Pancreatic toxicity as an adverse effect induced by meglumine antimoniate therapy in a clinical trial for cutaneous leishmaniasis

Submitted by Sandra Infurna ([email protected]) on 2016-12-27T10:48:27Z No. of bitstreams: 1 fatima_silva_etal_IOC_2016.pdf: 112932 bytes, checksum: 233a7fb3d4c489237c45cf9f4a61d544 (MD5)Approved for entry into archive by Sandra Infurna ([email protected]) on 2016-12-27T11:13:55Z (GMT) No. of bitstreams: 1 fatima_silva_etal_IOC_2016.pdf: 112932 bytes, checksum: 233a7fb3d4c489237c45cf9f4a61d544 (MD5)Made available in DSpace on 2016-12-27T11:13:55Z (GMT). No. of bitstreams: 1 fatima_silva_etal_IOC_2016.pdf: 112932 bytes, checksum: 233a7fb3d4c489237c45cf9f4a61d544 (MD5) Previous issue date: 2016Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evando Chagas (INI). Laboratório de Pesquisa Clínica e Vigilância em Leishmanioses. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evando Chagas (INI). Laboratório de Pesquisa Clínica em Epidemiologia. Rio de Janeiro, RJ. Brasil / Universidade Federal do Rio de Janeiro (UFRJ). Rio de Janeiro, RJ, Brasil / Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ). Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evando Chagas (INI). Laboratório de Pesquisa Clínica e Vigilância em Leishmanioses. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evando Chagas (INI). Laboratório de Pesquisa Clínica e Vigilância em Leishmanioses. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evando Chagas (INI). Laboratório de Pesquisa Clínica e Vigilância em Leishmanioses. Rio de Janeiro, RJ. Brasil / Universidade Federal do Rio de Janeiro (UFRJ). Rio de Janeiro, RJ, Brasil / Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ). Fellow researcher (“Jovem Cientista do Nosso Estado”). Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evando Chagas (INI). Laboratório de Pesquisa Clínica e Vigilância em Leishmanioses. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evando Chagas (INI). Laboratório de Pesquisa Clínica e Vigilância em Leishmanioses. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evando Chagas (INI). Laboratório de Pesquisa Clínica e Vigilância em Leishmanioses. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evando Chagas (INI). Laboratório de Pesquisa Clínica e Vigilância em Leishmanioses. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evando Chagas (INI). Laboratório de Pesquisa Clínica e Vigilância em Leishmanioses. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evando Chagas (INI). Laboratório de Pesquisa Clínica e Vigilância em Leishmanioses. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz (FIOCRUZ). Instituto Oswaldo Cruz (IOC). Laboratório de Imunoparasitologia. Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evando Chagas (INI). Laboratório de Pesquisa Clínica e Vigilância em Leishmanioses. Rio de Janeiro, RJ. Brasil / Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Fellow researcher (“Jovem Cientista do Nosso Estado”). Rio de Janeiro, RJ, Brasil.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evando Chagas (INI). Laboratório de Pesquisa Clínica e Vigilância em Leishmanioses. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evando Chagas (INI). Laboratório de Pesquisa Clínica e Vigilância em Leishmanioses. Rio de Janeiro, RJ. Brasil.Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evando Chagas (INI). Laboratório de Pesquisa Clínica e Vigilância em Leishmanioses. Rio de Janeiro, RJ. Brasil / Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). Fellow researcher. Rio de Janeiro, RJ, Brasil / Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Fellow researcher (“Cientista do Nosso Estado”). Rio de Janeiro, RJ, Brasil.American tegumentary leishmaniasis is an infectious disease caused by a protozoan of the genus Leishmania. Pentavalent antimonials are the first choice drugs for cutaneous leishmaniasis (CL), although doses are controversial. In a clinical trial for CL we investigated the occurrence of pancreatic toxicity with different schedules of treatment with meglumine antimoniate (MA). Seventy-two patients were allocated in two different therapeutic groups: 20 or 5 mg of pentavalent antimony (Sb5+)/kg/day for 20 or 30 days, respectively. Looking for adverse effects, patients were asked about abdominal pain, nausea, vomiting or anorexia in each medical visit. We performed physical examinations and collected blood to evaluate serum amylase and lipase in the pre-treatment period, and every 10 days during treatment and one month post-treatment. Hyperlipasemia occurred in 54.8% and hyperamylasemia in 19.4% patients. Patients treated with MA 20 mg Sb5+ presented a higher risk of hyperlipasemia (p = 0.023). Besides, higher MA doses were associated with a 2.05 higher risk ratio (p = 0.003) of developing more serious (moderate to severe) hyperlipasemia. The attributable fraction was 51% in this group. Thirty-six patients presented abdominal pain, nausea, vomiting or anorexia but only 47.2% of those had hyperlipasemia and/ or hyperamylasemia. These findings suggest the importance of the search for less toxic therapeutic regimens for the treatment of CL

