RESUMO
The aim of this study was to describe a case of a patient with ocular toxoplasmosis, which has resulted in Kyrieleis plaques formation (segmental periarteritis associated with severe inflammation) and later follow-up and alternative treatment due to documented allergy to sulfonamide. A 33-year-old Brazilian woman diagnosed with acute toxoplasmosis, initially treated with sulfonamide, developed a critical cutaneous rash. Cotrimoxazole was changed to clindamycin and pyrimethamine, and prednisone was started. The medication was maintained for 45 days. Four months later, she developed retinal lesions suggestive of toxoplasmosis with Kyrieleis plaques in the upper temporal vessels. Pyrimethamine, clindamycin, and prednisone were initiated until healing. She presented reactivation months later, and a suppressive treatment with pyrimethamine was instituted for one year. This is the first report to use the combination of clindamycin with pyrimethamine in the treatment and recurrence prophylaxis for OT in a documented allergy to sulfonamide.
Assuntos
Clindamicina , Pirimetamina , Sulfonamidas , Toxoplasmose Ocular , Humanos , Feminino , Adulto , Pirimetamina/uso terapêutico , Pirimetamina/efeitos adversos , Toxoplasmose Ocular/tratamento farmacológico , Sulfonamidas/uso terapêutico , Sulfonamidas/efeitos adversos , Clindamicina/uso terapêutico , Recidiva , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Combinação Trimetoprima e Sulfametoxazol/efeitos adversos , Hipersensibilidade a Drogas/etiologia , Brasil , Antiprotozoários/uso terapêutico , Antiprotozoários/efeitos adversos , Resultado do Tratamento , Prednisona/uso terapêuticoRESUMO
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
There are little data on pentamidine as a treatment for paediatric cutaneous leishmaniasis (CL). The objective of this study was to describe the effectiveness and safety of pentamidine over a 10-year period. Every child seen in French Guiana between 2010 and 2020 with proven CL and treated with pentamidine was included. In total, 55 children met the inclusion criteria - 23 girls and 32 boys. There were 38 patients (38/55, 69%) with a > 50% improvement at 1â month after pentamidine treatment and a complete cure at 3â months; 16 children had a < 50% improvement at 1â month and were given a second dose. Of these 16, 8 showed a complete cure at 3â months, 5 were lost to follow-up and 3 showed therapeutic failure at 3â months. The overall cure rate was 84% (46/55) after one or two doses. In terms of the safety of pentamidine, no severe adverse events (grade ≥ 3) were reported.
Assuntos
Antiprotozoários , Leishmaniose Cutânea , Masculino , Feminino , Humanos , Criança , Pentamidina/efeitos adversos , Antiprotozoários/efeitos adversos , Guiana Francesa/epidemiologia , Leishmaniose Cutânea/tratamento farmacológico , Injeções IntramuscularesRESUMO
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
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.
Assuntos
Antiprotozoários , Hipertermia Induzida , Leishmaniose Cutânea , Compostos Organometálicos , Adulto , Antiprotozoários/efeitos adversos , Humanos , Hipertermia Induzida/efeitos adversos , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Cutânea/etiologia , Meglumina/uso terapêutico , Antimoniato de Meglumina/uso terapêutico , Compostos Organometálicos/uso terapêutico , Fosforilcolina/análogos & derivados , Resultado do TratamentoAssuntos
Antiprotozoários , Leishmaniose Cutânea , Leishmaniose Mucocutânea , Leishmaniose Visceral , Antiprotozoários/efeitos adversos , Cardiotoxicidade/tratamento farmacológico , Humanos , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Visceral/tratamento farmacológico , Fosforilcolina/efeitos adversos , Fosforilcolina/análogos & derivados , Estados UnidosRESUMO
Abstract Post-kala-azar dermal leishmaniasis is a skin disorder occurring in 5-10% of visceral leishmaniasis patients after treatment with miltefosine,the first-line drug for this skin disorder. We reported a case of acute anterior uveitis,a rare adverse effect, experienced by a patient treated with miltefosine for post-kala-azar dermal leishmaniasis. This adverse effect developed after 15 days of miltefosine consumption, and the patient himself discontinued the treatment. The ophthalmic complication was completely resolved with antibiotics and steroid eye drops. After recovery from the ophthalmic complication, the patient was successfully treated with liposomal amphotericin B for the skin lesions.
