Genetic variations within the DPD gene (DPYD) can lead to reduced or absent DPD activity, and individuals who are heterozygous or homozygous for these variations may have partial or complete DPD deficiency; an estimated 0.2% of individuals have complete DPD deficiency. Those with partial or complete DPD deficiency have a significantly increased risk of severe or even fatal drug toxicities when treated with fluoropyrimidines; examples of toxicities include myelosuppression, neurotoxicity and hand-foot syndrome. Mechanism of action
5-FU acts in several ways, but principally as a thymidylate synthase (TS) inhibitor. Interrupting the action of this enzyme blocks synthesis of the pyrimidine thymidylate (dTMP), which is a nucleotide required for DNA replication. Thymidylate synthase methylates deoxyuridine monophosphate (dUMP) to form thymidine monophosphate (dTMP). Administration of 5-FU causes a scarcity in dTMP, so rapidly dividing cancerous cells undergo cell death via thymineless death. Calcium folinate provides an exogenous source of reduced folinates and hence stabilises the 5-FU-TS complex, hence enhancing 5-FUs cytotoxicity. History
In 1954, Abraham Cantarow and Karl Paschkis found liver tumors absorbed radioactive uracil more readily than did normal liver cells. Charles Heidelberger, who had earlier found that fluorine in fluoroacetic acid inhibited a vital enzyme, asked Robert Duschinsky and Robert Schnitzer at Hoffmann-La Roche to synthesize fluorouracil. Some credit Heidelberger and Duschinsky with the discovery that 5-fluorouracil markedly inhibited tumors in mice. The original 1957 report in Nature has Heidelberger as lead author, along with N. K. Chaudhuri, Peter Danneberg, Dorothy Mooren, Louis Griesbach, Robert Duschinsky, R. J. Schnitzer, E. Pleven, and J. Scheiner.
However, dapsone can potentially cause severe side effects, meaning that sometimes steroids or other antibiotics should be used instead, although these alternative treatments are much less effective.An August 2015 review notes that dapsone is reported to be effective against generalized granuloma annulare.Dapsone has been used as a monomer in the design of dye adsorbent polymers. Contraindications and precautions
People with porphyria, anemia, cardiac disease, lung disease, HIV infection, G6PD deficiency, and liver impairment are at higher risks of adverse effects when using dapsone. Adverse effects
Hypersensitivity reactions occur in 1.4% of persons treated with dapsone, and can be fatal in medical settings with low resources. It is a form of severe cutaneous adverse reactions (SCARs) in which a SCARs disorder, primarily the DRESS syndrome or a DRESS syndrome-like reaction occurs. Blood
Hemolysis is the most prominent side-effect, occurring in about 20 % of patients treated with dapsone, although it is dose-related. It may lead to hemolytic anemia and methemoglobinemia. The side-effect is more common and severe in those with glucose-6-phosphate dehydrogenase deficiency, leading to the dapsone-containing antimalarial combination Lapdap being withdrawn from clinical use. A case of hemolysis in a neonate from dapsone in breast milk has been reported. Agranulocytosis occurs rarely when dapsone is used alone but more frequently in combination regimens for malaria prophylaxis. Abnormalities in white blood cell formation, including aplastic anemia, are rare, yet are the cause of the majority of deaths attributable to dapsone therapy.Methemoglobinemia occurs in about 15 % of patients treated with long-term dapsone at standard doses (100 mg/day).