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1.
JNMA J Nepal Med Assoc ; 56(211): 711-715, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30381772

RESUMO

Methotrexate is an antimetabolite drug with antineoplastic and immunomodulatory properties, useful as an antineoplastic agent in various haematological and solid tumours. MTX toxicity can occur because of accidental ingestion/overdose by the patient or because of prescription error. The toxic effects manifest as severe mucositis or as organ damage (bone marrow depression, renal/hepatic injury). The toxicity usually results from parenteral overdose or repeated chronic drug ingestion. Acute high dose ingestion does not result in MTX toxicity because of saturable absorption kinetics. We present a case of MTX toxicity occurring as a result of prescription error resulting in repeat daily dosing of the drug, and the challenges associated with the management of the same, in a patient with multiple comorbidities. The present case emphasizes on a note of caution on the part of the prescriber and the suggestions regarding the measures which can be taken to avoid MTX toxicity. Keywords: drug overdose; Methotrexate; mucositis; pancytopenia.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Erros Médicos/efeitos adversos , Metotrexato , Administração dos Cuidados ao Paciente/métodos , Comorbidade , Doença da Artéria Coronariana/complicações , Diabetes Mellitus Tipo 2/complicações , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/fisiopatologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/terapia , Nutrição Enteral/métodos , Antagonistas do Ácido Fólico/administração & dosagem , Antagonistas do Ácido Fólico/toxicidade , Humanos , Falência Renal Crônica/complicações , Masculino , Metotrexato/administração & dosagem , Metotrexato/toxicidade , Pessoa de Meia-Idade , Diálise Renal/métodos
2.
Reprod Toxicol ; 80: 92-104, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29859881

RESUMO

We discuss the possibilities to prevent the post-exposure teratogenic effects of several teratogens: valproic acid (VPA), diabetes and alcohol. Co-administration of folic acid with VPA reduced the rate of Neural Tube Defects (NTD) and other anomalies in rodents, but apparently not in pregnant women. Antioxidants or the methyl donor S-adenosyl methionine prevented Autism Spectrum Disorder (ASD) like behavior in mice and rats. In vivo and in vitro studies demonstrated that antioxidants, arachidonic acid, myoinositol and nutritional agents may prevent diabetes-embryopathy. Prevention of alcohol-induced embryonic and fetal injuries and neurodevelopmental deficits was achieved by supplementation of zinc, choline, vasoactive intestinal proteins (VIP related peptides), antioxidants and folic acid. While the animal research described in this review is indicative of possible preventions of the different teratogenic effects, this is not yet the focus in human research. Future research should promote further knowledge where our current understanding is the vaguest, human prevention.


Assuntos
Anormalidades Induzidas por Medicamentos/prevenção & controle , Antioxidantes/administração & dosagem , Diabetes Gestacional , Ácido Fólico/administração & dosagem , Gravidez em Diabéticas , Efeitos Tardios da Exposição Pré-Natal/prevenção & controle , Teratogênicos/toxicidade , Anormalidades Induzidas por Medicamentos/etiologia , Animais , Antioxidantes/uso terapêutico , Diabetes Gestacional/metabolismo , Etanol/toxicidade , Etil-Éteres , Feminino , Ácido Fólico/uso terapêutico , Antagonistas do Ácido Fólico/toxicidade , Humanos , Estresse Oxidativo , Gravidez , Gravidez em Diabéticas/metabolismo , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Compostos de Sulfidrila , Ácido Valproico/toxicidade
3.
Drug Chem Toxicol ; 41(1): 51-61, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28298149

RESUMO

Methotrexate (MTX) is a folic acid antagonist that is widely used to treat a variety of diseases. One of the most serious side effects of MTX therapy is hepatotoxicity. The potential molecular cytotoxic mechanisms of MTX toward isolated rat hepatocytes were investigated using Accelerated Cytotoxicity Mechanism Screening (ACMS) techniques. A concentration and time dependent increase in cytotoxicity and reactive oxygen species (ROS) formation and a decrease in mitochondrial membrane potential (MMP) were observed with MTX. Furthermore, a significant increase in MTX (300 µM)-induced cytotoxicity and ROS formation were observed when glutathione (GSH)-depleted hepatocytes were used whereas addition of N-acetylcysteine (a GSH precursor) decreased cytotoxicity. Catalase inactivation also increased MTX-induced cytotoxicity, while the direct addition of catalase to the hepatocytes decreased cytotoxicity. MTX treatment in isolated rat mitochondria caused swelling and significantly decreased adenosine triphosphate (ATP) and GSH content, and cytochrome c release. Potent antioxidants such as mesna, resveratrol and Trolox decreased MTX-induced cytotoxicity and ROS formation and increased MMP. This study suggests that MTX-induced cytotoxicity caused by ROS formation and GSH oxidation leads to oxidative stress and mitochondrial injury in rat hepatocytes.


