High frequency of skin reactions in patients with leishmaniasis treated with meglumine antimoniate contaminated with heavy metals: a comparative approach using historical controls

Abstract

Key words: pentavalent antimony -heavy metals -cutaneous leishmaniasis -lead -arsenic -toxicity Pentavalent antimonials had been, for many years, the first-choice drugs for the treatment of leishmaniasis (Marsden 1985, Herwaldt & Berman 1992, Berman 1997. Two salts are commercially available, meglumine antimoniate and sodium stibogluconate. They are used by the IM or IV route. In Brazil, patients with cutaneous leishmaniasis are treated with meglumine antimoniate, 10-20 mg/kg/day IM or IV, for 20-30 days following the recommendations of the Brazilian Ministry of Health. The drug usually causes mild to moderate adverse events that rarely lead to treatment suspension. Myalgias, arthralgias, abdominal symptoms, headache, elevation of aminotransferases and amylase, and electrocardiographic changes affecting the ST segment and QTc are the most frequent events (Marsden 1985, Ballow et al. 1987, Franke et al. 1990, Gasser et al. 1994, Berman 1997. Rarely, severe toxicity is observed such as acute renal and hepatic failure (Kopke et al. 1993), thrombocytopenia (Hepburn 1993) and even sudden death, probably due to cardiac rhythm disturbances (Chulay et al. 1985). The presence of trivalent antimony contaminating pentavalent antimonials for clinical use was demonstrated and could explain the toxic events observed during treatment (Franco et al. 1995). Pharmacokinetics of both drugs is comparable and it is assumed that they produce similar therapeutic effects (Chulay et al. 1988 be different for each drug and formal comparisons of sodium stibogluconate and meglumine antimoniate are scarce. We recently compared the efficacy, safety and toxicity of sodium stibogluconate produced in China (sodium stibogluconate BP88® Shandong, Xinhua, China) with meglumine antimoniate (Rhodia Farma, Ltda., São Paulo, Brazil) and our conclusions suggest that sodium stibogluconate was more toxic than the drug produced by Rhodia Farma Ltda. (Saldanha et al. 1999(Saldanha et al. , 2000. There are no definite criteria to evaluate the quality of antimonials. High osmolarity could be a marker of higher toxicity as shown by one report from India (Sundar et al. 1998). We had measured the osmolarity and pH of different lots of meglumine antimoniate and that physico-chemical properties appear to be stable at least during a three-year period (Romero et al. 1996). The presence of metals such as lead has been reported as a cause of poisoning in patients treated with traditional Chinese remedies (Wu et al. 1996) but there is little information about this kind of contamination in pharmaceutical products (Popinska et al. 1999). Flores et al. (2000) drew attention to the fact that routine quality control of drugs with the appropriate methods to detect heavy metals has been traditionally neglected. Contamination of antimonials with heavy metals such as lead, arsenic and cadmium is not expected unless poor quality control of manufacturing process allows the use of impure salts. We use historical controls (patients with cutaneous leishmaniasis) treated with the un...

In vitro and in vivo activity of meglumine antimoniate produced at Farmanguinhos-Fiocruz, Brazil, against Leishmania (Leishmania) amazonensis, L (L.) chagasi and L (Viannia) braziliensis

“…The epidemiological and the clinical investigation led to physical chemistry analysis of the batches, which resulted in the detection of heavy metals (Silva Junior 2001). The higher frequency of skin reactions in patients was attributed to the presence of heavy metals (Romero et al 2003).…”

Flow analysis-hydride generation-gas phase derivative molecular absorption spectrophotometric determination of antimony in antileishmanial drugs

“…Contamination of leishmanicidal pharmaceutical products with this type of species such as lead and arsenic is not expected unless poor quality control of manufacturing process allows the use of impure active chemicals. 4 Arsenic is the most probable impurity of antimonial drugs. 4 Arsenic can generate gaseous AsH 3 which could enhance or suppress the true response signal of SbH 3 .…”

“…4 Arsenic is the most probable impurity of antimonial drugs. 4 Arsenic can generate gaseous AsH 3 which could enhance or suppress the true response signal of SbH 3 . Therefore, the presence of this inter-element as impurity of real samples was explored by FA-HG-FTIR at different concentration ratios.…”

“…3 Although being old medicines, safety and quality control of these drugs have not been comprehensively evaluated so far. 4,5 Thus, the development of simple, low cost, fast methodologies is important, especially for developing countries. 6 Several analytical methodologies have been developed for the determination of antimony in different aqueous and solid matrices, which have been reviewed by different authors.…”

Synthesis and Antileishmanial Activities of Novel 3-Substituted Quinolines

“…Despite the great advances in many scientific fields, the 92-year-old antimonials (29) are still the main treatment in the majority of developing countries. In addition, problems have occurred with the manufacture and supply of antimonials in developing countries (20) and high levels of arsenic contaminants have also been described (22). Secondline drugs, such as pentamidine and amphotericin B, are important in combined therapy or in cases of antimony treatment failures (3).…”