RESUMO
The multifactorial basis of therapeutic response can obscure the relation between antimicrobial drug susceptibility and clinical outcome. To discern the relationship between parasite susceptibility to meglumine antimoniate (SbV) and therapeutic outcome of cutaneous leishmaniasis, risk factors for treatment failure were considered in evaluating this relationship in ninety-one cutaneous leishmaniasis patients and corresponding clinical strains of Leishmania (Viannia) panamensis. Parasite susceptibility to 32 µg SbV/mL (plasma Cmax) was evaluated in primary human macrophages, PBMCs, and U937 macrophages. Early parasitological response to treatment was determined in lesions of a subgroup of patients, and pathogenicity of Sb-resistant and sensitive clinical strains was compared in BALB/c mice. Parasite survival in cell models and patient lesions was determined by qRT-PCR of Leishmania 7SLRNA transcript. Parasite loads in BALB/c mice were quantified by limiting dilution analysis. The disparate Sb-susceptibility of parasite subpopulations distinguished by isoenzyme profiles (zymodemes) was manifest in all cell models. Notably, Sb-resistance defined by parasite survival, was most effectively discerned in U937 macrophages compared with primary human host cells, significantly higher among strains from patients who failed treatment than cured and, significantly associated with treatment failure. Each unit increase in transformed survival rate corresponded to a 10.6-fold rise in the odds of treatment failure. Furthermore, treatment failure was significantly associated with naturally Sb-resistant zymodeme 2.3 strains, which also produced larger lesions and parasite burdens in BALB/c mice than Sb-sensitive zymodeme 2.2 strains. The confounding effect of host risk factors for treatment failure in discerning this association was evidenced in comparing strains from patients with and without the defined risk factors for treatment failure. These results establish the association of natural resistance to meglumine antimoniate with treatment failure, the importance of host risk factors in evaluating drug susceptibility and treatment outcome, and the clinical and epidemiological relevance of natural Sb-resistance in L. (V.) panamensis subpopulations.
Assuntos
Antiprotozoários , Resistência a Medicamentos , Leishmaniose Cutânea , Macrófagos , Antimoniato de Meglumina , Meglumina , Camundongos Endogâmicos BALB C , Compostos Organometálicos , Falha de Tratamento , Animais , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/parasitologia , Antimoniato de Meglumina/uso terapêutico , Antimoniato de Meglumina/farmacologia , Humanos , Antiprotozoários/uso terapêutico , Antiprotozoários/farmacologia , Feminino , Meglumina/uso terapêutico , Meglumina/farmacologia , Compostos Organometálicos/uso terapêutico , Compostos Organometálicos/farmacologia , Camundongos , Macrófagos/parasitologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Masculino , Leishmania guyanensis/efeitos dos fármacos , Adulto , Pessoa de Meia-Idade , Adulto Jovem , Carga Parasitária , AdolescenteRESUMO
Besides being scarce, the drugs available for treating cutaneous leishmaniasis have many adverse effects. Ozone is an option to enhance the standard treatment due to the wound-healing activity reported in the literature. In this study, we evaluated the efficiency of ozonated sunflower oil as an adjuvant in treating cutaneous lesions caused by Leishmania amazonensis. BALB/c mice were infected with L. amazonensis, and after the lesions appeared, they were treated in four different schedules using the drug treatment with meglumine antimoniate (Glucantime®), with or without ozonated oil. After thirty days of treatment, the lesions' thickness and their parasitic burden, blood leukocytes, production of NO and cytokines from peritoneal macrophages and lymph node cells were analyzed. The group treated with ozonated oil plus meglumine antimoniate showed the best performance, improving the lesion significantly. The parasitic burden showed that ozonated oil enhanced the leishmanicidal activity of the treatment, eliminating the parasites in the lesion. Besides, a decrease in the TNF levels from peritoneal macrophages and blood leukocytes demonstrated an immunomodulatory action of ozone in the ozonated oil-treated animals compared to the untreated group. Thus, ozonated sunflower oil therapy has been shown as an adjuvant in treating Leishmania lesions since this treatment enhanced the leishmanicidal and wound healing effects of meglumine antimoniate.
Assuntos
Antiprotozoários , Leishmaniose Cutânea , Ozônio , Animais , Camundongos , Antimoniato de Meglumina/farmacologia , Antimoniato de Meglumina/uso terapêutico , Óleo de Girassol/uso terapêutico , Antiprotozoários/farmacologia , Meglumina/farmacologia , Meglumina/uso terapêutico , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/parasitologia , Cicatrização , Ozônio/uso terapêutico , Camundongos Endogâmicos BALB CRESUMO
INTRODUCTION: American 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. METHODS: A 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. RESULTS: The 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. CONCLUSION: Although 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.
