RESUMO
Abstract Methotrexate is an effective medication to control several diseases; however, it can be very toxic, being myelosuppression one of its main adverse effects, which increases in severity and frequency in patients with renal failure. We present the case of a 68-year-old man with chronic, end-stage renal disease associated with ANCA vasculitis, under treatment with peritoneal dialysis, who received the medication at a low dose, indicated by disease activity, which presented as a complication with severe pancytopenia with mucositis that improved with support measures and multiple-exchange peritoneal dialysis. We reviewed 20 cases published to date of pancytopenia associated with methotrexate in patients on dialysis and found high morbidity and mortality, which is why its use in this type of patient is not recommended. However, when this complication occurs, a therapeutic option could be the use of multiple-exchange peritoneal dialysis in addition to supportive therapy for drug-related toxicity, although it is recognized that studies are required to show the role of multiple-exchange peritoneal dialysis in the removal of this medication.
Resumo Apesar de sua toxicidade, o metotrexato é um medicamento eficaz no controle de várias doenças. A mielossupressão, um de seus principais efeitos adversos, aumenta em gravidade e frequência nos pacientes com insuficiência renal. Apresentamos o caso de um homem de 68 anos de idade com doença renal terminal relacionada à vasculite associada ao ANCA em diálise peritoneal, que recebeu a medicação em dose baixa em função da atividade da doença e que teve como complicação pancitopenia grave com mucosite, tratada com medidas de suporte e diálise peritoneal com múltiplas trocas. Revisamos 20 casos publicados até o presente momento sobre pancitopenia associada a metotrexato em pacientes em diálise. Foi identificada alta morbidade e mortalidade, razão pela qual seu uso nesse tipo de paciente não é recomendado. No entanto, quando esta complicação ocorre, uma opção terapêutica pode ser o uso de diálise peritoneal com múltiplas trocas, além da terapia de suporte para toxicidade medicamentosa. Maiores estudos são necessários para demonstrar o papel da diálise peritoneal com múltiplas trocas na remoção desse medicamento.
Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Vasculite/tratamento farmacológico , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , Diálise Peritoneal/métodos , Antagonistas do Ácido Fólico/efeitos adversos , Antagonistas do Ácido Fólico/uso terapêutico , Falência Renal Crônica/terapia , Pancitopenia/etiologia , Pancitopenia/terapia , Choque Séptico/etiologia , Choque Séptico/tratamento farmacológico , Metotrexato/sangue , Resultado do Tratamento , Mucosite/etiologia , Mucosite/tratamento farmacológico , Antagonistas do Ácido Fólico/sangue , Antibacterianos/uso terapêuticoRESUMO
Leishmaniasis is one of the major neglected tropical diseases in the world and it is considered endemic in 88 countries. This disease is transmitted by a Leishmania spp. infected sandfly and it may lead to cutaneous or systemic manifestations. The preconized treatment has low efficacy and there are cases of resistance to some drugs. Therefore, the search for new efficient molecular targets that can lead to the preparation of new drugs must be pursued. This review aims to evaluate both Leishmania enzymes PTR1 and DHFR-TS as potential drug targets, highlight their inhibitors and to discuss critically the use of chemoinformatics to elucidate interactions and propose new molecules against these enzymes.
Assuntos
Antiprotozoários/farmacologia , Antagonistas do Ácido Fólico/farmacologia , Leishmania/efeitos dos fármacos , Leishmania/enzimologia , Complexos Multienzimáticos/antagonistas & inibidores , Oxirredutases/antagonistas & inibidores , Timidilato Sintase/antagonistas & inibidores , Animais , Antiprotozoários/química , Antiprotozoários/uso terapêutico , Descoberta de Drogas , Antagonistas do Ácido Fólico/química , Antagonistas do Ácido Fólico/uso terapêutico , Humanos , Leishmania/metabolismo , Leishmaniose/tratamento farmacológico , Leishmaniose/parasitologia , Terapia de Alvo Molecular , Complexos Multienzimáticos/metabolismo , Oxirredutases/metabolismo , Tetra-Hidrofolato Desidrogenase/metabolismo , Timidilato Sintase/metabolismoRESUMO
Methotrexate is an effective medication to control several diseases; however, it can be very toxic, being myelosuppression one of its main adverse effects, which increases in severity and frequency in patients with renal failure. We present the case of a 68-year-old man with chronic, end-stage renal disease associated with ANCA vasculitis, under treatment with peritoneal dialysis, who received the medication at a low dose, indicated by disease activity, which presented as a complication with severe pancytopenia with mucositis that improved with support measures and multiple-exchange peritoneal dialysis. We reviewed 20 cases published to date of pancytopenia associated with methotrexate in patients on dialysis and found high morbidity and mortality, which is why its use in this type of patient is not recommended. However, when this complication occurs, a therapeutic option could be the use of multiple-exchange peritoneal dialysis in addition to supportive therapy for drug-related toxicity, although it is recognized that studies are required to show the role of multiple-exchange peritoneal dialysis in the removal of this medication.