Assuntos
Citocromos c/metabolismo , Antagonistas do Ácido Fólico/toxicidade , Hepatócitos/efeitos dos fármacos , Metotrexato/toxicidade , Mitocôndrias Hepáticas/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Trifosfato de Adenosina/metabolismo , Animais , Antioxidantes/farmacologia , Catalase/metabolismo , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Hepatócitos/enzimologia , Hepatócitos/patologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias Hepáticas/enzimologia , Mitocôndrias Hepáticas/patologia , Dilatação Mitocondrial/efeitos dos fármacos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Fatores de Tempo
4.
Nucleic Acids Res ; 45(5): 2472-2489, 2017 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-27924000

RESUMO

The biogenesis of ribosomes in vivo is an essential process for cellular functions. Transcription of ribosomal RNA (rRNA) genes is the rate-limiting step in ribosome biogenesis controlled by environmental conditions. Here, we investigated the role of folate antagonist on changes of DNA double-strand breaks (DSBs) landscape in mouse embryonic stem cells. A significant DSB enhancement was detected in the genome of these cells and a large majority of these DSBs were found in rRNA genes. Furthermore, spontaneous DSBs in cells under folate deficiency conditions were located exclusively within the rRNA gene units, representing a H3K4me1 hallmark. Enrichment H3K4me1 at the hot spots of DSB regions enhanced the recruitment of upstream binding factor (UBF) to rRNA genes, resulting in the increment of rRNA genes transcription. Supplement of folate resulted in a restored UBF binding across DNA breakage sites of rRNA genes, and normal rRNA gene transcription. In samples from neural tube defects (NTDs) with low folate level, up-regulation of rRNA gene transcription was observed, along with aberrant UBF level. Our results present a new view by which alterations in folate levels affects DNA breakage through epigenetic control leading to the regulation of rRNA gene transcription during the early stage of development.


Assuntos
Quebras de DNA de Cadeia Dupla , Deficiência de Ácido Fólico/genética , Regulação da Expressão Gênica no Desenvolvimento , Genes de RNAr , Proteínas Pol1 do Complexo de Iniciação de Transcrição/metabolismo , Transcrição Gênica , Animais , Células Cultivadas , Células-Tronco Embrionárias/metabolismo , Feto/metabolismo , Antagonistas do Ácido Fólico/toxicidade , Deficiência de Ácido Fólico/metabolismo , Fase G1/genética , Histonas/metabolismo , Leucovorina/farmacologia , Metotrexato/toxicidade , Camundongos , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/metabolismo
5.
Bioorg Med Chem ; 25(1): 221-232, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27816268

RESUMO

Novel series of naphthyl bearing 1,2,3-triazoles (4a-t) were synthesized and evaluated for their in vitro antiplasmodial activity against pyrimethamine (Pyr)-sensitive and resistant strains of Plasmodium falciparum. The synthesized compounds were assessed for their cytotoxicity employing human embryonic kidney cell line (HEK-293), and none of them was found to be toxic. Among them 4j, 4k, 4l, 4m, 4n, 4t exhibited significant antiplasmodial activity in both strains, of which compounds 4m, 4n and 4t (∼3.0-fold) displayed superior activity to Pyr against resistant strain. Pyr and selected compounds (4n, 4p and 4t) that repressed parasite development also inhibited PfDHFR activity of the soluble parasite extract, suggesting that anti-parasitic activity of these compounds is a result of inhibition of the parasite DHFR. In silico studies suggest that activity of these compounds might be enhanced due to π-π stacking.


Assuntos
Antiprotozoários/farmacologia , Antagonistas do Ácido Fólico/farmacologia , Naftalenos/farmacologia , Triazóis/farmacologia , Antiprotozoários/síntese química , Antiprotozoários/química , Antiprotozoários/toxicidade , Cristalografia por Raios X , Ensaios Enzimáticos , Antagonistas do Ácido Fólico/síntese química , Antagonistas do Ácido Fólico/química , Antagonistas do Ácido Fólico/toxicidade , Células HEK293 , Humanos , Simulação de Acoplamento Molecular , NADP/metabolismo , Naftalenos/síntese química , Naftalenos/química , Naftalenos/toxicidade , Plasmodium falciparum/efeitos dos fármacos , Pirimetamina/química , Triazóis/síntese química , Triazóis/química , Triazóis/toxicidade
6.
PLoS One ; 10(3): e0121869, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25822193

RESUMO

DNA methylation is thought to be involved in the etiology of neural tube defects (NTDs). However, the exact mechanism between DNA methylation and NTDs remains unclear. Herein, we investigated the change of methylation in mouse model of NTDs associated with folate dysmetabolism by use of ultraperformance liquid chromatography tandem mass spectrometry (UPLC/MS/MS), liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/MS), microarray, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and Real time quantitative PCR. Results showed that NTD neural tube tissues had lower concentrations of 5-methyltetrahydrofolate (5-MeTHF, P = 0.005), 5-formyltetrahydrofolate (5-FoTHF, P = 0.040), S-adenosylmethionine (SAM, P = 0.004) and higher concentrations of folic acid (P = 0.041), homocysteine (Hcy, P = 0.006) and S-adenosylhomocysteine (SAH, P = 0.045) compared to control. Methylation levels of genomic DNA decreased significantly in the embryonic neural tube tissue of NTD samples. 132 differentially methylated regions (35 low methylated regions and 97 high methylated regions) were selected by microarray. Two genes (Siah1b, Prkx) in Wnt signal pathway demonstrated lower methylated regions (peak) and higher expression in NTDs (P<0.05; P<0.05). Results suggest that DNA hypomethylation was one of the possible epigenetic variations correlated with the occurrence of NTDs induced by folate dysmetabolism and that Siah1b, Prkx in Wnt pathway may be candidate genes for NTDs.


