Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.095
Filtrar
1.
J. bras. nefrol ; 41(3): 427-432, July-Sept. 2019. tab
Artigo em Inglês | LILACS | ID: biblio-1040255

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 terapêutico
2.
Postgrad Med ; 131(8): 589-596, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31399001

RESUMO

No new drugs for treatment of toxoplasmosis have been approved in over 60 years, despite the burden of toxoplasmosis on human society. The small selection of effective drugs is limited by important side effects, often limiting patient use. This perspective highlights promising late-stage drug candidates in the treatment of toxoplasmosis. Presently, drugs target the tachyzoite form of the parasite Toxoplasma gondii responsible for the acute infection but do not eradicate the tissue cyst form underlying chronic infection. Pyrimethamine - the first-line and only approved drug for treatment of toxoplasmosis in the United States - inhibits parasite DNA synthesis by inhibiting dihydrofolate reductase (DHFR). Two novel DHFR inhibitors with improved potency and selectivity for parasite DHFR over human DHFR are in clinical-stage development. One of the most advanced and promising therapeutic targets, demonstrating potential to treat both acute and chronic toxoplasmosis, is the calcium-dependent protein kinase 1 (CDPK1) which plays an essential role in the intracellular replicative cycle of the parasite, and has no direct mammalian homolog. Two CDPK1 inhibitor programs have identified potent and selective lead series, demonstrating acceptable systemic and CNS exposure, and in vivo efficacy in animal models of acute and chronic infection. Physicians need a better arsenal of parasiticidal drugs for the treatment of toxoplasmosis, particularly those active against tissue cysts.


Assuntos
Antiprotozoários/uso terapêutico , Proteínas de Ligação ao Cálcio/antagonistas & inibidores , Antagonistas do Ácido Fólico/uso terapêutico , Proteínas de Protozoários/antagonistas & inibidores , Toxoplasmose/tratamento farmacológico , Doença Aguda , Animais , Antiprotozoários/efeitos adversos , Antiprotozoários/farmacologia , Doença Crônica , Antagonistas do Ácido Fólico/efeitos adversos , Antagonistas do Ácido Fólico/farmacologia , Humanos , Proteínas Quinases , Pirimetamina/uso terapêutico , Tetra-Hidrofolato Desidrogenase , Toxoplasma , Estados Unidos
3.
Eur J Pediatr ; 178(8): 1275-1281, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31230197

RESUMO

Immunoglobulin A (IgA) vasculitis (Henoch-Schonlein purpura (HSP)) is the most common vasculitis in children. It is characterized by purpuric rash, arthritis, gastrointestinal, and/or renal involvement. Spontaneous resolution is the typical outcome. In chronic cutaneous manifestations of IgA vasculitis, dapsone seems to show a good effectiveness. Multiple case reports and case series about dapsone in chronic IgA vasculitis are available. However, no clear evaluation of its indications, its effectiveness, or its usage guidelines (optimal dosage or duration of treatment) is available. We reviewed the published cases of IgA vasculitis treated by dapsone and compared them with 2 similar cases that we encountered. Seventeen patients (ranging from 22 months old to 16 years old) with severe or persistent clinical signs of IgA vasculitis were included. Dapsone showed good results on the resolution of cutaneous lesions but not on renal manifestations. Complications (methemoglobinemia) were observed on 1 patient. Half of the patients relapsed after treatment discontinuation. The difference between the time lapse before initiation and the duration of the treatment was not significant.Conclusion: We suggest that dapsone can have a positive effect in chronic IgA vasculitis when cutaneous manifestations last more than 6 weeks at the dosage of 1-2 mg/kg once per day during 1 week. What is Known: • IgA vasculitis or Henoch-Schonlein purpura is the most common vasculitis in children and affects mostly small vessels of the skin, kidney, and gastrointestinal tract. It resolves spontaneously in most of the cases. Exceptionally, cutaneous lesions can last several weeks. • Dapsone is a bacteriostatic antibacterial sulfonamide drug found to be effective in the treatment of some inflammatory dermatological diseases like IgA vasculitis. What is New: • Dapsone is effective against chronic purpuric lesion (> 6 weeks) at the minimal dose of 1 mg/kg/day. • Relapse occurs frequently after discontinuation but responds after a second course of treatment. A longer duration of treatment or a delay in treatment by dapsone does not seem to influence the relapse rate.


