Transcriptome profiling identifies genes/pathways associated with experimental resistance to paromomycin in Leishmania donovani.

Widespread resistance towards antimony and reports of relapses following miltefosine treatment has severely affected the management of visceral leishmaniasis (VL) in the Indian subcontinent. Paromomycin (PMM), an aminoglycoside antibiotic, has been licensed for VL treatment in India in 2007. Although its use is still restricted in the field, unraveling the molecular mechanism of resistance towards PMM is the key to preserve the drug. In this study, PMM resistant lines were selected up to 100 µM of PMM in three distinct field isolates of Leishmania donovani at promastigote stage. The resistance induced at promastigote level was also evident in amastigotes which showed 6 fold decreases in PMM susceptibility. Comparative transcriptome profiling of PMM resistant (PMM-R) and the corresponding PMM sensitive (PMM-S) parasites revealed modulated expression of 500 genes (1.5 fold cut off) in PMM-R parasites. Selected genes were validated for their modulated expression by quantitative real-time PCR. Functional classification and pathway analysis of modulated genes indicated probable adaptations in drug resistant lines which included a) reduced oxidative phosphorylation; b) increased glycosomal succinate fermentation and substrate level phosphorylation; c) dependency on lipids and amino acids for energy generation; d) reduced DNA synthesis and increased DNA damage repair and e) decreased protein synthesis and degradation. Interestingly, PMM-R parasites showed a marked increase in PMM susceptibility in presence of verapamil and amlodipine, antagonists of Ca2+ channel that are also modulators of ABC transporters. Moreover, infection of macrophages by PMM-R parasites led to modulated nitric oxide (NO) levels while reactive oxygen species (ROS) level remained unaltered. The present study highlights the putative mechanisms of PMM resistance in Leishmania.

Chest X-ray Artifact Caused by Bilateral 99mTc-Antimony Trisulfite Injection for Sentinel Node Imaging in a Patient With Breast Cancer.

A 52-year-old woman diagnosed with invasive ductal carcinoma of both breasts had a chest x-ray for preoperative assessment. A striking artifact was noted by the x-ray technologist, who, as a result, became very concerned about radiation exposure from the patient. The patient had undergone bilateral sentinel lymph node injections in the nuclear medicine department with Tc-antimony trisulfite colloid just 2 hours before the chest x-ray. Radiation exposure to the x-ray technologist was determined to be similar to 8 hours of naturally occurring background radiation (∼2.96 µSv).

Varicella zoster virus reactivation during or immediately following treatment of tegumentary leishmaniasis with antimony compounds

Antimony compounds are the cornerstone treatments for tegumentary leishmaniasis. The reactivation of herpes virus is a side effect described in few reports. We conducted an observational study to describe the incidence of herpes zoster reactivation during treatment with antimony compounds. The global incidence of herpes zoster is approximately 2.5 cases per 1,000 persons per month (or 30 cases per 1,000 persons per year). The estimated incidence of herpes zoster in patients undergoing antimony therapy is higher than previously reported.

Evidências clínicas e imunológicas da eficácia do tratamento da leishmaniose cutânea com baixas doses de antimonial pentavalente na manutenção de cura por longo tempo / Evidence from clinical and immunological effectiveness of cutaneous leishmaniasis treatment with low doses of pentavalent antimony in curing maintained for a long time

O tratamento para leishmaniose cutânea (LC) utilizando antimoniais foi iniciado em 1912, no Brasil. O uso da forma pentavalente (Sb5+) se iniciou na década de 1940, e apesar de ainda ser eficaz para curar a LC efeitos adversos graves podem acontecer. Outras opções de tratamento, como pentamidina e anfotericina B também são de administração parenteral. Na tentativa de reduzir os efeitos adversos dos Sb5+, esquemas terapêuticos em doses baixas já evidenciaram ser seguros no tratamento da LC no Rio de Janeiro, sejam doses de apenas 5mg Sb5+/kg/dia por 30 dias (DB), aplicação intralesional (IL) ou em esquema de uso de uma ampola três vezes por semana (2ª/4ª/6ª) até a cura clínica...

