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1.
BMC Infect Dis ; 20(1): 671, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32933490

RESUMO

BACKGROUND: The increasing antimalarial drug resistance is a significant hindrance to malaria control and elimination programs. For the last six decades, chloroquine (CQ) plus pyrimethamine remains the first-line treatment for P. vivax malaria. Regions where both P. falciparum and P. vivax co-exist, P. vivax is exposed to antifolate drugs due to either misdiagnosis or improper treatment that causes selective drug pressure to evolve. Therefore, the present study aims to estimate antimalarial drug resistance among the complicated and uncomplicated P. vivax patients. METHODS: A total of 143 P. vivax malaria positive patients were enrolled in this study, and DNA was isolated from their blood samples. Pvcrt-o, Pvmdr-1, Pvdhps, and Pvdhfr genes were PCRs amplified, and drug resistance-associated gene mutations were analyzed. Statistical analysis of the drug resistance genes and population diversity was performed using MEGA vs. 7.0.21 and DnaSP v software. RESULTS: Among the CQ resistance marker gene Pvcrt-o, the prevalence of K10 insertion was 17.5% (7/40) and 9.5% (7/73) of complicated and uncomplicated P vivax group isolates respectively. In Pvmdr-1, double mutant haplotype (M958/L1076) was found in 99% of the clinical isolates. Among the pyrimethamine resistance-associated gene Pvdhfr, the double mutant haplotype I13P33F57R58T61N117I173 was detected in 23% (11/48) in complicated and 20% (17/85) in uncomplicated group isolates. In the sulphadoxine resistance-associated Pvdhps gene, limited polymorphism was observed with the presence of a single mutant (D459A) among 16 and 5% of the clinical isolates in the complicated and uncomplicated group respectively. CONCLUSION: The study presents the situations of polymorphism in the antimalarial drug resistance-associated genes and emphasizes the need for regular surveillance. It is imperative for the development of suitable antimalarial drug policy in India.


Assuntos
Antimaláricos/uso terapêutico , Resistência a Medicamentos/genética , Malária Vivax/tratamento farmacológico , Plasmodium vivax/genética , Proteínas de Protozoários/genética , Adolescente , Criança , Pré-Escolar , Cloroquina/uso terapêutico , DNA de Protozoário/genética , DNA de Protozoário/metabolismo , Feminino , Antagonistas do Ácido Fólico/uso terapêutico , Haplótipos , Humanos , Índia , Masculino , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Plasmodium vivax/isolamento & purificação , Polimorfismo de Nucleotídeo Único , Adulto Jovem
2.
Nat Rev Clin Oncol ; 17(6): 349-359, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32152484

RESUMO

Folate receptor α (FRα) came into focus as an anticancer target many decades after the successful development of drugs targeting intracellular folate metabolism, such as methotrexate and pemetrexed. Binding to FRα is one of several methods by which folate is taken up by cells; however, this receptor is an attractive anticancer drug target owing to the overexpression of FRα in a range of solid tumours, including ovarian, lung and breast cancers. Furthermore, using FRα to better localize effective anticancer therapies to their target tumours using platforms such as antibody-drug conjugates, small-molecule drug conjugates, radioimmunoconjugates and, more recently, chimeric antigen receptor T cells could further improve the outcomes of patients with FRα-overexpressing cancers. FRα can also be harnessed for predictive biomarker research. Moreover, imaging FRα radiologically or in real time during surgery can lead to improved functional imaging and surgical outcomes, respectively. In this Review, we describe the current status of research into FRα in cancer, including data from several late-phase clinical trials involving FRα-targeted therapies, and the use of new technologies to develop FRα-targeted agents with improved therapeutic indices.