Assuntos
Dapsona/uso terapêutico , Antagonistas do Ácido Fólico/uso terapêutico , Púrpura de Schoenlein-Henoch/tratamento farmacológico , Pré-Escolar , Doença Crônica , Feminino , Humanos , Masculino , Púrpura de Schoenlein-Henoch/diagnóstico
4.
Molecules ; 24(6)2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30909399

RESUMO

Dihydrofolate reductase inhibitors are an important class of drugs, as evidenced by their use as antibacterial, antimalarial, antifungal, and anticancer agents. Progress in understanding the biochemical basis of mechanisms responsible for enzyme selectivity and antiproliferative effects has renewed the interest in antifolates for cancer chemotherapy and prompted the medicinal chemistry community to develop novel and selective human DHFR inhibitors, thus leading to a new generation of DHFR inhibitors. This work summarizes the mechanism of action, chemical, and anticancer profile of the DHFR inhibitors discovered in the last six years. New strategies in DHFR drug discovery are also provided, in order to thoroughly delineate the current landscape for medicinal chemists interested in furthering this study in the anticancer field.


Assuntos
Antineoplásicos/farmacologia , Antagonistas do Ácido Fólico/farmacologia , Animais , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Descoberta de Drogas , Avaliação Pré-Clínica de Medicamentos , Ácido Fólico/metabolismo , Antagonistas do Ácido Fólico/química , Antagonistas do Ácido Fólico/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Relação Estrutura-Atividade , Tetra-Hidrofolato Desidrogenase/química , Tetra-Hidrofolato Desidrogenase/metabolismo
5.
Target Oncol ; 14(2): 149-158, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30904980

RESUMO

BACKGROUND: Peripheral T-cell lymphoma (PTCL) is associated with poor prognosis, particularly in patients with relapsed/refractory (R/R) disease. Pralatrexate, a folate analogue inhibitor, was the first drug approved to treat R/R PTCL. OBJECTIVE: As the distribution of PTCL subtypes differs between populations and few patients in the pivotal trial of pralatrexate were Asian, this study investigated the safety and efficacy of pralatrexate as monotherapy in Chinese patients with R/R PTCL. PATIENTS AND METHODS: In this single-arm, open-label, multicenter study, 71 patients with R/R PTCL (median [range] 2 [1-14] prior systemic treatments) were recruited from 15 centers in China and received pralatrexate IV 30 mg/m2/week for 6 weeks in 7-week cycles (with vitamin B12/folate). The primary endpoint was objective response rate (ORR) per central review (null hypothesis: ORR < 15%). RESULTS: The study's primary objective was met: ORR (95% CI) was 52% (40-64%) (p < 0.001) and responses were observed across pre-specified patient subgroups. Median (95% CI) duration of response was 8.7 (3.3-14.1) months and first response was observed in Cycle 1 for most (84%) patients. Median (95% CI) progression-free survival and overall survival was 4.8 (3.1-8.1) months and 18.0 (10.4-NA) months, respectively. The most common treatment-emergent adverse events were stomatitis (68% [Grade 3/4: 20%]), anemia (49% [Grade 3/4: 24%]) and alanine aminotransferase increase (41% [Grade 3/4: 4%]). CONCLUSIONS: These results demonstrate that pralatrexate may represent a promising treatment option for Chinese patients with R/R PTCL. The ORR of 52% compared favorably with prior studies of pralatrexate in other populations and there were no unanticipated side effects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03349333.


