available evidence on the effectiveness of mifamurtide in addition to a standard chemotherapy regimen for the treatment of high-grade osteosarcoma is limited and therefore no definitive conclusions can be made.
https://doi.org/10.11124/jbisrir-2016-003105Current Cancer Drug Targets · 2017 · 18 citations
The Role of Mifamurtide in Chemotherapy-induced Osteoporosis of Children with Osteosarcoma
AbstractBACKGROUND: Osteosarcoma is the most frequent malignant bone tumor in childhood and young adulthood. Long-term survivors of osteosarcoma patients show high prevalence of osteoporosis and fractures. The immunomodulatory mifamurtide, which modulates macrophages activity, improves disease outcome. OBJECTIVE: To evaluate the role of mifamurtide on macrophage component of bone, the osteoclasts, during chemotherapy in children with osteosarcoma. METHOD: Osteoclasts, obtained from peripheral blood cells of healthy donors were harvested in the presence or not of mifamurtide. Moreover, osteoclast cultures were obtained from osteosarcoma patients, at onset and during chemotherapy, alone or with mifamurtide. Pro-osteoporotic tartrateresistant acid phosphatase (TRAP), phosphokinase-β-2 (PKCβ2), vanilloid receptor type 1 (TRPV1), and anti-osteoporotic cannabinoid receptor type 2 (CB2) biomarkers were analyzed by bio-molecular (qPCR), biochemical (Western Blotting), and morphological (TRAP assay) approaches. RESULTS: Osteoclasts from osteosarcoma patients show significant increase of TRAP and decrease of CB2 with respect to osteoclasts from healthy donors. This osteoclast hyperactivity is more evident in osteoclasts from osteosarcoma patients during chemotherapy. Mifamurtide reduces pro-osteoporotic TRAP, PKCβ2, TRPV1 levels and increases CB2 in osteoclasts from healthy donors. Moreover, chemotherapy-induced effects on bone resorption markers are fully reverted in osteoclasts derived from osteosarcoma patients in chemotherapy plus mifamurtide. CONCLUSION: Our data suggest a new therapeutic role for mifamurtide as possible anti-resorption agent in chemotherapy-induced osteoporosis in children with osteosarcoma.
https://doi.org/10.2174/1568009616666161215163426The JBI Database of Systematic Reviews and Implementation Reports · 2014 · 1 citations
Effectiveness of mifamurtide in addition to standard chemotherapy for high-grade osteosarcoma: a systematic review protocol
AbstractReview question/objective The objective of this review is to present the best available evidence related to the treatment of osteosarcoma with mifamurtide in addition to standard chemotherapy. The specific review question to be addressed is: What effect does mifamurtide have on event-free survival, overall survival, and quality of life as an adjunct to chemotherapy for high-grade non-metastatic and metastatic osteosarcoma patients? Background Osteosarcoma (also called osteogenic sarcoma) is the most common primary malignant tumor of osteoid tissues in bone.1-3 Osteosarcoma is microscopically different to normal bone tissue. This tissue is derived from mesenchymal cells which exhibit osteoblastic differentiation and produce malignant osteoid and immature bone.1 The Enneking Staging System classifies osteosarcoma into high grade, intermediate grade, or low grade based on histological characteristics.4 In addition, there are different histological subtypes of high-grade osteosarcoma such as osteoblastic, chondroblastic, fibroblastic, small cell, teleangiectatic, high-grade surface, pagetoid, extra-skeletal and post-radiation.4, 5 High-grade osteosarcomas are the fastest growing type of osteosarcoma. This review will focus on the most common of the three types of high-grade osteosarcoma (osteoblastic, chondroblastic and fibroblastic) which account for 80-90% of osteosarcoma diagnoses.4-6 Osteosarcoma is diagnosed in about 1000 individuals in both Europe and the United States of America each year.7, 8 Osteosarcoma usually develops during periods of rapid bone growth. As such, most cases of osteosarcoma that occur in children and young adults are high-grade.4 Adults aged over 60 years who develop osteosarcoma often have other predisposing factors such as a history of radiation exposure, hereditary disorders including retinoblastoma, Li-Fraumeni syndrome, Rothmund Thomas syndrome, Werner syndrome and Bloom syndrome, or Paget's disease (a benign condition characterized by abnormal development of new bone cells).9, 10 In children and young adults osteosarcoma usually develops in areas of rapid bone growth such as near the ends of the long bones.11 Osteosarcoma begins with a pain and is often mistaken for "growing pains".10 Many patients present to a doctor with pain following an injury to the affected area or when a pathological fracture occurs.4 When diagnosed, 70-80% of patients present with localized disease (non-metastatic), while 20-25% of patients present with metastatic osteosarcoma