Phase I study of lapatinib plus trametinib in patients with KRAS -mutant colorectal,non-small cell lung,and pancreatic cancer

KRAS oncogene mutations cause sustained signaling through the MAPK pathway. Concurrent inhibition of MEK, EGFR, and HER2 resulted in complete inhibition of tumor growth in KRAS-mutant (KRASm) and PIK3CA wild-type tumors, in vitro and in vivo. In this phase I study, patients with advanced KRASm and PIK3CA wild-type colorectal cancer (CRC), non-small cell lung cancer (NSCLC), and pancreatic cancer, were treated with combined lapatinib and trametinib to assess the recommended phase 2 regimen (RP2R). Patients received escalating doses of continuous or intermittent once daily (QD) orally administered lapatinib and trametinib, starting at 750 mg and 1 mg continuously, respectively. Thirty-four patients (16 CRC, 15 NSCLC, three pancreatic cancers) were enrolled across six dose levels and eight patients experienced dose-limiting toxicities, including grade 3 diarrhea (n = 2), rash (n = 2), nausea (n = 1), multiple grade 2 toxicities (n = 1), and aspartate aminotransferase elevation (n = 1), resulting in the inability to receive 75% of planned doses (n = 2) or treatment delay (n = 2). The RP2R with continuous dosing was 750 mg lapatinib QD plus 1 mg trametinib QD and with intermittent dosing 750 mg lapatinib QD and trametinib 1.5 mg QD 5 days on/2 days off. Regression of target lesions was seen in 6 of the 24 patients evaluable for response, with one confirmed partial response in NSCLC. Pharmacokinetic results were as expected. Lapatinib and trametinib could be combined in an intermittent dosing schedule in patients with manageable toxicity. Preliminary signs of anti-tumor activity in NSCLC have been observed and pharmacodynamic target engagement was demonstrated.     

高效液相色谱法测定人血浆中阿莫西林浓度及药代动力学

高效液相色谱法测定人血浆中阿莫西林浓度及药代动力学谭力周继红罗楠袁倚盛（南京军区南京总医院中心仪器分析科，南京２１０００１）阿莫西林（ａｍｏｘｉｃｉｌｉｎ）为β内酰胺类抗生素，其抗菌谱广，口服受食物影响小，对大多数病人耐受性良好，因而在临床上得以广泛...     

Effect of cisplatin-containing chemotherapy on lithium serum concentrations.

OBJECTIVE: A case in which a possible cisplatin interference with lithium pharmacokinetics is evaluated. DATA SYNTHESIS: A 36-year-old woman with disseminated cervical cancer and multiple metastatic lesions in both kidneys was being treated with five courses of bleomycin, vindesine, mitomycin C, and cisplatin. The patient had also been taking lithium carbonate for the management of a manic-depressive disorder. Serum and urinary lithium concentrations were measured daily during the first course of chemotherapy and on a periodic basis during and between the consecutive courses. Lithium concentrations remained within the therapeutic range during the first course and increased later in association with deterioration of the patient's renal function secondary to progressive disease in both kidneys. This required dose adjustments of lithium. CONCLUSIONS: Lithium therapy should be guided by serial serum concentrations in such patients.     

Decomposition of mitomycin and anthracycline cytostatics in cell culture media

The chemical stability of members of two groups of cytostatics, mitomycins and anthracyclines, has been studied in four different cell culture media enriched with serum. Stability was determined with the use of high performance liquid chromatography. In the group of mitomycins, the 7-aminomitosanes appeared to be relatively stable during a seven days incubation period at 37 degrees C when compared to the 7-methoxy congeners. The anthracycline derivatives, 4-demethoxy-daunorubicin, doxorubicin and its 4'-analogues showed half-lives of about 10-20 hours. Doxorubicinol and daunorubicin were found to be more stable. Anthracycline degradation products could be traced with the use of thin layer chromatography. All main degradation products originate from hydrolytic reactions. No enzymatic conversions could be observed. These observations may be of importance for the correct interpretation of the effects of mitomycins or anthracyclines on cells incubated in a cell culture medium.     

抗胆碱药3-(2-苯基-2-环戊基-2-羟基-乙氧基)奎宁环烷的立体化学和构效关系

研究了强效抗胆碱药dl-3-(2-苯基-2-环戊基-2-羟基-乙氧基)-奎宁环烷的四个光学异构体的两种不对称合成方法,用HPLC检测了异构体含量,讨论了构效关系。     

Application of a radioimmunoassay for determination of levels of zalcitabine (ddC) in human plasma, urine, and cerebrospinal fluid.

A specific and sensitive radioimmunoassay for the determination of levels of zalcitabine in human plasma, urine, and cerebrospinal fluid has been developed. Commercially available radiolabel and antiserum (Sigma Chemicals) were used after dilution in assay buffer. Prior to the immunoassay, standard and patient samples were subjected to solid-phase extraction on silica columns in order to obtain purified samples. The lower limit of quantitation was determined to be 1 ng/ml. Intra- and interassay variations were less than 11% for a number of quality control samples of drug in plasma and urine. Results from parallelism studies with plasma and urine demonstrated that samples outside the standard range (1 to 30 ng/ml) could be diluted by blank plasma or assay buffer, respectively. A large number of related compounds and potentially coadministered drugs were tested for cross-reactivity. Stability tests showed that heat treatment for 30 min at 60 degrees C or storage for 1 month at -30 degrees C did not affect zalcitabine concentrations in plasma or urine. The radioimmunoassay with solid-phase extraction for sample cleanup discussed here has been successfully applied in a pharmacokinetic study of a single patient, demonstrating its applicability for clinical pharmacokinetic research with zalcitabine.