Assuntos
Antagonistas do Ácido Fólico/efeitos adversos , Antagonistas do Ácido Fólico/uso terapêutico , Falência Renal Crônica/terapia , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , Diálise Peritoneal/métodos , Vasculite/tratamento farmacológico , Adulto , Idoso , Antibacterianos/uso terapêutico , Feminino , Antagonistas do Ácido Fólico/sangue , Humanos , Masculino , Metotrexato/sangue , Pessoa de Meia-Idade , Mucosite/tratamento farmacológico , Mucosite/etiologia , Pancitopenia/etiologia , Pancitopenia/terapia , Choque Séptico/tratamento farmacológico , Choque Séptico/etiologia , Resultado do TratamentoRESUMO
Spinal cord injury (SCI) is a condition producing irreversible damage to the neurological function. Among the leading mechanisms associated to cell death after SCI, excitotoxicity, oxidative stress, inflammatory response and apoptosis are considered potential targets to prevent tissue damage. We recently reported that dapsone an anti-inflammatory drug, decreases the activity of myeloperoxidase, lipid peroxidation, improve neurological function and increase the amount of spared tissue after SCI in rats. In this study, we characterized the anti-apoptotic effect of dapsone administered at 12.5 mg/kg/24 h dose, starting at 3 and 5 h after SCI. We monitored the activity of caspases-8, 9, and 3 and quantitated Annexin V and TUNEL positive cells in the core of the lesion. Results showed increased activities of caspase-8, 9 and 3 at 72 h by SCI to reach increments of 69, 143 and 293 %, respectively, as compared to sham group. Meanwhile, dapsone, administered at 3 and 5 after SCI, reduced caspase-8 activity by 36 and 44 % respectively, whereas the activity of caspase-9 was diminished by 37 %. Likewise, the activity of caspase-3 showed a decrease of 38 %. Finally, both Annexin V and TUNEL-positive cells were significantly reduced by DDS as compared to untreated SCI animals. Results showed that dapsone exerted anti-apoptotic effect after SCI.
Assuntos
Apoptose/efeitos dos fármacos , Dapsona/farmacologia , Dapsona/uso terapêutico , Antagonistas do Ácido Fólico/farmacologia , Antagonistas do Ácido Fólico/uso terapêutico , Traumatismos da Medula Espinal/tratamento farmacológico , Traumatismos da Medula Espinal/patologia , Animais , Caspases/metabolismo , Feminino , Marcação In Situ das Extremidades Cortadas , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Recuperação de Função Fisiológica/efeitos dos fármacos , Traumatismos da Medula Espinal/enzimologiaRESUMO
PURPOSE: To investigate ocular involvement (prevalence, incidence, lesion characteristics) following postnatally acquired infection with an "atypical" genotype of Toxoplasma gondii during a well-characterized 2001 outbreak in Santa Isabel do Ivaí, Brazil, attributed to a contaminated municipal reservoir. DESIGN: Prospective longitudinal cohort study. METHODS: We performed ophthalmic examinations on 290 of 454 individuals with serologic evidence of T gondii infection during the epidemic (positive IgM antibody tests). Prevalence of ophthalmic findings (intraocular inflammatory reactions [including transient, isolated retinal whitening without clinically apparent retinal necrosis] and necrotizing retinochoroiditis) at initial examination (baseline) and incidence of new findings during 10.5 months of follow-up were calculated. Cumulative risks of ophthalmic events were determined (Kaplan-Meier technique). RESULTS: Ocular involvement was present in 33 of 288 IgM+ individuals (11.5%) at baseline, including 17 with focal retinal whitening only and 13 with necrotizing retinochoroiditis. Incidence of new ocular involvement was estimated to be 1.73 events per 100 person-months (PM); cumulative risk at 10.5 months was 30.1%. Incident necrotizing retinochoroiditis was more common among those with focal retinal whitening at baseline (6.7/100 PM) than among those with no ocular involvement at baseline (1.11/100 PM; hazard ratio 6.07 [1.94-19.01]; P < .0001). CONCLUSIONS: Waterborne infection with an atypical genotype of T gondii is associated with substantial risk of ocular involvement. Lesions may continue to develop during the first year after infection. The increased risk of late necrotizing retinochoroiditis associated with isolated focal retinal whitening at presentation suggests the early presence of parasites in the retina, despite initial lack of observable retinal necrosis.