Assuntos
Metilação de DNA/efeitos dos fármacos , Antagonistas do Ácido Fólico/toxicidade , Ácido Fólico/metabolismo , Metotrexato/toxicidade , Defeitos do Tubo Neural/etiologia , Defeitos do Tubo Neural/metabolismo , Animais , Proteínas Quinases Dependentes de AMP Cíclico/genética , Metilação de DNA/genética , Modelos Animais de Doenças , Desenvolvimento Embrionário/efeitos dos fármacos , Desenvolvimento Embrionário/genética , Feminino , Deficiência de Ácido Fólico/complicações , Camundongos , Defeitos do Tubo Neural/genética , Gravidez , Proteínas Serina-Treonina Quinases , Espectrometria de Massas em Tandem , Ubiquitina-Proteína Ligases/genética , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/genética
7.
Mol Cell Biochem ; 398(1-2): 223-31, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25245820

RESUMO

The causal metabolic pathway and the underlying mechanism between folate deficiency and neural tube defects (NTDs) remain obscure. Thymidylate (dTMP) is catalyzed by thymidylate synthase (TS) using the folate-derived one-carbon unit as the sole methyl donor. This study aims to examine the role of dTMP biosynthesis in the development of neural tube in mice by inhibition of TS via a specific inhibitor, raltitrexed (RTX). Pregnant mice were intraperitoneally injected with various doses of RTX on gestational day 7.5, and embryos were examined for the presence of NTDs on gestational day 11.5. TS activity and changes of dUMP and dTMP levels were measured following RTX treatment at the optimal dose. DNA damage was determined by detection of phosphorylated replication protein A2 (RPA2) and γ-H2AX in embryos with NTDs induced by RTX. Besides, apoptosis and proliferation were also analyzed in RTX-treated embryos with NTDs. We found that NTDs were highly occurred by the treatment of RTX at the optimal dose of 11.5 mg/kg b/w. RTX treatment significantly inhibited TS activity. Meanwhile, dTMP was decreased associated with the accumulation of dUMP in RTX-treated embryos. Phosphorylated RPA2 and γ-H2AX were significantly increased in RTX-treated embryos with NTDs compared to control. More apoptosis and decreased proliferation were also found in embryos with NTDs induced by RTX. These results indicate that impairment of dTMP biosynthesis caused by RTX led to the development of NTDs in mice. DNA damage and imbalance between apoptosis and proliferation may be potential mechanisms.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Dano ao DNA , Embrião de Mamíferos/efeitos dos fármacos , Defeitos do Tubo Neural/metabolismo , Quinazolinas/toxicidade , Tiofenos/toxicidade , Animais , Western Blotting , Nucleotídeos de Desoxiuracil/metabolismo , Embrião de Mamíferos/metabolismo , Embrião de Mamíferos/patologia , Feminino , Antagonistas do Ácido Fólico/administração & dosagem , Antagonistas do Ácido Fólico/toxicidade , Idade Gestacional , Histonas/metabolismo , Injeções Intraperitoneais , Masculino , Camundongos Endogâmicos C57BL , Defeitos do Tubo Neural/induzido quimicamente , Defeitos do Tubo Neural/genética , Fosforilação/efeitos dos fármacos , Gravidez , Subunidades Proteicas/metabolismo , Quinazolinas/administração & dosagem , Proteína de Replicação A/metabolismo , Tiofenos/administração & dosagem , Timidina Monofosfato/metabolismo , Timidilato Sintase/antagonistas & inibidores , Timidilato Sintase/metabolismo
8.
Clin Invest Med ; 37(1): E19-25, 2014 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-24502808

RESUMO

PURPOSE: The purpose of this study was to investigate the effect of carvacrol (CAR) on methotrexate (MTX)-induced renal damage in rats. METHODS: Twenty-four male rats were equally divided into three groups: group I, control treatment; group II, MTX-treated; and group III, MTX+CAR-treated. A single dose of CAR (73 mg/kg) was administered intraperitoneally to group III on the first day of the experiment and a single dose of MTX (20 mg/kg) was administered intraperitoneally to groups II and III on the second day of the experiment. Blood samples and kidney tissue were obtained from each animal on day 8 for the measurement of malondialdehyde (MDA), total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI). Light microscopy was used for histopathological examination of kidney specimens. RESULTS: MDA, TOS and OSI levels were significantly greater in the group receiving MTX alone relative to the control animals, while the TAS level was significantly reduced in the MTX group compared with the control group. The administration of CAR was associated with significantly decreased MDA, TOS, and OSI levels and increased TAS levels relative to the rats treated with MTX alone. Animals treated with CAR exhibited decreased tubular degeneration and architectural impairment relative to animals treated with MTX alone; however, the difference in histological scores did not meet the threshold of statistical significance. CONCLUSIONS: MTX treatment results in oxidative damage to the rat kidney; damage which is partially abrogated by the administration of CAR.