Assuntos
Humanos , Uveíte/induzido quimicamente , Uveíte/tratamento farmacológico , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Visceral/complicações , Leishmaniose Visceral/tratamento farmacológico , Antiprotozoários/efeitos adversos , Fosforilcolina/análogos & derivadosRESUMO
Post-kala-azar dermal leishmaniasis is a skin disorder occurring in 5-10% of visceral leishmaniasis patients after treatment with miltefosine,the first-line drug for this skin disorder. We reported a case of acute anterior uveitis,a rare adverse effect, experienced by a patient treated with miltefosine for post-kala-azar dermal leishmaniasis. This adverse effect developed after 15 days of miltefosine consumption, and the patient himself discontinued the treatment. The ophthalmic complication was completely resolved with antibiotics and steroid eye drops. After recovery from the ophthalmic complication, the patient was successfully treated with liposomal amphotericin B for the skin lesions.
Assuntos
Antiprotozoários , Leishmaniose Cutânea , Leishmaniose Visceral , Uveíte , Antiprotozoários/efeitos adversos , Humanos , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Visceral/complicações , Leishmaniose Visceral/tratamento farmacológico , Fosforilcolina/análogos & derivados , Uveíte/induzido quimicamente , Uveíte/tratamento farmacológicoRESUMO
INTRODUCTION: Leishmaniasis is a neglected tropical disease caused by protozoa of the genus Leishmania. Worldwide, approximately 1.5-2 million new cases of leishmaniasis and 20,000-30,000 deaths occurs each year. Effective treatment for all forms of leishmaniasis have numerous adverse effects contributing to poor adherence and/or treatment interruption by the patient. Development of novel therapies, as multitarget drugs, for example, can contribute to accelerate discover safer, more active, and patient-compliant drugs for leishmaniasis treatment. AREAS COVERED: In this review, authors summarize pharmaceutical agents for treatment of leishmaniasis developed between 2014 and 2019, which includes synthetic and natural drugs for specific treatments, as well as considering new approaches and strategies using drug delivery system. EXPERT OPINION: Universities or public research institutes produced most of the patents related to pharmaceutical agents for treatment of leishmaniasis in this review, and the majority of the inventions disclosed did not conduct clinical trials. In other words, there is still a lot of investment to be done for the identification of new drugs.
Assuntos
Antiprotozoários/administração & dosagem , Desenvolvimento de Medicamentos , Leishmaniose/tratamento farmacológico , Animais , Antiprotozoários/efeitos adversos , Antiprotozoários/farmacologia , Sistemas de Liberação de Medicamentos , Humanos , Leishmaniose/parasitologia , Adesão à Medicação , Patentes como AssuntoRESUMO
Objectives: Cutaneous leishmaniasis is a neglected disease, associated with high morbidity, which is partially due to the toxicity of available therapies. The pentavalent antimonial derivatives intralesional infiltration has proven to be as effective as the intravenous drug-based therapy, however, there is a lack of robust safety data.Methods: Phase II, uncontrolled, unicenter clinical trial to assess the safety profile of a standardized meglumine antimionate intralesional therapy, based on weekly infiltrations.Results: Fifty-three patients were studied, predominantly men (60%) and young adults (43.7 ± 17.1 years). Overall, 86.9% of the patients had at least one clinical adverse event. Local events were the most frequent (83%), followed by systemic ones (47.3%). Fourteen participants (26%) presented biochemical abnormalities. In all cases, laboratorial alterations were classified as mild and treatment discontinuation was not required. Differently, the two hypersensitivity (3.8%) reactions observed led to permanent treatment interruption. QTc interval prolongation was recorded in 14 patients (25.5%). The following risk associations to adverse events were identified in the multiple analysis: hypertension with systemic clinical events and smoking with QT interval prolongation.Expert commentary: In general, MA-IL was well tolerated and although associated with local and systemic adverse events, there was a low risk of high intensity or severe complications.
