Pharmaceutical applications of computer-aided methods in analytical spectroscopy and liquid chromatography

SIGLEAvailable from British Library Document Supply Centre- DSC:D65153/86 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Research Article - Evaluation of Dimethylformamide (DMF) as an Organic Modifier in Hydrophobicity Index (Rm) Determination

Purpose: Ideal behaviour of mixtures of organic modifier and water is reflected by a linear relationship between refractive index and fraction of organic modifier in the mixture. This study was carried out to investigate dimethylformamide (DMF) as an organic modifier in hydrophobicity index (Rm) determination. Method: We quantitatively evaluated the problem of partial miscibility of phases associated with the reversed phase thin layer chromatographic (RPTLC) system, using liquid paraffin as stationary phase and acetone/water mixtures as mobile phase. Ideality of behaviour of acetone/water mixtures was investigated by refractive index measurements. Rm values of compounds were determined using mixtures of acetone and water as mobile phase. Results: DMF/water mixture behaved ideally across the whole concentration range investigated (0-100%) while acetone/water mixture deviated from ideal behaviour when the concentration of acetone in the mixture was 80%. DMF also gave a better extrapolation of Rm value from linear regression of partition data than acetone for bezafibrate used as a test-drug molecule. Conclusion: DMF is a better organic modifier than acetone in this RPTLC system. These findings could be extended to drug-receptor and drug design studies. The use of dimethylformamide (DMF) in preference to acetone as organic modifier is proposed in this study

TAK-264 (MLN0264) in previously treated Asian patients with advanced gastrointestinal carcinoma expressing guanylyl cyclase C: Results from an open-label, non-randomized phase 1 study

Purpose This phase 1 dose-escalation portion of the study evaluated the safety, pharmacokinetics (PK), and antitumor activity of TAK-264 in Asian patients with advanced gastrointestinal (GI) carcinoma or metastatic or recurrent gastric or gastroesophageal junction adenocarcinoma expressing guanylyl cyclase C (GCC). Materials and Methods Adult patients with advanced GI malignancies expressing GCC (H-score >= 10) received TAK-264 on day 1 of 3-week cycles as 30-minute intravenous infusions for up to 1 year or until disease progression or unacceptable toxicity. The primary objectives were to evaluate the safety profile including dose-limiting toxicities (DLTs) during cycle 1, determine the maximum tolerated dose (MTD), and characterize the PK profile of TAK-264. Results Twelve patients were enrolled and treated with 1.2 mg/kg (n=3), 1.5 mg/kg (n=3), or 1.8 mg/kg TAK-264 (n=6). Median number of treatment cycles received was two (range, 1 to 10). None of the patients experienced a DLT and the MTD was not determined. Ten patients (83%) experienced adverse events (AEs). The most common were neutropenia, anorexia, and nausea (each reported by four patients). Five patients (42%) experienced grade. 3 AEs consisting of tumor hemorrhage and hypertension, ascites, adrenal insufficiency, neutropenia and asthenia. Serum exposure to TAK-264 increased proportionally with the dose and the median half-life was approximately 5.5-6.6 days. No patients experienced an objective response. Conclusion TAK-264 demonstrated a manageable safety profile with limited antitumor activity consistent with studies conducted in Western patients with advanced GI malignancies. TAK-264 exposure increased proportionally with the dose