Antimony therapy was first used to treat cutaneous leishmaniasis (CL) in 1912.Pentavalent antimonial (Sb5+) compounds were introduced as leishmaniasis therapy in the 1940s and are still efficient in curing CL, but they may cause serious adverse effects. Although there are other options for CL treatment, such as pentamidine and amphotericin B, similar to Sb5+, these drugs are also administered parenterally. To reduce the adverse effects of antimony, low-dose therapies were attempted and were proven safe in curing CL in patients in the state of Rio de Janeiro. Different schedules as 5mgSb5+/day/30 days (LowD), intralesional therapy (IL), or use of one ampoule three-times-a-week until clinical cure were proven to be efficient to cure CL...

The effect of age on the frequency of adverse reactions caused by antimony in the treatment of American tegumentary leishmaniasis in Governador Valadares, State of Minas Gerais, Brazil / Efeito da idade na frequência das reações adversas provocadas pelo antimônio no tratamento de pacientes com leishmaniose tegumentar americana, em Governador Valadares, Estado de Minas Gerais, Brasil

INTRODUCTION: Governador Valadares is an endemic area of American tegumentary leishmaniasis (ATL). The detection rate was 15.36 per 100,000 habitants from 2001 to 2006 (Miranda, 2008). This study aimed to analyze the effects of age on the frequency of adverse reactions caused by antimony in the treatment of ATL in the City of Governador Valadares, State of Minas Gerais, Brazil, during 2009. METHODS: Data were collected from the forms of the Information System for Notifiable Diseases, and from charts, questionnaires, and home visits to patients. RESULTS: The study included 40 patients, 26 (65%) of whom were males. Individuals over the age of 50 had a 66% higher rate of adverse effects than subjects who were 50 years old or less (CI 95%, 1.14-2.41). The average age of individuals who reported some type of adverse effect was 44.11 years (SD = 20.14), while the average age of the group that did not report any adverse effect was of 25.46 years (SD = 18.37; p < 0.01). Clinical healing was 67.5%, and 10% of patients discontinued the treatment. CONCLUSIONS: In the treatment of ATL, the age of patients should be considered, because most adverse reactions occur in individuals over 50 years of age. For this reason, the drug should be used with restriction in these cases.

INTRODUÇÃO: Governador Valadares constitui uma área endêmica de leshmaniose tegumentar americana (LTA) e o coeficiente de detecção foi de 15,36/100.000 habitantes no período de 2001 a 2006 (Miranda, 2008). Este estudo teve como objetivo analisar o efeito da idade na frequência das reações adversas provocadas pelo antimônio no tratamento de pacientes com LTA, em Governador Valadares, Estado de Minas Gerais, Brasil, no período de janeiro a dezembro de 2009. MÉTODOS: Para coleta de dados foram utilizados: ficha de notificação do Sistema de Informação de Agravos de Notificação (SINAN), prontuários, questionário e visitas domiciliares aos pacientes. RESULTADOS: Participaram do estudo 40 pacientes, sendo 26 (65%) do sexo masculino. Os indivíduos acima de 50 anos de idade tiveram prevalência 66% maior de reações adversas que as pessoas com idade de 50 ou menos (IC 95% -1,14-2,41). A média de idade dos indivíduos que relataram algum tipo de reação adversa foi de 44,11 anos (DP=20,14), enquanto no grupo que não relatou reação adversa, a média de idade foi de 25,46 anos (DP=18,37) e p < 0,01. A cura clínica foi de 67,5% e 10% dos pacientes abandonaram o tratamento. CONCLUSÕES: No tratamento da LTA, a idade do paciente deve ser considerada; pois ocorrem mais reações adversas em indivíduos acima de 50 anos de idade, que nesses casos o medicamento deve ser utilizado com restrição.

Associations of multiple metals with kidney outcomes in lead workers.