Assuntos
Antiprotozoários/administração & dosagem , Leishmaniose Cutânea/tratamento farmacológico , Antimoniato de Meglumina/administração & dosagem , Adulto , Antiprotozoários/efeitos adversos , Hipersensibilidade a Drogas/etiologia , Feminino , Humanos , Injeções Intralesionais , Masculino , Antimoniato de Meglumina/efeitos adversos , Pessoa de Meia-Idade , RiscoRESUMO
Cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL) are endemic diseases in America, especially in some countries such as Colombia. Among the therapeutic options is amphotericin B (AB). Nevertheless, its lipid-associated formulations have better safety profiles and effectiveness in other diseases, so far with no comparative studies in CL or MCL. We conducted a retrospective descriptive study describing the effectiveness and adverse effects of AB deoxycholate (ABD), AB colloidal dispersion (ABCD), and liposomal AB (LAB) as third-line treatments for CL and MCL. The effectiveness of LAB (88.5%) was greater than those of ABCD (66.6%) and ABD (80.8%). There were also fewer adverse effects in the LAB group (46.2%) than in the ABD (96.1%) and ABCD (80.9%) groups. LAB is an alternative for the treatment of CL and MCL in patients with therapeutic failure to first- and second-line drugs; findings suggest it might be less toxic and more effective than ABD and ABCD.
Assuntos
Anfotericina B/efeitos adversos , Anfotericina B/uso terapêutico , Ácido Desoxicólico/uso terapêutico , Leishmaniose Cutânea/tratamento farmacológico , Leishmaniose Mucocutânea/tratamento farmacológico , Antiprotozoários/efeitos adversos , Antiprotozoários/uso terapêutico , Coloides , Colômbia/epidemiologia , Ácido Desoxicólico/efeitos adversos , Combinação de Medicamentos , Humanos , Leishmaniose Cutânea/epidemiologia , Leishmaniose Mucocutânea/epidemiologia , Estudos RetrospectivosRESUMO
Pentavalent antimonials are the first-line drug treatment for American tegumentary leishmaniasis. We report on a patient with chronic renal failure on hemodialysis who presented with cutaneous lesions of leishmaniasis for four months. The patient was treated with intravenous meglumine under strict nephrological surveillance, but cardiotoxicity, acute pancreatitis, pancytopenia, and cardiogenic shock developed rapidly. Deficient renal clearance of meglumine antimoniate can result in severe toxicity, as observed in this case. These side effects are related to cumulative plasma levels of the drug. Therefore, second-line drugs like amphotericin B are a better choice for patients on dialysis.
Assuntos
Antiprotozoários/efeitos adversos , Leishmaniose Cutânea/complicações , Leishmaniose Cutânea/tratamento farmacológico , Antimoniato de Meglumina/efeitos adversos , Insuficiência Renal Crônica/complicações , Adulto , Anfotericina B/uso terapêutico , Antiprotozoários/uso terapêutico , Brasil , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Leishmaniose Cutânea/patologia , Masculino , Diálise RenalRESUMO
BACKGROUND: Liposomal amphotericin B (L-AMB) has been used for mucosal leishmaniasis (ML), but comparative studies on L-AMB and other drugs used for the treatment of ML have not been conducted. The present study aimed to evaluate the outcome of patients with ML who were treated with L-AMB. METHODS: This is a 15-year retrospective study of Brazilian patients with a confirmed diagnosis of ML. The therapeutic options for the treatment of ML consisted of L-AMB, amphotericin B lipid complex (ABLC), deoxycholate amphotericin B (d-AMB), itraconazole, antimonial pentavalent, or pentamidine. Healing, cure rate and adverse effects (AEs) associated with the drugs used to treat this condition were analyzed. RESULTS: In 71 patients, a total of 105 treatments were evaluated. The outcome of the treatment with each drug was compared, and results showed that L-AMB was superior to other therapeutic regimens (P = 0.001; odds ratio [OR] = 4.84; 95% confidence interval [CI] = 1.78-13.17). d-AMB had worse AEs than other treatment regimens (P = 0.001, OR = 0.09; 95% CI = 0.09-0.43). Approximately 66% of the patients presented with AEs during ML treatment. Although L-AMB was less nephrotoxic than d-AMB, it was associated with acute kidney injury compared with other drugs (P <0.05). CONCLUSION: L-AMB was more effective than other therapies for the treatment of ML. However, a high incidence of toxicity was associated with its use. Therapeutic choices should be reassessed, and the development of new drugs is necessary for the treatment of ML.
