Abstract
Various forms of arsenic were used in China and elsewhere for over 5,000 years. Following the initial success of intravenous arsenic trioxide (i.v. As2O3), we revived an oral formulation of pure As2O3 in 1998 for the treatment of acute promyelocytic leukemia (APL). We were the first to produce a 1 mg/ml oral-As2O3 solution and showed that it had comparable bioavailability to i.v. As2O3. Moreover, we also reported that intracellular arsenic concentrations were considerably higher than the corresponding plasma values. Our oral-As2O3 was patented internationally and registered in Hong Kong for the treatment of APL. Safety, tolerability and clinical efficacy was confirmed in long-term follow-up studies. We have extended the use of oral-As2O3 to frontline induction of newly diagnosed APL. With these findings, we are moving toward an era of completely oral and chemotherapy-free management of APL.
Highlights
AND INITIAL OBSERVATIONSOver many centuries and even millennia, numerous accounts have attested that imbibing arsenicals was a powerful means of poisoning as well as a purported remedy for treating many diseases [1,2,3,4]
The primary objective of this initiative was to determine whether the systemic bioavailability of an in-house locally developed oral As2O3 formulation would be comparable to that following commercially available i.v. dosing, when administered to patients with relapsed/refractory acute promyelocytic leukemia (APL) or acute myeloid leukemia
We showed that after an oral administration, meaningful cerebrospinal fluid (CSF) levels of arsenic were achieved implying its benefit in the prophylaxis or treatment of central nervous system (CNS) disease [38, 39]
Summary
Over many centuries and even millennia, numerous accounts have attested that imbibing arsenicals was a powerful means of poisoning as well as a purported remedy for treating many diseases [1,2,3,4]. Besides the burdensome quality of life impairments and medication costs of such recurrent i.v. treatment, patients inevitably incurred additional expenses. With memories of Fowler’s solution, we revived oral-As2O3 or the “modern” liquor arsenicalis in 1998 as a means of treating APL patients. This stemmed from two sets of key historical observations. Treating patients with an oral As2O3 formulation manufactured in accordance with Good Manufacturing Practice (GMP) could have the potential to confer important benefits with a degree of confidence and safety that was never attained by Fowler’s solution. And fatal cardiac arrhythmias associated with excessive electrocardiographic QTc interval prolongation were a recognized feature of parenteral treatment [14,15,16]
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