OBJECTIVES: Environmental exposure to multiple metals is common. A number of metals cause nephrotoxicity with acute and/or chronic exposure. However, few epidemiologic studies have examined the impact of metal coexposure on kidney function. Therefore, the authors evaluated associations of antimony and thallium with kidney outcomes and assessed the impact of cadmium exposure on those associations in lead workers. METHODS: Multiple linear regression was used to examine associations between ln-urine thallium, antimony and cadmium levels with serum creatinine- and cystatin-C-based glomerular filtration measures and ln-urine N-acetyl-ß-D-glucosaminidase (NAG). RESULTS: In 684 participants, median urine thallium and antimony were 0.39 and 0.36 µg/g creatinine, respectively. After adjustment for lead dose, urine creatinine and kidney risk factors, higher ln-urine thallium was associated with higher serum creatinine- and cystatin-C-based estimates of glomerular filtration rate; associations remained significant after adjustment for antimony and cadmium (regression coefficient for serum creatinine-based estimates of glomerular filtration rate =5.2 ml/min/1.73 m2; 95% CI =2.4 to 8.0). Antimony associations with kidney outcomes were attenuated by thallium and cadmium adjustment; thallium and antimony associations with NAG were attenuated by cadmium. CONCLUSIONS: Urine thallium levels were significantly associated with both serum creatinine- and cystatin-C-based glomerular filtration measures in a direction opposite that expected with nephrotoxicity. Given similarities to associations recently observed with cadmium, these results suggest that interpretation of urine metal values, at exposure levels currently present in the environment, may be more complex than previously appreciated. These results also support multiple metal analysis approaches to decrease the potential for inaccurate risk conclusions.

Possible links between sickle cell crisis and pentavalent antimony.

For over 60 years, pentavalent antimony (Sb(v)) has been the first-line treatment of leishmaniasis. Sickle cell anemia is a disease caused by a defect in red blood cells, which among other things can cause vasooclusive crisis. We report the case of a 6-year-old child with leishmaniasis who during treatment with meglumine antimoniate developed a sickle cell crisis (SCC). No previous reports describing the relationship between antimonial drugs and sickle cell disease were found. Reviews of both the pathophysiology of SCC and the mechanism of action of Sb(v) revealed that a common pathway (glutathione) may have resulted in the SCC. ChemoText, a novel database created to predict chemical-protein-disease interactions, was used to perform a more expansive and systematic review that was able to support the association between glutathione, Sb(v), and SCC. Although suggestive evidence to support the hypothesis, additional research at the bench would be needed to prove Sb(v) caused the SCC.

Alteração na função renal e pancreatite: efeitos adversos do tratamento da leishmaniose visceral / Change in renal function and pancreatitis: adverse effects of the treatment of visceral leishmaniasis

Introdução: Estudos têm demonstrado que a Leishmania sp. causa glomerulonefrites mesangial, membranoproliferativa focal e difusa, e nefrite intersticial. Estas alterações podem levar à ocorrência de proteinúria, alterações do sedimento urinário e perda da função renal. Como medicação de primeira escolha para o tratamento de LVA é recomendado o antimonial pentavalente, que possui boa eficácia, mas apresenta riscos de cardiotoxicidade, nefrotoxicidade e hepatotoxicidade. A Anfotecina B é utilizada como segunda escolha, mas esta droga também é nefrotóxica. O objetivo do presente trabalho é relatar o comprometimento da função renal em um paciente com diagnóstico de LVA, e que desenvolveu pancreatite após o tratamento com glucantime e apresentou melhoras nesse quadro após uso de anfotericina B, apresentando, porém, um quadro de nefrotoxicidade devido ao uso da segunda droga. Materiais e metodologia: Estudo retrospectivo de prontuário do caso de um paciente do sexo masculino, 64 anos, com diagnóstico de leishmaniose visceral. Na admissão apresentava creatinina sérica de 1,2mg/dL, uréia de 30 mg/dL, potássio de 4,6 mEq/L, proteinúria de 3+ e hematúria com 10 hemácias/campo. Após o tratamento com glucantime houve redução dos níveis de creatinina e desaparecimento da proteinúria. Porém, houve o aparecimento de pancreatite, com amilase 351mg/dL e lipase 1421 mg/dL. Devido a este efeito adverso, desencadeado pelo antimonial, foi utilizada a anfotericina B, que provocou uma piora da função renal, com creatinina 1,8 mg/dL. Após ajuste do intervalo entre as doses de anfotericina B houve normalização da função renal. Este caso ilustra os efeitos adversos relacionados ao tratamento da LVA. Conclusão: É necessário instituir um monitoramento laboratorial sistematizado da função renal e dos níveis séricos da amilase/lipase em pacientes que estejam sob tratamento de leishmaniose com antimonial pentavalente ou anfotericina B.

