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Wikipedia

Cyclophosphamide

January 23, 2023

Cyclophosphamide (CP), also known as cytophosphane among other names,[3] is a medication used as chemotherapy and to suppress the immune system.[4] As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer, small cell lung cancer, neuroblastoma, and sarcoma.[4] As an immune suppressor it is used in nephrotic syndrome, granulomatosis with polyangiitis, and following organ transplant, among other conditions.[4][5] It is taken by mouth or injection into a vein.[4]

Cyclophosphamide
Clinical data
Pronunciation/ˌsaɪkloʊˈfɒsfəˌmaɪd, -lə-/[1][2]
Trade namesLyophilized Cytoxan, Endoxan, Cytoxan, Neosar, Procytox, Revimmune, Cycloblastin
AHFS/Drugs.comMonograph
MedlinePlusa682080
Pregnancy
category
  • AU: D
Routes of
administration		By mouth, by injection into a vein
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: ℞-only
  • UK: POM (Prescription only)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability>75% (by mouth)
Protein binding>60%
MetabolismLiver
Elimination half-life3–12 hours
ExcretionKidney
Identifiers
  • (RS)-N,N-bis(2-chloroethyl)-1,3,2-oxazaphosphinan-2-amine 2-oxide
CAS Number
  • 50-18-0 Y
PubChem CID
  • 2907
DrugBank
  • DB00531 Y
ChemSpider
  • 2804 Y
UNII
  • 6UXW23996M
KEGG
  • D07760 Y
ChEBI
  • CHEBI:4027 Y
ChEMBL
  • ChEMBL88 Y
CompTox Dashboard (EPA)
  • DTXSID5020364
ECHA InfoCard100.000.015
Chemical and physical data
FormulaC7H15Cl2N2O2P
Molar mass261.08 g·mol−1
3D model (JSmol)
  • Interactive image
Melting point2 °C (36 °F)
  • O=P1(OCCCN1)N(CCCl)CCCl
  • InChI=1S/C7H15Cl2N2O2P/c8-2-5-11(6-3-9)14(12)10-4-1-7-13-14/h1-7H2,(H,10,12) Y
  • Key:CMSMOCZEIVJLDB-UHFFFAOYSA-N Y
  (verify)

Most people develop side effects.[4] Common side effects include low white blood cell counts, loss of appetite, vomiting, hair loss, and bleeding from the bladder.[4] Other severe side effects include an increased future risk of cancer, infertility, allergic reactions, and pulmonary fibrosis.[4] Cyclophosphamide is in the alkylating agent and nitrogen mustard family of medications.[4] It is believed to work by interfering with the duplication of DNA and the creation of RNA.[4]

Cyclophosphamide was approved for medical use in the United States in 1959.[4] It is on the World Health Organization's List of Essential Medicines.[6]

Medical uses

Cyclophosphamide is used to treat cancers and autoimmune diseases. It is used to quickly control the disease. Due to its toxicity, it is replaced as soon as possible by less toxic drugs. Regular and frequent laboratory evaluations are required to monitor kidney function, avoid drug-induced bladder complications and screen for bone marrow toxicity.

Cancer

 
A Cyclophosphamide IV drip

The main use of cyclophosphamide is with other chemotherapy agents in the treatment of lymphomas, some forms of brain cancer, neuroblastoma, leukemia and some solid tumors.[7]

Oncovet C (Chemovet S.A.), is the first-based drug approved in Latin America for veterinary use for canine and feline cancer (carcinomas of anal sacs, bladder carcinomas, urethral carcinomas, hemangiosarcomas, lymphomas, mast cell tumor, osteosarcomas, soft tissue sarcoma), feline cancers (mammary carcinomas, hemangiosarcomas, lymphomas, plasmacytomas, chronic lymphocytic leukemia, acute myelogenous leukemia, mast cell tumor). It can be administered in different treatment schemes, such as induction therapy, adjuvant, neoadjuvant, maintenance and metronomic chemotherapy.

Autoimmune diseases

Cyclophosphamide decreases the immune system's response, and although concerns about toxicity restrict its use to patients with severe disease, it remains an important treatment for life-threatening autoimmune diseases where disease-modifying antirheumatic drugs (DMARDs) have been ineffective. For example, systemic lupus erythematosus with severe lupus nephritis may respond to pulsed cyclophosphamide. Cyclophosphamide is also used to treat minimal change disease,[8] severe rheumatoid arthritis, granulomatosis with polyangiitis,[5] Goodpasture syndrome[9] and multiple sclerosis.[10]

Because of its potential side effects such as amenorrhea or ovarian failure, cyclophosphamide is used for early phases of treatment and later substituted by other medications, such as mycophenolic acid or ACA.[11][12]

AL amyloidosis

Cyclophosphamide, used in combination with thalidomide or lenalidomide and dexamethasone has documented efficacy as an off-label treatment of AL amyloidosis. It appears to be an alternative to the more traditional treatment with melphalan in people who are ill-suited for autologous stem cell transplant.[13][7]

Graft-versus-host disease

Graft-versus-host disease (GVHD) is a major barrier for allogeneic stem cell transplant because of the immune reactions of donor T cell against the person receiving them. GVHD can often be avoided by T-cell depletion of the graft.[14] The use of a high dose cyclophosphamide post-transplant in a half matched or haploidentical donor hematopoietic stem cell transplantation reduces GVHD, even after using a reduced conditioning regimen.[15][16]

Contraindications

Like other alkylating agents, cyclophosphamide is teratogenic and contraindicated in pregnant women (pregnancy category D) except for life-threatening circumstances in the mother. Additional relative contraindications to the use of cyclophosphamide include lactation, active infection, neutropenia or bladder toxicity.[7]

Cyclophosphamide is a pregnancy category D drug and causes birth defects. First trimester exposure to cyclophosphamide for the treatment of cancer or lupus displays a pattern of anomalies labeled "cyclophosphamide embryopathy", including growth restriction, ear and facial abnormalities, absence of digits and hypoplastic limbs.[17]

Side effects

Adverse drug reactions from cyclophosphamide are related to the cumulative medication dose and include chemotherapy-induced nausea and vomiting,[18] bone marrow suppression,[19] stomach ache, hemorrhagic cystitis, diarrhea, darkening of the skin/nails, alopecia (hair loss) or thinning of hair, changes in color and texture of the hair, lethargy, and profound gonadotoxicity. Other side effects may include easy bruising/bleeding, joint pain, mouth sores, slow-healing existing wounds, unusual decrease in the amount of urine or unusual tiredness or weakness.[citation needed] Potential side effects also include leukopenia, infection, bladder toxicity, and cancer.[20]

Pulmonary injury appears rare,[21] but can present with two clinical patterns: an early, acute pneumonitis and a chronic, progressive fibrosis.[22] Cardiotoxicity is a major problem with people treated with higher dose regimens.[23]

High-dose intravenous cyclophosphamide can cause the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and a potentially fatal hyponatremia when compounded by intravenous fluids administered to prevent drug-induced cystitis.[24] While SIADH has been described primarily with higher doses of cyclophosphamide, it can also occur with the lower doses used in the management of inflammatory disorders.[25]

Bladder bleeding

Acrolein is toxic to the bladder epithelium and can lead to hemorrhagic cystitis, which is associated with microscopic or gross hematuria and occasionally dysuria.[26] Risks of hemorrhagic cystitis can be minimized with adequate fluid intake, avoidance of nighttime dosage and mesna (sodium 2-mercaptoethane sulfonate), a sulfhydryl donor which binds and detoxifies acrolein.[27] Intermittent dosing of cyclophosphamide decreases cumulative drug dose, reduces bladder exposure to acrolein and has equal efficacy to daily treatment in the management of lupus nephritis.[28]