Assuntos
Aminopterina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Antagonistas do Ácido Fólico/uso terapêutico , Linfoma de Células T Periférico/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Terapia de Salvação , Adulto , Idoso , Aminopterina/uso terapêutico , Feminino , Seguimentos , Humanos , Linfoma de Células T Periférico/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Prognóstico , Taxa de Sobrevida , Adulto Jovem
6.
Australas J Dermatol ; 60(3): 200-208, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30809800

RESUMO

Cutaneous T-cell lymphoma is an uncommon group of non-Hodgkin's lymphoma primarily affecting the skin. It is comprised of a variety of entities with different clinical behaviours and prognosis. Mycosis fungoides is the commonest subtype, and Sézary syndrome is a much rarer form of cutaneous T-cell lymphoma. At this stage, control rather than cure is the goal of therapy, with particular emphasis placed on preserving quality of life. Our review of the efficacy, safety profile and accessibility of treatment modalities for mycosis fungoides/Sézary syndrome is a tailored guide for the clinician treating these rare conditions.


Assuntos
Linfoma Cutâneo de Células T/terapia , Neoplasias Cutâneas/terapia , Antineoplásicos/uso terapêutico , Antagonistas do Ácido Fólico/uso terapêutico , Glucocorticoides/uso terapêutico , Humanos , Fatores Imunológicos/uso terapêutico , Interferons/uso terapêutico , Linfoma Cutâneo de Células T/patologia , Estadiamento de Neoplasias , Fotoferese , Fototerapia , Radioterapia/métodos , Neoplasias Cutâneas/patologia , Transplante de Células-Tronco
8.
Eur J Clin Microbiol Infect Dis ; 38(2): 409-412, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30483998

RESUMO

The in vitro and in vivo antimicrobial activities of dihydrofolate reductase (DHFR) inhibitors are inhibited in the presence of free thymidine in the growth milieu and in rodent efficacy models. However, for thymidine kinase (TK) deficient mutant bacteria, the presence of free thymidine does not impact the activity of DHFR inhibitors, and these mutants were used to assess the in vivo efficacy of the DHFR inhibitor, iclaprim. The efficacies of iclaprim, trimethoprim, and vancomycin were evaluated in a systemic mouse infection model. Female CD-1 mice were infected intraperitoneally (IP) with wild-type Staphylococcus aureus ATCC 25923 (MSSA) or AW 6 (MRSA) or their corresponding isogenic TK-deficient mutant S. aureus strains AH 1246 and AH 1252. Iclaprim showed potent antibacterial activity against both the TK-deficient mutant S. aureus strains, with PD50 values of 1.8 and < 0.5 mg/kg, respectively, for strains AH 1246 and AH 1252. In contrast, poor antibacterial activity was observed against corresponding wild-type (TK competent) S. aureus strains, with PD50 values of 10.8 and 2.2 mg/kg, respectively, for strains ATCC 25923 and AW 6. This study confirms that thymidine plays an important antagonistic role when determining the efficacy of DHFR inhibitors in vivo. This is the first study to show that iclaprim is active against TK-deficient S. aureus strains in a systemic mouse infection model, and that TK-deficient mutants may be used to evaluate iclaprim's activity in rodent models in vivo.


Assuntos
Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Infecções Estafilocócicas/tratamento farmacológico , Staphylococcus aureus/efeitos dos fármacos , Timidina Quinase/deficiência , Animais , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Modelos Animais de Doenças , Feminino , Antagonistas do Ácido Fólico/uso terapêutico , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/enzimologia , Staphylococcus aureus Resistente à Meticilina/genética , Camundongos , Staphylococcus aureus/enzimologia , Staphylococcus aureus/genética , Resultado do Tratamento
9.
Pediatr Dermatol ; 36(1): e46-e47, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30338555

RESUMO

We report the case of an infant born with perioral vesicles that rapidly spread to involve his mouth and the majority of his body. Histopathology, immunofluorescence, and enzyme-linked immunohistochemistry assays confirmed a diagnosis of epidermolysis bullosa acquisita (EBA). His mother had no history of EBA, and serum indirect immunofluorescence was negative. The patient improved rapidly with local wound care and oral dapsone.