Introdution: Studies have shown that Leishmania sp causes glomurelonephritis characterized by mesangialcell proliferation, focal and diffuse membranoproliferative glomerulonephrittis and interstitial nephritis. These alterations may lead to the occurrence of proteinurea, alterations in urinary sedimentation and loss of renalfunction. Pentavalent antimoniate is recommended as a first choice in the treatment of AVL; this drug isefficient, but it presents the risk of cardiotoxicity, nephrotoxicity and hepatotoxicity. Amphotericin B is used as a second choice drug, but it is also nephrotoxic and may cause reactions. The objective of the present report is to demonstrate the impairment of renal function in a patient with visceral leishmaniasis who developed pancreatitis after treatment with glucantime and improved after treatment with amphotericin B, presenting, however, a case of nephrotoxicity due to the use of this second drug. Materials and methods: We report acase of a 64 year-old male patient, diagnosed with visceral leishmaniasis. On admission the patient presented creatinine 1.2mg/dL, urea 30 mg/dL, potassium 4.6 mEq/L, proteinurea 3+ and hematuria 10/field. After treatment with antimoniate a decrease in creatinine levels and the disappearance of proteinurea were observed; however, the patient developed pancreatitis, and an increase in the levels of amylase 351 mg/dL and lipase 1421 mg/dLwas verified. Due to this adverse effect triggered by the antimonial, amphotericin B was used, which provokeda worsening of the renal function, with creatinine 1.8mg/dL. After adjusting the interval between doses of amphotericin B, renal function returned to normality. This case illustrates the adverse effects related to the treatment of AVL. Conclusion: There must be a laboratorial follow up of the renal function and sera levels of amylase and lipase in patients under treatment with pentavalente antimoniate or anfotericin B.

Antimony-based antileishmanial compounds prolong the cardiac action potential by an increase in cardiac calcium currents.

Antimonial agents are a mainstay for the treatment of leishmaniasis, a group of protozoal diseases that includes visceral leishmaniasis, or Kala Azar. Chemotherapy with trivalent potassium antimony tartrate (PAT) and, more importantly, pentavalent antimony-carbohydrate complexes, such as sodium stibogluconate (SSG), has been reported to prolong the QT interval and produce life-threatening arrhythmias. PAT is chemically related to As2O3, which alters cardiac excitability by inhibition of human ether a-go-go related gene (hERG) trafficking and an increase of cardiac calcium currents. In this study, we report that PAT does not block hERG currents on short-term exposure but reduces current density on long-term exposure (IC50, 11.8 microM) and inhibits hERG maturation on Western blots (IC50, 62 microM). Therapeutic concentrations of 0.3 microM PAT increase cardiac calcium currents from -4.8 +/- 0.7 to -7.3 +/- 0.5 pA/pF at 10 mV. In marked contrast, pentavalent SSG, the drug of choice for the treatment of leishmaniasis, did not affect hERG/IKr or any other cardiac potassium current at therapeutic concentrations. However, both cardiac sodium and calcium currents were significantly increased on long-term exposure to 30 microM SSG in isolated guinea pig ventricular myocytes. We propose that the increase in calcium currents from -3.2 +/- 0.3 to -5.1 +/- 0.3 pA/pF at 10 mV prolongs APD90 from 464 +/- 35 to 892 +/- 64 ms. Our data suggest that conversion of Sb(V) into active Sb(III) in patients produces a common mode of action for antimonial drugs, which define a novel compound class that increases cardiac risk not by a reduction of hERG/IKr currents but-for the first time-by an increase in cardiac calcium currents.

Clinical features, epidemiology, and efficacy and safety of intralesional antimony treatment of cutaneous leishmaniasis: recent experience in Turkey.

A total of 1,030 patients, 40.2% men and 59.8% women, identified during the period of October 1998 to November 2002 as having cutaneous leishmaniasis (CL), were studied; 1,431 lesions were identified in the 1,030 patients. One lesion was present in 80.7% of the patients. The size of the lesions (longest axis) was 13.6 mm (standard, 12.1 mm; range 3-150 mm). Most of the lesions were of the papular type (51.2%), although several atypical clinical presentations of CL were observed. The duration of the disease ranged between 1 and 72 mo (mean duration, 10.8 mo). The clinical suspicion of CL was confirmed by the observation of amastigotes on lesion tissue samples stained by Giemsa. The test was positive in 851 of 1,030 patients (82.6%). Intralesional meglumine antimonate solution (85 mg Sb/ml, 0.2-1 ml, depending on the size of the lesion) weekly until complete cure or up to 20 wk was used for first-line therapy of 890 patients (86.4%). We found that this regimen of intralesional Sb has an efficacy of 97.2% with a low relapse rate of 3.9% and no serious adverse side effects.

