Cyclophosphamide ( CP ), also known as cytophosphane among others, is a drug used as chemotherapy and to suppress the immune system. As chemotherapy is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer, small cell lung cancer, neuroblastoma, and sarcoma. As an immune suppressant used in nephrotic syndrome, granulomatosis with polyangiitis, and after organ transplantation. This is taken by mouth or injection into blood vessels.
Most people develop side effects. Common side effects include low white blood cell count, loss of appetite, vomiting, hair loss, and bleeding from the bladder. Other severe side effects include an increased risk of future cancer, infertility, allergic reactions, and pulmonary fibrosis. Cyclophosphamide is in the pharmaceutical and drug neptizing agent of the drug family. It works by interrupting DNA duplication and RNA creation.
Cyclophosphamide was approved for medical use in the United States in 1959. This is the List of Essential Medicines of the World Health Organization, the most effective and safe medicines needed in the health system. The cost of wholesale in developing countries is about 3.65 to 14.30 USD per bottle 1 g. In the United Kingdom, this dose weighed on the NHS around 17.06 pounds. In the United States, this dose by mouth is about 19.56 USD.
Video Cyclophosphamide
Medical use
Cyclophosphamide is used to treat cancer and autoimmune diseases. This is used to control the disease quickly. Due to its toxicity, it is replaced as soon as possible by the less toxic drugs. Routine and frequent laboratory evaluations are required to monitor kidney function, avoiding drug induced bladder complications and screening for bone marrow toxicity.
Cancer
The main use of cyclophosphamide is with other chemotherapy agents in the treatment of lymphoma, some forms of brain cancer, neuroblastoma, leukemia and some solid tumors.
Autoimmune Disease
Cyclophosphamide lowers the immune system response, and although concerns about toxicity limit its use in patients with severe illness, it remains an important treatment for life-threatening autoimmune diseases in which disease-modifying anti-disease drugs (DMARDs) are ineffective. For example, systemic lupus erythematosus with severe lupus nephritis may respond to a pulsating cyclophosphamide. Cyclophosphamide is also used to treat minimal change diseases, severe rheumatoid arthritis, granulomatosis with polyangiitis, Goodpasture syndrome and multiple sclerosis.
AL amyloidosis
Cyclophosphamide, used in combination with thalidomide or lenalidomide and dexamethasone has documented efficacy as a treatment without AL amyloidosis labeling. It appears to be an alternative to more traditional treatments with melfalan in people not suited for autologous stem cell transplants.
Maps Cyclophosphamide
Contraindications
Like other alkylation agents, cyclophosphamide is teratogenic and contraindicated in pregnant women (pregnancy category D) except for maternal life-threatening conditions. Additional relative contraindications to the use of cyclophosphamide include lactation, active infection, neutropenia or bladder toxicity.
Cyclophosphamide is a category D pregnancy drug and causes birth defects. The first trimester exposure to cyclophosphamide for the treatment of cancer or lupus features an anomalous pattern labeled "cyclophosphamide embryopathy," including growth restriction, ears and facial abnormalities, absence of hypoplastic figures and limbs.
Side effects
Adverse drug reactions from cyclophosphamide are associated with cumulative drug doses and include chemotherapy-induced nausea and vomiting, bone marrow suppression, abdominal pain, haemorrhagic cystitis, diarrhea, darkening of the skin/nails, alopecia (hair loss) or hair thinning, discoloration and texture hair and lethargy. Other side effects may include easy bruising/bleeding, joint pain, mouth sores, slow wound healing, unusual drop of urine or fatigue or unusual weakness.
Pulmonary injury appears rare, but may present with two clinical patterns: early acute pneumonitis and chronic progressive fibrosis. Cardiotoxicity is a major problem with people treated with higher dosage regimens.
High doses of intravenous cyclophosphamide may cause inappropriate antidiuretic hormone secretion syndrome (SIADH) and potentially fatal hyponatremia when aggravated by intravenous fluids administered to prevent drug-induced cystitis. While SIADH has been described primarily with high doses of cyclophosphamide, it can also occur with lower doses used in the management of inflammatory disorders.
Bladder hemorrhage
Akrolein is toxic to the bladder epithelium and can cause haemorrhagic cystitis, which is associated with microscopic or rough hematuria and sometimes dysuria. The risk of hemorrhagic cystitis can be minimized by adequate fluid intake, avoiding nighttime doses and mesna (sodium 2-mercaptoethane sulfonate), sulfhydryl donors that bind and detoxify acrolein. The intermittent dose of cyclophosphamide decreases the cumulative drug dose, reduces bladder exposure to acrolein and has the same efficacy for daily treatment in the management of lupus nephritis.
Infection
Neutropenia or lymphopenia arising from the use of cyclophosphamide can affect people against various bacterial, fungal, and opportunistic infections. There are no published guidelines that include PJP prophylaxis for people with rheumatologic diseases who receive immunosuppressive drugs, but some advocate their use when receiving high-dose drugs.
Infertility
Cyclophosphamide has been found to significantly increase the risk of early menopause in women and infertility in men and women, possibly increasing with cumulative drug doses and increasing patient age. Such infertility is usually temporary, but it can be permanent. The use of leuprolide in women of reproductive age prior to intermittently cyclophosphamide dosing may reduce the risk of early menopause and infertility.
Cancer
Cyclophosphamide is carcinogenic and may increase the risk of developing lymphoma, leukemia, skin cancer, transitional cell carcinoma of the bladder or other malignancies. Myeloproliferative neoplasms, including acute leukemia, non-Hodgkin's 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 without history. Secondary acute myeloid leukemia (AML-associated therapy, or "t-AML") is thought to occur either by mutations inducing cyclophosphamide or choosing for high-risk myeloid clones.