Infection

Neutropenia or lymphopenia arising secondary to cyclophosphamide usage can predispose people to a variety of bacterial, fungal and opportunistic infections.[29] No published guidelines cover PCP prophylaxis for people with rheumatological diseases receiving immunosuppressive drugs, but some advocate its use when receiving high-dose medication.[30][31]

Infertility

Cyclophosphamide has been found to significantly increase the risk of premature menopause in females and of infertility in males and females, the likelihood of which increases with cumulative drug dose and increasing patient age. Such infertility is usually temporary, but can be permanent.[32] The use of leuprorelin in women of reproductive age before administration of intermittently dosed cyclophosphamide may diminish the risks of premature menopause and infertility.[33]

Cancer

Cyclophosphamide is carcinogenic and may increase the risk of developing lymphomas, leukemia, skin cancer, transitional cell carcinoma of the bladder or other malignancies.[34] Myeloproliferative neoplasms, including acute leukemia, non-Hodgkin lymphoma and multiple myeloma, occurred in 5 of 119 rheumatoid arthritis patients within the first decade after receiving cyclophosphamide, compared with one case of chronic lymphocytic leukemia in 119 rheumatoid arthritis patients with no history.[35] Secondary acute myeloid leukemia (therapy-related AML, or "t-AML") is thought to occur either by cyclophosphamide-inducing mutations or selecting for a high-risk myeloid clone.[36]

This risk may be dependent on dose and other factors, including the condition, other agents or treatment modalities (including radiotherapy), treatment length and intensity. For some regimens, it is rare. For instance, CMF-therapy for breast cancer (where the cumulative dose is typically less than 20 grams of cyclophosphamide) carries an AML risk of less than 1/2000, with some studies finding no increased risk compared to background. Other treatment regimens involving higher doses may carry risks of 1–2% or higher.

Cyclophosphamide-induced AML, when it happens, typically presents some years after treatment, with incidence peaking around 3–9 years. After nine years, the risk falls to background. When AML occurs, it is often preceded by a myelodysplastic syndrome phase, before developing into overt acute leukemia. Cyclophosphamide-induced leukemia will often involve complex cytogenetics, which carries a worse prognosis than de novo AML.[citation needed]

Pharmacology

Oral cyclophosphamide is rapidly absorbed and then converted by mixed-function oxidase enzymes (cytochrome P450 system) in the liver to active metabolites.[37][38] The main active metabolite is 4-hydroxycyclophosphamide, which exists in equilibrium with its tautomer, aldophosphamide. Most of the aldophosphamide is then oxidised by the enzyme aldehyde dehydrogenase (ALDH) to make carboxycyclophosphamide. A small proportion of aldophosphamide freely diffuses into cells, where it is decomposed into two compounds, phosphoramide mustard and acrolein.[39] The active metabolites of cyclophosphamide are highly protein bound and distributed to all tissues, are assumed to cross the placenta and are known to be present in breast milk.[40]

It is specifically in the oxazaphosphorine group of medications.[41]

Cyclophosphamide metabolites are primarily excreted in the urine unchanged, and drug dosing should be appropriately adjusted in the setting of renal dysfunction.[42] Drugs altering hepatic microsomal enzyme activity (e.g., alcohol, barbiturates, rifampicin, or phenytoin) may result in accelerated metabolism of cyclophosphamide into its active metabolites, increasing both pharmacologic and toxic effects of the drug; alternatively, drugs that inhibit hepatic microsomal enzymes (e.g. corticosteroids, tricyclic antidepressants, or allopurinol) result in slower conversion of cyclophosphamide into its metabolites and consequently reduced therapeutic and toxic effects.[43]

Cyclophosphamide reduces plasma pseudocholinesterase activity and may result in prolonged neuromuscular blockade when administered concurrently with succinylcholine.[44][45] Tricyclic antidepressants and other anticholinergic agents can result in delayed bladder emptying and prolonged bladder exposure to acrolein.[citation needed]

Mechanism of action

The main effect of cyclophosphamide is due to its metabolite phosphoramide mustard. This metabolite is only formed in cells that have low levels of ALDH. Phosphoramide mustard forms DNA crosslinks both between and within DNA strands at guanine N-7 positions (known as interstrand and intrastrand crosslinkages, respectively). This is irreversible and leads to cell apoptosis.[46]

Cyclophosphamide has relatively little typical chemotherapy toxicity as ALDHs are present in relatively large concentrations in bone marrow stem cells, liver and intestinal epithelium. ALDHs protect these actively proliferating tissues against toxic effects of phosphoramide mustard and acrolein by converting aldophosphamide to carboxycyclophosphamide that does not give rise to the toxic metabolites phosphoramide mustard and acrolein. This is because carboxycyclophosphamide cannot undergo β-elimination (the carboxylate acts as an electron-donating group, nullifying the potential for transformation), preventing nitrogen mustard activation and subsequent alkylation.[26][47][48]

Cyclophosphamide induces beneficial immunomodulatory effects in adaptive immunotherapy. Suggested mechanisms include:[49]

  1. Elimination of T regulatory cells (CD4+CD25+ T cells) in naive and tumor-bearing hosts
  2. Induction of T cell growth factors, such as type I IFNs, and/or
  3. Enhanced grafting of adoptively transferred, tumor-reactive effector T cells by the creation of an immunologic space niche.

Thus, cyclophosphamide preconditioning of recipient hosts (for donor T cells) has been used to enhance immunity in naïve hosts, and to enhance adoptive T cell immunotherapy regimens, as well as active vaccination strategies, inducing objective antitumor immunity.

History

As reported by O. M. Colvin in his study of the development of cyclophosphamide and its clinical applications,

Phosphoramide mustard, one of the principal toxic metabolites of cyclophosphamide, was synthesized and reported by Friedman and Seligman in 1954[50] …It was postulated that the presence of the phosphate bond to the nitrogen atom could inactivate the nitrogen mustard moiety, but the phosphate bond would be cleaved in gastric cancers and other tumors which had a high phosphamidase content. However, in studies carried out after the clinical efficacy of cyclophosphamide was demonstrated, phosphoramide mustard proved to be cytotoxic in vitro (footnote omitted), but to have a low therapeutic index in vivo.[51]

Cyclophosphamide and the related nitrogen mustard–derived alkylating agent ifosfamide were developed by Norbert Brock and ASTA (now Baxter Oncology).[52] Brock and his team synthesised and screened more than 1,000 candidate oxazaphosphorine compounds.[53] They converted the base nitrogen mustard into a nontoxic "transport form". This transport form was a prodrug, subsequently actively transported into cancer cells. Once in the cells, the prodrug was enzymatically converted into the active, toxic form. The first clinical trials were published at the end of the 1950s.[54][55][56] In 1959 it became the eighth cytotoxic anticancer agent to be approved by the FDA.[26]

Society and culture

The abbreviation CP is common, although abbreviating drug names is not best practice in medicine.[57]

Research

Because of its impact on the immune system, it is used in animal studies. Rodents are injected intraperitoneally with either a single dose of 150 mg/kg or two doses (150 and 100 mg/kg) spread over two days.[58] This can be used for applications such as:

  • The EPA may be concerned about potential human pathogenicity of an engineered microbe when conducting an MCAN review. Particularly for bacteria with potential consumer exposure they require testing of the microbe on immuno-compromised rats.[59]
  • Cyclophosphamide provides a positive control when studying immune-response of a new drug.[60]