Assuntos
Dapsona/uso terapêutico , Epidermólise Bolhosa Adquirida/diagnóstico , Antagonistas do Ácido Fólico/uso terapêutico , Ensaio de Imunoadsorção Enzimática , Epidermólise Bolhosa Adquirida/terapia , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Imuno-Histoquímica , Recém-Nascido , Masculino , Pele/patologia
10.
Drug Deliv Transl Res ; 9(1): 366-378, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30280318

RESUMO

Macrophages play a key role in the pathophysiology of rheumatoid arthritis (RA). Notably, positive correlations have been reported between synovial macrophage infiltration and disease activity as well as therapy outcome in RA patients. Hence, macrophages can serve as an important target for both imaging disease activity and drug delivery in RA. Folate receptor ß (FRß) is a glycosylphosphatidyl (GPI)-anchored plasma membrane protein being expressed on myeloid cells and activated macrophages. FRß harbors a nanomolar binding affinity for folic acid allowing this receptor to be exploited for RA disease imaging (e.g., folate-conjugated PET tracers) and therapeutic targeting (e.g., folate antagonists and folate-conjugated drugs). This review provides an overview of these emerging applications in RA by summarizing and discussing properties of FRß, expression of FRß in relation to macrophage polarization, FRß-targeted in vivo imaging modalities, and FRß-directed drug targeting.


Assuntos
Artrite Reumatoide/metabolismo , Receptor 2 de Folato/metabolismo , Macrófagos/metabolismo , Animais , Artrite Reumatoide/diagnóstico por imagem , Artrite Reumatoide/tratamento farmacológico , Ácido Fólico/metabolismo , Antagonistas do Ácido Fólico/farmacologia , Antagonistas do Ácido Fólico/uso terapêutico , Humanos , Tomografia por Emissão de Pósitrons
11.
Int J Dermatol ; 58(4): 408-415, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30074624

RESUMO

Erythema elevatum diutinum (EED) is a rare cutaneous leukocytoclastic vasculitis thought to be related to increased levels of circulating antibodies. It has been shown to be associated with HIV infection, tuberculosis, as well as various autoimmune diseases. A retrospective review of all cases of EED indexed in PubMed between 1990 and 2014 was performed. Inclusion criteria for articles was availability of full text in English and a biopsy-confirmed diagnosis of EED. All other articles were excluded. Cases were stratified by age and anatomic location of the lesions. Treatment response was coded as "complete," "partial," and "none." A total of 133 cases of EED with 381 lesions detailed in case reports and case series were included. Twenty-one cases were associated with HIV. Of 47 patients with reported paraproteinemias, IgA paraproteinemia was found in 57.45%, IgG paraproteinemia in 29.8%, IgM paraproteinemia in 10.6%, and IgD paraproteinemia in 2.1% of cases. Of 40 (30.1%) patients with reported comorbid autoimmune disease, rheumatoid arthritis was associated with 10 cases. Cancer was found to be associated with 9.77% of cases. Seventy-five patients were treated with dapsone, with 36 (48%) achieving complete treatment response, 24 (32%) achieving partial response, and seven (9.3%) achieving no response. Keeping the clinical associations of EED in mind, especially malignancy, is critical in management of the disease. More structured studies need to take place in order to fully define the mechanisms and strength of these associations.


Assuntos
Artrite Reumatoide/epidemiologia , Infecções por HIV/epidemiologia , Neoplasias/epidemiologia , Paraproteinemias/epidemiologia , Vasculite Leucocitoclástica Cutânea/tratamento farmacológico , Vasculite Leucocitoclástica Cutânea/epidemiologia , Comorbidade , Dapsona/uso terapêutico , Antagonistas do Ácido Fólico/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade
12.
Eur J Dermatol ; 28(6): 764-774, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30591425

