Thermodynamic parameters of complexation of naphto-15-crown-5 with four alkaline earth ions in aqueous media was determined using titration microcalorimetry at 298.15 K. The stability of the complexes, thermal effect and entropy effect of the complexation is discussed on the basis of the guest ions structure and the solvent effect. The stability constants tendency to vary with ion radius was interpreted. Complex of naphtha-15-crown-5 with calcium ion is very stable due to the synergism of static electric interaction and size selectivity between the host and the guest.
Calorimetry ; methods ; Crown Ethers ; chemistry ; Ions ; chemistry ; Macromolecular Substances ; analysis ; chemistry ; Metals, Alkaline Earth ; chemistry ; Microchemistry ; methods

Amines ; chemistry ; isolation & purification ; Amino Alcohols ; chemistry ; isolation & purification ; Anti-Bacterial Agents ; Avidin ; chemistry ; isolation & purification ; Crown Ethers ; Cyclodextrins ; chemistry ; Electrophoresis, Capillary ; methods ; Polysaccharides ; Serum Albumin ; Stereoisomerism

Clinical studies have established the clinical application of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) adjuvant targeted therapy. Compared with chemotherapy, the high efficiency and low toxicity of targeted therapy increases the survival benefit of patients. Icotinib was the first EGFR-TKI with independent intellectual property rights in China and the third EGFR-TKI to be marketed in the world. In order to summarize the experience of icotinib and other EGFR-TKIs in the adjuvant treatment of non-small cell lung cancer and further standardize and guide the clinical application of icotinib, experts from the China International Exchange and Promotive Association for Medical and Health Care and the Guangdong Association of Thoracic Diseases have organized an expert consensus on the adjuvant treatment of non-small cell lung cancer with icotinib, which is expected to provide clinicians with evidence-based medical evidences for postoperative targeted drug using.
Humans ; Carcinoma, Non-Small-Cell Lung ; Lung Neoplasms/surgery* ; Consensus ; Mutation ; ErbB Receptors/genetics* ; Crown Ethers/therapeutic use* ; Protein Kinase Inhibitors/therapeutic use*

BACKGROUNDThe preclinical experiments and studies of congener drugs show icotinib, a new epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, can specifically bind to the tyrosine kinase domain of the EGFR, block the EGFR related signal, thereby inhibit the growth of tumor cell. The objective of this study was to investigate the safety, tolerability and dose-related biologic effects of icotinib in patients with non-small cell lung cancer (NSCLC) in a Chinese patient population.

METHODSThis was an open-label, phase I, dose escalation, safety/tolerability trial of oral icotinib (100 to 400 mg), administered twice per day for 28-continuous-day cycles until disease progression or undue toxicity.

RESULTSForty patients with stage IIIB (15%) or IV (85%) NSCLC were included in the study. They had mainly adenocarcinoma (85%), with a performance status (PS) of 0 (45%) or 1 (55%) and less than half the patients (45%) had histories of smoking and all were pretreated by at least one regimen of chemotherapy. Patients were assigned to three dose levels of 150 mg b.i.d, 200 mg b.i.d, or 125 mg t.i.d. The follow-up periods ranged from 5 to 80 weeks. Adverse events were found in 35% patients, most of which were mild and reversible. The adverse events mainly occurred in the first 4 weeks and included rash (25%), diarrhea, nausea and abdominal distention. One definite interstitial lung disease (ILD) was found in a patient in the dose of 200 mg b.i.d. According to an 8-week assessment, one (2.5%) patient receiving 150 mg gained complete response (CR) that persisted for 44 weeks, seven (17.50%) patients had partial remission (PR), and 18 (45%) patients had stable disease (SD). The objective response including CR + PR was 20%. The median time of progression-free survival for the 40 patients was 20 weeks (range: 12 to 32 weeks). The response was not affected by pathological type, history of smoking, or numbers of previous therapeutic regimens. No relationship between dose, response, adverse effect, or duration of the study was observed.

CONCLUSIONSIcotinib, given as oral twice daily, showed favorable safety and tolerability. Mild and reversible rash, diarrhea, and nausea were the main adverse events. Antitumor activity was obvious at each dose in heavily pretreated patients. Pharmacodynamic evaluations and further phase II/III trials are in progress.

Aged ; Aged, 80 and over ; Antineoplastic Agents ; therapeutic use ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; mortality ; pathology ; Crown Ethers ; therapeutic use ; Disease-Free Survival ; Female ; Humans ; Male ; Middle Aged ; Quinazolines ; therapeutic use ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors

OBJECTIVETo guide the optimal selection among first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in clinical practice. This review attempted to provide a thorough comparison among three first-generation EGFR-TKIs, namely icotinib, erlotinib, and gefitinib, with regard to their molecular structure, pharmacokinetic parameters, clinical data, adverse reactions, and contraindications.