Assuntos
Antiprotozoários , Surdez , Perda Auditiva , Leishmaniose Cutânea , Compostos Organometálicos , Ototoxicidade , Zumbido , Humanos , Masculino , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Feminino , Antimoniato de Meglumina/efeitos adversos , Zumbido/induzido quimicamente , Zumbido/diagnóstico , Zumbido/tratamento farmacológico , Meglumina/efeitos adversos , Antiprotozoários/uso terapêutico , Estudos Longitudinais , Estudos Prospectivos , Compostos Organometálicos/efeitos adversos , Leishmaniose Cutânea/diagnóstico , Leishmaniose Cutânea/tratamento farmacológico , Perda Auditiva/induzido quimicamente , Perda Auditiva/diagnósticoRESUMO
Leishmaniasis is a disease caused by Leishmania spp., affecting millions of people around the world. For decades, its treatment has been based on pentavalent antimonials, which notoriously cause toxic side effects in patients. In this study, epoxy-α-lapachone incorporated into an oil-in-water-type microemulsion (ELAP-ME) and meglumine antimoniate (MA) were assayed in monotherapy and in combination (ELAP-ME/MA) in BALB/c mice infected with Leishmania (Leishmania) amazonensis. In general, there was a reduction in paw lesion size (up to 37% reduction) and decreases of parasite loads in the footpad (â¼40%) and lymph nodes (â¼31%) of animals treated with ELAP-ME/MA, when compared to the non-treated control groups. Analyses of serum biochemical parameters revealed that the ELAP-ME/MA showed lower renal and hepatic toxicity when compared to MA 2-doses/week monotherapy. These findings indicate that the ELAP-ME/MA combination may be a promising approach for the treatment of cutaneous leishmaniasis.
Assuntos
Antiprotozoários , Leishmania , Leishmaniose Cutânea , Naftoquinonas , Compostos Organometálicos , Humanos , Animais , Camundongos , Antimoniato de Meglumina/uso terapêutico , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/parasitologia , Meglumina/uso terapêutico , Compostos Organometálicos/uso terapêutico , Camundongos Endogâmicos BALB CRESUMO
BACKGROUND: Adhesive small bowel obstruction is one of the most common causes of surgical emergencies, representing about 15% of hospital admissions. Defining the need and timing of surgical intervention still remains a challenge. AIMS: To report the experience of using meglumine-based water-soluble contrast in a tertiary hospital in southern Brazil, comparing with the world literature. METHODS: Patients suspected of having adhesive small bowel obstruction, according to their clinical conditions, underwent an established protocol, consisting of the administration of water-soluble contrast, followed by plain abdominal radiograph within 12 hours and by a new clinical evaluation. The protocol was initiated after starting conservative management, including fasting and placement of a nasogastric tube, as well as intravenous fluid reposition. RESULTS: A total of 126 patients were submitted to the protocol. The water-soluble contrast test sensitivity and specificity after the first radiograph were 94.6 and 91.0%, respectively; after the second radiograph, these values were 92.3 and 100%. The general test values for sensitivity and specificity were 91.9 and 100%, respectively. CONCLUSIONS: The measure parameters evaluated in this study were similar to those found in the literature, contributing to endorse the importance of this test in the evaluation of patients with adhesive small bowel obstruction. The particular relevance of this study was the similar results that were found using a different type of meglumine-based contrast, which is available in Brazil.