RESUMO

The efficacy of alemtuzumab for the treatment of refractory Sézary syndrome (SS) versus other third-line agents such as pralatrexate and gemcitabine is poorly characterized. To elucidate the effectiveness of alemtuzumab versus other third-line options for the treatment of refractory SS, we conducted a meta-analysis of existing data. A systematic review was performed in March 2017 based on a search using Ovid-MEDLINE® and OVID-EMBASE® for articles evaluating single-agent alemtuzumab, gemcitabine, or pralatrexate for the treatment of SS and mycosis fungoides (MF). Twenty-two publications were identified that fulfilled all search criteria (total n = 323 patients), with six publications of lower quality being excluded from our analysis in order to decrease the risk of bias (final: n = 308 patients; 93 with SS and 147 with MF). Across all studies, alemtuzumab was significantly more effective in patients with SS (overall response rate [ORR]: 81%; complete response rate [CRR]: 38%) than patients with MF (ORR: 29%; CRR: 8%). However, gemcitabine was more effective than alemtuzumab or pralatrexate in treating MF. Alemtuzumab-treated patients had more frequent side effects, which were influenced by route of administration and dose. There was a lower incidence of lymphopenia and other serious adverse events in patients treated with subcutaneous (38%) compared to intravenous regimens (68%), and lower-dose (5%) compared to high-dose alemtuzumab regimens (54%). No significant differences were found in the effectiveness of different routes of administration or dosing regimens. Our review supports the use of low-dose subcutaneous alemtuzumab as a third-line treatment for SS.


Assuntos
Alemtuzumab/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Micose Fungoide/tratamento farmacológico , Síndrome de Sézary/tratamento farmacológico , Neoplasias Cutâneas/diagnóstico por imagem , Aminopterina/análogos & derivados , Aminopterina/uso terapêutico , Antimetabólitos Antineoplásicos/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Antagonistas do Ácido Fólico/uso terapêutico , Humanos , Retratamento
13.
Invest Ophthalmol Vis Sci ; 59(12): 4909-4920, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30347085

RESUMO

Purpose: Temporal and reversible control of protein expression in vivo is a central goal for many gene therapies, especially for strategies involving proteins that are detrimental to physiology if constitutively expressed. Accordingly, we explored whether protein abundance in the mouse retina could be effectively controlled using a destabilizing Escherichia coli dihydrofolate reductase (DHFR) domain whose stability is dependent on the small molecule, trimethoprim (TMP). Methods: We intravitreally injected wild-type C57BL6/J mice with an adeno-associated vector (rAAV2/2[MAX]) constitutively expressing separate fluorescent reporters: DHFR fused to yellow fluorescent protein (DHFR.YFP) and mCherry. TMP or vehicle was administered to mice via oral gavage, drinking water, or eye drops. Ocular TMP levels post treatment were quantified by LC-MS/MS. Protein abundance was measured by fundus fluorescence imaging and western blotting. Visual acuity, response to light stimulus, retinal structure, and gene expression were evaluated after long-term (3 months) TMP treatment. Results: Without TMP, DHFR.YFP was efficiently degraded in the retina. TMP achieved ocular concentrations of ∼13.6 µM (oral gavage), ∼331 nM (drinking water), and ∼636 nM (eye drops). Oral gavage and TMP eye drops stabilized DHFR.YFP as quickly as 6 hours, whereas continuous TMP drinking water could stabilize DHFR.YFP for ≥3 months. Stabilization was completely and repeatedly reversible following removal/addition of TMP in all regimens. Long-term TMP treatment had no impact on retina function/structure and had no effect on >99.9% of tested genes. Conclusions: This DHFR-based conditional system is a rapid, efficient, and reversible tool to effectively control protein expression in the retina.


Assuntos
Antagonistas do Ácido Fólico/uso terapêutico , Terapia Genética , Vetores Genéticos , Substâncias Luminescentes/metabolismo , Parvovirinae/genética , Retina/efeitos dos fármacos , Tetra-Hidrofolato Desidrogenase/genética , Trimetoprima/uso terapêutico , Administração Oral , Animais , Proteínas de Bactérias/metabolismo , Western Blotting , Cromatografia Líquida , Eletrorretinografia , Escherichia coli/enzimologia , Injeções Intravítreas , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Plasmídeos , Reação em Cadeia da Polimerase em Tempo Real , Retina/metabolismo , Espectrometria de Massas em Tandem , Tetra-Hidrofolato Desidrogenase/metabolismo , Acuidade Visual/fisiologia
14.
Clin Lung Cancer ; 19(6): 467-475, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30369425