3 Sensitivity, specificity, predictive values, false positives and false negatives in the diagnosis of cochlear toxicity from self-reported hearing loss and tinnitus in relation to the ototoxicity alteration at three different frequencies ranges of tone threshold audiometry in 102 patients with American Tegumentary Leishmaniasis treated with meglumine antimoniate.

Evandro Chagas National Institute of Infectious Diseases, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.</p

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IntroductionAmerican Tegumentary Leishmaniasis (ATL) treatment is based on pentavalent antimonials (Sb5+), but these drugs have been associated to several adverse effects. Hearing loss and tinnitus during treatment with meglumine antimoniate (MA) have already been reported. This study aimed to describe the usefulness of self-reporting of hearing loss and tinnitus in diagnosing MA-induced ototoxicity.MethodsA prospective longitudinal study was conducted with 102 patients with parasitological diagnosis of ATL, treated with different MA schemes. The presence of clinical auditory toxicity was defined as the emergence or worsening of self-reporting hearing loss and/or tinnitus during monitoring. Measures of sensitivity, specificity, and the positive and negative predictive value of the patient’s self-reporting of hearing loss and tinnitus in relation to the result of the audiometric test (considered the gold standard) were calculated.ResultsThe age of the evaluated patients ranged from 15 to 81 years, with a median of 41 years, and most were male (73.5%). Seventy-five patients (73.5%) had cutaneous leishmaniasis and 27 (26.5%) mucosal leishmaniasis. Eighty-six patients (84.3%) received intramuscular (IM) treatment and 16 (15.7%) were treated with intralesional MA. During treatment, 18 (17,6%) had tinnitus and 7 (6,9%) had complaint of hearing loss. 53 (52%) patients had cochlear toxicity confirmed by tone threshold audiometry and high frequency audiometry, from which 60% received a dose of 20 mg Sb5+/kg/day (p = 0.015) and 96.2% were treated with IM MA (p = 0.001). Tinnitus has greater specificity and positive predictive value than hearing loss, with a low number of false positives, but with a high false negative value.ConclusionAlthough the large number of false negatives suggests that self-report of hearing loss or tinnitus cannot be considered a good screening test for referring the patient to an audiometry, the low number of false positives suggests the need to value the patient’s complaint for referral. Otherwise, this study reinforces the importance of audiological monitoring during treatment with MA, especially in those patients with self-reporting of hearing loss or tinnitus when treated with 20 mg Sb5+/kg/day via IM.</div

Sensitivity, specificity, predictive values, false positives and false negatives in the diagnosis of cochlear toxicity from self-reported hearing loss in relation to the ototoxicity alteration at three different frequencies ranges of tone threshold audiometry in 102 patients with American Tegumentary Leishmaniasis treated with meglumine antimoniate.

Evandro Chagas National Institute of Infectious Diseases, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.</p

Sensitivity, specificity, predictive values, false positives and false negatives in the diagnosis of cochlear toxicity from self-reported tinnitus in relation to the ototoxicity alteration at three different frequencies ranges of tone threshold audiometry in 102 patients with American Tegumentary Leishmaniasis treated with meglumine antimoniate.

Evandro Chagas National Institute of Infectious Diseases, Oswaldo Cruz Foundation, Rio de Janeiro, Brazil.</p