Assuntos
Rim/efeitos dos fármacos , Rim/patologia , Metotrexato/toxicidade , Monoterpenos/farmacologia , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Cimenos , Antagonistas do Ácido Fólico/toxicidade , Rim/metabolismo , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar
9.
J Appl Toxicol ; 34(8): 862-9, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23836430

RESUMO

Apoptosis and proliferation play important roles in embryonic development and are required for neural tube closure. The antifolate drug methotrexate (MTX) induces folate dysmetabolism by inhibition of dihydrofolate reductase and causes abnormal apoptosis and proliferation. In this study, we established an animal model of neural tube defects (NTDs) using MTX to investigate the role of apoptosis and proliferation in NTDs caused by folate deficiency. Differential gene expressions were studied by microarray and reverse transcription-polymerase chain reaction in the NTD animal model. Results showed that 30.8% of NTDs were caused by using MTX in treatment regimens. Microarray indicated that 166 genes were significantly different between the control and NTD mice, including four apoptosis-related genes (Endog, Trp53, Casp3, Bax) and three proliferation-related genes (Ptch1, Pla2g4a, Foxg1). Levels of Endog, Trp53, Casp3, Bax (fold change>1.5) were upregulated but Ptch1, Pla2g4a, Foxg1 (fold change<0.67) were downregulated (P<0.05). These results were confirmed by reverse transcription-polymerase chain reaction. TUNEL, immunohistochemical assays and Western blot were further used to detect apoptosis and proliferation in the NTD animal model. It was found that apoptosis in neuroepithelial cells was increased as determined by TUNEL (P<0.05). Expressions of caspase-3 were significantly enhanced (P<0.05) but expressions of phosphohistone H3 were greatly decreased (P<0.05). These results concluded that MTX caused a folate and folate-associated dysmetabolism, and further induced abnormal apoptosis and proliferation, which may play a critical role in the occurrence of NTDs caused by folate deficiency.


Assuntos
Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Antagonistas do Ácido Fólico/toxicidade , Metotrexato/toxicidade , Neurulação/efeitos dos fármacos , Animais , Caspase 3/genética , Caspase 3/metabolismo , Modelos Animais de Doenças , Regulação para Baixo , Desenvolvimento Embrionário/efeitos dos fármacos , Células Epiteliais/efeitos dos fármacos , Feminino , Ácido Fólico/metabolismo , Deficiência de Ácido Fólico/complicações , Deficiência de Ácido Fólico/embriologia , Histonas/genética , Histonas/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Análise em Microsséries , Defeitos do Tubo Neural/embriologia , Gravidez , Tetra-Hidrofolato Desidrogenase/metabolismo , Regulação para Cima
10.
J Basic Clin Physiol Pharmacol ; 25(2): 249-53, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24285126

RESUMO

BACKGROUND: Trimethoprim-sulfamethoxazole (TMP-SMX) is a broad-spectrum antibiotic. However, its use is associated with toxic reactions. Virgin coconut oil (VCO), derived from coconut, has been widely used throughout history for its medicinal value. The aim of this study was to investigate the beneficial actions of VCO against TMP-SMX-induced alterations in serum biochemical end points. METHODS: Twenty rats were divided into four groups. Group 1 (control) received no drug, whereas group 2 received TMP-SMX (8/40 mg/kg) twice daily for 7 days. Group 3 was administered coconut oil at a dose of 600 mg/kg body weight per day. The last group was treated with TMP-SMX (8/40 mg/kg) and coconut oil (600 mg/kg) simultaneously. Blood samples were collected from all groups on the 8th day of the experiment for measurement of serum biochemical parameters. Organ weights and coefficients were also evaluated. RESULTS: TMP-SMX caused a significant (p<0.05) increase in the levels of serum total bilirubin, lactate dehydrogenase, and alkaline phosphatase by 192%, 67%, and 41%, respectively, relative to controls. This was followed by a significant reduction in triglyceride and relative kidney weight by 40% and 7%, respectively. There were no significant differences (p>0.05) in the activities of serum aminotransferases, total acid phosphatase, γ-glutamyl transferase, uric acid, cholesterol, albumin, and urea levels. Supplementation of VCO ameliorated TMP-SMX-induced effects by restoring the levels of total bilirubin, alkaline phospahatase, and lactate dehydrogenase. CONCLUSIONS: The results of this study demonstrate that the active components of coconut oil had protective effects against the toxic effects induced by TMP-SMX administration, especially in the liver of rats.


Assuntos
Anti-Infecciosos/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Antagonistas do Ácido Fólico/toxicidade , Óleos de Plantas/uso terapêutico , Combinação Trimetoprima e Sulfametoxazol/toxicidade , Animais , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Óleo de Coco , Rim/efeitos dos fármacos , Testes de Função Renal , Testes de Função Hepática , Masculino , Tamanho do Órgão/efeitos dos fármacos , Óleos de Plantas/administração & dosagem , Ratos Wistar
11.
Arch Med Res ; 44(6): 415-21, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23973195

RESUMO

BACKGROUND AND AIMS: T. gondii is a causal agent of encephalitis in immunocompromised patients. Pyrimethamine (PYR) has been the treatment of choice for toxoplasmosis. The aim of this study was to analyze the effect of nitazoxanide and pyrimethamine on astrocytes infected with T. gondii in vitro. METHODS: Rat astrocytes were cultured and infected with T. gondii. The effect of nitazoxanide (10, 20 and 30 µg/mL) and pyrimethamine (7, 10 and 13 µg/mL) on astrocytes infected was evaluated at 24 and 48 h post-infection. Tachyzoites and astrocytes were detected by the immunocytochemical method. T. gondii viability in astrocytes infected and treated with NTZ and PYR as well as NTZ and PYR cytotoxicity on astrocytes in vitro were evaluated by the MTT assay. RESULTS: The number of parasites in astrocytes treated with the drugs was significantly reduced when compared to control (p <0.001) at 24 and 48 h. Nitazoxanide produced 97% T. gondii death in a concentration of 10 µg/mL in 48 h infected astrocytes. At 48 h, the death rate of T. gondii was higher when treated with nitazoxanide than with pyrimethamine. A higher toxicity rate in astrocyte was observed when using pyrimethamine at 40 µg/mL. CONCLUSIONS: Nitazoxanide reduced T. gondii infection more efficiently than pyrimethamine and is not cytotoxic to astrocytes at the administered dose.