RESUMO

BACKGROUND: Pemetrexed is a folate analog inhibitor for the treatment of non-small-cell lung cancer (NSCLC) and malignant pleural mesothelioma. Folic acid and vitamin B12 supplementation before initiating pemetrexed is necessary because of high rates of cytopenias without supplementation. However, the timing of supplementation has not been thoroughly investigated. PATIENTS AND METHODS: This was a single-center, retrospective study investigating patients receiving pemetrexed from January 1, 2012, to June 30, 2015, who received same-day vitamin B12 supplementation versus ≥ 1 day before pemetrexed. The objective was to evaluate safety outcomes in patients who received vitamin B12 on the same day as pemetrexed (group A) versus vitamin B12 ≥ 1 day (group B) before pemetrexed. RESULTS: Two hundred eighty-one patients met the inclusion criteria: 137 patients in group A (same-day administration of vitamin B12) and 144 patients in group B (median time of vitamin B12 administration before pemetrexed, 7 days; range, 1-42 days). Mean changes in hematologic indices from cycle (C) 1 to C2 or C2 to C3 did not differ significantly between groups. There were no significant differences in clinical events between C1 and C2 or C2 and C3 requiring supportive care. There was a significant difference noted in treatment delay in C3 [28/114 (24.6%) group A vs. 14/118 (11.9%) group B, P = .0164]. In group A, significant predictors of delay in C3 were baseline hemoglobin (mean 13.3 g/dL vs. 12.4 g/dL, P = .0137) and ANC (mean 6 × 109/L vs. 5 × 109/L, P = .0003). CONCLUSION: Same-day vitamin B12 and pemetrexed administration is a safe practice in NSCLC and malignant pleural mesothelioma patients.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/prevenção & controle , Antagonistas do Ácido Fólico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/tratamento farmacológico , Pemetrexede/uso terapêutico , Neoplasias Pleurais/tratamento farmacológico , Deficiência de Vitamina B 12/prevenção & controle , Vitamina B 12/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Feminino , Antagonistas do Ácido Fólico/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Pemetrexede/efeitos adversos , Estudos Retrospectivos , Deficiência de Vitamina B 12/etiologia
16.
Adv Exp Med Biol ; 1108: 37-48, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30191431

RESUMO

This study seeks to define factors affecting the development of adverse reactions to intensive therapy of toxoplasmic retinochoroiditis with antifolate agents (pyrimethamine/sulfadoxine) and antibiotics followed by secondary antifolate prophylaxis. The study was of retrospective and observational nature. Medical files were reviewed of 551 patients suffering from ocular toxoplasmosis during 1994-2013. All patients were treated with the same protocol: 3-week intensive pyrimethamine/sulfadoxine plus antibiotic/steroid therapy. Three hundred and fourteen out of the 551 patients qualified for the subsequent 6-month long secondary antifolate prophylaxis. The type and occurrence rate of adverse reactions were taken into account. The probability of an adverse reaction during the intensive therapy phase was 33.4%. Hypertransaminasemia was the most common event observed in 24.6% of the patients, but it assumed a severe character in just 0.9%, with male gender and age over 25 years being the predisposing factors. Less common adverse effects included thrombocytopenia (8.3%), hypersensitivity skin reactions (3.0%), and abdominal pain (1.4%). The adverse effects of secondary antifolate prophylaxis, most commonly hypersensitivity skin reactions and hypertransaminasemia, followed by thrombocytopenia and abdominal pain, were observed in 4.9% of the patients. Ten of them (2.7%) had to discontinue the treatment while eight others continued with pyrimethamine alone without further adverse effects, which suggests that discontinuation of the sulfonamide decreased the propensity for adverse reactions. The treatment strategy in these patients differed from previous reports in that it used lower doses of pyrimethamine/sulfonamide, with no folinic acid supplementation. Nonetheless, the rate and severity of adverse events were no greater than those noticed with traditional regimens, with higher antifolate doses and folinic acid supplementation. We conclude that the dose and drug-mitigated treatment strategy we employed deserves consideration as a promising alternative to traditional treatments for ocular toxoplasmosis.