which most commonly occurs in lungs, lymph nodes or other bones.6 Currently, high-grade non-metastatic and metastatic osteosarcoma treatment involves neoadjuvant multiagent conventional chemotherapy (cisplatin, doxorubicin, high-dose methotrexate, and ifosfamide), surgical resection of macroscopically detected tumor and postoperative adjuvant chemotherapy.1, 5 The preoperative chemotherapeutic treatment offers the time to achieve tumor shrinkage and induces tumor necrosis in primary tumor to facilitate tumor resection. It also offers time to study the histological effect of preoperative chemotherapy on primary tumor to possibly alter postoperative chemotherapy.12 The degree of tumor necrosis is a prognostic marker used to validate the effectiveness of neoadjuvant chemotherapy treatment.12 Current treatment for osteosarcoma achieves 60-70% event-free survival for patients without metastases and approximately 20% event-free survival for patients with metastases.8, 13 Innovative therapeutic approaches, such as the use of immune activators (stimulants) used in combination with existing multiagent chemotherapy, are needed to aid in preventing tumor recurrence and improvement of survival rates in patients with high-grade osteosarcoma.14 Novel target-selective treatment strategies are necessary for high-grade osteosarcoma targeting the residual micrometastases. Mifamurtide (also known as muramyl tripeptide [MTP] and muramyl tripeptide phosphatidylethanolamine [MTP-PE]), is a fully synthetic lipophilic analogue of muramyl dipeptide (MDP), the smallest naturally-occurring immune stimulatory component of bacterial cell walls.6-8, 15 Both mifamurtide and MDP stimulate immune responses via binding to nucleotide-binding oligomerization domain-containing protein 2 (NOD2), an intracellular pattern recognition receptor expressed primarily in monocytes, macrophages and dendritic cells.2 By binding to NOD2, mifamurtide activates the nuclear factor (NF)-kB pathway, leading to an increased production of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin 1 (IL-1), interleukin 6 (IL-6), interleukin 8 (IL-8), interferon gamma (IFN-gamma), and immune stimulation markers plasma neopterin and serum C-reactive protein.13, 16 Activation of tumoricidal macrophages and monocytes may potentially help to eradicate residual micrometastases that are resistant to postoperative adjuvant chemotherapy.2, 8, 17 The immunostimulatory effects of mifamurtide are similar to MDP with the advantage of a longer half-life in plasma and with less pyrogenic effects. Stimulation of the innate immune defense by mifamurtide can be measured by: (1) analysis of blood plasma cytokine levels such as rapid induction of circulating TNF-α and IL-6 (one to two hours postinfusion); (2) prolonged elevations in plasma neopterin (24 hours postinfusion) and serum C-reactive protein (72 hours postinfusion); and (3) fibrosis of the area from where the tumor was removed, inflammatory macrophage infiltration into the lesions, and change in the malignant characteristic (e.g. morphology) of tumor.16, 18-20 There are two formulations of mifamurtide in use, the free-drug form (MTP-PE) and the liposomal-encapsulated form liposomal MTP-PE (L-MTP-PE). Liposomal MTP-PE is specifically designed to deliver the drug to macrophages and monocytes and is ten times less toxic than MTP-PE.2, 16, 21, 22 The standard protocol of delivery of both forms of mifamurtide is 2 mg/m2 infused intravenously over a one-hour period twice a week for 12 weeks, then once a week for 12-24 weeks.2, 6, 7, 23 One study found that the addition of mifamurtide to standard chemotherapy in 662 eligible patients improved six year overall survival from 70% to 78%, and reduced the risk of death from osteosarcoma by one third.7 Potential adverse effects (AEs) of mifamurtide in patients undergoing standard chemotherapy also require clarification. There is some suggestion that there may be minor adverse events; however the evidence has yet to be systematically examined. One study23 reported potential infusion-related adverse events (IRAEs) and AEs. Another study13 also reported short-term side effects such as fever, headache, flu-like symptoms and rigors. Participants in a separate study experienced significant serious AEs; however they were not systematically recorded.24 A preliminary search of The Cochrane Library, JBI Database of Systematic Reviews and Implementation Reports and PubMed revealed no systematic reviews either published or underway on this topic. Hence a systematic review is required to identify and synthesize the best available evidence on the effectiveness of mifamurtide as an adjunct to chemotherapy for high-grade, resectable, non-metastatic and metastatic osteosarcoma.
https://doi.org/10.11124/jbisrir-2014-1774Journal of Clinical Oncology · 2017 · 1 citations
Efficiency and toxicity of mifamurtid in childhood osteosarcoma.