References

  1. ^ . OxfordDictionaries.com. Archived from the original on August 25, 2012. Retrieved 2016-01-20.
  2. ^ "cyclophosphamide". Merriam-Webster Dictionary.
  3. ^ "NCI Drug Dictionary". National Cancer Institute. 2 February 2011. from the original on 25 April 2015. Retrieved 20 December 2016.
  4. ^ a b c d e f g h i j "Cyclophosphamide". The American Society of Health-System Pharmacists. from the original on 2 January 2017. Retrieved 8 December 2016.
  5. ^ a b Pagnoux C (September 2016). "Updates in ANCA-associated vasculitis". European Journal of Rheumatology. 3 (3): 122–133. doi:10.5152/eurjrheum.2015.0043. PMC 5058451. PMID 27733943.
  6. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  7. ^ a b c Brayfield, A, ed. (9 January 2017). "Cyclophosphamide: Martindale: The Complete Drug Reference". MedicinesComplete. London, UK: Pharmaceutical Press. Retrieved 12 August 2017.
  8. ^ Brenner & Rector's The Kidney (11th ed.). Philadelphia: Elsevier. 2020. pp. 1007–1091. ISBN 978-0-323-53265-5.
  9. ^ DeVrieze BW, Hurley JA (2019). "Goodpasture Syndrome (Anti-glomerular Basement Membrane Antibody Disease)". StatPearls. Treasure Island, USA: StatPearls Publishing. PMID 29083697.
  10. ^ La Mantia, L.; Milanese, C.; Mascoli, N.; D'Amico, R.; Weinstock-Guttman, B. (2007-01-24). "Cyclophosphamide for multiple sclerosis". Cochrane Database of Systematic Reviews (1): CD002819. doi:10.1002/14651858.CD002819.pub2. ISSN 1469-493X. PMC 8078225. PMID 17253481.
  11. ^ Davis LS, Reimold AM (April 2017). "Research and therapeutics-traditional and emerging therapies in systemic lupus erythematosus". Rheumatology. 56 (suppl_1): i100–i113. doi:10.1093/rheumatology/kew417. PMC 5850311. PMID 28375452.
  12. ^ Singh, Jasvinder A.; Hossain, Alomgir; Kotb, Ahmed; Wells, George A. (2016). "Comparative effectiveness of immunosuppressive drugs and corticosteroids for lupus nephritis: a systematic review and network meta-analysis". Systematic Reviews. 5 (1): 155. doi:10.1186/s13643-016-0328-z. ISSN 2046-4053. PMC 5020478. PMID 27619512.
  13. ^ Gertz MA (December 2014). "Immunoglobulin light chain amyloidosis: 2014 update on diagnosis, prognosis, and treatment". American Journal of Hematology. 89 (12): 1132–40. doi:10.1002/ajh.23828. PMID 25407896. S2CID 85480421.
  14. ^ Or-Geva N, Reisner Y (March 2016). "The evolution of T-cell depletion in haploidentical stem-cell transplantation". British Journal of Haematology. 172 (5): 667–84. doi:10.1111/bjh.13868. PMID 26684279. S2CID 1093277.
  15. ^ Fuchs EJ (June 2015). "HLA-haploidentical blood or marrow transplantation with high-dose, post-transplantation cyclophosphamide". Bone Marrow Transplantation. 50 Suppl 2: S31–6. doi:10.1038/bmt.2015.92. PMC 4634886. PMID 26039204.
  16. ^ Robinson TM, O'Donnell PV, Fuchs EJ, Luznik L (April 2016). "Haploidentical bone marrow and stem cell transplantation: experience with post-transplantation cyclophosphamide". Seminars in Hematology. 53 (2): 90–7. doi:10.1053/j.seminhematol.2016.01.005. PMC 4806368. PMID 27000732.
  17. ^ Enns GM, Roeder E, Chan RT, Ali-Khan Catts Z, Cox VA, Golabi M (September 1999). "Apparent cyclophosphamide (cytoxan) embryopathy: a distinct phenotype?". American Journal of Medical Genetics. 86 (3): 237–41. doi:10.1002/(SICI)1096-8628(19990917)86:3<237::AID-AJMG8>3.0.CO;2-V. PMID 10482872.
  18. ^ Singh G, Fries JF, Williams CA, Zatarain E, Spitz P, Bloch DA (February 1991). "Toxicity profiles of disease modifying antirheumatic drugs in rheumatoid arthritis". The Journal of Rheumatology. 18 (2): 188–94. PMID 1673721.
  19. ^ Lohrmann HP (1984). "The problem of permanent bone marrow damage after cytotoxic drug treatment". Oncology. 41 (3): 180–4. doi:10.1159/000225819. PMID 6374556.
  20. ^ Singh JA, Hossain A, Kotb A, Wells G (September 2016). "Risk of serious infections with immunosuppressive drugs and glucocorticoids for lupus nephritis: a systematic review and network meta-analysis". BMC Medicine. 14 (1): 137. doi:10.1186/s12916-016-0673-8. PMC 5022202. PMID 27623861.
  21. ^ Twohig KJ, Matthay RA (March 1990). "Pulmonary effects of cytotoxic agents other than bleomycin". Clinics in Chest Medicine. 11 (1): 31–54. doi:10.1016/S0272-5231(21)00670-5. PMID 1691069.
  22. ^ Malik SW, Myers JL, DeRemee RA, Specks U (December 1996). "Lung toxicity associated with cyclophosphamide use. Two distinct patterns". American Journal of Respiratory and Critical Care Medicine. 154 (6 Pt 1): 1851–6. doi:10.1164/ajrccm.154.6.8970380. PMID 8970380.
  23. ^ Floyd JD, Nguyen DT, Lobins RL, Bashir Q, Doll DC, Perry MC (October 2005). "Cardiotoxicity of cancer therapy". Journal of Clinical Oncology. 23 (30): 7685–96. doi:10.1200/JCO.2005.08.789. PMID 16234530.
  24. ^ Bressler RB, Huston DP (March 1985). "Water intoxication following moderate-dose intravenous cyclophosphamide". Archives of Internal Medicine. 145 (3): 548–9. doi:10.1001/archinte.145.3.548. PMID 3977522.
  25. ^ Salido M, Macarron P, Hernández-García C, D'Cruz DP, Khamashta MA, Hughes GR (2003). "Water intoxication induced by low-dose cyclophosphamide in two patients with systemic lupus erythematosus". Lupus. 12 (8): 636–9. doi:10.1191/0961203303lu421cr. PMID 12945725. S2CID 26125211.
  26. ^ a b c Emadi A, Jones RJ, Brodsky RA (November 2009). "Cyclophosphamide and cancer: golden anniversary". Nature Reviews. Clinical Oncology. 6 (11): 638–47. doi:10.1038/nrclinonc.2009.146. PMID 19786984. S2CID 18219134.
  27. ^ Monach PA, Arnold LM, Merkel PA (January 2010). "Incidence and prevention of bladder toxicity from cyclophosphamide in the treatment of rheumatic diseases: a data-driven review". Arthritis and Rheumatism. 62 (1): 9–21. doi:10.1002/art.25061. PMID 20039416.
  28. ^ Boumpas DT, Austin HA, Vaughn EM, Klippel JH, Steinberg AD, Yarboro CH, Balow JE (September 1992). "Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis". Lancet. 340 (8822): 741–5. doi:10.1016/0140-6736(92)92292-n. PMID 1356175. S2CID 8800101.
  29. ^ Pryor BD, Bologna SG, Kahl LE (September 1996). "Risk factors for serious infection during treatment with cyclophosphamide and high-dose corticosteroids for systemic lupus erythematosus". Arthritis and Rheumatism. 39 (9): 1475–82. doi:10.1002/art.1780390906. PMID 8814058.
  30. ^ Suryaprasad A, Stone JH (July 2008). "When is it safe to stop Pneumocystis jiroveci pneumonia prophylaxis? Insights from three cases complicating autoimmune diseases". Arthritis and Rheumatism. 59 (7): 1034–9. doi:10.1002/art.23822. PMID 18576286.
  31. ^ Kronbichler A, Jayne DR, Mayer G (March 2015). "Frequency, risk factors and prophylaxis of infection in ANCA-associated vasculitis". European Journal of Clinical Investigation (Review). 45 (3): 346–68. doi:10.1111/eci.12410. PMID 25627555. S2CID 870510.