Assuntos
Diatrizoato de Meglumina , Obstrução Intestinal , Humanos , Diatrizoato de Meglumina/uso terapêutico , Aderências Teciduais/diagnóstico por imagem , Meios de Contraste/uso terapêutico , Obstrução Intestinal/diagnóstico por imagem , Obstrução Intestinal/cirurgia , Meglumina/uso terapêutico , ÁguaRESUMO
BACKGROUND: Meglumine antimoniate (MA) remains the main treatment for cutaneous leishmaniasis (CL). Uncontrolled studies suggest that intralesional MA (IL-MA) may be noninferior and safer than systemic MA (S-MA). METHODS: Multicenter, randomized, controlled, open-label, phase 3 clinical trial to evaluate the efficacy and toxicity of IL-MA in 3 infiltrations at 14-day intervals compared with S-MA (10-20 mg Sb5+/kg/day, 20 days) for CL, with noninferiority margin of 20%. Primary and secondary outcomes were definitive cure at day 180 and epithelialization rate at day 90 of treatment, respectively. A 2-year follow-up was performed to assess relapses and emergence of mucosal lesions. Adverse events (AEs) were monitored according to the Division of AIDS AE grading system. RESULTS: We evaluated 135 patients. The cure rates (95% confidence interval) for IL-MA and S-MA treatment were, respectively, 82.8% (70.5-91.4) and 67.8% (53.3-78.3) per protocol (PP) and 70.6% (58.3-81.0) and 59.7% (47.0-71.5) per intention to treat (ITT). The epithelialization rates of the IL-MA and S-MA treatment were, respectively, 79.3% (66.6-88 + 8) and 71.2% (57.9-82.2) PP and 69.1% (55.2-78.5) and 64.2% (50.0-74.2) ITT. AEs in the IL-MA and S-MA groups were, respectively, clinical, 45.6% and 80.6%; laboratory, 26.5% and 73.1%; and electrocardiogram, 8.8% and 25.4%. Ten participants in the S-MA group and 1 in the IL-MA group were discontinued due to severe or persistent AEs. CONCLUSIONS: IL-MA provides a similar cure rate and results in less toxicity compared with S-MA and may be used as first-line therapy for CL patients. CLINICAL TRIALS REGISTRATION: REBEC: RBR-6mk5n4.
Assuntos
Antiprotozoários , Leishmaniose Cutânea , Compostos Organometálicos , Humanos , Antimoniato de Meglumina/uso terapêutico , Antimoniato de Meglumina/efeitos adversos , Antiprotozoários/efeitos adversos , Meglumina/efeitos adversos , Brasil , Resultado do Tratamento , Compostos Organometálicos/efeitos adversos , Leishmaniose Cutânea/tratamento farmacológicoRESUMO
INTRODUÇÃO: A amiloidose por transtirretina (TTR) é um distúrbio sistêmico caracterizado pela deposição extracelular de fibrilas amiloides e compostas por TTR, que é uma proteína de transporte plasmático de tiroxina e vitamina A produzida predominantemente pelo fígado. A polineuropatia amiloidótica familiar relacionada à transtirretina (PAF-TTR) é uma doença multissistêmica rara, progressiva, hereditária e altamente incapacitante. É um distúrbio autossômico dominante e até o momento mais de 100 mutações de TTR diferentes foram identificadas em todo o mundo, essas mutações desestabilizam a proteína TRR. PAF-TTR é uma doença multissintomática que pode apresentar neuropatia periférica (sensorial e motora), neuropatia autonômica, comprometimento gastrointestinal, cardiomiopatia, nefropatia ou deposição ocular. As manifestações clínicas da amiloidose sistêmica são determinadas principalmente pela proteína precursora e pelos órgãos envolvidos. No entanto, há considerável sobreposição clínica entre todos os tipos de amiloidose. Estimativas de preva
Assuntos
Humanos , Pré-Albumina/efeitos dos fármacos , Oligonucleotídeos Antissenso/uso terapêutico , Neuropatias Amiloides Familiares/tratamento farmacológico , Meglumina/antagonistas & inibidores , Sistema Único de Saúde , Brasil , Análise Custo-Benefício/economiaRESUMO
BACKGROUND: This cross-sectional study compared the general impact of cutaneous leishmaniasis (CL) and patient satisfaction with treatment and health services as perceived by those undergoing different therapeutic regimens in an endemic region in South-Eastern Brazil. We also investigated the factors associated with both outcomes (general impact and satisfaction). METHODS: We included 84 patients with CL treated between 2018 and 2019 with intravenous meglumine antimoniate, liposomal amphotericin B, or intralesional meglumine antimoniate therapy. Data were collected through interviews that assessed sociodemographic characteristics, comorbidity status, access and use of health services for CL diagnosis and treatment, and the items of the Cutaneous Leishmaniasis Impact Questionnaire (CLIQ). The CLIQ is a psychometric questionnaire previously validated to assess the general impact of CL on patient satisfaction with treatment and health services. Multivariate logistic regression analysis was used to identify the factors associated with high CL impact and low patient satisfaction. RESULTS: The general impact of CL and patient satisfaction with treatment and health services were not significantly associated with the therapeutic regimen. High CL impact was associated with low family income (odds ratio [OR]:3.3; 95% confidence interval [CI]:1.0-10.3), occurrence of complications/adverse effects during treatment (OR:7.7; 95%CI:2.4-25.6), and additional costs during diagnosis and/or treatment (OR:12.1; 95% CI:2.8-52.4). Low satisfaction was associated with high disease impact (OR: 9.5; 95% CI:2.7-33.9), occurrence of complications/adverse effects (OR:4.2; 95% CI:1.3-13.0), and high family income (OR:7.1; 95%CI:1.7-28.2). CONCLUSIONS: Our data support public health policies aimed at reducing the impact of CL and its treatment as well as the use of therapy with fewer adverse effects.
