High-Dose Immune Suppression without Hematopoietic Stem Cells for Autoimmune Diseases
Richard K. Burt, Alberto M. Marmont in Stem Cell Therapy for Autoimmune Disease, 2019
The unique pharmacology of cyclophosphamide accounts for its potent immunosuppressive properties and its ability to spare hematopoietic stem cells. Cyclophosphamide is a pro-drug that is converted in the liver to 4-hydroxycyclophosphamide and its tautomer aldophosphamide (Fig. 1). Aldophosphamide diffuses freely into the cell and is converted to the active compound phosphoramide mustard, or inactivated by aldehyde dehydrogenase to form carboxyphosphamide.17-19 Lymphoid cells, including natural killer cells, B and T lymphocytes, have low levels of aldehyde dehydrogenase and are rapidly killed by high doses of cyclophosphamide. Interestingly, primitive hematopoietic stem cells possess high levels of aldehyde dehydrogenase rendering them highly resistant to cyclophosphamide.17-19 Although the CD34 pool is markedly reduced in severe aplastic anemia, the high response rate in aplastic anemia to immunosuppressive therapy attests to the fact that healthy hematopoietic stem cells remain in most cases of aplastic anemia.
A Review on Medicinal Plants used in Cardioprotective Remedies in Traditional Medicine
Anne George, Oluwatobi Samuel Oluwafemi, Blessy Joseph, Sabu Thomas, Sebastian Mathew, V. Raji in Holistic Healthcare, 2017
Cyclophosphamide (CP) is widely used as an antineoplastic and immunosuppressant agent. It is used for the treatment of chronic and acute leukemias, multiple myeloma, lymphomas, rheumatic arthritis and as immunosuppressive agent for bone marrow transplantation. High dose CP associated cardiotoxicity occurs within 10 d of its administration.78 The two active metabolite of CP are phosphoramide mustard and acrolein. CP is activated by hepatic P450 enzyme. The major active circulating metabolite called 4-hydroxycyclophosphamide is generated by hydroxylation, which is converted intracellularly to aldophosphamide. Aldophosphamide is metabolized to phosphoramide mustard and acrolein. Of these, phosphoramide mustard is associated with therapeutic effect of CP, while, acrolein is believed to be responsible for its cytotoxic effects. The mechanism underlying CP induced cardiotoxicity is associated with generation of free radicals by these metabolites.22 CP induced oxidative stress disrupts the inner mitochondrial membrane of heart leading to the permeability of calcium ions (Table 11.6).79
Toxicity of Antineoplastic Chemotherapy in Children
Sam Kacew in Drug Toxicity and Metabolism in Pediatrics, 1990
The pharmacology of CTX is incompletely understood because of the large number of active and inactive metabolites produced during CTX degradation. CTX is well absorbed after oral administration with low doses (1 to 2 mg/kg), resulting in virtually 100% absorption.48 Higher doses give variable absorption. Peak absorption is within 3 h after oral ingestion and reaches a plateau for approximately 10 h thereafter. CTX is inactive until metabolized by the hepatic P450 microsomal enzymes to 4-hydroxycyclophosphamide (4HC) and aldophosphamide. Drugs such as phenobarbital which induce P450 enzymes will shorten the half-life of CTX; however, the clinical efficacy of CTX does not appear to be reduced by more rapid metabolism.49 Aldophosphamide is metabolized to acrolein (an inactive metabolite) and phosphoramide mustard (a highly active alkylating agent). Metabolites are excreted in the urine and it is felt that acrolein is responsible for the hemorrhagic cystitis induced by CTX. There is little CNS penetration.