Assuntos
Antineoplásicos/uso terapêutico , Receptor 1 de Folato/metabolismo , Imunoconjugados/uso terapêutico , Fatores Imunológicos/uso terapêutico , Imagem Molecular , Neoplasias/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/terapia , Carcinoma Epitelial do Ovário/diagnóstico por imagem , Carcinoma Epitelial do Ovário/metabolismo , Carcinoma Epitelial do Ovário/terapia , Neoplasias do Endométrio/diagnóstico por imagem , Neoplasias do Endométrio/metabolismo , Neoplasias do Endométrio/terapia , Feminino , Corantes Fluorescentes , Ácido Fólico , Antagonistas do Ácido Fólico/uso terapêutico , Humanos , Imunoterapia Adotiva , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/terapia , Maitansina/análogos & derivados , Maitansina/uso terapêutico , Mesotelioma/diagnóstico por imagem , Mesotelioma/metabolismo , Mesotelioma/terapia , Terapia de Alvo Molecular , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Imagem Óptica , Neoplasias Ovarianas/diagnóstico por imagem , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/terapia , Cintilografia , Nanomedicina Teranóstica , Moduladores de Tubulina/uso terapêutico
3.
Cancer Lett ; 470: 134-140, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31733288

RESUMO

Cancer is a disease of uncontrolled cell growth and a major cause of death worldwide. Many molecular events characterize tumor initiation and progression. Global gene expression analyses using next-generation sequencing, proteomics and metabolomics show genomic, epigenetic, and metabolite concentration changes in various tumors. Molecular alterations identified include multiple cancer-driving mutations, gene fusions, amplifications, deletions, and post-translational modifications. Data integration from many high-throughput platforms unraveled dysregulation in many metabolic pathways in cancer. Since cancer cells are fast-growing, their metabolic needs are enhanced, hence the requirement for de novo synthesis of essential metabolites. One critical requirement of fast-growing cells and a historically important pathway in cancer is the nucleotide biosynthetic pathway and its enzymes are valuable targets for small molecule inhibition. Purines and pyrimidines are building blocks of DNA synthesis and due to their excessive growth, cancer cells extensively utilize de novo pathways for nucleotide biosynthesis. Methotrexate, one of the early chemotherapeutic agents, targets dihydrofolate reductase of the folate metabolic pathway that is involved in nucleotide biosynthesis. In this review, we discuss the nucleotide biosynthetic pathways in cancer and targeting opportunities.


Assuntos
Antimetabólitos Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Neoplasias/patologia , Nucleotídeos de Purina/biossíntese , Nucleotídeos de Pirimidina/biossíntese , Antimetabólitos Antineoplásicos/uso terapêutico , Vias Biossintéticas/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Inibidores Enzimáticos/uso terapêutico , Antagonistas do Ácido Fólico/farmacologia , Antagonistas do Ácido Fólico/uso terapêutico , Humanos , Metotrexato/farmacologia , Metotrexato/uso terapêutico , Neoplasias/tratamento farmacológico , Processamento de Proteína Pós-Traducional , S-Adenosilmetionina/metabolismo , Tetra-Hidrofolato Desidrogenase/metabolismo , Tetra-Hidrofolatos/metabolismo
4.
J Antibiot (Tokyo) ; 73(1): 5-27, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31578455

RESUMO

The development of new mechanisms of resistance among pathogens, the occurrence and transmission of genes responsible for antibiotic insensitivity, as well as cancer diseases have been a serious clinical problem around the world for over 50 years. Therefore, intense searching of new leading structures and active substances, which may be used as new drugs, especially against strain resistant to all available therapeutics, is very important. Dihydrofolate reductase (DHFR) has attracted a lot of attention as a molecular target for bacterial resistance over several decades, resulting in a number of useful agents. Trimethoprim (TMP), (2,4-diamino-5-(3',4',5'-trimethoxybenzyl)pyrimidine) is the well-known dihydrofolate reductase inhibitor and one of the standard antibiotics used in urinary tract infections (UTIs). This review highlights advances in design, synthesis, and biological evaluations in structural modifications of TMP as DHFR inhibitors. In addition, this report presents the differences in the active site of human and pathogen DHFR. Moreover, an excellent review of DHFR inhibition and their relevance to antimicrobial and parasitic chemotherapy was presented.