Predictors of an unsatisfactory response to pentavalent antimony in the treatment of American visceral leishmaniasis

Although treatment of visceral leishmaniasis with pentavalent antimony is usually successful, some patients require second-line drug therapy, most commonly with amphotericin B. To identify the clinical characteristics that predict an inadequate response to pentavalent antimony, a case-control study was undertaken in Teresina, Piaui, Brazil. Over a two-year period, there were 19 cases of VL in which the staff physicians of a hospital prescribed second-line therapy with amphotericin B after determining that treatment with pentavalent antimony had failed. The control group consisted of 97 patients that were successfully treated with pentavalent antimony. A chart review using univariate and multivariate analysis was performed. The cure rate was 90 percent with amphotericin B. The odds ratio for the prescription of amphotericin B was 10.2 for children less than one year old, compared with individuals aged over 10 years. Patients who presented coinfection had an OR of 7.1 while those on antibiotics had an OR of 2.8. These data support either undertaking a longer course of therapy with pentavalent antimony for children or using amphotericin B as a first-line agent for children and individuals with coinfections. It also suggests that chemoprophylaxis directed toward bacterial coinfection in small children with VL may be indicated

Unanswered questions in arsenic toxicology.

Arsenic (As) is one of the most important environmental global toxicants. In various countries and for decades people have been and currently are exposed to inorganic As through geogenically contaminated drinking water. An increased incidence of diseases mediated by this toxic element is the consequence of long-term exposure. Despite past extensive research on the toxicology of As, many questions remained unanswered, making risk assessment difficult. For instance, it is still not known how the carcinogenicity of As is mechanistically operative. Moreover, there is an increasing debate on whether the metabolic methylation of As has to be considered a detoxification process. Furthermore, it is historically documented that long-term intake of small amounts of As can lead to an acquired increased tolerance to its acute toxicity. It is not known whether this tolerance may be associated with a reduced chronic toxicity as well. In contrast to nonhuman cells, the selection of As-induced self-tolerance in human cells in vitro had been unsuccessful until now. However, we recently selected As-resistant human hepatoma HepG2 sublines that have low-level tolerance to As. Besides an approximately twofold elevated resistance to As cytotoxicity, this tolerance was associated with a significantly suppressed induction of As-mediated genotoxicity, which was evident in the cytokinesis-block micronucleus test. Additional questions arise when we consider several factors suspected to modulate the long-term toxicity of arsenic in vitro, variables that may either enhance or suppress the environmental genotoxicity and carcinogenicity of the metalloid. Besides malnutrition, these are single nutritional factors such as selenium and possible drinking water co-contaminants such as antimony. For instance, in the case of selenium, we could show that antimony (III) is able to suppress As genotoxicity. Taken together, research answers in many fields of As toxicology are needed in order to reduce the uncertainties in risk assessment of environmental As.

High frequency of serious side effects from meglumine antimoniate given without an upper limit dose for the treatment of visceral leishmaniasis in human immunodeficiency virus type-1-infected patients.

Organic pentavalent antimonials are one of the mainstays of treatment for visceral leishmaniasis (VL). Few data are available on the toxicity and efficacy of these drugs at the dosing schedule recommended by the Centers for Disease Control and Prevention (CDC) (Atlanta, GA). We analyzed 25 VL episodes in human immunodeficiency virus (HIV)-infected patients who were treated with meglumine antimoniate (MA) at the CDC-recommended dose in southern Spain. Adverse effects were observed in 14 (56%) VL episodes. In 7 (28%), treatment with MA was permanently discontinued due to serious adverse effects that included acute pancreatitis, acute renal failure, and leukopenia. Three (12%) patients died during therapy due to severe acute pancreatitis attributable to MA. The dosing regimen of MA currently recommended for treating VL is associated with a high rate of serious side effects in HIV-1-infected patients.

Pediatric visceral leishmaniasis in southern France.