Assuntos
Anfotericina B/uso terapêutico , Antiprotozoários/uso terapêutico , Leishmania braziliensis , Leishmaniose Mucocutânea/tratamento farmacológico , Injúria Renal Aguda/induzido quimicamente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anfotericina B/efeitos adversos , Antimônio/efeitos adversos , Antimônio/uso terapêutico , Antiprotozoários/efeitos adversos , Brasil , Estudos de Coortes , Ácido Desoxicólico/efeitos adversos , Ácido Desoxicólico/uso terapêutico , Combinação de Medicamentos , Feminino , Humanos , Itraconazol/efeitos adversos , Itraconazol/uso terapêutico , Lipossomos , Masculino , Pessoa de Meia-Idade , Pentamidina/efeitos adversos , Pentamidina/uso terapêutico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Ocular toxoplasmosis (OT) is the most common cause of posterior uveitis, leading to visual impairment in a high proportion of patients. Antibiotics and corticosteroids lower the risk of permanent visual impairment by reducing the size of the retinochoroidal scar, the risk of recurrence, and the severity and duration of acute symptoms. Although OT is a very common cause of infectious posterior uveitis, its treatment remains controversial. Through our systematic review and meta-analysis, we aim to provide the best possible evidence-based information on the safety and effectiveness of the different antibiotic regimes for OT. METHODS: This systematic review protocol has been developed based on PRISMA-P guidelines for reporting systematic reviews evaluating health care interventions. We will include all published and unpublished randomized controlled trials (RCTs) comparing different antibiotics used for the treatment of OT. We will consider changes in visual acuity, number of recurrences, improvement or worsening of ocular inflammation, size of lesion, and adverse effects as our outcomes. Screening, data extraction, and quality assessment will be undertaken by two reviewers with disagreements resolved through discussion. Studies that compared antibiotics with placebo will be excluded. The reviews will be assessed for quality and relevance. We will assess the risk of bias in five domains according to Cochrane group's tool. The type of data will dictate measures of treatment effect. We will use a random-effects model to calculate our meta-analysis, as eligible studies represent clinically varied populations of participants. DISCUSSION: The strength of our study will lie in the exhaustive and systematic nature of the literature search, as well as in its methods for assessing quality and analyzing RCT data. Considering the controversial efficacy of the treatment for OT, our study will contribute to improving the existing evidence on the effectiveness of different antibiotics. Future studies may be conducted to increase physicians' awareness of antibiotic therapies, improving the health of patients with OT. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018085468.
Assuntos
Antibacterianos , Antiprotozoários , Toxoplasmose Ocular , Humanos , Antibacterianos/efeitos adversos , Antibacterianos/uso terapêutico , Antiprotozoários/efeitos adversos , Antiprotozoários/uso terapêutico , Toxoplasma/efeitos dos fármacos , Toxoplasmose Ocular/tratamento farmacológico , Resultado do Tratamento , Metanálise como Assunto , Revisões Sistemáticas como AssuntoRESUMO
Abstract: Pentavalent antimonials are the first-line drug treatment for American tegumentary leishmaniasis. We report on a patient with chronic renal failure on hemodialysis who presented with cutaneous lesions of leishmaniasis for four months. The patient was treated with intravenous meglumine under strict nephrological surveillance, but cardiotoxicity, acute pancreatitis, pancytopenia, and cardiogenic shock developed rapidly. Deficient renal clearance of meglumine antimoniate can result in severe toxicity, as observed in this case. These side effects are related to cumulative plasma levels of the drug. Therefore, second-line drugs like amphotericin B are a better choice for patients on dialysis.