Abstracte22010 Background: There are only few data concerning efficiency and toxicity of mifamurtide in children with osteosarcoma (OS). The aim of this study was to evaluate efficiency and side effects of mifamurtide in childhood OS. Methods: We retrospectively analyzed the data of 18 patients with OS and who received mifamurtide between January 2012 and December 2016. Four hundred seventy seven doses of 2 mg/m 2 intravenous mifamurtide, along with paracetamol premedication were given in 15 patients with primary non-metastatic OS after complete surgical resection and 3 patients with progressive OS. Results: There were 11 males and 7 females, and the median age was 14 years (ranged, 9-18). The median follow-up time was 20 months (ranged, 7-51). The metaphyseal plates around the knee was the most frequent disease location with 94.4%. The median necrosis percentage was 94 (range, 35-100). All patients received Euromos protocol. The most common side effects were chills and fever (17/18). These reactions were observed in 4 patients during every administration, in only one patient at last administration and in the remaining 12 patients during first or first two administration. Headache, myalgia and arthralgia were observed in 2 patients during every infusion. In another one case, headache was observed during only first two infusions and he also hearing loss was developed (could be related CisPlatin) Back pain was observed in two patient during first infusion but one them suffered with severe back pain after few doses and stoped Mifamurtid. . Grade 3-4 neutropenia, trombocytopenia, abnormal liver enzymes and abnormal BUN and creatinin levels were not observed in patients who received mifamurtide alone after completion of chemotherapy. Of the 15 patients with primary non-metastatic OS treated with the addition of mifamurtide to chemotherapy, 13 showed complet remission for median 24 months (ranged,16-36) and 2 patients are still under treatment with complet remission. Of the 3 patients with progressive disease, 2 died and 1 had progressive disease for 51 months. Conclusions: Mifamurtide therapy is safe and well tolerated in childhood OS. Chills and fever were the major side effects, These events were transient and often no longer observed in subsequent administrations.
https://doi.org/10.1200/jco.2017.35.15_suppl.e22010European Journal of Hospital Pharmacy · 2013 · 0 citations · open access
DGI-034 Evaluation of the Efficacy and Safety of Mifamurtide in Osteogenic Sarcoma Treatment in Paediatric Patients
Abstract<h3>Background</h3> Osteosarcoma is a relatively common bone tumour; with an incidence of 0.2 to 3/100 000, it is an orphan disease. Mifamurtide has managed to increase survival without increasing side effects. <h3>Purpose</h3> To evaluate the safety and efficacy of mifamurtide in two paediatric patients diagnosed with osteogenic sarcoma. <h3>Materials and Methods</h3> We conducted a prospective study of two paediatric patients diagnosed with osteogenic sarcoma. Weekly, we attended the oncology sessions and we tracked them during the chemotherapy, and after that, through the electronic clinical history. Mifamurtide is indicated in children, adolescents and young adults for the treatment of high-grade resectable non-metastatic osteosarcoma after surgical resection. It is used in combination with post-operative chemotherapy. In the two cases, the treatment followed the SEOP-SO-2010 guidelines of the Spanish Society of Paediatric Oncology for 37 weeks. After surgery (week 15) mifamurtide was started as adjuvant treatment: 2 mg/m<sup>2</sup> twice weekly for the first 12 weeks and followed by once-weekly for an additional 24 weeks, for a total of 48 infusions in 36 weeks<i>.</i> <h3>Results</h3> Chemotherapy started according to protocol, the patients were aged 12 and 15 years (July and November 2010, respectively). One patient had a flu-like reaction after the first dose of mifamurtide, so the following doses were administered with premedication (acetaminophen and dexchlorpheniramine). Other side effects: anaemia and thrombocytopenia, requiring human stimulating factors and platelet concentrates; vomiting was treated with aprepitant. When chemotherapy finished, the patients were in complete remission, this situation continues today, 10 and 13 months later. <h3>Conclusions</h3> The SEOP protocol plus mifamurtide achieved complete remission in both cases. The use of mifamurtide can be considered safe and it did not increase side effects, we observed only a flu-like reaction attributed to mifamurtide which resolved with premedication. The effectiveness of mifamurtide in osteogenic sarcoma treatment cannot be considered as assessed due to the small sample size. No conflict of interest.
https://doi.org/10.1136/ejhpharm-2013-000276.300Disease module: DeepOracle (Open Targets). Approved indication: ChEMBL drug_indication (max_phase=4). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works, resolved on OpenAlex.
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