Assuntos
Desenvolvimento de Medicamentos/métodos , Antagonistas do Ácido Fólico/farmacologia , Tetra-Hidrofolato Desidrogenase/metabolismo , Trimetoprima/farmacologia , Antibacterianos , Desenho de Fármacos , Descoberta de Drogas , Antagonistas do Ácido Fólico/uso terapêutico , Humanos , Trimetoprima/uso terapêutico
6.
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
7.
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
8.
Future Med Chem ; 11(16): 2107-2130, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31370699

RESUMO

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/metabolismo
9.
Leuk Lymphoma ; 60(13): 3300-3303, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31184235
10.
Bioorg Med Chem Lett ; 29(15): 1874-1880, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31176699

RESUMO

Pneumocystis pneumonia (PCP) caused by Pneumocystis jirovecii (pj) can lead to serious health consequences in patients with an immunocompromised system. Trimethoprim (TMP), used as first-line therapy in combination with sulfamethoxazole, is a selective but only moderately potent pj dihydrofolate reductase (pjDHFR) inhibitor, whereas non-clinical pjDHFR inhibitors, such as, piritrexim and trimetrexate are potent but non-selective pjDHFR inhibitors. To meet the clinical needs for a potent and selective pjDHFR inhibitor for PCP treatment, fourteen 6-substituted pyrido[3,2-d]pyrimidines were developed. Comparison of the amino acid residues in the active site of pjDHFR and human DHFR (hDHFR) revealed prominent amino acid differences which could be exploited to structurally design potent and selective pjDHFR inhibitors. Molecular modeling followed by enzyme assays of the compounds revealed 15 as the best compound of the series with an IC50 of 80 nM and 28-fold selectivity for inhibiting pjDHFR over hDHFR. Compound 15 serves as the lead analog for further structural variations to afford more potent and selective pjDHFR inhibitors.


Assuntos
Antagonistas do Ácido Fólico/uso terapêutico , Pneumocystis carinii/patogenicidade , Pneumocystis/efeitos dos fármacos , Pirimidinas/uso terapêutico , Trimetoprima/uso terapêutico , Antagonistas do Ácido Fólico/farmacologia , Humanos , Modelos Moleculares , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Trimetoprima/farmacologia
11.
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
12.
Brief Funct Genomics ; 18(5): 314-328, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31119263

RESUMO

Plasmodium falciparum and Plasmodium vivax, the two protozoan parasite species that cause the majority of cases of human malaria, have developed resistance to nearly all known antimalarials. The ability of malaria parasites to develop resistance is primarily due to the high numbers of parasites in the infected person's bloodstream during the asexual blood stage of infection in conjunction with the mutability of their genomes. Identifying the genetic mutations that mediate antimalarial resistance has deepened our understanding of how the parasites evade our treatments and reveals molecular markers that can be used to track the emergence of resistance in clinical samples. In this review, we examine known genetic mutations that lead to resistance to the major classes of antimalarial medications: the 4-aminoquinolines (chloroquine, amodiaquine and piperaquine), antifolate drugs, aryl amino-alcohols (quinine, lumefantrine and mefloquine), artemisinin compounds, antibiotics (clindamycin and doxycycline) and a napthoquinone (atovaquone). We discuss how the evolution of antimalarial resistance informs strategies to design the next generation of antimalarial therapies.


Assuntos
Antimaláricos/uso terapêutico , Resistência a Medicamentos/genética , Malária/tratamento farmacológico , Plasmodium falciparum/genética , Plasmodium vivax/genética , Aminoquinolinas/uso terapêutico , Antibacterianos/uso terapêutico , Artemisininas/uso terapêutico , Atovaquona/uso terapêutico , Resistência a Múltiplos Medicamentos/genética , Antagonistas do Ácido Fólico/uso terapêutico , Humanos , Plasmodium falciparum/crescimento & desenvolvimento , Plasmodium falciparum/patogenicidade , Plasmodium vivax/crescimento & desenvolvimento , Plasmodium vivax/patogenicidade , Quinina/uso terapêutico
13.
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
14.
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
15.
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
17.
J Biomol Struct Dyn ; 37(16): 4181-4199, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30648473