Assuntos
Humanos , Masculino , Adulto , Leishmaniose Cutânea/complicações , Leishmaniose Cutânea/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Antimoniato de Meglumina/efeitos adversos , Antiprotozoários/efeitos adversos , Brasil , Anfotericina B/uso terapêutico , Diálise Renal , Leishmaniose Cutânea/patologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Antiprotozoários/uso terapêuticoRESUMO
Cutaneous leishmaniasis (CL) is not a life-threatening condition. However, its treatment can cause serious adverse effects and may sometimes lead to death. Recently, safer local treatments have been included among therapies acceptable to New World CL cases, but the use of intralesional meglumine antimoniate (IL-MA) is recommended to be performed in reference centers, for patients with single cutaneous lesions <3 cm in diameter at any location except the head and periarticular regions; the volume of injected MA should not exceed 5 mL. In this study we compared two groups of patients with CL treated with MA in a primary health care unit in Brazil. Patients were treated with systemic MA (n = 76) or IL-MA (n = 30). In the IL-MA group, 93% of patients had one or more of the following lesion characteristics: two or more lesions, lesions >3 cm in diameter, lesions located in the head or in periarticular regions, or had been administered IL-MA volumes >5 mL. Patients responded well (68.4% and 66.7% for the MA and IL-MA groups, respectively). When a second cycle of treatment was necessary, the responses were 72.4% and 90%, respectively. There were no significant differences between groups. In the IL-MA group, 43% had mild to moderate adverse effects, without needing treatment discontinuation. Results suggest that the treatment of CL lesions with IL-MA is simple, efficient, and safe.
Assuntos
Antiprotozoários/administração & dosagem , Leishmaniose Cutânea/tratamento farmacológico , Antimoniato de Meglumina/administração & dosagem , Atenção Primária à Saúde , Adolescente , Adulto , Instituições de Assistência Ambulatorial , Antiprotozoários/efeitos adversos , Brasil , Feminino , Humanos , Injeções Intralesionais , Injeções Intramusculares , Injeções Intravenosas , Masculino , Antimoniato de Meglumina/efeitos adversos , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto JovemRESUMO
The aim of this study was to evaluate in vitro the efficacy of cordycepin and pentostatin (alone or combined) against Trypanosoma cruzi, as well as the therapeutic efficiency of protocols of cordycepin and pentostatin combinations in mice experimentally infected with T. cruzi. In vitro, the cordycepin (3'-deoxyadenosine) and pentostatin (deoxycoformycin) exerted potent trypanocidal effect against T. cruzi (Colombian strain), similarly to benznidazole, which is the reference drug. For epimastigotes, the lethal dose of cordycepin capable of killing 50% (LD50) and 20% (LD20) of the parasites was 0.072 and 0.031â¯mg/mL, respectively and for trypomastigotes was 0.047 and 0.015â¯mg/mL, respectively. The combined use of cordycepin and pentostatin resulted in a LD50 and LD20 for epimastigotes of 0.068 and 0.027â¯mg/mL, respectively, as well as 0.056 and 0.018â¯mg/mL for trypomastigotes, respectively. In vivo, the combined use of cordycepin and pentostatin did not show the expected curative effect, however it was able to control the parasitema in the peak period. In summary, the combination of cordycepin and pentostatin showed no curative effect in mice infected by T. cruzi, despite the in vitro reduction of epimastigotes and trypomastigotes.
