23256-30-6 Usage
Description
Nifurtimox, a nitrofuran derivative, is a hypoxia-activated cytotoxin that specifically targets and kills clonogenic tumor cells under hypoxic conditions. It is primarily used to treat Chagas disease and African trypanosomiasis, and has shown effectiveness in inhibiting the growth of neuroblastoma and medulloblastoma cells. Manufactured by Bayer and marketed under the trade name Lampits, nifurtimox was developed specifically for the treatment of American trypanosomiasis (Chagas' disease) and is one of two drugs approved for this purpose. It is an orange solid.
Uses
1. Used in Antiprotozoal Applications:
Nifurtimox is used as an antiprotozoal agent for its effectiveness against Trypanosoma cruzi, the parasite responsible for Chagas disease. It is cidal against both the trypomastigote and amastigote forms of the parasite and is active against both extraand intracellular forms.
2. Used in Chagas Disease Treatment:
Nifurtimox is used as a treatment for Chagas disease, caused by Trypanosoma cruzi. It has been shown to be the most active and least toxic agent in preclinical studies and has been used in Latin America since the late 1960s and early 1970s.
3. Used in African Trypanosomiasis Treatment:
Nifurtimox is used as a treatment for second-stage human African trypanosomiasis (HAT) caused by Trypanosoma brucei gambiense. There has been a resurgence of interest in and use of nifurtimox for this purpose, especially when benznidazole, an alternative drug, is not available or effective.
4. Used in Combination Therapy:
Nifurtimox is used in combination with corticosteroids to prevent myocardial inflammation and destroy parasites within the heart. This combination therapy helps in managing the side effects of the drug, which may include nausea, vomiting, insomnia, nervous excitation, vertigo, and skin rashes.
5. Used in Drug Development:
Nifurtimox serves as a basis for the development of new drugs and therapies for various diseases, including cancer and parasitic infections. Its unique properties as a hypoxia-activated cytotoxin make it a promising candidate for further research and development in the pharmaceutical industry.
Pharmacology and mechanism of action
Nifurtimox is a nitrofuran derivative that has trypanocidal activity against both the trypomastigote forms (extracellular) and the amastigote forms (intracellular) of Trypanosoma (T.) cruzi. Under experimental conditions amastigotes are 10 times more sensitive to the drug than the trypomastigotes[1]. The mechanism of action of the drug is not clearly known. Its trypanocidal action may be related to its ability to undergo partial reduction to form chemically reactive radicals that cause production of superoxide anion, hydrogen peroxide and hydroxyl radicals. These free radicals react with cellular macromolecules and cause membrane injury, enzyme inactivation, damage to DNA, and mutagenesis [2].
Indications
Treatment of American trypanosomiasis (Chagas’ disease) due to Trypanosoma cruzi. The drug may also be used in patients with Trypanosoma brucei gambiense sleeping sickness who are refractory to other treatments.
Indications
Nifurtimox (Lampit) is a nitrofuran derivative whose
likely mechanism of action for killing of trypanosomes
is through the production of activated forms of oxygen.
Nifurtimox is reduced to the nitro anion radical, which
reacts with oxygen to produce superoxide and hydrogen
peroxide. The free radical metabolites, an absence of
parasite catalase, and a peroxide deficiency lead to lipid
peroxidation and cell damage. This production of activated
oxygen results in toxicity to the protozoal cells.
Side effects
Side effects of nifurtimox are frequent and can be encountered in up to 40% in children, and up to 70% in adults treated for acute and chronic Chagas’ disease. Common side effects include anorexia, nausea, vomiting, abdominal pain, excitation, sleeping difficulties, dizziness, headache and joint and muscle pains [3]. During treatment, half of the patients may interrupt therapy because of side effects. Other rare side effects include skin eruptions and paraesthesia [4].
Side effects
Although side effects occur in approximately half
the patients treated with nifurtimox, it is necessary to
discontinue treatment in only a minority. Nausea, vomiting,
abdominal pain, skin rashes, headache, insomnia,
convulsions, and myalgia all have been reported.
Contraindications and precautions
The drug should be given with caution to patients with a history of convulsions, brain injury, peripheral neuropathy and psychiatric illness. Dosage reductions may be considered in patients with liver diseases.
Interactions
Concomitant administration of nifurtimox with melarsoprol[5] or eflornithine[6]have been reported to have synergistic effects in experimental animals (mice) infected with Trypanosoma brucei species. The clinical implication of this is unknown.
Preparations
Lampit (Bayer). Tablets 30 mg, 120 mg.
References
1. Webster LT Jr (1990). Drugs used in the chemotherapy of profozoal infections. In: Goodman & Gilman’s The Pharmacological Basis of Therapeutics, 8th edn, edited by A.G.Gilman, T.W.Rall, A.S.Nies, P.Taylor, (New York: Pergamon Press), pp. 1010–1011.