  32. ^ Balow JE, Austin HA, Tsokos GC, Antonovych TT, Steinberg AD, Klippel JH (January 1987). "NIH conference. Lupus nephritis". Annals of Internal Medicine. 106 (1): 79–94. doi:10.7326/0003-4819-106-1-79. PMID 3789582.
  33. ^ Periti P, Mazzei T, Mini E (2002). "Clinical pharmacokinetics of depot leuprorelin". Clinical Pharmacokinetics. 41 (7): 485–504. doi:10.2165/00003088-200241070-00003. PMID 12083977. S2CID 10873321.
  34. ^ Bernatsky S, Clarke AE, Suissa S (February 2008). "Hematologic malignant neoplasms after drug exposure in rheumatoid arthritis". Archives of Internal Medicine. 168 (4): 378–81. doi:10.1001/archinternmed.2007.107. PMID 18299492.
  35. ^ Radis CD, Kahl LE, Baker GL, Wasko MC, Cash JM, Gallatin A, Stolzer BL, Agarwal AK, Medsger TA, Kwoh CK (August 1995). "Effects of cyclophosphamide on the development of malignancy and on long-term survival of patients with rheumatoid arthritis. A 20-year followup study". Arthritis and Rheumatism. 38 (8): 1120–7. doi:10.1002/art.1780380815. PMID 7639809.
  36. ^ Larson RA (2007). "Etiology and management of therapy-related myeloid leukemia". Hematology. American Society of Hematology. Education Program. 2007: 453–9. doi:10.1182/asheducation-2007.1.453. PMID 18024664.
  37. ^ Cohen JL, Jao JY (August 1970). "Enzymatic basis of cyclophosphamide activation by hepatic microsomes of the rat". The Journal of Pharmacology and Experimental Therapeutics. 174 (2): 206–10. PMID 4393764.
  38. ^ Huttunen KM, Raunio H, Rautio J (September 2011). "Prodrugs--from serendipity to rational design". Pharmacological Reviews. 63 (3): 750–71. doi:10.1124/pr.110.003459. PMID 21737530. S2CID 25381232.
  39. ^ Boddy AV, Yule SM (April 2000). "Metabolism and pharmacokinetics of oxazaphosphorines". Clinical Pharmacokinetics. 38 (4): 291–304. doi:10.2165/00003088-200038040-00001. PMID 10803453. S2CID 39787288.
  40. ^ Wiernik PH, Duncan JH (May 1971). "Cyclophosphamide in human milk". Lancet. 1 (7705): 912. doi:10.1016/s0140-6736(71)92474-3. PMID 4102054.
  41. ^ Giraud, B; et al. (2010), "Oxazaphosphorines: new therapeutic strategies for an old class of drugs", Expert Opin Drug Metab Toxicol, 6 (8): 919–938, doi:10.1517/17425255.2010.487861, PMID 20446865, S2CID 695545.
  42. ^ Haubitz M, Bohnenstengel F, Brunkhorst R, Schwab M, Hofmann U, Busse D (April 2002). "Cyclophosphamide pharmacokinetics and dose requirements in patients with renal insufficiency". Kidney International. 61 (4): 1495–501. doi:10.1046/j.1523-1755.2002.00279.x. PMID 11918757.
  43. ^ Donelli MG, Bartosek I, Guaitani A, Martini A, Colombo T, Pacciarini MA, Modica R (April 1976). "Importance of pharmacokinetic studies on cyclophosphamide (NSC-26271) in understanding its cytotoxic effect". Cancer Treatment Reports. 60 (4): 395–401. PMID 1277213.
  44. ^ Koseoglu V, Chiang J, Chan KW (December 1999). "Acquired pseudocholinesterase deficiency after high-dose cyclophosphamide". Bone Marrow Transplantation. 24 (12): 1367–8. doi:10.1038/sj.bmt.1702097. PMID 10627651.
  45. ^ Vigouroux D, Voltaire L (1995). "[Prolonged neuromuscular block induced by mivacurium in a patient treated with cyclophosphamide]" [Prolonged neuromuscular block induced by mivacurium in a patient treated with cyclophosphamide]. Annales Françaises d'Anesthésie et de Réanimation (in French). 14 (6): 508–10. doi:10.1016/S0750-7658(05)80493-9. PMID 8745976. INIST:2947795.
  46. ^ Hall AG, Tilby MJ (September 1992). "Mechanisms of action of, and modes of resistance to, alkylating agents used in the treatment of haematological malignancies". Blood Reviews. 6 (3): 163–73. doi:10.1016/0268-960X(92)90028-O. PMID 1422285.
  47. ^ Kohn FR, Sladek NE (October 1985). "Aldehyde dehydrogenase activity as the basis for the relative insensitivity of murine pluripotent hematopoietic stem cells to oxazaphosphorines". Biochemical Pharmacology. 34 (19): 3465–71. doi:10.1016/0006-2952(85)90719-1. PMID 2996550.
  48. ^ Friedman OM, Wodinsky I, Myles A (April 1976). "Cyclophosphamide (NSC-26271)-related phosphoramide mustards- recent advances and historical perspective". Cancer Treatment Reports. 60 (4): 337–46. PMID 1277209.
  49. ^ Sistigu A, Viaud S, Chaput N, Bracci L, Proietti E, Zitvogel L (July 2011). "Immunomodulatory effects of cyclophosphamide and implementations for vaccine design". Seminars in Immunopathology. 33 (4): 369–83. doi:10.1007/s00281-011-0245-0. PMID 21611872. S2CID 3360104.
  50. ^ Friedman OM, Seligman AM (1954). "Preparation of N-Phosphorylated Derivatives of Bis-β-chloroethylamine1a". Journal of the American Chemical Society. 76 (3): 655–8. doi:10.1021/ja01632a006.
  51. ^ Colvin OM (August 1999). "An overview of cyclophosphamide development and clinical applications". Current Pharmaceutical Design. 5 (8): 555–60. PMID 10469891.
  52. ^ U.S. Patent 3,018,302
  53. ^ Brock N (August 1996). "The history of the oxazaphosphorine cytostatics". Cancer. 78 (3): 542–7. doi:10.1002/(SICI)1097-0142(19960801)78:3<542::AID-CNCR23>3.0.CO;2-Y. PMID 8697402.
  54. ^ Wilmanns, Hilmar (1958). Chemotherapie maligner Tumoren [Chemotherapy of malignant tumors]. Asta-Forschung und Therapie (in German). OCLC 73296245.[page needed]
  55. ^ Gross R, Wulf G (1959). "Klinische und experimentelle Erfahrungen mit zyk lischen und nichtzyklischen Phosphamidestern des N-Losl in der Chemotherapie von Tumoren" [Clinical and experimental experiences with metallic cyclical and non-cyclical Phosphamidestern the N-losl in the chemotherapy of tumors]. Strahlentherapie (in German). 41: 361–7.
  56. ^ Brock N (January 1989). "Oxazaphosphorine cytostatics: past-present-future. Seventh Cain Memorial Award lecture". Cancer Research. 49 (1): 1–7. PMID 2491747.
  57. ^ Institute for Safe Medication Practices, ISMP's List of Error-Prone Abbreviations, Symbols, and Dose Designations (PDF), (PDF) from the original on 2011-10-27.
  58. ^ Zuluaga AF, Salazar BE, Rodriguez CA, Zapata AX, Agudelo M, Vesga O (March 2006). "Neutropenia induced in outbred mice by a simplified low-dose cyclophosphamide regimen: characterization and applicability to diverse experimental models of infectious diseases". BMC Infectious Diseases. 6 (1): 55. doi:10.1186/1471-2334-6-55. PMC 1434751. PMID 16545113.
  59. ^ "EPA: Notifications, FY 1998 to Present - Biotechnology Program under the Toxic Substances Control Act (TSCA) | New Chemicals Program | US EPA". from the original on 2015-06-21. Retrieved 2015-07-01.
  60. ^ Huyan XH, Lin YP, Gao T, Chen RY, Fan YM (September 2011). "Immunosuppressive effect of cyclophosphamide on white blood cells and lymphocyte subpopulations from peripheral blood of Balb/c mice". International Immunopharmacology. 11 (9): 1293–7. doi:10.1016/j.intimp.2011.04.011. PMID 21530682.

External links

  • "Cyclophosphamide". Drug Information Portal. U.S. National Library of Medicine.
  • U.S. Patent 3,018,302 Novel cyclic phosphoric acid ester amides, and the production thereof. (patent for cyclophosphamide).


January 23, 2023
cyclophosphamide, also, known, cytophosphane, among, other, names, medication, used, chemotherapy, suppress, immune, system, chemotherapy, used, treat, lymphoma, multiple, myeloma, leukemia, ovarian, cancer, breast, cancer, small, cell, lung, cancer, neuroblas. Cyclophosphamide CP also known as cytophosphane among other names 3 is a medication used as chemotherapy and to suppress the immune system 4 As chemotherapy it is used to treat lymphoma multiple myeloma leukemia ovarian cancer breast cancer small cell lung cancer neuroblastoma and sarcoma 4 As an immune suppressor it is used in nephrotic syndrome granulomatosis with polyangiitis and following organ transplant among other conditions 4 5 It is taken by mouth or injection into a vein 4 CyclophosphamideClinical dataPronunciation ˌ s aɪ k l oʊ ˈ f ɒ s f e ˌ m aɪ d l e 1 2 Trade namesLyophilized Cytoxan Endoxan Cytoxan Neosar Procytox Revimmune CycloblastinAHFS Drugs comMonographMedlinePlusa682080PregnancycategoryAU DRoutes ofadministrationBy mouth by injection into a veinATC codeL01AA01 WHO Legal statusLegal statusAU S4 Prescription only CA only UK POM Prescription only US only In general Prescription only Pharmacokinetic dataBioavailability gt 75 by mouth Protein binding gt 60 MetabolismLiverElimination half life3 12 hoursExcretionKidneyIdentifiersIUPAC name RS N N bis 2 chloroethyl 1 3 2 oxazaphosphinan 2 amine 2 oxideCAS Number50 18 0 YPubChem CID2907DrugBankDB00531 YChemSpider2804 YUNII6UXW23996MKEGGD07760 YChEBICHEBI 4027 YChEMBLChEMBL88 YCompTox Dashboard EPA DTXSID5020364ECHA InfoCard100 000 015Chemical and physical dataFormulaC 7H 15Cl 2N 2O 2PMolar mass261 08 g mol 13D model JSmol Interactive imageMelting point2 C 36 F SMILES O P1 OCCCN1 N CCCl CCClInChI InChI 1S C7H15Cl2N2O2P c8 2 5 11 6 3 9 14 12 10 4 1 7 13 14 h1 7H2 H 10 12 YKey CMSMOCZEIVJLDB UHFFFAOYSA N Y verify Most people develop side effects 4 Common side effects include low white blood cell counts loss of appetite vomiting hair loss and bleeding from the bladder 4 Other severe side effects include an increased future risk of cancer infertility allergic reactions and pulmonary fibrosis 4 Cyclophosphamide is in the alkylating agent and nitrogen mustard family of medications 4 It is believed to work by interfering with the duplication of DNA and the creation of RNA 4 Cyclophosphamide was approved for medical use in the United States in 1959 4 It is on the World Health Organization s List of Essential Medicines 6 Contents 1 Medical uses 1 1 Cancer 1 2 Autoimmune diseases 1 3 AL amyloidosis 1 4 Graft versus host disease 2 Contraindications 3 Side effects 3 1 Bladder bleeding 3 2 Infection 3 3 Infertility 3 4 Cancer 4 Pharmacology 5 Mechanism of action 6 History 7 Society and culture 8 Research 9 References 10 External linksMedical uses EditCyclophosphamide is used to treat cancers and autoimmune diseases It is used to quickly control the disease Due to its toxicity it is replaced as soon as possible by less toxic drugs Regular and frequent laboratory evaluations are required to monitor kidney function avoid drug induced bladder complications and screen for bone marrow toxicity Cancer Edit A Cyclophosphamide IV drip The main use of cyclophosphamide is with other chemotherapy agents in the treatment of lymphomas some forms of brain cancer neuroblastoma leukemia and some solid tumors 7 Oncovet C Chemovet S A is the first based drug approved in Latin America for veterinary use for canine and feline cancer carcinomas of anal sacs bladder carcinomas urethral carcinomas hemangiosarcomas lymphomas mast cell tumor osteosarcomas soft tissue sarcoma feline cancers mammary carcinomas hemangiosarcomas lymphomas plasmacytomas chronic lymphocytic leukemia acute myelogenous leukemia mast cell tumor It can be administered in different treatment schemes such as induction therapy adjuvant neoadjuvant maintenance and metronomic chemotherapy Autoimmune diseases Edit Cyclophosphamide decreases the immune system s response and although concerns about toxicity restrict its use to patients with severe disease it remains an important treatment for life threatening autoimmune diseases where disease modifying antirheumatic drugs DMARDs have been ineffective For example systemic lupus erythematosus with severe lupus nephritis may respond to pulsed cyclophosphamide Cyclophosphamide is also used to treat minimal change disease 8 severe rheumatoid arthritis granulomatosis with polyangiitis 5 Goodpasture syndrome 9 and multiple sclerosis 10 Because of its potential side effects such as amenorrhea or ovarian failure cyclophosphamide is used for early phases of treatment and later substituted by other medications such as mycophenolic acid or ACA 11 12 AL amyloidosis Edit Cyclophosphamide used in combination with thalidomide or lenalidomide and dexamethasone has documented efficacy as an off label treatment of AL amyloidosis It appears to be an alternative to the more traditional treatment with melphalan in people who are ill suited for autologous stem cell transplant 13 7 Graft versus host disease Edit Graft versus host disease GVHD is a major barrier for allogeneic stem cell transplant because of the immune reactions of donor T cell against the person receiving them GVHD can often be avoided by T cell depletion of the graft 14 The use of a high dose cyclophosphamide post transplant in a half matched or haploidentical donor hematopoietic stem cell transplantation reduces GVHD even after using a reduced conditioning regimen 15 16 Contraindications EditLike other alkylating agents cyclophosphamide is teratogenic and contraindicated in pregnant women pregnancy category D except for life threatening circumstances in the mother Additional relative contraindications to the use of cyclophosphamide include lactation active infection neutropenia or bladder toxicity 7 Cyclophosphamide is a pregnancy category D drug and causes birth defects First trimester exposure to cyclophosphamide for the treatment of cancer or lupus displays a pattern of anomalies labeled cyclophosphamide embryopathy including growth restriction ear and facial abnormalities absence of digits and hypoplastic limbs 17 Side effects EditAdverse drug reactions from cyclophosphamide are related to the cumulative medication dose and include chemotherapy induced nausea and vomiting 18 bone marrow suppression 19 stomach ache hemorrhagic cystitis diarrhea darkening of the skin nails alopecia hair loss or thinning of hair changes in color and texture of the hair lethargy and profound gonadotoxicity Other side effects may include easy bruising bleeding joint pain mouth sores slow healing existing wounds unusual decrease in the amount of urine or unusual tiredness or weakness citation needed Potential side effects also include leukopenia infection bladder toxicity and cancer 20 Pulmonary injury appears rare 21 but can present with two clinical patterns an early acute pneumonitis and a chronic progressive fibrosis 22 Cardiotoxicity is a major problem with people treated with higher dose regimens 23 High