Miscellaneous

ARSENIC TRIOXIDE (TRISENOX, ATO)

Although arsenic's accolades primarily revolve around its reputation as an almond-flavored poison, as it was depicted in Frank Capra's 1944 film Arsenic and Old Lace, it has an older and more admirable history as a medicinal agent. In the eighteenth century, Thomas Fowler compounded a potassium-bicarbonate-based solution of arsenic trioxide (As2O3) that was used empirically to treat a variety of diseases.56 In 1910, Nobel prize winner Paul Ehrlich created the organic arsenical compound salvarsan that was best known as the "magic bullet" for syphilis, but also found use in treating hypertension, ulcers, heartburn, and chronic rheumatism.57 With evolutions in medicine and the concerns for toxicity, arsenic's use declined over time. In the late 1970s, observational studies preformed in China reported the effectiveness of arsenic trioxide as part of a treatment regimen for APL.58 These results have since been confirmed in trials in the United States, leading to FDA approval in September 2000.59-61

Similar to tretinoin, arsenic has been shown to cause degradation of PML-RAR-a, promoting cellular differentiation.62 However, arsenic acts primary on the PML gene and restores the cell's apoptotic ability, while tretinoin targets the RAR-a gene and reverses the differentiation arrest. Yet, the degradation of PML-RAR-a may not be the sole mechanism of action.62 Arsenic is thought to also act through the intracellular environment to influence apoptosis, differentiation, growth arrest, and angiogenesis.

The multiple mechanisms of actions suggest that arsenic may have antitumor activity in other hemato-logical malignancies, such as multiple myeloma, the

Table 102.4 Dosing adjustments13, 28, 64

Drug Necessary dosing adjustment

Imatinib (GleevecĀ®) Discontinue if liver transaminases are >5 times upper limit of normal or bilirubin is >3 times upper limit of normal. May resume at a reduced dose once transaminase level is <2.5 times upper limit of normal and/or bilirubin is <1.5 times upper limit of normal. Neutropenia may also necessitate dose reductions.

Interferon-a-2a Dose reductions of 50% or withholding individual doses may be needed when severe adverse events occur. (RoferonĀ®-A)

Interferon-a-2b Dose reductions of 50% or withholding individual doses may be needed when severe adverse events occur.

(IntronĀ®-A) Administration should be withheld for a neutrophil count <1000/mm3, or a platelet count <50,000/mm3.

myelodysplasic syndromes, and a variety of solid tumors.63 Most of the available data is preliminary and published in abstract form, and therefore must be interpreted with caution. Arsenic's use continues to be explored, and novel combination strategies are being studied to expand its potential use.

Pharmacokinetics/metabolism

Arsenic is administered solely by the intravenous route. Oral formulations are no longer used due to the high occurrence of severe gastrointestinal toxicity.58 After intravenous injection, peak levels are achieved 4 h from the end of the infusion. Arsenic is metabolized by methylation in the liver and excreted primarily in the bile. Arsenic is preferentially distributed in tissues containing significant amounts of sulfhydryl group-containing proteins; mainly in the liver, kidneys, heart, lung, hair, and nails.61 The drug is rapidly eliminated with an half-life of 12 h.61

Toxicity

There are several adverse events associated with arsenic trioxide that warrant careful monitoring and

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