Assuntos
Antiprotozoários , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Leishmaniose Cutânea , Compostos Organometálicos , Humanos , Antimoniato de Meglumina , Antiprotozoários/efeitos adversos , Estudos Transversais , Satisfação do Paciente , Leishmaniose Cutânea/tratamento farmacológico , Classe Social , Compostos Organometálicos/efeitos adversos , MegluminaRESUMO
Dogs living in areas of Leishmania (Viannia) braziliensis transmission may present canine tegumentary leishmaniasis (CTL) characterized by cutaneous or muzzle ulcers as well as asymptomatic L. braziliensis infection. It is not clear if dogs participate in the transmission chain of L. braziliensis to humans. However, dogs may remain with chronic ulcers for a long time, and as there are no public policies about CTL, these animals die or are sacrificed. Here we compare the efficacy of intralesional meglumine antimoniate with intralesional 0.9% NaCl solution in CTL treatment. This randomized control study included 32 dogs with cutaneous or muzzle lesions who had L. braziliensis DNA detected by PCR in tissue biopsied. Group one received 5ml of intralesional Glucantime, and group two received 5ml 0.9% NaCl solution, both applied in the four cardinal points on days 0, 15, and 30. Cure was defined as complete healing of the ulcers in the absence of raised borders on day 90. There was no difference in animals' demographic and clinical features in the two groups (p >.05). While at the endpoint, the cure rate was 87.5% in the group test, and in those who received 0.9 NaCl the cure rate was only 12.5%. As important as the high cure rate, the healing time was faster in dogs treated with antimony than in those treated with saline (p < .001). Intralesional meglumine antimoniate is effective in the treatment of dogs with L. braziliensis infection and accelerates the healing time of CTL.
Assuntos
Antiprotozoários , Leishmania braziliensis , Leishmaniose Cutânea , Compostos Organometálicos , Humanos , Cães , Animais , Antimoniato de Meglumina/uso terapêutico , Antiprotozoários/uso terapêutico , Meglumina/uso terapêutico , Leishmaniose Cutânea/patologia , Solução Salina/uso terapêutico , Úlcera/tratamento farmacológico , Compostos Organometálicos/uso terapêuticoRESUMO
BACKGROUND: Systemic pentavalent antimonials, mainly meglumine antimoniate, continue to be the first-choice drugs for treatment of cutaneous leishmaniasis (CL) despite their toxicity, difficulty of administration and high cost. In the search for therapeutic alternatives, combining two treatment interventions has emerged as a potential alternative to either reduce the use of antimonials with the associated toxicities, or to increase efficacy. Here, we report the results of a recently completed trial assessing the efficacy and safety of a combination of thermotherapy (TT) plus a short course of miltefosine (MLT) for the treatment of uncomplicated CL in Colombia and Peru. METHODS: A multicenter, randomized, evaluator-blinded, phase II, controled clinical trial was conducted. Adult volunteers with a parasitologically confirmed diagnosis of uncomplicated CL were randomly allocated to receive either a single session of TT or a combination of TT plus a short course of MLT (3 weeks). Therapeutic response outcomes and safety were assessed. RESULTS: 130 subjects were included in the study, of whom 64 were randomly assigned to the TT arm and 66 to the TT + MLT arm. Cure at 3 months' follow-up was achieved in 57.8% (n = 37) and 80.3% (n = 53) in the TT and TT + MLT groups, respectively, in the intention to treat analysis. The TT + MLT regimen was better that TT alone (p = 0.0055). The presence of vesicles at the site of heat application was the most common adverse event reported associated with the use of TT; while vomiting (31.8%) and elevation of liver enzymes (28.8%) were the most frequent adverse events reported associated with the use of MLT. CONCLUSION: The combination of TT plus a short course of MLT was shown to be significantly better than TT alone for the treatment of uncomplicated CL in the New World. TRIAL REGISTRATION: Registered in clinicaltrials.gov NCT02687971.