Assuntos
Anti-Infecciosos/efeitos adversos , Antagonistas do Ácido Fólico/efeitos adversos , Toxoplasmose Ocular/tratamento farmacológico , Anti-Infecciosos/uso terapêutico , Feminino , Antagonistas do Ácido Fólico/uso terapêutico , Humanos , Masculino , Pirimetamina/efeitos adversos , Pirimetamina/uso terapêutico , Estudos Retrospectivos , Sulfadoxina/efeitos adversos , Sulfadoxina/uso terapêutico
17.
ChemMedChem ; 13(20): 2150-2158, 2018 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-30152195

RESUMO

Trypanosoma brucei is the agent of human African trypanosomiasis (HAT), a neglected disease that threatens the lives of 65 million people in sub-Saharan Africa every year. Unfortunately, available therapies are unsatisfactory, due primarily to safety issues and development of drug resistance. Over the last decades significant effort has been made in the discovery of new potential anti-HAT agents, with help from the World Health Organization (WHO) and private-public partnerships such as the Drugs for Neglected Diseases Initiative (DNDi). Whereas antifolates have been a valuable source of drugs against bacterial infections and malaria, compounds effective against T. brucei have not yet been identified. Considering the relatively simple folate metabolic pathway in T. brucei, along with results obtained in this research field so far, we believe that further investigations might lead to effective chemotherapeutic agents. Herein we present a selection of the more promising results obtained so far in this field, underlining the opportunities that could lead to successful therapeutic approaches in the future.


Assuntos
Antagonistas do Ácido Fólico/uso terapêutico , Ácido Fólico/metabolismo , Tripanossomicidas/uso terapêutico , Trypanosoma brucei brucei/efeitos dos fármacos , Tripanossomíase Africana/tratamento farmacológico , Animais , Antagonistas do Ácido Fólico/farmacologia , Humanos , Doenças Negligenciadas/tratamento farmacológico , Tripanossomicidas/farmacologia , Trypanosoma brucei brucei/metabolismo , Trypanosoma brucei rhodesiense/efeitos dos fármacos , Trypanosoma brucei rhodesiense/metabolismo
18.
Medicine (Baltimore) ; 97(27): e11036, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29979376

RESUMO

INTRODUCTION: Ovarian cancer is the most deadly gynecologic cancer, and the therapy is very difficult. Apatinib is a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor-2. At present, there are few studies or case reports on apatinib treatment for patients with ovarian cancer. CASE PRESENTATION: A 75-year-old Chinese woman had a medical history of ovarian high-grade serous papillary adenocarcinoma, who got many lines of chemotherapy and apatinib-an antiangiogenesis drug therapy. Either alone or in combination, apatinib may extend the survival time of patients with advanced ovarian cancer. CONCLUSION: Apatinib may be an option for advanced ovarian cancer after failure of chemotherapy or other targeted therapy. The role of apatinib in the treatment of advanced ovarian cancer needs further study.


Assuntos
Adenocarcinoma Papilar/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Piridinas/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adenocarcinoma Papilar/patologia , Idoso , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno Ca-125/sangue , Intervalo Livre de Doença , Feminino , Antagonistas do Ácido Fólico/uso terapêutico , Humanos , Proteínas de Membrana/sangue , Metástase Neoplásica/tratamento farmacológico , Neoplasias Ovarianas/patologia , Pemetrexede/administração & dosagem , Pemetrexede/efeitos adversos , Pemetrexede/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Recidiva , Resultado do Tratamento
19.
Nature ; 559(7715): 632-636, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29995852