dose intravenous cyclophosphamide can cause the syndrome of inappropriate antidiuretic hormone secretion SIADH and a potentially fatal hyponatremia when compounded by intravenous fluids administered to prevent drug induced cystitis 24 While SIADH has been described primarily with higher doses of cyclophosphamide it can also occur with the lower doses used in the management of inflammatory disorders 25 Bladder bleeding Edit Acrolein is toxic to the bladder epithelium and can lead to hemorrhagic cystitis which is associated with microscopic or gross hematuria and occasionally dysuria 26 Risks of hemorrhagic cystitis can be minimized with adequate fluid intake avoidance of nighttime dosage and mesna sodium 2 mercaptoethane sulfonate a sulfhydryl donor which binds and detoxifies acrolein 27 Intermittent dosing of cyclophosphamide decreases cumulative drug dose reduces bladder exposure to acrolein and has equal efficacy to daily treatment in the management of lupus nephritis 28 Infection Edit Neutropenia or lymphopenia arising secondary to cyclophosphamide usage can predispose people to a variety of bacterial fungal and opportunistic infections 29 No published guidelines cover PCP prophylaxis for people with rheumatological diseases receiving immunosuppressive drugs but some advocate its use when receiving high dose medication 30 31 Infertility Edit Cyclophosphamide has been found to significantly increase the risk of premature menopause in females and of infertility in males and females the likelihood of which increases with cumulative drug dose and increasing patient age Such infertility is usually temporary but can be permanent 32 The use of leuprorelin in women of reproductive age before administration of intermittently dosed cyclophosphamide may diminish the risks of premature menopause and infertility 33 Cancer Edit Cyclophosphamide is carcinogenic and may increase the risk of developing lymphomas leukemia skin cancer transitional cell carcinoma of the bladder or other malignancies 34 Myeloproliferative neoplasms including acute leukemia non Hodgkin lymphoma and multiple myeloma occurred in 5 of 119 rheumatoid arthritis patients within the first decade after receiving cyclophosphamide compared with one case of chronic lymphocytic leukemia in 119 rheumatoid arthritis patients with no history 35 Secondary acute myeloid leukemia therapy related AML or t AML is thought to occur either by cyclophosphamide inducing mutations or selecting for a high risk myeloid clone 36 This risk may be dependent on dose and other factors including the condition other agents or treatment modalities including radiotherapy treatment length and intensity For some regimens it is rare For instance CMF therapy for breast cancer where the cumulative dose is typically less than 20 grams of cyclophosphamide carries an AML risk of less than 1 2000 with some studies finding no increased risk compared to background Other treatment regimens involving higher doses may carry risks of 1 2 or higher Cyclophosphamide induced AML when it happens typically presents some years after treatment with incidence peaking around 3 9 years After nine years the risk falls to background When AML occurs it is often preceded by a myelodysplastic syndrome phase before developing into overt acute leukemia Cyclophosphamide induced leukemia will often involve complex cytogenetics which carries a worse prognosis than de novo AML citation needed Pharmacology EditOral cyclophosphamide is rapidly absorbed and then converted by mixed function oxidase enzymes cytochrome P450 system in the liver to active metabolites 37 38 The main active metabolite is 4 hydroxycyclophosphamide which exists in equilibrium with its tautomer aldophosphamide Most of the aldophosphamide is then oxidised by the enzyme aldehyde dehydrogenase ALDH to make carboxycyclophosphamide A small proportion of aldophosphamide freely diffuses into cells where it is decomposed into two compounds phosphoramide mustard and acrolein 39 The active metabolites of cyclophosphamide are highly protein bound and distributed to all tissues are assumed to cross the placenta and are known to be present in breast milk 40 It is specifically in the oxazaphosphorine group of medications 41 Cyclophosphamide metabolites are primarily excreted in the urine unchanged and drug dosing should be appropriately adjusted in the setting of renal dysfunction 42 Drugs altering hepatic microsomal enzyme activity e g alcohol barbiturates rifampicin or phenytoin may result in accelerated metabolism of cyclophosphamide into its active metabolites increasing both pharmacologic and toxic effects of the drug alternatively drugs that inhibit hepatic microsomal enzymes e g corticosteroids tricyclic antidepressants or allopurinol result in slower conversion of cyclophosphamide into its metabolites and consequently reduced therapeutic and toxic effects 43 Cyclophosphamide reduces plasma pseudocholinesterase activity and may result in prolonged neuromuscular blockade when administered concurrently with succinylcholine 44 45 Tricyclic antidepressants and other anticholinergic agents can result in delayed bladder emptying and prolonged bladder exposure to acrolein citation needed Mechanism of action EditThe main effect of cyclophosphamide is due to its metabolite phosphoramide mustard This metabolite is only formed in cells that have low levels of ALDH Phosphoramide mustard forms DNA crosslinks both between and within DNA strands at guanine N 7 positions known as interstrand and intrastrand crosslinkages respectively This is irreversible and leads to cell apoptosis 46 Cyclophosphamide has relatively little typical chemotherapy toxicity as ALDHs are present in relatively large concentrations in bone marrow stem cells liver and intestinal epithelium ALDHs protect these actively proliferating tissues against toxic effects of phosphoramide mustard and acrolein by converting aldophosphamide to carboxycyclophosphamide that does not give rise to the toxic metabolites phosphoramide mustard and acrolein This is because carboxycyclophosphamide cannot undergo b elimination the carboxylate acts as an electron donating group nullifying the potential for transformation preventing nitrogen mustard activation and subsequent alkylation 26 47 48 Cyclophosphamide induces beneficial immunomodulatory effects in adaptive immunotherapy Suggested mechanisms include 49 Elimination of T regulatory cells CD4 CD25 T cells in naive and tumor bearing hosts Induction of T cell growth factors such as type I IFNs and or Enhanced grafting of adoptively transferred tumor reactive effector T cells by the creation of an immunologic space niche Thus cyclophosphamide preconditioning of recipient hosts for donor T cells has been used to enhance immunity in naive hosts and to enhance adoptive T cell immunotherapy regimens as well as active vaccination strategies inducing objective antitumor immunity History EditAs reported by O M Colvin in his study of the development of cyclophosphamide and its clinical applications Phosphoramide mustard one of the principal toxic metabolites of cyclophosphamide was synthesized and reported by Friedman and Seligman in 1954 50 It was postulated that the presence of the phosphate bond to the nitrogen atom could inactivate