Assuntos
Antiparasitários/farmacologia , Astrócitos/parasitologia , Pirimetamina/farmacologia , Tiazóis/farmacologia , Toxoplasma/efeitos dos fármacos , Toxoplasmose/tratamento farmacológico , Animais , Antiparasitários/toxicidade , Astrócitos/efeitos dos fármacos , Sobrevivência Celular , Células Cultivadas , Feminino , Antagonistas do Ácido Fólico/farmacologia , Antagonistas do Ácido Fólico/toxicidade , Humanos , Camundongos , Pessoa de Meia-Idade , Nitrocompostos , Pirimetamina/toxicidade , Ratos , Ratos Wistar , Tiazóis/toxicidade , Toxoplasmose/parasitologia
12.
Drug Des Devel Ther ; 7: 449-75, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23818757

RESUMO

BACKGROUND: There is a dearth of treatment options for community-acquired and nosocomial Pseudomonas infections due to several rapidly emerging multidrug resistant phenotypes, which show resistance even to combination therapy. As an alternative, developing selective promiscuous hybrid compounds for simultaneous modulation of multiple targets is highly appreciated because it is difficult for the pathogen to develop resistance when an inhibitor has activity against multiple targets. METHODS: In line with our previous work on phytochemical-antibiotic combination assays and knowledge-based methods, using a fragment combination approach we here report a novel drug design strategy of conjugating synergistic phytochemical-antibiotic combinations into a single hybrid entity for multi-inhibition of P. aeruginosa DNA gyrase subunit B (GyrB)/topoisomerase IV subunit B (ParE) and dihydrofolate reductase (DHFR) enzymes. The designed conjugates were evaluated for their multitarget specificity using various computational methods including docking and dynamic simulations, drug-likeness using molecular properties calculations, and pharmacophoric features by stereoelectronic property predictions. RESULTS: Evaluation of the designed hybrid compounds based on their physicochemical properties has indicated that they are promising drug candidates with drug-like pharmacotherapeutic profiles. In addition, the stereoelectronic properties such as HOMO (highest occupied molecular orbital), LUMO (lowest unoccupied molecular orbital), and MEP (molecular electrostatic potential) maps calculated by quantum chemical methods gave a good correlation with the common pharmacophoric features required for multitarget inhibition. Furthermore, docking and dynamics simulations revealed that the designed compounds have favorable binding affinity and stability in both the ATP-binding sites of GyrB/ParE and the folate-binding site of DHFR, by forming strong hydrogen bonds and hydrophobic interactions with key active site residues. CONCLUSION: This new design concept of hybrid "phyto-drug" scaffolds, and their simultaneous perturbation of well-established antibacterial targets from two unrelated pathways, appears to be very promising and could serve as a prospective lead in multitarget drug discovery.


Assuntos
Antibacterianos/farmacologia , DNA Topoisomerase IV/antagonistas & inibidores , Desenho de Fármacos , Antagonistas do Ácido Fólico/farmacologia , Pseudomonas aeruginosa/efeitos dos fármacos , Inibidores da Topoisomerase II , Trifosfato de Adenosina/metabolismo , Antibacterianos/química , Sítios de Ligação , Antagonistas do Ácido Fólico/química , Antagonistas do Ácido Fólico/toxicidade , Metotrexato/química , Metotrexato/farmacologia , Modelos Moleculares , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Eletricidade Estática , Tetra-Hidrofolato Desidrogenase/química
13.
Exp Toxicol Pathol ; 65(7-8): 995-1002, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23517751

RESUMO

The sequential changes in the placenta from rats exposed to methotrexate were examined histopathologically. Methotrexate was intraperitoneally administered at 0.2mg/kg/day during gestation days (GDs) 11-12 or GDs 13-14, and the placentas were sampled on GDs 13, 15, 17 and 21. The fetal mortality rates tended to increase throughout the experimental period, and fetal weights were significantly decreased on GD13 in the GD11,12-treated group. A significant reduction in placental weights was detected on GDs 13 and 15 in the GD11,12-treated group. Histopathologically, in the GD11,12-treated group, a significant thinning of the basal zone was detected throughout the experimental period, whereas the thickness of the labyrinth zone decreased significantly during GDs 13-17. The severity of thinning of the basal zone was higher than that of the labyrinth zone. In addition, a marked decrease in glycogen cell-islands in the basal zone was detected on GD 15. A significant decrease in Phospho-Histone H3-positive cells and a significant increase in terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells were detected on GD 13 in the basal zone of the GD11,12-treated group. In the GD13,14-treated group, there were no other significant changes in placentas and fetuses throughout the experimental period other than thinning of the labyrinth zone on GD 17. These results suggest that component cells of the basal and labyrinth zones during GDs 11-12 are more highly sensitive for methotrexate than those during GDs 13-14 and methotrexate affects the component cells of basal zone more strongly than those of the labyrinth zone.