This risk may depend on the dose and other factors, including conditions, other agents or treatment modalities (including radiotherapy), length and intensity of treatment. For some regimens, very rarely. For example, CMF therapy for breast cancer (where cumulative doses are usually 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 1-2% or higher risk. Cyclophosphamide-induced AML, when it occurs, usually appears several years after treatment, with an incidence peaking around 3-9 years. After nine years, the risk falls into the background. When AML occurs, it is often preceded by the phase of myelodysplastic syndrome, before it develops into acute open leukemia. Cyclophosphamide-induced leukemia often involves complex cytogenetics, which leads to a worse prognosis than de novo AML.
Pharmacology
Oral cyclophosphamide is rapidly absorbed and then converted by a mixed functional oxidation enzyme (cytochrome P450 system) in the liver for active metabolites. The main active metabolite is 4-hydroxycyclophosphamide, which is in equilibrium with the tautomer, aldophosphamide. Most of the aldophosphamide is then oxidized by the enzyme dehydrogenase aldehyde (ALDH) to make carboxylicophosphamide. A small portion of the aldophosphamide freely diffuses into the cell, where it decomposes into two compounds, mustard phosphoramide and acrolein. Active metabolites of cyclophosphamide are highly protein bound and distributed to all tissues, assumed to cross the placenta and are known to exist in breast milk.
Especially in the drug group oksazafosporin.
The metabolism of cyclophosphates is mainly excreted in the unchanged urine, and the dosage of the drug must be appropriately adjusted in the setting of renal dysfunction. Drugs that alter the activity of liver microsomal enzymes (eg, alcohol, barbiturates, rifampicin, or phenytoin) may produce accelerated cyclophosphamide metabolism into its active metabolites, increasing the pharmacological and toxic effects of the drug; Alternatively, drugs that inhibit liver microsomal enzymes (eg corticosteroids, tricyclic antidepressants, or allopurinol) result in slower cyclophosphamide conversion into their metabolites and consequently reduce therapeutic and toxic effects.
Cyclophosphamide reduces plasma pseudocolinesterase activity and may cause prolonged neuromuscular blockade when administered simultaneously with succinylcholine. Tricyclic antidepressants and other anticholinergic agents can lead to delayed bladder emptying and prolonged bladder exposure to acrolein.
Action mechanism
The main effect of cyclophosphamide is due to its metabolite phosphoramide mustard. These metabolites only form in cells that have low ALDH levels. Mustard phosphoramide forms DNA bonds both between and within the DNA strands at the guanine position of N-7 (known as interstrand and intrastrand crosslinkages, respectively). It can not be changed and leads to cell apoptosis.
Cyclophosphamide has relatively little chemotherapy toxicity because ALDH is present in relatively large concentrations in bone marrow stem cells, liver and intestinal epithelium. ALDHs protect this proliferating active tissue against the toxic effects of mustard and acrolein phosphoramide by converting the aldophosphamide into carboxyrophosphamide which does not produce toxicamosamide mustard and acrolein metabolites. This is because carboxycyclophosphamide can not undergo? -completion (carboxylate acts as an electron-donating group, prohibits transformation), prevents activation of the nitrogenous and subsequent alkyl ions.
Cyclophosphamide induces beneficial immunomodulatory effects in adaptive immunotherapy. Suggested mechanisms include:
- Elimination of regulatory T cells (CD4 CD25 T cells) in naive host and tumor-bearing
- Induction of T cell growth factors, such as type I IFN, and/or
- Increased tumor-reactive tumor T cell transplant adopted by immunologic space creation.
Thus, preconditioning cyclophosphamide from host receptors (for donor T cells) has been used to enhance immunity in host naÃÆ'¯ve, and to improve the regimen of T cell immunotherapy that is adopted, as well as an active vaccination strategy, which promotes 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 main toxic metabolites of cyclophosphamide, synthesized and reported by Friedman and Seligman in 1954... It is postulated that the presence of phosphate bonds with nitrogen atoms can inactivate nitrogen mustard moiety, but the phosphate bonds will be cleaved in gastric cancer and other tumors that have high phosphamidase content. However, in studies conducted after clinical efficacy of cyclophosphamide was demonstrated, mustard phosphoramide proved to be in vitro in vitro (footnote omitted), but had a low therapeutic index in vivo .
Cyclophosphamide and nitrogen associated with mustard derived from alkylating agent ifosfamide were developed by Norbert Brock and ASTA (now Baxter Oncology). Brock and his team synthesize and screen more than 1,000 candidate oxazaphosphorine compounds. They transform the basic nitrogen barrier into a non-toxic "transport form". This form of transport is prodrug, then actively transported to cancer cells. Once in a cell, the prodrug is enzymatically converted into an active, toxic form. The first clinical trial was published in the late 1950s. In 1959 became the eighth cytotoxic anticancer agent approved by the FDA.
Society and culture
CP abbreviation is common, although abbreviating the name of the drug is not the best practice in medicine.
Research
Because of its impact on the immune system, it is used in animal studies. Rodents are injected intraperitoneally with a single dose of 150 mg/kg or two doses (150 and 100 mg/kg) spread over two days. This can be used for apps like:
- The EPA may be concerned about the potential pathogenicity of humans from engineering microbes when conducting MCAN reviews. Especially for bacteria with potential consumer exposure they require testing of microbes in immuno compromised mice
- Cyclophosphamide provides positive control when studying the immune response of a new drug.
References
External links
- US. National Library of Medicine: Drug Information Portal - Cyclophosphamide
Source of the article : Wikipedia
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