RESUMO

The chemotherapeutic drug methotrexate inhibits the enzyme dihydrofolate reductase1, which generates tetrahydrofolate, an essential cofactor in nucleotide synthesis2. Depletion of tetrahydrofolate causes cell death by suppressing DNA and RNA production3. Although methotrexate is widely used as an anticancer agent and is the subject of over a thousand ongoing clinical trials4, its high toxicity often leads to the premature termination of its use, which reduces its potential efficacy5. To identify genes that modulate the response of cancer cells to methotrexate, we performed a CRISPR-Cas9-based screen6,7. This screen yielded FTCD, which encodes an enzyme-formimidoyltransferase cyclodeaminase-that is required for the catabolism of the amino acid histidine8, a process that has not previously been linked to methotrexate sensitivity. In cultured cancer cells, depletion of several genes in the histidine degradation pathway markedly decreased sensitivity to methotrexate. Mechanistically, histidine catabolism drains the cellular pool of tetrahydrofolate, which is particularly detrimental to methotrexate-treated cells. Moreover, expression of the rate-limiting enzyme in histidine catabolism is associated with methotrexate sensitivity in cancer cell lines and with survival rate in patients. In vivo dietary supplementation of histidine increased flux through the histidine degradation pathway and enhanced the sensitivity of leukaemia xenografts to methotrexate. The histidine degradation pathway markedly influences the sensitivity of cancer cells to methotrexate and may be exploited to improve methotrexate efficacy through a simple dietary intervention.


Assuntos
Histidina/metabolismo , Metotrexato/farmacologia , Metotrexato/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Amônia-Liases/deficiência , Amônia-Liases/genética , Amônia-Liases/metabolismo , Animais , Sistemas CRISPR-Cas/genética , Linhagem Celular Tumoral , Feminino , Antagonistas do Ácido Fólico/farmacologia , Antagonistas do Ácido Fólico/uso terapêutico , Glutamato Formimidoiltransferase/deficiência , Glutamato Formimidoiltransferase/genética , Glutamato Formimidoiltransferase/metabolismo , Histidina/farmacologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Nucleotídeos/biossíntese , Proteína Carregadora de Folato Reduzido/genética , Proteína Carregadora de Folato Reduzido/metabolismo , Tetra-Hidrofolato Desidrogenase/metabolismo , Tetra-Hidrofolatos/deficiência , Tetra-Hidrofolatos/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
20.
J Am Chem Soc ; 140(28): 8797-8806, 2018 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-29940110

RESUMO

The utilization of nanotechnology for the delivery of a wide range of anticancer drugs has the potential to reduce adverse effects of free drugs and improve the anticancer efficacy. However, carrier materials and/or chemical modifications associated with drug delivery make it difficult for nanodrugs to achieve clinical translation and final Food and Drug Administration (FDA) approvals. We have discovered a molecular recognition strategy to directly assemble two FDA-approved small-molecule hydrophobic and hydrophilic anticancer drugs into well-defined, stable nanostructures with high and quantitative drug loading. Molecular dynamics simulations demonstrate that purine nucleoside analogue clofarabine and folate analogue raltitrexed can self-assemble into stable nanoparticles through molecular recognition. In vitro studies exemplify how the clofarabine:raltitrexed nanoparticles could greatly improve synergistic combination effects by arresting more G1 phase of the cell cycle and reducing intracellular deoxynucleotide pools. More importantly, the nanodrugs increase the blood retention half-life of the free drugs, improve accumulation of drugs in tumor sites, and promote the synergistic tumor suppression property in vivo.


Assuntos
Antineoplásicos/química , Clofarabina/química , Ácido Fólico/análogos & derivados , Nanopartículas/química , Quinazolinas/química , Tiofenos/química , Animais , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Clofarabina/farmacocinética , Clofarabina/uso terapêutico , Ácido Fólico/farmacocinética , Ácido Fólico/uso terapêutico , Antagonistas do Ácido Fólico/química , Antagonistas do Ácido Fólico/farmacocinética , Antagonistas do Ácido Fólico/uso terapêutico , Células HeLa , Humanos , Interações Hidrofóbicas e Hidrofílicas , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Dinâmica Molecular , Nanopartículas/uso terapêutico , Nanopartículas/ultraestrutura , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Quinazolinas/farmacocinética , Quinazolinas/uso terapêutico , Ratos , Tiofenos/farmacocinética , Tiofenos/uso terapêutico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA