ABSTRACT
In modern drug discovery process, ADME/Tox properties should be determined as early as possible in the test cascade to allow a timely assessment of their property profiles. To help medicinal chemists in designing new compounds with improved pharmacokinetics, the knowledge of the soft spot position or the site of metabolism (SOM) is needed. In recent years, large number of in silico approaches for metabolism prediction have been developed and reported. Among these methods, QSAR models and combined quantum mechanics/molecular mechanics (QM/MM) methods for predicting drug metabolism have undergone significant advances. This review provides a perspective of the utility of QSAR and QM/MM approaches on drug metabolism prediction, highlighting the present challenges, limitations, and future perspectives in medicinal chemistry.
Subject(s)
Pharmaceutical Preparations/metabolism , Quantitative Structure-Activity Relationship , Quantum Theory , PharmacokineticsABSTRACT
Topotecan is an important cytotoxic drug that has gained broad acceptance in clinical use for the treatment of refractory ovarian and small-cell lung cancer. The lactone active form of topotecan can be hydrolyzed in vivo, decreasing the drug's therapeutic efficacy. Lipid encapsulation may promote in vivo stabilization by removing topotecan from aqueous media. Earlier reports of topotecan lipid nanoencapsulation have focused on liposomal encapsulation; however, the higher stability and cost-effectiveness of solid lipid nanoparticles (SLN) highlight the potential of these nanoparticles as an advantageous carrier for topotecan. The initial motivation for this work was to develop, for the first time, solid lipid nanoparticles and nanostructured lipid carriers (NLC) with a high drug loading for topotecan. A microemulsion technique was employed to prepare SLNs and NLCs and produced homogeneous, small size, negatively charged lipid nanoparticles with high entrapment efficiency and satisfactory drug loading. However, low recovery of topotecan was observed when the microemulsion temperature was high and in order to obtain high quality nanoparticles, and precise control of the microemulsion temperature is critical. Nanoencapsulation sustained topotecan release and improved its chemical stability and cytotoxicity. Surprisingly, there were no significant differences between the NLCs and SLNs, and both are potential carriers for topotecan delivery.
Subject(s)
Drug Delivery Systems , Nanoparticles/chemistry , Topoisomerase I Inhibitors/chemistry , Topotecan/chemistry , Cell Survival/physiology , Delayed-Action Preparations , Drug Carriers/chemistry , Drug Compounding , Drug Evaluation, Preclinical , Drug Stability , Emulsions/chemistry , Freeze Drying , Humans , K562 Cells , Lipids/chemistry , Nanoparticles/administration & dosage , Nanoparticles/toxicity , Nanostructures/analysis , Nanostructures/chemistry , Nanostructures/toxicity , Particle Size , Solubility , Surface Properties , Temperature , Topoisomerase I Inhibitors/administration & dosage , Topoisomerase I Inhibitors/metabolism , Topoisomerase I Inhibitors/toxicity , Topotecan/administration & dosage , Topotecan/metabolism , Topotecan/toxicity , Trypan BlueABSTRACT
OBJECTIVES: To examine the association between methylenetetrahydrofolate reductase (MTHFR) (C677T and A1298C), methionine synthase (MTR) A2756G and methionine synthase reductase (MTRR) A66G gene polymorphisms and total homocysteine (tHcy), methylmalonic acid (MMA) and S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) levels; and to evaluate the potential interactions with folate or cobalamin (Cbl) status. SUBJECTS/METHODS: Two hundred seventy-five healthy women at labor who delivered full-term normal babies. Cbl, folate, tHcy, MMA, SAM and SAH were measured in serum specimens. The genotypes for polymorphisms were determined by PCR-restriction fragment length polymorphism (RFLP). RESULTS: Serum folate, MTHFR 677T allele and MTR 2756AA genotypes were the predictors of tHcy levels in pregnant women. Serum Cbl and creatinine were the predictors of SAM/SAH ratio and MMA levels, respectively. The gene polymorphisms were not determinants for MMA levels and SAM/SAH ratios. Low levels of serum folate were associated with elevated tHcy in pregnant women, independently of the gene polymorphisms. In pregnant women carrying MTHFR 677T allele, or MTHFR 1298AA or MTRR 66AA genotypes, lower Cbl levels were associated with higher levels of tHcy. Lower SAM/SAH ratio was found in MTHFR 677CC or MTRR A2756AA genotypes carriers when Cbl levels were lower than 142 pmol/l. CONCLUSIONS: Serum folate and MTHFR C677T and MTR A2576G gene polymorphisms were the determinants for tHcy levels. The interaction between low levels of serum Cbl and MTHFR (C677T or A1298C) or MTRR A66G gene polymorphisms was associated with increased tHcy.
Subject(s)
5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase/genetics , Ferredoxin-NADP Reductase/genetics , Homocysteine/blood , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Polymorphism, Restriction Fragment Length , Pregnancy/blood , Adolescent , Adult , Alleles , Analysis of Variance , Female , Folic Acid/blood , Gene Frequency , Genotype , Humans , Methylmalonic Acid/blood , Polymerase Chain Reaction , Pregnancy/genetics , S-Adenosylhomocysteine/blood , S-Adenosylmethionine/blood , Vitamin B 12/blood , Young AdultABSTRACT
Este artigo tem como objetivo apresentar os procedimentos básicos para se escrever um artigo técnico-científico, bem como indicar os principais erros cometidos por quem escreve um artigo, visando com isto, facilitar o ingresso dos jovens no campo da divulgação científica (AU)
ABSTRACT
O presente artigo traz uma análise do processo do aprendizado da conscienciologia, comparando o grau de entendimento dos seus conteúdos e, verificando a existência de pelo menos duas possibilidades de compreensão dos postulados desta ciência, uma superficial e calcada na maneira convencional de se ver o mundo e, outra, mais profunda, embasada na apreensão integral das idéias desta ciência (AU)