Assuntos
Coriorretinite/epidemiologia , Surtos de Doenças , Toxoplasma/isolamento & purificação , Toxoplasmose Ocular/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antiprotozoários/sangue , Antiprotozoários/uso terapêutico , Brasil/epidemiologia , Criança , Pré-Escolar , Coriorretinite/diagnóstico , Coriorretinite/tratamento farmacológico , Coriorretinite/parasitologia , Estudos de Coortes , Doenças Endêmicas , Ensaio de Imunoadsorção Enzimática , Feminino , Antagonistas do Ácido Fólico/uso terapêutico , Humanos , Imunoglobulina M/sangue , Incidência , Lactente , Recém-Nascido , Leucovorina/uso terapêutico , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Pirimetamina/uso terapêutico , Estudos Soroepidemiológicos , Sulfadiazina/uso terapêutico , Toxoplasma/imunologia , Toxoplasmose Ocular/diagnóstico , Toxoplasmose Ocular/tratamento farmacológico , Toxoplasmose Ocular/parasitologia , Água/parasitologia , Abastecimento de ÁguaRESUMO
Researches on DH have shown that it is not just a bullous skin disease, but a cutaneous-intestinal disorder caused by hypersensitivity to gluten. Exposure to gluten is the starting point of an inflammatory cascade capable of forming autoantibodies that are brought to the skin, where they are deposited, culminating in the formation of skin lesions. These lesions are vesico-bullous, pruritic, and localized especially on elbows, knees and buttocks, although atypical presentations can occur. Immunofluorescence of perilesional area is considered the gold standard for diagnosis, but serological tests help in cases where it is negative. Patients who follow glutenfree diets have better control of symptoms on the skin and intestine, as well as lower risks of progression to lymphoma. Dapsone remains the main drug for treatment, but it requires monitoring of possible side effects, some potentially lethal.
Assuntos
Feminino , Humanos , Masculino , Dermatite Herpetiforme/patologia , Dermatite Herpetiforme/terapia , Doença Celíaca/etiologia , Doença Celíaca/patologia , Doença Celíaca/terapia , Dieta Livre de Glúten , Dapsona/uso terapêutico , Dermatite Herpetiforme/etiologia , Técnica Direta de Fluorescência para Anticorpo , Antagonistas do Ácido Fólico/uso terapêutico , Pele/patologiaRESUMO
Researches on DH have shown that it is not just a bullous skin disease, but a cutaneous-intestinal disorder caused by hypersensitivity to gluten. Exposure to gluten is the starting point of an inflammatory cascade capable of forming autoantibodies that are brought to the skin, where they are deposited, culminating in the formation of skin lesions. These lesions are vesico-bullous, pruritic, and localized especially on elbows, knees and buttocks, although atypical presentations can occur. Immunofluorescence of perilesional area is considered the gold standard for diagnosis, but serological tests help in cases where it is negative. Patients who follow gluten-free diets have better control of symptoms on the skin and intestine, as well as lower risks of progression to lymphoma. Dapsone remains the main drug for treatment, but it requires monitoring of possible side effects, some potentially lethal.
