5-Aminosalicylic Acid (5-ASA) And Fluorouracil (5-FU)
Mesalazine (INN, BAN), also known as mesalamine (USAN) or 5-aminosalicylic acid (5-ASA), is an aminosalicylate anti-inflammatory drug used to treat inflammatory bowel disease, including ulcerative colitis, or inflamed anus or rectum, and to maintain remission in Crohn's disease.
It is sold in an oral form to maintain remission in Crohn's disease, and as a rectal suppository and an enema for the lower bowel conditions. It is generic and sold under many brand names worldwide, and there are many formulations.
There are no data on use in pregnant women, but the drug does cross the placenta and is excreted in breast milk. The drug should not be used in children under two, people with kidney disease, or people who are allergic to aspirin.
Side effects are primarily gastrointestinal but may include headache; GI effects include nausea, diarrhea, and abdominal pain. There have been scattered reports of various problems when the oral form is used, including problems caused by myelosuppression (leukopenia, neutropenia, agranulocytosis, aplastic anemia, and thrombocytopenia, as well as hair loss, peripheral neuropathy, pancreatitis, liver problems, myocarditis and pericarditis, allergic and fibrotic lung reactions, lupus erythematosus-like reactions and rash (including urticaria), drug fever, interstitial nephritis and nephrotic syndrome, usually reversible on withdrawal. Very rarely, use of mesalazine has been associated with an exacerbation of the symptoms of colitis, Stevens-Johnson syndrome and erythema multiforme.
mesalazine is the active moiety of sulfasalazine, which is metabolized to sulfapyridine and mesalazine. It is also the active component of the prodrug Balsalazide along with the inert carrier molecule 4-aminobenzoyl-beta-alanine.
Fluorouracil (5-FU) (trade name Adrucil among others) is a medication which is used in the treatment of cancer.
It is a suicide INHibitor and works through irreversible INHibition of thymidylate synthase. It belongs to the family of drugs called the antimetabolites. It is also a pyrimidine analog.
It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.
Fluorouracil has been given systemically for anal, breast, colorectal, oesophageal, stomach, pancreatic and skin cancers (especially head and neck cancers). It has also been given topically (on the skin) for actinic keratoses, skin cancers and Bowen's disease and as eye drops for the treatment of ocular surface squamous neoplasia.
It is contraindicated in patients that are severely debilitated or in patients with bone marrow suppression due to either radiotherapy or chemotherapy. It is likewise contraindicated in pregnant or breastfeeding women. It should also be avoided in patients that do not have malignant illnesses.
Adverse effects by frequency include:
During systemic use
Common (> 1% frequency):
- Diarrhea (see below for details)
- Myelosuppression (see below for details)
- Alopecia (hair loss)
- Hand-foot syndrome
- Maculopapular eruption
- Cardiotoxicity (see below for details)
- Persistent hiccups
- Mood disorders (irritability, anxiety, depression)
Uncommon (0.1–1% frequency):
- GI ulceration and bleeding
- Nail disorders
- Vein pigmentation
- Cerebellar syndrome
- Visual changes
- Lacrimation (the expulsion of tears without any emotional or physiologic reason)
Rare (< 0.1% frequency):
- Allergic reactions
- Fever without signs of infection
Diarrhea is severe and may be dose-limiting and is exacerbated by co-treatment with calcium folinate. Neutropenia tends to peak about 9–14 days after beginning treatment. Thrombocytopenia tends to peak about 7–17 days after the beginning of treatment and tends to recover about 10 days after its peak. Cardiotoxicity is a fairly common side effect, but usually, this cardiotoxicity is just angina or symptoms associated with coronary artery spasm, but in about 0.55% of those receiving the drug will develop life-threatening cardiotoxicity. Life-threatening cardiotoxicity includes arrhythmias, ventricular tachycardia, and cardiac arrest, secondary to transmural ischemia.
During topical use
Common (> 1% frequency):
- Local pain
Uncommon (0.1–1% frequency):
- hyper- or hypopigmentation
5-FU injection and topical even in small doses cause both acute central nervous system (CNS) damage and progressively worsening delayed degeneration of the CNS in mice. This latter effect is caused by 5-FU-induced damage to the oligodendrocytes that produce the insulating myelin sheaths.
The United States package insert warns that acute cerebellar syndrome has been observed following injection of fluorouracil and may persist after cessation of treatment. Symptoms include Ataxia, nystagmus, and dysmetria.
There is very little difference between the minimum effective dose and a maximum tolerated dose of 5-FU, and the drug exhibits marked individual pharmacokinetic variability. Therefore, an identical dose of 5-FU may result in a therapeutic response with acceptable toxicity in some patients and unacceptable and possibly life-threatening toxicity in others. Both overdosing and underdosing are of concern with 5-FU, although several studies have shown that the majority of colorectal cancer patients treated with 5-FU are underdosed based on today's dosing standard, body surface area (BSA). The limitations of BSA-based dosing prevent oncologists from being able to accurately titer the dosage of 5-FU for the majority of individual patients, which results in sub-optimal treatment efficacy or excessive toxicity.
Numerous studies have found significant relationships between concentrations of 5-FU in blood plasma and both desirable or undesirable effects on patients. Studies have also shown that dosing based on the concentration of 5-FU in plasma can greatly increase desirable outcomes while minimizing negative side effects of 5-FU therapy. One such test that has been shown to successfully monitor 5-FU plasma levels and which "may contribute to improved efficacy and safety of commonly used 5-FU-based chemotherapies" is the My5-FU test.
Its use should be avoided in patients receiving drugs known to modulate dihydropyrimidine dehydrogenase (such as the antiviral drug sorivudine). It may also increase the INR and prothrombin times in patients on warfarin. Fluoruracil's efficacy is decreased when used alongside allopurinol which can be used to decrease fluorouracil-induced stomatitis through use of allopurinol mouthwash.
In 2003 it was discovered that a closely related compound is produced by a marine sponge, Phakellia fusca. This is significant because fluorine-containing organic compounds exist only rarely in nature, and also because manmade anticancer drugs are not frequently found to have analogues in nature.
The name "fluorouracil" is the INN, USAN, USP name, and BAN. The form "5-fluorouracil" is often used; it shows that there is a fluorine atom on the 5th carbon of a uracil ring.