Assuntos
Apoptose/efeitos dos fármacos , Antagonistas do Ácido Fólico/toxicidade , Metotrexato/toxicidade , Placenta/efeitos dos fármacos , Placenta/patologia , Animais , Feminino , Peso Fetal/efeitos dos fármacos , Imuno-Histoquímica , Marcação In Situ das Extremidades Cortadas , Exposição Materna/efeitos adversos , Gravidez , Ratos , Ratos Wistar
14.
J Appl Toxicol ; 33(9): 915-23, 2013 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22806879

RESUMO

Impaired folate metabolism is considered a risk factor for neural tube defects (NTDs). However, the relationship between folate deficiency and the risk of NTDs remains unclear, because experimentally induced dietary folate deficiency is insufficient to cause NTDs in non-mutant mice. Methotrexate (MTX) is a specific folate antagonist that competitively inhibits dihydrofolate reductase (DHFR) activity. The objective of this study was to develop a folate dysmetabolism murine model, and study the development of NTDs and its mechanism. Pregnant mice were injected with different doses of MTX [0, 0.5, 1.0, 3.0, 4.5 and 6.0 mg kg(-1) body weight (b/w) intraperitoneally (i.p.)] on gestational day 7.5 and sacrificed on gestational day 11.5. DHFR activity in embryonic tissues was detected, and folate concentrations were analyzed using LC/MS/MS. Copy number variations (CNVs) in neural tube tissues were detected using array comparative genomic hybridization (aCGH). A dose of MTX 4.5 mg kg(-1) b/w, resulted in the highest incidence of NTDs (31.4%) compared with the other groups, and DHFR activities, 5-MeTHF and 5-FoTHF concentrations in embryonic tissues decreased significantly after MTX injection. Furthermore, we found three high-confidence CNVs on chromosome X using aCGH, which was confirmed by RT-PCR and MassARRAY. These results indicate that MTX could cause a folate-associated dysmetabolism, which is similar to that of dietary folate deficiency in mice. The presence of CNVs in neural tube tissues was associated with the development of NTDs.


Assuntos
Antagonistas do Ácido Fólico/toxicidade , Instabilidade Genômica/efeitos dos fármacos , Metotrexato/toxicidade , Defeitos do Tubo Neural/patologia , Anormalidades Induzidas por Medicamentos/etiologia , Anormalidades Induzidas por Medicamentos/patologia , Animais , Cromatografia Líquida , Hibridização Genômica Comparativa , Variações do Número de Cópias de DNA/efeitos dos fármacos , Dieta , Relação Dose-Resposta a Droga , Desenvolvimento Embrionário/efeitos dos fármacos , Inibidores Enzimáticos/metabolismo , Feminino , Ácido Fólico/metabolismo , Antagonistas do Ácido Fólico/administração & dosagem , Deficiência de Ácido Fólico/metabolismo , Deficiência de Ácido Fólico/patologia , Masculino , Metotrexato/administração & dosagem , Camundongos , Camundongos Endogâmicos C57BL , Tubo Neural/efeitos dos fármacos , Tubo Neural/embriologia , Tubo Neural/patologia , Defeitos do Tubo Neural/induzido quimicamente , Defeitos do Tubo Neural/embriologia , Gravidez , Reação em Cadeia da Polimerase em Tempo Real , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem , Tetra-Hidrofolato Desidrogenase/metabolismo
15.
Expert Opin Drug Metab Toxicol ; 8(8): 959-72, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22594656

RESUMO

INTRODUCTION: Alcohol has long been suspected to be a triggering and precipitating factor of psoriasis. Alcohol misuse is common in patients with moderate-to-severe psoriasis and appears to impair treatment outcome. AREAS COVERED: In this article, the authors review the available data regarding the metabolic and toxicological interactions between anti-psoriasis systemic drugs and ethanol and/or alcoholic beverages. Special attention is given to the influence of alcohol consumption on the hepatotoxic risk of some anti-psoriasis drugs. The article was prepared using a MEDLINE literature search. EXPERT OPINION: The available knowledge highlights the existence of a few significant pharmacological interactions, such as the reduced exposure to cyclosporine by red wine, the possible increase of cyclosporine levels following a heavy acute alcohol intake, and, especially, the conversion of acitretin to etretinate, in the presence of ethanol, with important implications in females of child-bearing potential. There are limited data on the contributing role of alcohol in the hepatotoxicity induced by some anti-psoriasis drugs and the existing information on this topic is still controversial. However, further investigation is needed to assess the relevance of interactions between alcohol consumption and drug therapy for psoriasis, under both pharmacological and toxicological perspectives. Long-term prospective studies on large cohorts of patients are warranted to disclose the actual significance of such potential interactions in clinical practice.