the nitrogen mustard moiety but the phosphate bond would be cleaved in gastric cancers and other tumors which had a high phosphamidase content However in studies carried out after the clinical efficacy of cyclophosphamide was demonstrated phosphoramide mustard proved to be cytotoxic in vitro footnote omitted but to have a low therapeutic index in vivo 51 Cyclophosphamide and the related nitrogen mustard derived alkylating agent ifosfamide were developed by Norbert Brock and ASTA now Baxter Oncology 52 Brock and his team synthesised and screened more than 1 000 candidate oxazaphosphorine compounds 53 They converted the base nitrogen mustard into a nontoxic transport form This transport form was a prodrug subsequently actively transported into cancer cells Once in the cells the prodrug was enzymatically converted into the active toxic form The first clinical trials were published at the end of the 1950s 54 55 56 In 1959 it became the eighth cytotoxic anticancer agent to be approved by the FDA 26 Society and culture EditThe abbreviation CP is common although abbreviating drug names is not best practice in medicine 57 Research EditBecause of its impact on the immune system it is used in animal studies Rodents are injected intraperitoneally with either a single dose of 150 mg kg or two doses 150 and 100 mg kg spread over two days 58 This can be used for applications such as The EPA may be concerned about potential human pathogenicity of an engineered microbe when conducting an MCAN review Particularly for bacteria with potential consumer exposure they require testing of the microbe on immuno compromised rats 59 Cyclophosphamide provides a positive control when studying immune response of a new drug 60 References Edit cyclophosphamide definition of cyclophosphamide in English from the Oxford dictionary OxfordDictionaries com Archived from the original on August 25 2012 Retrieved 2016 01 20 cyclophosphamide Merriam Webster Dictionary NCI Drug Dictionary National Cancer Institute 2 February 2011 Archived from the original on 25 April 2015 Retrieved 20 December 2016 a b c d e f g h i j Cyclophosphamide The American Society of Health System Pharmacists Archived from the original on 2 January 2017 Retrieved 8 December 2016 a b Pagnoux C September 2016 Updates in ANCA associated vasculitis European Journal of Rheumatology 3 3 122 133 doi 10 5152 eurjrheum 2015 0043 PMC 5058451 PMID 27733943 World Health Organization 2019 World Health Organization model list of essential medicines 21st list 2019 Geneva World Health Organization hdl 10665 325771 WHO MVP EMP IAU 2019 06 License CC BY NC SA 3 0 IGO a b c Brayfield A ed 9 January 2017 Cyclophosphamide Martindale The Complete Drug Reference MedicinesComplete London UK Pharmaceutical Press Retrieved 12 August 2017 Brenner amp Rector s The Kidney 11th ed Philadelphia Elsevier 2020 pp 1007 1091 ISBN 978 0 323 53265 5 DeVrieze BW Hurley JA 2019 Goodpasture Syndrome Anti glomerular Basement Membrane Antibody Disease StatPearls Treasure Island USA StatPearls Publishing PMID 29083697 La Mantia L Milanese C Mascoli N D Amico R Weinstock Guttman B 2007 01 24 Cyclophosphamide for multiple sclerosis Cochrane Database of Systematic Reviews 1 CD002819 doi 10 1002 14651858 CD002819 pub2 ISSN 1469 493X PMC 8078225 PMID 17253481 Davis LS Reimold AM April 2017 Research and therapeutics traditional and emerging therapies in systemic lupus erythematosus Rheumatology 56 suppl 1 i100 i113 doi 10 1093 rheumatology kew417 PMC 5850311 PMID 28375452 Singh Jasvinder A Hossain Alomgir Kotb Ahmed Wells George A 2016 Comparative effectiveness of immunosuppressive drugs and corticosteroids for lupus nephritis a systematic review and network meta analysis Systematic Reviews 5 1 155 doi 10 1186 s13643 016 0328 z ISSN 2046 4053 PMC 5020478 PMID 27619512 Gertz MA December 2014 Immunoglobulin light chain amyloidosis 2014 update on diagnosis prognosis and treatment American Journal of Hematology 89 12 1132 40 doi 10 1002 ajh 23828 PMID 25407896 S2CID 85480421 Or Geva N Reisner Y March 2016 The evolution of T cell depletion in haploidentical stem cell transplantation British Journal of Haematology 172 5 667 84 doi 10 1111 bjh 13868 PMID 26684279 S2CID 1093277 Fuchs EJ June 2015 HLA haploidentical blood or marrow transplantation with high dose post transplantation cyclophosphamide Bone Marrow Transplantation 50 Suppl 2 S31 6 doi 10 1038 bmt 2015 92 PMC 4634886 PMID 26039204 Robinson TM O Donnell PV Fuchs EJ Luznik L April 2016 Haploidentical bone marrow and stem cell transplantation experience with post transplantation cyclophosphamide Seminars in Hematology 53 2 90 7 doi 10 1053 j seminhematol 2016 01 005 PMC 4806368 PMID 27000732 Enns GM Roeder E Chan RT Ali Khan Catts Z Cox VA Golabi M September 1999 Apparent cyclophosphamide cytoxan embryopathy a distinct phenotype American Journal of Medical Genetics 86 3 237 41 doi 10 1002 SICI 1096 8628 19990917 86 3 lt 237 AID AJMG8 gt 3 0 CO 2 V PMID 10482872 Singh G Fries JF Williams CA Zatarain E Spitz P Bloch DA February 1991 Toxicity profiles of disease modifying antirheumatic drugs in rheumatoid arthritis The Journal of Rheumatology 18 2 188 94 PMID 1673721 Lohrmann HP 1984 The problem of permanent bone marrow damage after cytotoxic drug treatment Oncology 41 3 180 4 doi 10 1159 000225819 PMID 6374556 Singh JA Hossain A Kotb A Wells G September 2016 Risk of serious infections with immunosuppressive drugs and glucocorticoids for lupus nephritis a systematic review and network meta analysis BMC Medicine 14 1 137 doi 10 1186 s12916 016 0673 8 PMC 5022202 PMID 27623861 Twohig KJ Matthay RA March 1990 Pulmonary effects of cytotoxic agents other than bleomycin Clinics in Chest Medicine 11 1 31 54 doi 10 1016 S0272 5231 21 00670 5 PMID 1691069 Malik SW Myers JL DeRemee RA Specks U December 1996 Lung toxicity associated with cyclophosphamide use Two distinct patterns American Journal of Respiratory and Critical Care Medicine 154 6 Pt 1 1851 6 doi 10 1164 ajrccm 154 6 8970380 PMID 8970380 Floyd JD Nguyen DT Lobins RL Bashir Q Doll DC Perry MC October 2005 Cardiotoxicity of cancer therapy Journal of Clinical Oncology 23 30 7685 96 doi 10 1200 JCO 2005 08 789 PMID 16234530 Bressler RB Huston DP March 1985 Water intoxication following moderate dose intravenous cyclophosphamide Archives of Internal Medicine 145 3 548 9 doi 10 1001 archinte 145 3 548 PMID 3977522 Salido M Macarron P Hernandez Garcia C D Cruz DP Khamashta MA Hughes GR 2003 Water intoxication induced by low dose cyclophosphamide in two patients with systemic lupus erythematosus Lupus 12 8 636 9 doi 10 1191 0961203303lu421cr PMID 12945725 S2CID 26125211 a b c Emadi A Jones RJ Brodsky RA November 2009 Cyclophosphamide and cancer golden anniversary Nature Reviews Clinical Oncology 6 11 638 47 doi 10 1038 nrclinonc 2009 146 PMID 19786984 S2CID 18219134 Monach PA Arnold LM Merkel PA January 2010 Incidence and prevention of bladder toxicity from cyclophosphamide in the treatment of rheumatic diseases a data driven review Arthritis and Rheumatism 62 1 9 21 doi 10 1002 art 25061 PMID 20039416 Boumpas DT Austin HA Vaughn EM Klippel JH Steinberg AD Yarboro CH Balow JE September 1992 Controlled trial of pulse methylprednisolone versus two regimens of pulse cyclophosphamide in severe lupus