Assuntos
Antiprotozoários/farmacologia , Doença de Chagas/tratamento farmacológico , Desoxiadenosinas/farmacologia , Pentostatina/farmacologia , Trypanosoma cruzi/efeitos dos fármacos , Análise de Variância , Animais , Antiprotozoários/efeitos adversos , Antiprotozoários/uso terapêutico , Doença de Chagas/parasitologia , Desoxiadenosinas/uso terapêutico , Relação Dose-Resposta a Droga , Quimioterapia Combinada , Feminino , Coração/efeitos dos fármacos , Dose Letal Mediana , Camundongos , Miocárdio/patologia , Doenças Negligenciadas/tratamento farmacológico , Doenças Negligenciadas/parasitologia , Nifurtimox/efeitos adversos , Nifurtimox/uso terapêutico , Nitroimidazóis/efeitos adversos , Nitroimidazóis/uso terapêutico , Dinâmica não Linear , Parasitemia/prevenção & controle , Pentostatina/uso terapêutico , Distribuição Aleatória , Análise de RegressãoRESUMO
OBJECTIVES: Meglumine antimoniate (MA; Glucantime®), the 80-year-old first-line systemic treatment for all forms of American tegumentary leishmaniasis (ATL) caused by Leishmania (Viannia) braziliensis, Leishmania (Viannia) guyanensis and Leishmania (Leishmania) amazonensis, is highly toxic, presents adverse side-effects and may not attain clinical and parasitological cure. This critical review examines the necessity for intramuscular/intravenous administration of MA, the alternatives to this approach, and the possibilities of developing affordable, accessible and non-toxic drugs or new delivery methods. METHOD: PubMed searches were performed using the terms 'cutaneous leishmaniasis' or 'American tegumentary leishmaniasis' in combination with 'meglumine antimoniate' or 'N-methyl glucamine' or 'drug repositioning' or 'nanotechnology'. Searches covered a period of 20 years of peer reviewed journals and technical bulletins. We explored the mode of action, pharmacokinetics, toxicity and efficacy of MA, evaluated the progress of ATL therapy in Brazil, and examined the potential of drug repositioning and nanotechnology in accelerating the introduction and/or optimisation of an alternative treatment. RESULTS: The evidence suggests that ATL therapy will continue to rely on systemic MA in the foreseeable future even though an intralesional subcutaneous route has evolved over the last 10 years. The chances of developing a novel drug for ATL or a new mode of delivery of MA are low. While MA nanocarriers afford a promising approach, this technology is still in its infancy. A more immediate solution would be the production of a bioequivalent of miltefosine, an efficacious oral agent no longer protected by patent. CONCLUSION: Development of a contemporary treatment requires governmental commitment in bringing together private and public sectors.
OBJECTIFS: L'antimoniate de méglumine (AM; Glucantime®), le traitement systémique de première intention vieux de 80 ans pour toutes les formes de la leishmaniose tégumentaire américaine (LTA) causée par Leishmania (Viannia) braziliensis, L. (V.) guyanensis et L. (Leishmania) amazonensis, est hautement toxique, présente des effets secondaires indésirables et peut ne pas aboutir à une guérison clinique et parasitologique. Cette analyse critique examine la nécessité d'une administration intramusculaire/intraveineuse d'AM, les alternatives à cette approche et les possibilités de développement de médicaments abordables, accessibles et non toxiques ou de nouvelles méthodes d'administration. MÉTHODE: Des recherches sur PubMed ont été effectuées en utilisant les termes «leishmaniose cutanée¼ ou «leishmaniose tégumentaire américaine¼ en combinaison avec «antimoniate de méglumine ¼ ou «N-méthyl glucamine¼ ou «repositionnement de médicament¼ ou «nanotechnologie¼. Les recherches ont porté sur une période de 20 ans d'articles revue par des pairs et de bulletins techniques. Nous avons exploré le mode d'action, la pharmacocinétique, la toxicité et l'efficacité de l'AM, évalué les progrès du traitement de la LTA au Brésil et examiné le potentiel du repositionnement de médicaments et de la nanotechnologie pour accélérer l'introduction et/ou l'optimisation d'un traitement alternatif. RÉSULTATS: Les données suggèrent que le traitement de la LTA continuera à s'appuyer sur l'AM systémique dans un avenir proche, même si une voie sous-cutanée intralésionnelle a évolué au cours des 10 dernières années. Les chances de développer un nouveau médicament pour la LTA ou un nouveau mode d'administration d'AM sont faibles. Alors que les nanocarriers d'AM offrent une approche prometteuse, cette technologie en est encore à ses balbutiements. Une solution plus immédiate consisterait à produire un bioéquivalent de miltéfosine, un agent oral efficace, qui n'est plus protégé par un brevet. CONCLUSION: Le développement d'un traitement contemporain nécessite un engagement gouvernemental pour réunir les secteurs privés et publiques.