Protective effect of myricetin, apigenin, and hesperidin pretreatments on cyclophosphamide-induced immunosuppression
Published in Immunopharmacology and Immunotoxicology, 2021
Mehmet Berköz, Serap Yalın, Ferbal Özkan-Yılmaz, Arzu Özlüer-Hunt, Mirosław Krośniak, Renata Francik, Oruç Yunusoğlu, Abdullah Adıyaman, Hava Gezici, Ayhan Yiğit, Seda Ünal, Davut Volkan, Metin Yıldırım
Cyclophosphamide is an alkylating agent widely used alone or in combination with diverse drugs in the chemotherapy of cancer [30]. Immunosuppression is known to be the major as well as a dose-limiting adverse toxic effect of cyclophosphamide [31]. The administration of cyclophosphamide has been shown to damage the normal tissue DNA, killing healthy immune cells, and arresting the proliferation and differentiation of macrophages, B and T lymphocytes, which can lead to suppression of the humoral and cellular immune responses [32]. The immunomodulatory activities of drugs, plant extracts and plant bioactive compounds are gaining more and more importance in the field of cancer research [33]. However, the desired primary goal of treatment is to mediate prevention of immunosuppression resulting from cyclophosphamide treatment with phytochemicals without reducing or blocking the cytotoxic effects of cyclophosphamide [33,34]. In this direction, the immunomodulatory effects of many phytochemicals have been examined in numerous studies [31–33]. This study examined the administration of myricetin, apigenin, and hesperidin at low and high doses and evaluated their immunomodulatory activity under cyclophosphamide-induced immunosuppression conditions.
Cryoglobulinemic vasculitis with primary Sjögren’s syndrome: A case report
Published in Modern Rheumatology, 2018
Jumpei Hasegawa, Noriko Hayami, Junichi Hoshino, Tatsuya Suwabe, Keiichi Sumida, Koki Mise, Toshiharu Ueno, Masayuki Yamanouchi, Naoki Sawa, Kenichi Ohashi, Takeshi Fujii, Kenmei Takaichi, Yoshifumi Ubara
Ramos-Casals et al. [11] mentioned four treatment strategies for cryoglobulinemic vasculitis, which were conventional immunosuppression, plasmapheresis, antiviral therapy, and biological therapy. Conventional immunosuppressive therapy with high-dose glucocorticoids and cyclophosphamide is used for systemic vasculitis. Plasmapheresis can rapidly remove circulating cryoglobulins and is useful in patients with life-threatening conditions such as hyperviscosity syndrome, but the rebound of the cryoglobulin level can be rapid and plasmapheresis does not address the underlying disease. Antiviral therapy is the key treatment for patients with HCV infection. Cyclophosphamide is metabolized in the liver, where it is converted to the active metabolite phosphoramide mustard and the non-alkylating metabolite acrolein. Cyclophosphamide can cause various severe toxicities, especially malignancy, when it is used over the long term.
Hippocampal neuroinflammation following combined exposure to cyclophosphamide and naproxen in ovariectomized mice
Published in International Journal of Neuroscience, 2023
Samantha Pavlock, Deirdre M. McCarthy, Anisha Kesarwani, Pascal Jean-Pierre, Pradeep G. Bhide
Naproxen and aldophosphamide, the active metabolite of CP, share a binding site on serum albumin.38 Naproxen binds with a higher affinity than aldophosphamide.38 Therefore, when CP and naproxen are both present, naproxen displaces aldophosphamide from the binding site, leading to an increase in unbound, free aldophosphamide in the serum. Since aldophosphamide crosses the blood brain barrier, it likely increases neuroinflammation.38 Therefore, in the presence of naproxen, the effects of CP on inflammation may have been augmented. One implication of this finding is that naproxen may not be a suitable anti-inflammatory drug to address neuroinflammation produced by CP. However, NSAIDs as a class have significant beneficial effects in multiple cancers due to their ability to reduce cell proliferation, induce apoptosis, and sensitize cancer cells to the anti-proliferative actions of chemotherapy drugs [Review in Hilovska et al. (2015)8] Therefore, combining naproxen with CP likely will produce other benefits even if it did not reduce neuroinflammation. In addition, as mentioned earlier, beginning naproxen exposure after CP exposure and continuing naproxen for a longer period, perhaps after CP exposure has ended, may improve the benefit profile of naproxen. Future studies will address these possibilities.
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