Busulfan
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| Non-proprietary name | Busulfan | ||||||||||||||||||
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| Molecular formula | C 6 H 14 O 6 S 2 | ||||||||||||||||||
| Brief description |
beige solid |
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| Mechanism of action |
Alkylans |
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| Molar mass | 246.30 g · mol -1 | ||||||||||||||||||
| Physical state |
firmly |
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| Melting point |
114-117 ° C |
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| As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions . | |||||||||||||||||||
Busulfan is a synthetic cytostatic drug used to treat certain cancers. It is one of the alkylating agents .
Origin and manufacture
Busulfan is produced synthetically by reacting 1,4-butanediol with methanesulfonyl chloride. In contrast to other cytostatics such as vincristine , topotecan or paclitaxel, it does not come from any plant or its extracts.
Mechanism of action
Busulfan is a bifunctional alkylane. The bifunctionality results from two methanesulfonate groups that are found at the ends of the C4 chain. The two methanesulfonate groups are good leaving groups and are easily substituted with nucleophiles . It is primarily DNA that is alkylated , but other molecules in the cell can also be targets for alkylation by busulfan.
application areas
Bulsulfan is used in chronic myeloid leukemia (CML) and conditioning treatment prior to stem cell transplantation . The effects of busulfan in the treatment of Philadelphia chromosome negative chronic myeloid leukemia are weaker than in the treatment of Philadelphia chromosome positive CML. Busulfan is typically used in combination with cyclophosphamide for conditioning prior to stem cell transplantation.
administration
Busulfan can be given orally as a tablet or intravenously as an infusion.
Side effects
Bone marrow toxicity (leukopenia, anemia, thrombopenia)
The most important and possibly most serious side effect is myelotoxicity (toxicity on the bone marrow and blood formation) with subsequent anemia , leukopenia and thrombopenia . This side effect occurs with busulfan administration in all patients; only the severity, the duration and the possible side effects depend on the dose and characteristics of the patient such as pre-existing damage to the bone marrow, or continuous administration of busulfan or other cytostatics, etc.
When busulfan is used as part of the pre-stem cell transplant conditioning treatment, leukocytes drop to a median nadir four days after transplant . The number of neutrophils (ANC) recovers within 13 days after transplantation, if G-CSF ( Filgrastim , Lenograstim ) is used prophylactically . 98% of all patients on busulfan with conditioning prior to stem cell transplantation had platelet counts of less than 25,000 / µl. The median thrombopenia occurred 5–6 days after transplantation. 69% of all patients had anemia with a hemoglobin of less than 8.0 g / dl.
Infections
In many cases, leukopenia and especially neutropenia lead to an increased incidence of bacterial and mycotic (fungal) infections. These can be mild, but mostly they are more serious infections of the lower airways ( pneumonia ) or even blood poisoning ( sepsis ). The latter are life-threatening. The decrease in lymphocytes ( lymphopenia ) in the context of leukopenia also leads to an increased incidence of viral infections. These can also be severe and life-threatening ( herpes simplex encephalitis , disseminated varicella , etc.).
Seizure
Seizures have been observed using high doses of busulfan as in pre-stem cell transplant conditioning . These occur securely under peroral administration; However, since the intravenous dose achieves the same plasma concentrations of busulfan, a risk of seizures can also be assumed with intravenous administration. For this reason, patients with high-dose busulfan are simultaneously administered prophylaxis against seizures with phenytoin . Prophylactic treatment with phenytoin should be started before the first dose of busulfan. The administration of busulfan to patients with convulsive disorders should therefore be carried out with special caution.
Liver damage
High levels of busulfan can cause liver damage. In particular, hepatic vein occlusion ( veno-occlusive disease , VOD ) can occur. Patients who have previously received radiotherapy to the liver are at greater risk of developing VOD compared to non-irradiated patients. The risk is also increased for patients who have completed more than three cycles of chemotherapy or who have previously had a stem cell transplant combined with chemotherapy that inhibits bone marrow formation ( myelo ablative ). The incidence is 7.7 to 12% of patients with stem cell transplantation using busulfan, the corresponding mortality was 3%.
Pulmonary fibrosis (busulfan lung)
A pulmonary fibrosis after treatment with busulfan is a very rare but very serious complication. It typically occurs with a delay (4 months to 10 years after busulfan, 4 years on average). There is no known effective treatment for pulmonary fibrosis. If the course is severe, a lung transplant may be inevitable.
Carcinogenicity, mutagenicity, embryotoxicity
Chromosomal changes during or after treatment with busulfan have been demonstrated in both animals and humans. The development of secondary (therapy-associated) acute leukemia has been reported with treatment with busulfan. The secondary leukemia occurred 5–8 years after busulfan treatment. Due to its carcinogenic and mutagenic properties, busulfan is considered to be embryotoxic . Busulfan treatment during pregnancy significantly increases the risk of damage to the embryo.
Amenorrhea and infertility
Low-dose busulfan administered over long periods (months or years) in the treatment of chronic myeloid leukemia leads to suppression of ovarian function in pre-menopausal women. This results in a lack of ovulation, followed by a lack of menstrual bleeding ( amenorrhea ). In men treated with busulfan, azoospermia and testicular atrophy were found.
Contraindications (contraindications)
Historical
In 1953, DA Galton first demonstrated the effectiveness of busulfan in chronic myeloid leukemia (CML).
Finished medicinal products
Busilvex (D), Myleran (D)
Web links
- US package insert Busulfan peroral (PDF; 195 kB) Freely accessible.
- US package insert for intravenous busulfan (PDF; 516 kB) Freely accessible.
Individual evidence
- ↑ a b c Entry on busulfan in the GESTIS substance database of the IFA , accessed on February 10, 2017(JavaScript required) .
- ↑ Data sheet Busulfan at Sigma-Aldrich , accessed on May 13, 2017 ( PDF ).
- ↑ Entry on busulfan in the ChemIDplus database of the United States National Library of Medicine (NLM) .