2. Docampo R, Moreno SNJ, Stoppani AOM, Leon W, Cruz FS, Villalta F, Muniz RFA (1981). Mechanism of nifurtimox toxicity in different forms of Trypanosoma cruzi. Biochem Pharmacol, 30, 1947–1981.
3. Gutteridge WE (1985). Existing chemotherapy and its limitations. Br Med Bull, 41, 162–168.
4. Wegner DHG, Rohwedder RW (1972). The effects of nifurtimox in acute Chagas’ infection. Arzneimittelforschung, 22, 1624–1635.
5. Jennings FW (1991). Chemotherapy of CNS-trypanosomiasis: the combined use of the arsenicals and nitro-compounds. Trop Med Parasitol, 42, 139–142.
6. Jennings FW (1988). The potentiation of arsenicals with difluoromethylornithine (DFMO): experimental studies in murine trypanosomiasis. Bull Soc Pathol Exot, 81, 595–607.
Pharmaceutical Applications
A water-soluble synthetic compound available for oral use. It
exhibits antibacterial activity typical of the group, but its most
notable property is its activity against trypanosomes, especially
Trypanosoma cruzi.
A plasma concentration of 0.5–1 mg/L is achieved c. 2 h
after an oral dose of 15 mg/kg. The plasma half-life is 2–4 h. In
common with other nitrofurans, it is rapidly and extensively
metabolized, so that less than 1% of a dose is excreted intact
in the urine. In renal failure, clearance is somewhat reduced
but the half-life is unchanged.
Adverse events are common. Many patients experience
anorexia, which may be combined with vomiting and abdominal
pain. There may also be neurological reactions such as restlessness,
insomnia, headache and disorientation.
It is used in the treatment of Chagas disease (South
American trypanosomiasis). It has also found some use in the
treatment of African sleeping sickness in combination with
eflornithine.
Biochem/physiol Actions
Nifurtimox is a nitrofurane derivative used to treat diseases caused by trypanosomes. Nifurtimox was discovered empirically and its mechanism of action is unclear. It is believed that nifurtimox exerts its biological activity through the bioreduction of the nitro-group to a nitro-anion radical which undergoes redox-cycling with molecular oxygen.
Mechanism of action
The drug is given orally and is well absorbed from
the gastrointestinal tract. It is rapidly metabolized, and
only low levels are found in blood and tissues.The drug
is excreted in the urine, primarily in the form of
metabolites.
Clinical Use
Nifurtimox is trypanocidal and exerts an effect on
the trypomastigote and amastigote forms of T. cruzi. It
is effective in the treatment of the acute form of
Chagas’ disease but is less effective once the disease becomes
chronic. The drug is moderately well tolerated,
and treatment generally lasts 3 to 4 months. Cure rates
of 80 to 90% have been reported. Since much of the tissue
damage caused by the disease is irreversible, early
diagnosis and treatment are important. Nifurtimox has
also been used in T. gambiense infection with meningoencephalopathic involvement.
Synthesis
Nifurtimox, 1,1-dioxide 4-[(5-nitrofuryliden)amino]-3-methylthiomorpholine
(37.4.7), is made by the following scheme. Interaction of 2-mercaptoethanol with propylene
oxide in the presence of potassium hydroxide gives (2-hydroxyethyl)-(2-hydroxypropylsulfide) (37.4.3), which undergoes intramolecular dehydration using potassium bisulfate to
make 2-methyl-1,4-oxithiane (37.4.4). Oxidation of this using hydrogen peroxide gives
2-methyl-1,4-oxithian-4,4-dioxide (37.4.5), which when reacted with hydrazine transforms
to 4-amino-3-methyltetrahydro-1,4-thiazin-1,1-dioxide (37.4.6). Reacting this with 5-nitrofurfurol gives the corresponding hydrazone—the desired nifurtimox.
Check Digit Verification of cas no
The CAS Registry Mumber 23256-30-6 includes 8 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 5 digits, 2,3,2,5 and 6 respectively; the second part has 2 digits, 3 and 0 respectively.
Calculate Digit Verification of CAS Registry Number 23256-30:
(7*2)+(6*3)+(5*2)+(4*5)+(3*6)+(2*3)+(1*0)=86
86 % 10 = 6
So 23256-30-6 is a valid CAS Registry Number.
InChI:InChI=1/C10H13N3O5S/c1-8-7-19(16,17)5-4-12(8)11-6-9-2-3-10(18-9)13(14)15/h2-3,6,8H,4-5,7H2,1H3/b11-6+
23256-30-6Relevant articles and documents
NITROFURAN COMPOUNDS FOR THE TREATMENT OF CANCER AND ANGIOGENESIS
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, (2008/06/13)
The invention is directed to the synthesis and use of nitrofuran compounds, especially Nifurtimox, as medicaments to treat cancer, especially neuroblastoma, and to inhibit angiogenesis. The invention also provides compositions, unit dosage forms, and kits comprising the compounds.