PURPOSE: The purposes of this study were to describe the characteristics of pediatric visceral leishmaniasis in southern France and to evaluate a new scheme of therapy. METHODS: Hospital records of 59 children with visceral leishmaniasis were retrospectively reviewed. The period of the study was from 1981 to 1997. RESULTS: All children but one lived or had previously dwelled in the south of France. None was coinfected with human immunodeficiency virus or known to be immunocompromised. The mean age was 31 months; 10 children were younger than 1 year when admitted to the hospital. The male:female ratio was 0.73. Fever and splenomegaly were present in 90 and 100%, respectively. Anemia, leukopenia and thrombocytopenia were commonly observed, especially in the youngest patients. Hypergammaglobulinemia was noted in 64%. A biopsy sample of the bone marrow was always performed, but direct microscopic examination failed to identify Leishmania in 13 (22%) cases. In these patients specific serology and genomic amplification with polymerase chain reaction were useful tools for the diagnosis. All patients were initially treated with meglumine antimonate (Glucantime). Twenty-six (44%) patients receiving the drug experienced at least one adverse event during treatment. Treatment failure occurred in six children (10%), who were subsequently cured with liposomal amphotericin B. Three additional children were treated with liposomal amphotericin B. All the children were finally cured and no death was observed. CONCLUSION: Our experience suggests that liposomal amphotericin B is effective therapy for visceral leishmaniasis in children.

Avaliação da tolerância e nefrotoxicidade do antimonial pentavalente administrado na dose de 40 mg Sb V/kg/dia, de 12/12 h, por 30 dias na forma cutâneo-mucosa de leishmaniose / The evaluation of the tolerance and nephrotoxicity of pentavalent antimony administered in a dose of 40 mg Sb V/kg/day, 12/12 hr, for 30 days in the mucocutaneous form of leishmaniasis

Foi avaliada a função renal de 11 pacientes com leishmaniose cutâneo-mucosa tratados com antimonial pentavalente na dose de 40mg SbV/kg/dia aplicada de 12/12 horas, em esquema contínuo, durante trinta dias. No estudo, um paciente apresentou insuficiência renal reversível e dois desenvolveram alterações enzimáticas hepáticas e eletrocardiográficas sendo o esquema terapêutico interrompido. Nos demais pacientes observou-se efeitos nefrotóxicos tais como diminuição da taxa de filtração glomerular, diminuição da capacidade de concentração urinária, avaliada por um jejum hídrico de 16 horas e aumento na fração de excreção de sódio. No exame do sedimento urinário observou-se um aumento no número de leucócitos e cilindros. Os resultados encontrados neste estudo sugerem que o tratamento com antimonial pentavalente na dose de 40mg SbV/kg/dia foi menos tolerado em virtude de seus efeitos tóxicos, não parecendo apresentar índice de cura superior ao esquema atualmente preconizado de 20mg SbV/kg/dia.

The renal function of eleven patients with mucocutaneous leishmaniasis was analyzed in a prospective study realized at the School Hospital of University of Brasília. The patients were treated with doses of 40 mg/kg/day of pentavalent antimony (Sb V), in a continuous scheme during thirty days. In this study three patients were excluded, one patient with reversible renal failure and two patients with hepatic and cardiac malfunctions. In the other eight patients, severe nephrotoxic effects were observed, like reduction of glomerular filtration rate, reduction of the urinary concentration capacity, evaluated by a sixteen hours hydric fasting and an increase of sodium fractional excretion. An increase in the number of leucocytes and cylinders were observed at the urinary sediment exam. Finally, the results shows that the treatment with pentavalent antimony in doses of 40 mg Sb/kg/day was less tolerated on account of its renal toxic effects. This scheme seems not be superior than the currently preconized scheme of 20 mg of Sb V/kg/day during 30 days.

The carcinogenicity of metals in humans.