RESUMO

Plasmodium falciparum dihydrofolate reductase enzyme (PfDHFR) is counted as one of the attractive and validated antimalarial drug targets. However, the point mutations in the active site of wild-type PfDHFR have developed resistance against the well-known antifolates. Therefore, there is a dire need for the development of inhibitors that can inhibit both wild-type and mutant-type DHFR enzyme. In the present contribution, we have constructed the common feature pharmacophore models from the available PfDHFR. A representative hypothesis was prioritized and then employed for the screening of natural product library to search for the molecules with complementary features responsible for the inhibition. The screened candidates were processed via drug-likeness filters and molecular docking studies. The docking was carried out on the wild-type PfDHFR (3QGT); double-mutant PfDHFR (3UM5 and 1J3J) and quadruple-mutant PfDHFR (1J3K) enzymes. A total of eight common hits were obtained from the docking calculations that could be the potential inhibitors for both wild and mutant type DHFR enzymes. Eventually, the stability of these candidates with the selected proteins was evaluated via molecular dynamics simulations. Except for SPECS14, all the prioritized candidates were found to be stable throughout the simulation run. Overall, the strategy employed in the present work resulted in the retrieval of seven candidates that may show inhibitory activity against PfDHFR and could be further exploited as a scaffold to develop novel antimalarials. Communicated by Ramaswamy H. Sarma.


Assuntos
Antimaláricos/química , Antagonistas do Ácido Fólico/química , Malária Falciparum/tratamento farmacológico , Proteínas de Protozoários/ultraestrutura , Tetra-Hidrofolato Desidrogenase/ultraestrutura , Animais , Antimaláricos/uso terapêutico , Domínio Catalítico/efeitos dos fármacos , Antagonistas do Ácido Fólico/uso terapêutico , Humanos , Malária Falciparum/parasitologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Plasmodium falciparum/efeitos dos fármacos , Plasmodium falciparum/patogenicidade , Proteínas de Protozoários/antagonistas & inibidores , Proteínas de Protozoários/química , Tetra-Hidrofolato Desidrogenase/química
18.
J Med Chem ; 62(3): 1562-1576, 2019 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-30624926

RESUMO

A safer treatment for toxoplasmosis would be achieved by improving the selectivity and potency of dihydrofolate reductase (DHFR) inhibitors, such as pyrimethamine (1), for Toxoplasma gondii DHFR ( TgDHFR) relative to human DHFR ( hDHFR). We previously reported on the identification of meta-biphenyl analog 2, designed by in silico modeling of key differences in the binding pocket between TgDHFR and hDHFR. Compound 2 improves TgDHFR selectivity 6.6-fold and potency 16-fold relative to 1. Here, we report on the optimization and structure-activity relationships of this arylpiperazine series leading to the discovery of 5-(4-(3-(2-methoxypyrimidin-5-yl)phenyl)piperazin-1-yl)pyrimidine-2,4-diamine 3. Compound 3 has a TgDHFR IC50 of 1.57 ± 0.11 nM and a hDHFR to TgDHFR selectivity ratio of 196, making it 89-fold more potent and 16-fold more selective than 1. Compound 3 was highly effective in control of acute infection by highly virulent strains of T. gondii in the murine model, and it possesses the best combination of selectivity, potency, and prerequisite drug-like properties to advance into IND-enabling, preclinical development.


Assuntos
Antiparasitários/uso terapêutico , Antagonistas do Ácido Fólico/uso terapêutico , Piperazinas/uso terapêutico , Pirimidinas/uso terapêutico , Toxoplasma/enzimologia , Toxoplasmose/tratamento farmacológico , Animais , Antiparasitários/síntese química , Antiparasitários/química , Cães , Feminino , Antagonistas do Ácido Fólico/síntese química , Antagonistas do Ácido Fólico/química , Humanos , Células MCF-7 , Células Madin Darby de Rim Canino , Camundongos , Estrutura Molecular , Piperazinas/síntese química , Piperazinas/química , Pirimidinas/síntese química , Pirimidinas/química , Relação Estrutura-Atividade , Tetra-Hidrofolato Desidrogenase/metabolismo
19.
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
20.
J Bras Nefrol ; 41(3): 427-432, 2019.
Artigo em Inglês, Português | MEDLINE | ID: mdl-30281061

RESUMO

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 Tratamento
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