nephritis Lancet 340 8822 741 5 doi 10 1016 0140 6736 92 92292 n PMID 1356175 S2CID 8800101 Pryor BD Bologna SG Kahl LE September 1996 Risk factors for serious infection during treatment with cyclophosphamide and high dose corticosteroids for systemic lupus erythematosus Arthritis and Rheumatism 39 9 1475 82 doi 10 1002 art 1780390906 PMID 8814058 Suryaprasad A Stone JH July 2008 When is it safe to stop Pneumocystis jiroveci pneumonia prophylaxis Insights from three cases complicating autoimmune diseases Arthritis and Rheumatism 59 7 1034 9 doi 10 1002 art 23822 PMID 18576286 Kronbichler A Jayne DR Mayer G March 2015 Frequency risk factors and prophylaxis of infection in ANCA associated vasculitis European Journal of Clinical Investigation Review 45 3 346 68 doi 10 1111 eci 12410 PMID 25627555 S2CID 870510 Balow JE Austin HA Tsokos GC Antonovych TT Steinberg AD Klippel JH January 1987 NIH conference Lupus nephritis Annals of Internal Medicine 106 1 79 94 doi 10 7326 0003 4819 106 1 79 PMID 3789582 Periti P Mazzei T Mini E 2002 Clinical pharmacokinetics of depot leuprorelin Clinical Pharmacokinetics 41 7 485 504 doi 10 2165 00003088 200241070 00003 PMID 12083977 S2CID 10873321 Bernatsky S Clarke AE Suissa S February 2008 Hematologic malignant neoplasms after drug exposure in rheumatoid arthritis Archives of Internal Medicine 168 4 378 81 doi 10 1001 archinternmed 2007 107 PMID 18299492 Radis CD Kahl LE Baker GL Wasko MC Cash JM Gallatin A Stolzer BL Agarwal AK Medsger TA Kwoh CK August 1995 Effects of cyclophosphamide on the development of malignancy and on long term survival of patients with rheumatoid arthritis A 20 year followup study Arthritis and Rheumatism 38 8 1120 7 doi 10 1002 art 1780380815 PMID 7639809 Larson RA 2007 Etiology and management of therapy related myeloid leukemia Hematology American Society of Hematology Education Program 2007 453 9 doi 10 1182 asheducation 2007 1 453 PMID 18024664 Cohen JL Jao JY August 1970 Enzymatic basis of cyclophosphamide activation by hepatic microsomes of the rat The Journal of Pharmacology and Experimental Therapeutics 174 2 206 10 PMID 4393764 Huttunen KM Raunio H Rautio J September 2011 Prodrugs from serendipity to rational design Pharmacological Reviews 63 3 750 71 doi 10 1124 pr 110 003459 PMID 21737530 S2CID 25381232 Boddy AV Yule SM April 2000 Metabolism and pharmacokinetics of oxazaphosphorines Clinical Pharmacokinetics 38 4 291 304 doi 10 2165 00003088 200038040 00001 PMID 10803453 S2CID 39787288 Wiernik PH Duncan JH May 1971 Cyclophosphamide in human milk Lancet 1 7705 912 doi 10 1016 s0140 6736 71 92474 3 PMID 4102054 Giraud B et al 2010 Oxazaphosphorines new therapeutic strategies for an old class of drugs Expert Opin Drug Metab Toxicol 6 8 919 938 doi 10 1517 17425255 2010 487861 PMID 20446865 S2CID 695545 Haubitz M Bohnenstengel F Brunkhorst R Schwab M Hofmann U Busse D April 2002 Cyclophosphamide pharmacokinetics and dose requirements in patients with renal insufficiency Kidney International 61 4 1495 501 doi 10 1046 j 1523 1755 2002 00279 x PMID 11918757 Donelli MG Bartosek I Guaitani A Martini A Colombo T Pacciarini MA Modica R April 1976 Importance of pharmacokinetic studies on cyclophosphamide NSC 26271 in understanding its cytotoxic effect Cancer Treatment Reports 60 4 395 401 PMID 1277213 Koseoglu V Chiang J Chan KW December 1999 Acquired pseudocholinesterase deficiency after high dose cyclophosphamide Bone Marrow Transplantation 24 12 1367 8 doi 10 1038 sj bmt 1702097 PMID 10627651 Vigouroux D Voltaire L 1995 Prolonged neuromuscular block induced by mivacurium in a patient treated with cyclophosphamide Prolonged neuromuscular block induced by mivacurium in a patient treated with cyclophosphamide Annales Francaises d Anesthesie et de Reanimation in French 14 6 508 10 doi 10 1016 S0750 7658 05 80493 9 PMID 8745976 INIST 2947795 Hall AG Tilby MJ September 1992 Mechanisms of action of and modes of resistance to alkylating agents used in the treatment of haematological malignancies Blood Reviews 6 3 163 73 doi 10 1016 0268 960X 92 90028 O PMID 1422285 Kohn FR Sladek NE October 1985 Aldehyde dehydrogenase activity as the basis for the relative insensitivity of murine pluripotent hematopoietic stem cells to oxazaphosphorines Biochemical Pharmacology 34 19 3465 71 doi 10 1016 0006 2952 85 90719 1 PMID 2996550 Friedman OM Wodinsky I Myles A April 1976 Cyclophosphamide NSC 26271 related phosphoramide mustards recent advances and historical perspective Cancer Treatment Reports 60 4 337 46 PMID 1277209 Sistigu A Viaud S Chaput N Bracci L Proietti E Zitvogel L July 2011 Immunomodulatory effects of cyclophosphamide and implementations for vaccine design Seminars in Immunopathology 33 4 369 83 doi 10 1007 s00281 011 0245 0 PMID 21611872 S2CID 3360104 Friedman OM Seligman AM 1954 Preparation of N Phosphorylated Derivatives of Bis b chloroethylamine1a Journal of the American Chemical Society 76 3 655 8 doi 10 1021 ja01632a006 Colvin OM August 1999 An overview of cyclophosphamide development and clinical applications Current Pharmaceutical Design 5 8 555 60 PMID 10469891 U S Patent 3 018 302 Brock N August 1996 The history of the oxazaphosphorine cytostatics Cancer 78 3 542 7 doi 10 1002 SICI 1097 0142 19960801 78 3 lt 542 AID CNCR23 gt 3 0 CO 2 Y PMID 8697402 Wilmanns Hilmar 1958 Chemotherapie maligner Tumoren Chemotherapy of malignant tumors Asta Forschung und Therapie in German OCLC 73296245 page needed Gross R Wulf G 1959 Klinische und experimentelle Erfahrungen mit zyk lischen und nichtzyklischen Phosphamidestern des N Losl in der Chemotherapie von Tumoren Clinical and experimental experiences with metallic cyclical and non cyclical Phosphamidestern the N losl in the chemotherapy of tumors Strahlentherapie in German 41 361 7 Brock N January 1989 Oxazaphosphorine cytostatics past present future Seventh Cain Memorial Award lecture Cancer Research 49 1 1 7 PMID 2491747 Institute for Safe Medication Practices ISMP s List of Error Prone Abbreviations Symbols and Dose Designations PDF archived PDF from the original on 2011 10 27 Zuluaga AF Salazar BE Rodriguez CA Zapata AX Agudelo M Vesga O March 2006 Neutropenia induced in outbred mice by a simplified low dose cyclophosphamide regimen characterization and applicability to diverse experimental models of infectious diseases BMC Infectious Diseases 6 1 55 doi 10 1186 1471 2334 6 55 PMC 1434751 PMID 16545113 EPA Notifications FY 1998 to Present Biotechnology Program under the Toxic Substances Control Act TSCA New Chemicals Program US EPA Archived from the original on 2015 06 21 Retrieved 2015 07 01 Huyan XH Lin YP Gao T Chen RY Fan YM September 2011 Immunosuppressive effect of cyclophosphamide on white blood cells and lymphocyte subpopulations from peripheral blood of Balb c mice International Immunopharmacology 11 9 1293 7 doi 10 1016 j intimp 2011 04 011 PMID 21530682 External links Edit Cyclophosphamide Drug Information Portal U S National Library of Medicine U S Patent 3 018 302 Novel cyclic phosphoric acid ester amides and the production thereof patent for cyclophosphamide Portal Medicine Retrieved from https en wikipedia org w index php title Cyclophosphamide amp oldid 1110887731, wikipedia, wiki, book, books, library,

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