Assuntos
Acitretina/toxicidade , Consumo de Bebidas Alcoólicas/efeitos adversos , Etanol/efeitos adversos , Etretinato/toxicidade , Ceratolíticos/toxicidade , Psoríase/tratamento farmacológico , Acitretina/metabolismo , Acitretina/farmacocinética , Administração Tópica , Consumo de Bebidas Alcoólicas/metabolismo , Doença Crônica , Etanol/metabolismo , Etretinato/metabolismo , Etretinato/farmacocinética , Antagonistas do Ácido Fólico/farmacocinética , Antagonistas do Ácido Fólico/toxicidade , Humanos , Ceratolíticos/farmacocinética , Pele/efeitos dos fármacos , Pele/patologia
16.
Birth Defects Res A Clin Mol Teratol ; 94(4): 187-207, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22434686

RESUMO

Methotrexate and aminopterin are folic acid antagonists that inhibit dihydrofolate reductase, resulting in a block in the synthesis of thymidine and inhibition of DNA synthesis. Methotrexate has been used for the treatment of malignancy, rheumatic disorders, and psoriasis and termination of intrauterine pregnancy. Recently, methotrexate has become a standard treatment for ectopic pregnancy. The misdiagnosis of an intrauterine pregnancy as an ectopic pregnancy can result in exposure of a continuing pregnancy to dose levels of methotrexate of 50 mg/m(2) (maternal body surface area). Experimental animal studies have associated methotrexate therapy with embryo death in mice, rats, rabbits, and monkeys. Structural malformations have been most consistently produced in rabbits at a maternal dose level of 19.2 mg/kg. Abnormalities in rabbits include hydrocephalus, microphthalmia, cleft lip and palate, micrognathia, dysplastic sacral and caudal vertebrate, phocomelia, hemimelia, syndactyly, and ectrodactyly. Based on human case reports of methotrexate exposure during pregnancy, a methotrexate embryopathy has been described that includes growth deficiency, microcephaly, hypoplasia of skull bones, wide fontanels, coronal or lambdoidal craniosynostosis, upswept frontal scalp hair, broad nasal bridge, shallow supraorbital ridges, prominent eyes, low-set ears, maxillary hypoplasia, epicanthal folds, short limbs, talipes, hypodactyly, and syndactyly. This syndrome may be associated with exposures between 6 and 8 weeks after conception and dose levels of 10 mg/week or greater. More recent case reports of methotrexate exposure for the misdiagnosis of ectopic pregnancy involve treatment before 6 weeks after conception and have raised the suggestion of a distinct syndrome due to such early exposures. Tetralogy of Fallot and perhaps other neural crest cell-related abnormalities may be features of this early syndrome. A disproportionality analysis of methotrexate and aminopterin case reports and series provides support for pulmonary atresia, craniosynostosis, and limb deficiencies as reported more often than expected in methotrexate-exposed children. Denominator-based data will be welcome to better define elements of a methotrexate embryopathy and possibly to distinguish an early exposure syndrome from anomalies traditionally associated with methotrexate exposure.


Assuntos
Anormalidades Induzidas por Medicamentos/etiologia , Anormalidades Múltiplas/induzido quimicamente , Metotrexato/toxicidade , Teratogênicos/toxicidade , Anormalidades Induzidas por Medicamentos/patologia , Anormalidades Múltiplas/patologia , Aminopterina/toxicidade , Animais , Feminino , Doenças Fetais/etiologia , Antagonistas do Ácido Fólico/toxicidade , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Gravidez , Complicações na Gravidez/tratamento farmacológico , Gravidez Ectópica/tratamento farmacológico , Coelhos , Ratos , Ratos Sprague-Dawley , Tetra-Hidrofolato Desidrogenase/efeitos dos fármacos
17.
Photochem Photobiol Sci ; 11(4): 653-60, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22234658

RESUMO

Nanoparticle (NP)-based targeted drug delivery involves cell-specific targeting followed by a subsequent therapeutic action from the therapeutic carried by the NP system. NPs conjugated with methotrexate (MTX), a potent inhibitor of dihydrofolate reductase (DHFR) localized in cytosol, have been under investigation as a delivery system to target cancer cells to enhance the therapeutic index of methotrexate, which is otherwise non-selectively cytotoxic. Despite improved therapeutic activity from MTX-conjugated NPs in vitro and in vivo, the therapeutic action of these conjugates following cellular entry is poorly understood; in particular it is unclear whether the therapeutic activity requires release of the MTX. This study investigates whether MTX must be released from a nanoparticle in order to achieve the therapeutic activity. We report herein light-controlled release of methotrexate from a dendrimer-based conjugate and provide evidence suggesting that MTX still attached to the nanoconjugate system is fully able to inhibit the activity of its enzyme target and the growth of cancer cells.


Assuntos
Dendrímeros/química , Antagonistas do Ácido Fólico/toxicidade , Metotrexato/toxicidade , Nanoconjugados/química , Tetra-Hidrofolato Desidrogenase/química , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Antagonistas do Ácido Fólico/síntese química , Antagonistas do Ácido Fólico/química , Humanos , Nanoconjugados/toxicidade , Neoplasias/tratamento farmacológico , Fotólise , Espectrofotometria Ultravioleta , Tetra-Hidrofolato Desidrogenase/metabolismo , Raios Ultravioleta
18.
Hum Exp Toxicol ; 30(8): 897-903, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-20813795