Assuntos
Dermatite Herpetiforme/patologia , Dermatite Herpetiforme/terapia , Doença Celíaca/etiologia , Doença Celíaca/patologia , Doença Celíaca/terapia , Dapsona/uso terapêutico , Dermatite Herpetiforme/etiologia , Dieta Livre de Glúten , Feminino , Técnica Direta de Fluorescência para Anticorpo , Antagonistas do Ácido Fólico/uso terapêutico , Humanos , Masculino , Pele/patologiaRESUMO
Aggressive T-cell lymphomas represent a particularly poor-prognosis subgroup of lymphomas. This is especially true for patients with recurrent or refractory disease who typically have a limited response to salvage therapy and an extremely poor overall survival. There is thus a strong need to develop potentially active drugs for these malignancies. Pralatrexate is a novel antifolate designed to have high affinity for the reduced folate carrier type 1. Preclinical and clinical studies have demonstrated that pralatrexate has significant activity against T-cell lymphomas.The dose-limiting toxicity for pralatrexate is mucositis,which could be abrogated with folic acid and vitamin B12 supplementation. Pralatrexate is now being evaluated in phase II clinical trials for the treatment of peripheral T-cell lymphoma, and in a phase I/II trial in combination with gemcitabine for the treatment of non-Hodgkin's lymphoma. Because of the limited therapies available for aggressive T-cell lymphoma, pralatrexate could secure a niche for the treatment of this condition, provided on going clinical trials and future phase III trials confirm the efficacy of the drug.
Assuntos
Aminopterina/análogos & derivados , Antineoplásicos/uso terapêutico , Antagonistas do Ácido Fólico/uso terapêutico , Linfoma de Células T/tratamento farmacológico , Aminopterina/uso terapêutico , Animais , Ensaios Clínicos como Assunto , HumanosRESUMO
OBJECTIVE: To investigate the clinical efficacy, safety, tolerability, and toxicity profile of a metabolically stable antifolate, CH-1504, compared to methotrexate (MTX) in the treatment of rheumatoid arthritis (RA). METHODS: A 24-week open-label trial of MTX and CH-1504 was performed in 20 patients with RA. RESULTS: Improvements in clinical and laboratory indicators were observed in both study groups. Improvement in the CH-1504 group was greater than in the MTX group. Both treatments were generally well tolerated; however, the liver function test abnormalities and gastrointestinal related adverse events expected with this class of medication were not seen with CH-1504. CONCLUSION: CH-1504 appears to be clinically efficacious and may possess a superior safety and tolerance profile compared to MTX.
Assuntos
Aminopterina/análogos & derivados , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Antagonistas do Ácido Fólico/uso terapêutico , Metotrexato/uso terapêutico , Adulto , Idoso , Aminopterina/efeitos adversos , Aminopterina/farmacologia , Aminopterina/uso terapêutico , Antirreumáticos/efeitos adversos , Antirreumáticos/farmacologia , Artrite Reumatoide/fisiopatologia , Feminino , Antagonistas do Ácido Fólico/efeitos adversos , Antagonistas do Ácido Fólico/farmacologia , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/fisiopatologia , Humanos , Fígado/efeitos dos fármacos , Fígado/fisiopatologia , Testes de Função Hepática , Masculino , Metotrexato/efeitos adversos , Metotrexato/farmacologia , Pessoa de Meia-IdadeRESUMO
Antimalarial drugs including the antifolate, pyrimethamine-sulfadoxine (PS), can modulate the prevalence and intensities of gametocytaemia following treatment of acute malaria infections. They may also directly influence the transmission and spread of drug insensitivity. Little is known of the effects of co-trimoxazole (Co-T), another antifolate antimalarial, on gametocytes in children with acute malaria infections. We compared the effects of Co-T and PS on the prevalence and intensities of gametocytaemia and gametocyte sex ratios in 102 children aged 0.5-12 years presenting with acute and uncomplicated falciparum malaria. Compared to pre-treatment, both drugs significantly increased gametocyte carriage post-initiation of treatment. However, gametocyte carriage was significantly lower on day 14 in those treated with Co-T than PS. Significant increase in gametocytaemia with time occurred in PS--but not Co-T-treated children. Kaplan-Meier survival curve of the cumulative probability of remaining gametocyte-free in children who were agametocytaemic at enrollment showed that by day 7 of follow up, children treated with PS had a significantly higher propensity to have developed gametocytes than in Co-T-treated children (Log-rank statistic 5.35, df = 1, P = 0.02). Gametocyte sex ratio changes were similar following treatment with both drugs. PS and Co-T treatment of acute malaria infections in children from this endemic area is associated with significant increases in prevalence and intensities of gametocytaemia but these effects are more marked in those treated with PS than Co-T.