Epidemiologic evidence on the relation between exposure to metals and cancer is reviewed. Human exposure to metals is common, with wide use in industry and long-term environmental persistence. Historically, the heaviest metal exposures occurred in the workplace or in environmental settings in close proximity to industrial sources. Among the general population, exposure to a number of metals is widespread but generally at substantially lower levels than have been found in industry. The carcinogenicity of arsenic, chromium, and nickel has been established. Occupational and environmental arsenic exposure is linked to increased lung cancer risk in humans, although experimental studies remain inconclusive. Experimental studies clearly demonstrate the malignant potential of hexavalent(VI) chromium compounds, with solubility being an important determining factor. Epidemiologic studies of workers in chromium chemical production and use link exposure to lung and nasal cancer. Experimental and epidemiologic data show that sparingly-soluble nickel compounds and possibly also the soluble compounds are carcinogens linked to lung and nasal cancer in humans. Some experimental and epidemiologic studies suggest that lead may be a human carcinogen, but the evidence is inconclusive. Although epidemiologic data are less extensive for beryllium and cadmium, the findings in humans of excess cancer risk are supported by the clear demonstration of carcinogenicity in experimental studies. Other metals, including antimony and cobalt, may be human carcinogens, but the experimental and epidemiologic data are limited.

Visceral leishmaniasis in patients infected with the human immunodeficiency virus.

The experience with 52 episodes of visceral leishmaniasis diagnosed in 43 patients is reported. The most common symptoms were fever (81%), splenomegaly (65%), hepatomegaly (63%), and pancytopenia (73%). In 79% of the patients, CD4+ cell counts were < 100 cells/mm3. Prior or simultaneous diagnosis of AIDS was made in 29 (67%) patients. Diagnosis was considered fortuitous in 19% of the episodes. In 27% of the episodes, the diagnosis was made on the basis of demonstration of parasites outside the reticuloendothelial system, chiefly blood (7 cases) and gastrointestinal mucosa (5 cases). Parasites were frequently observed or cultured from blood (22/37 episodes) or the digestive tract (8/9 episodes). High antimony doses were more effective than low doses in achieving clinical or parasitological cure (rate of cure, 80% vs. 40%, p = 0.11). Severe toxicity was observed in six (11.7%) of the 51 treated episodes. Severe AIDS-related diseases [odds ratio (OR) 10, p < 0.05] and CD4+ counts (OR 12, p < 0.05) were independent factors for early death. Prophylaxis with monthly pentamidine was not useful in reducing relapses of visceral leishmaniasis.

Cytogenetic observations after meglumine antimoniate therapy for visceral leishmaniasis.

Few data are available concerning the genotoxic effects of antimonial salts therapy in humans. A patient suffering from visceral leishmaniasis was treated for 15 days with a cumulative dose meglumine antimoniate 42.5 g. Peripheral blood lymphocytes sampled before treatment, 7 days later, and at the end of therapy (day 15) were examined for the presence of structural chromosome aberrations, sister chromatid exchanges (SCEs), and micronuclei in binucleated cells. The treatment resulted in an increase of binucleated cells carrying micronuclei, with no changes in chromosome structural aberrations or in mean SCE frequency. On the basis of these observations and of experimental results reported in the literature, we conclude that therapy with meglumine antimoniate apparently does not represent a mutagenic or carcinogenic risk to humans.

Mortality in a cohort of antimony smelter workers.

Animal studies show that antimony may cause lung cancer and heart and lung disease in rodents. In exposed humans, ECG abnormalities and heart and lung disease have been reported. This mortality study of 1,014 men employed between 1937 and 1971 in a Texas antimony smelter consisted primarily of workers of Spanish ancestry (n = 928, 91.5%). Hispanics are known to smoke at much lower rates than non-Hispanics, and their lung cancer and heart disease mortality is generally low. When ethnic-specific Texas lung cancer death rates were used for comparison, mortality from lung cancer among antimony workers was elevated (SMR) 1.39, 90% CI 1.01-1.88), and we observed a significant positive trend in mortality with increasing duration of employment. When ischemic heart disease death rates from three different Spanish-surnamed populations were used for comparison, the rate ratios for mortality from ischemic heart disease were 0.91 (90% CI 0.84-1.09), 1.22 (90% CI 0.78-1.89), and 1.49 (90% CI 0.84-2.63). Pneumoconiosis/ other lung disease death rates for Spanish-surnamed men were unavailable and so calculation of rate ratios used white males as a comparison population (SMR 1.22; 90% CI 0.80-1.80). These data suggest some increased mortality from lung cancer and perhaps nonmalignant respiratory heart disease in workers exposed to antimony. However, conclusions are limited by possible confounders and the difficulty of identifying appropriate referent groups.