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Methotrexate (MTX) is a folate antagonist drug used for several diseases, such as cancers, various ma-lignancies, rheumatoid arthritis (RA) and inflammatory bowel disease. Due to its structural features, including the presence of two carboxylic acid groups and its low native fluorescence, there are some challenges to develop analytical methods for its determination. MTX is metabolized to 7-hydroxymethotrexate (7-OH-MTX), 2,4-diamino-N10-methylpteroic acid (DAMPA), and the active MTX polyglutamates (MTXPGs) in the liver, intestine, and red blood cells (RBCs), respectively. Additionally, the drug has a narrow therapeutic range; hence, its therapeutic drug monitoring (TDM) is necessary to regulate the pharmacokinetics of the drug and to decrease the risk of toxicity. Due to environmental toxicity of MTX; its sensitive, fast and low cost determination in workplace environments is of great interest. A large number of methodologies including high performance liquid chromatography equipped with UV-visible, fluorescence, or electrochemical detection, liquid chromatography-mass spectroscopy, capillary electrophoresis, UV-visible spectrophotometry, and electrochemical methods have been developed for the quantitation of MTX and its metabolites in pharmaceutical, biological, and environ-mental samples. This paper will attempt to review several published methodologies and the instru-mental conditions, which have been applied to measure MTX and its metabolites within the last decade.
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Objective: To optimize and establish the best hydrolysis method of diethyl ester 4-amino-N5-formyl-N8,N10-dideazatetrahydrofolate through the optimization of simple compound of diethyl N-(4-aminobenzoyl)-L-glutamate.Methods: To increase the low yield of hydrolysis reaction of diethyl ester 4-amino-N5-formyl-N8,N10-dideazatetrahydrofolate due to the by-products and difficult purification, we studied the effect of NaOH and KOH, two kinds of alkalis, three concentrations between 0.175-1 mol/L and five types of reaction time involved in 20, 30, 60, 120 and 180 min on the common side chain diethyl N-(4-aminobenzoyl)-L-glutamate.A high performance liquid chromatography was established for measuring the target product and the by-products in reaction liquid in different reaction conditions.Finally, on the basis of the best hydrolysis method of diethyl ester 4-amino-N5-formyl-N8,N10-dideazatetrahydrofolate, we completed the optimization of the hydrolysis reaction conditions of diethyl ester 4-amino-N5-formyl-N8,N10-dideazatetrahydrofolate.Results: We developed the best reaction condition for the hydrolysis of diethyl ester 4-amino-N5-formyl-N8,N10-dideazatetrahydrofolate, which could be carried out easily and efficiently.The results indicated that treated with the optimized condition of 0.3 mol/L KOH in 60 min at the room temperature, diethyl ester 4-amino-N5-formyl-N8,N10-dideazatetrahydrofolate was converted into its diacid derivative in 95.6 % yield, which turned to be a better reaction condition compared with the previous reaction condition.The structures of those compounds were identified to be correct by 1H nuclear magnetic resonance(1H NMR), 13C nuclear magnetic resonance(13C NMR) and electrospray ionization time of flight mass spectrometry (ESI-MS).The purity of the diacid derivative of the compound was determined to be 96% by high performance liquid chromatography(HPLC).The new hydrolysis reaction condition could not only avoid the formation of single ester hydrolysis product and amide bond hydrolysis product, but also improve the yield of the hydrolysis reaction.Conclusion: We have developed an efficient reaction for the hydrolysis of diethyl ester 4-amino-N5-formyl-N8,N10-dideazatetrahydro.Since the final step of the synthesis of classical folic acid antagonists is always the catalyzed hydrolysis of the side chain glutamate, the reaction also has great significance for anti-folic acid anti-tumor inhibitors synthesis.
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Ronald Woodroof died of AIDS in September 12, 1992, seven years after he was diagnosed. A lower dose of AZT became widely used in later drug combinations that saved millions of lives". These words end the film Dallas Buyers Club, a recent, highly awarded movie, that tells the true story of a cowboy diagnosed with AIDS in 1985 and illegally receives the firsthand antiviral AZT but, due to the severe side effects that the drug afflicted, begins to experiment with and illicitly distribute among the "Club" non-FDA approved remedies in search of a better treatment for himself and other AIDS patients. Perhaps owing to an artistic strategy, the movie waits until the last couple of lines to do justice to AZT and the impact it had in dealing with AIDS at that day and age
Asunto(s)
Humanos , Antígenos VIH , Zidovudina , Fármacos Anti-VIH , AntirretroviralesRESUMEN
<p><b>OBJECTIVE</b>To compare the applicability of the SYBR Green-I assay with the standard schizont maturation assay, for determination of sensitivity of Plasmodium vivax (P. vivax) to chloroquine and a new antifolate WR 99210.</p><p><b>METHODS</b>The study was conducted at Mae Tao Clinic for migrant workers, Tak Province during April 2009 to July 2010. A total of 64 blood samples (1 mL blood collected into sodium heparinized plastic tube) were collected from patients with mono-infection with P. vivax malaria prior to treatment with standard regimen of a 3-day chloroquine. In vitro sensitivity of P. vivax isolates was evaluated by schizont maturation inhibition and SYBR Green-I assays.</p><p><b>RESULTS</b>A total of 30 out of 64 blood samples collected from patients with P. vivax malaria were successfully analyzed using both the microscopic schizont maturation inhibition and SYBR Green-I assays. The failure rates of the schizont maturation inhibition assay (50%) and the SYBR Green-I assay (54%) were similar (P=0.51). The median IC10s, IC50s and IC90s of both chloroquine and WR99210 were not significantly different from the clinical isolates of P. vivax tested. Based on the cut-off of 100 nM, the prevalences of chloroquine resistance determined by schizont maturation inhibition and SYBR Green-I assays were 19 and 11 isolates, respectively. The strength of agreement between the two methods was very poor for both chloroquine and WR99210.</p><p><b>CONCLUSIONS</b>On the basis of this condition and its superior sensitivity, the microscopic method appears better than the SYBR Green-I Green assay for assessing in vitro sensitivity of fresh P. vivax isolates to antimalarial drugs.</p>