RESUMO

Thymoquinone is the major active component derived from Nigella sativa. Methotrexate is a folic acid antagonist widely used in clinic. Aim of this study was to investigate the possible protective role of thymoquinone on testicular toxicity of methotrexate. Experiments were performed on male C57BL/6 mice (6 weeks old, 20 ± 2 g). The animals were divided into four groups with six mice in each group. Equivalent volumes of saline were injected intraperitoneally (i.p.) in the control group. In the thymoquinone group, mice received thymoquinone i.p. with a dose of 10 mg/kg/day for 4 days. Mice in the methotrexate group received single dose of methotrexate i.p., with a dose of 20 mg/kg. Finally, in the methotrexate plus thymoquinone group, in the first and the following 3 days after methotrexate administration, thymoquinone was injected with a dose of 10 mg/kg/day, i.p. At the end of the experiment, the left testis was quickly removed and divided into two parts for histological examination and biochemical analysis. Methotrexate alone increased total antioxidant capacity and myeloperoxidase activity compared to the controls. Thymoquinone treatment decreased total antioxidant capacity and prevented the increase in the myeloperoxidase activity. Light microscopy showed in mice that receiving methotrexate resulted in interstitial space dilatation, edema, severe disruption of the seminiferous epithelium and reduced diameter of the seminiferous tubules. Administration of thymoquinone reversed histological changes of methotrexate significantly. We suggest that thymoquinone use may decrease the destructive effects of methotrexate on testicular tissue of patients using this agent.


Assuntos
Antioxidantes/farmacologia , Benzoquinonas/farmacologia , Antagonistas do Ácido Fólico/toxicidade , Metotrexato/toxicidade , Nigella sativa/química , Testículo/efeitos dos fármacos , Animais , Injeções Intraperitoneais , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Testículo/enzimologia , Testículo/metabolismo , Testículo/patologia
19.
Bioorg Med Chem ; 18(22): 7773-85, 2010 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-20951595

RESUMO

In the process of drug discovery the lead-identification phase may be critical due to the likely poor safety profile of the candidates, causing the delay or even the abandonment of a certain project. Nowadays, combining molecular modeling and in vivo cellular evaluation can help to identify compounds with an enhanced safety profile. Previously, two quinoxalines have been identified as inhibitors of the folate-dependent proteins belonging to the thymidylate synthase cycle. Unfortunately, cytotoxic activity against a panel of cisplatin(cDDP)-sensitive ovarian carcinoma cell lines and their resistant counterparts was coupled with toxicity to non-tumorigenic Vero cells. Here we describe the application of a ligand-based virtual screening, and several [1,2,4]triazolo[4,3-a]quinoxalines were optimized to improve their ADME-tox profile. The resulting 4-(trifluoromethyl)-1-p-tolyl-[1,2,4]triazolo[4,3-a]quinoxaline (24), which interferes intracellularly with DHFR and TS reducing the protein levels like 5-FU, but without inducing TS ternary complex formation, was 2-times less toxic in vitro than cisplatin and 5-FU.


Assuntos
Antagonistas do Ácido Fólico/química , Ácido Fólico/metabolismo , Ligantes , Quinoxalinas/química , Triazóis/química , Linhagem Celular Tumoral , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/toxicidade , Ácido Fólico/química , Antagonistas do Ácido Fólico/farmacocinética , Antagonistas do Ácido Fólico/toxicidade , Humanos , Quinoxalinas/farmacocinética , Quinoxalinas/toxicidade , Tetra-Hidrofolato Desidrogenase/química , Tetra-Hidrofolato Desidrogenase/metabolismo , Timidilato Sintase/antagonistas & inibidores , Timidilato Sintase/metabolismo , Triazóis/farmacocinética , Triazóis/toxicidade
20.
Food Chem Toxicol ; 48(7): 1973-9, 2010 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-20451574

RESUMO

Methotrexate (MTX) is a folic acid antagonist widely used as a cytotoxic chemotherapeutic agent for leukemia and other malignancies. The purpose of this study was to investigate the damage caused by MTX on liver mitochondria and its protection by using antioxidant properties of lipoic acid. MTX substantially affects mitochondrial function by reducing glutathione levels leading to disturbances in antioxidant enzyme defense system. Lipoic acid occurs naturally in mitochondria as a coenzyme. In various studies lipoic acid has been convincingly shown to exhibit an antioxidant role when supplemented exogenously. We studied the effect of lipoic acid pre-treatment on the toxicity of MTX in mouse liver mitochondria focusing specifically on the oxidative stress. MTX caused a significant rise in the mitochondrial lipid peroxidation (LPO), protein carbonyl (PC) content and superoxide radical generation. It also affected the mitochondrial thiol profile. Pre-treatment of mice with lipoic acid (35 mg/kg) markedly lowered mitochondrial LPO, PC content and superoxide radical generation. It also restored decreased enzymatic and non-enzymatic antioxidants of mitochondria. It is suggested that lipoic acid has a potential role in suppressing MTX-induced mitochondrial toxicity, and it affords protection either by reversing the decline of antioxidants or by the directly scavenging the free radicals.


Assuntos
Antagonistas do Ácido Fólico/toxicidade , Metotrexato/antagonistas & inibidores , Metotrexato/toxicidade , Mitocôndrias Hepáticas/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ácido Tióctico/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , DNA/metabolismo , Radicais Livres/metabolismo , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Técnicas In Vitro , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Oxirredução , Carbonilação Proteica/efeitos dos fármacos , Compostos de Sulfidrila/metabolismo , Superóxido Dismutase/metabolismo , Superóxidos/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
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