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General information
Arsenic is a metallic element (symbol As; atomic no. 33), which exists in several allotropic forms. Various ores contain crystalline forms of arsenic salts: cobaltite contains cobalt arsenic sulfide; mispickel (arsenopyrite) iron arsenic sulfide; orpiment arsenic trisulfide; proustite (ruby silver ore) silver arsenic sulfide; realgar arsenic sulfide; and tennantite copper arsenic sulfide.
Arsenic has a long history of medicinal uses. Thomas Fowler introduced it in the form of potassium arsenite (Fowler’s solution) in the late 18th century to treat ague and Sir David Bruce used it in the late 19th century to treat trypanosomiasis. In the early 20th century Paul Ehrlich synthesized and tested a large series of arsenicals, in the hope of finding one that was effective in syphilis, and emerged with arsphenamine (Salvarsan, compound 606). Subsequently other arsenicals were synthesized, such as neoarsphenamine (for syphilis) and tryparsamide and acetarsol (for trypanosomiasis).
In recent times arsenic and arsenicals have been considered obsolete in medicine, because of their limited therapeutic value, multisystem toxicity, and apparent carcinogenic properties [ ]. However, arsenic compounds have been used to treat various types of leukemia [ ], including acute promyelocytic leukemia, chronic myelogenous leukemia, and multiple myeloma [ ]. Arsenic trioxide is effective in acute promyelocytic leukemia, achieving a complete remission rate of 60–90% [ , ]. It is particularly used in patients who are resistant to all-trans retinoic acid [ ]. Arsenic trioxide is also emerging as a therapy for multiple myeloma [ ].
Reports continue to be published on incidents related to the use of traditional herbal medications from China and elsewhere that contain arsenic among other toxic substances [ , ].
There are still occasional cases of patients with late effects from obsolete formulations such as Fowler’s solution or neoarsphenamine [ ]. As late as 1998 a case of severe chronic poisoning resulting in fatal multi-organ failure including hepatic portal fibrosis and subsequent angiosarcoma was traced back to exposure to arsenical salts used for the treatment of psoriasis many years before [ ]. In some non-Western countries arsenic is apparently still being used in dentistry for devitalization of inflamed pulp and sensitive dentine, and cases have been described in which this has resulted in arsenical necrosis of the jaws, affecting the maxilla or mandible [ ]. Some exposure to arsenic may still be occurring from traditional remedies of undeclared composition, and as with other metals there may be environmental contact, notably from semiconductor materials.
General adverse effects and adverse reactions
Chronic arsenic poisoning is marked by edema of the eyelids and face, mucosal inflammation, pruritus, anorexia, vomiting, and diarrhea. Long-term use of small doses can produce keratinization and dryness of the skin, sometimes with frank dermatitis and pigmentation; alopecia can follow, and basal cell epithelioma is a late effect [ ]. In the long run, as in the fatal cases noted in the introduction of this monograph, there is serious damage to internal organs.
The adverse effects of arsenic trioxide have been described in a patient with recurrent acute promyelocytic leukemia resistant to all-trans retinoic acid [ ].
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A 15-year-old African American girl, with multiple recurrent acute promyelocytic leukemia that had resisted conventional chemotherapy, was given arsenic trioxide (As 2 O 3 ) 10 mg intravenously for 28 days and again for a further 28 days after a 4-week break. She had a complete remission by morphological, cytogenetic, and molecular criteria. About 6 months later she again relapsed and had another course of arsenic trioxide, which produced a morphological, but not a cytogenic or molecular, remission. Arsenic trioxide was well tolerated. Skin dryness was treated with topical moisturizers. Gastrointestinal upset, including mild nausea without vomiting or cramping pain, occurred only during intravenous therapy. No other toxicity was noted.
In acute promyelocytic leukemia arsenic trioxide can cause a syndrome similar to the retinoic acid syndrome [ ], with fever, skin rash, edema, pleural effusion, pericardial effusion, and acute respiratory failure.
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A 37-year-old woman with acute promyelocytic leukemia was treated with all-trans retinoic acid, idarubicin, and cytosine arabinoside, with complete remission after one course. However, she had an episode of retinoic acid syndrome with fever, edema, and pericardial effusion, which resolved after all-trans retinoic acid was withdrawn. When her leukemia relapsed she was treated with arsenic trioxide 10 mg/day. Leukocytosis again developed, with symptoms (fever, skin rash, and edema) resembling the retinoic acid syndrome, which was quickly relieved by steroids. She received two courses of arsenic trioxide each for 30 days and her complete blood count returned to normal 2 weeks after the second course of treatment. The bone marrow also reached complete remission.
Drug studies
Observational studies
Organic arsenicals have been investigated for their potential as anticancer drugs [ ]. The use of arsenic trioxide in acute promyelocytic anemia is gaining more attention, and its adverse effects have been reviewed [ ]. During induction therapy, a leukocytosis can occasionally occur, which can be associated with fluid accumulation, pulmonary infiltration, prolongation of the QT interval, and dysrhythmias.
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