DATA SOURCESAn electronic literature search of the PubMed database and Google Scholar for all the available articles regarding gefitinib, icotinib, and erlotinib in the English language from January 2005 to December 2014 was used.

STUDY SELECTIONThe search terms or keywords included but not limited to "lung cancer", "nonsmall cell lung cancer (NSCLC)", "epidemiology", "EGFR", "TKIs", and "optimal selection ".

RESULTSAs suggested by this review, even though the three first-generation EGFR-TKIs share the quinazoline structure, erlotinib had the strongest apoptosis induction activity because of its use of a different side-chain. The pharmacokinetic parameters indicated that both erlotinib and icotinib are affected by food. The therapeutic window of erlotinib is narrow, and the recommended dosage is close to the maximum tolerable dosage. Icotinib enjoys a wider therapeutic window, and its concentration in the blood is within a safe dosage range even if it is administered with food. Based on multiple large-scale clinical trials, erlotinib is universally applied as the first-line treatment. In marked contrast, icotinib is available only in China as the second- or third-line therapeutic approach for treating advanced lung cancer. In addition, it exhibits a similar efficacy but better safety profile than gefitinib.

CONCLUSIONSAlthough there is a paucity of literature regarding whether icotinib is superior to erlotinib, its superior toxicity profile, noninferior efficacy, and lower cost indicate that it is a better alternative for Chinese patients living with advanced NSCLC.

Carcinoma, Non-Small-Cell Lung ; drug therapy ; Crown Ethers ; therapeutic use ; Erlotinib Hydrochloride ; therapeutic use ; Humans ; Lung Neoplasms ; drug therapy ; Protein Kinase Inhibitors ; therapeutic use ; Quinazolines ; therapeutic use ; Treatment Outcome

Acrylamides ; therapeutic use ; Aged ; Aniline Compounds ; therapeutic use ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; genetics ; Crown Ethers ; therapeutic use ; ErbB Receptors ; genetics ; metabolism ; Female ; Humans ; Lung Neoplasms ; drug therapy ; genetics ; Mutation ; genetics ; Quinazolines ; therapeutic use

BACKGROUNDThe preclinical experiments and several clinical studies showed icotinib, an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in Chinese patients with advanced non-small cell lung cancer (NSCLC) who failed previous chemotherapy. We performed a retrospective study of the efficacy and safety of icotinib monotherapy in a different and more recent sample of Chinese patients.

METHODSThe clinical data of 149 patients with advanced NSCLC who were admitted to Zhejiang Cancer Hospital from August 1, 2011 to July 31, 2012 were retrospectively analyzed. All patients were given icotinib treatment after the failure of previous chemotherapy. Univariate and multivariate analyses were conducted based on the Kaplan Meier method and Cox proportional hazards model.

RESULTSThe objective response rate was 33/149 and disease control rate was 105/149. No complete response occurred. Median progression free survival (PFS) with icotinib treatment was 5.03 months (95% CI: 3.51 to 6.55). Median overall survival was 12.3 months (95% CI: 10.68 to 13.92). Multivariate analysis showed that the mutation of EGFR and one regimen of prior chemotherapy were significantly associated with longer PFS. At least one drug related adverse event was observed in 65.8% (98/149) of patients, but mostly grade 1 or 2 and reversible and none grade 4 toxicity.

CONCLUSIONSIcotinib monotherapy is an effective and well tolerated regimen for Chinese patients with NSCLC after the failure of chemotherapy. It is a promising agent and further study with icotinib in properly conducted trials with larger patient samples and other ethnic groups is warranted.

Adult ; Aged ; Aged, 80 and over ; Antineoplastic Agents ; adverse effects ; therapeutic use ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; Crown Ethers ; adverse effects ; therapeutic use ; Female ; Humans ; Lung Neoplasms ; drug therapy ; Male ; Middle Aged ; Multivariate Analysis ; Proportional Hazards Models ; Quinazolines ; adverse effects ; therapeutic use ; Retrospective Studies

Human protein tyrosine kinases play an essential role in carcinogenesis and have been recognized as promising drug targets. By the end of 2012, eight small molecule tyrosine kinase inhibitors (TKIs) have been approved by State Food and Drug Administration of China for cancer treatment. In this paper, the pharmacokinetic characteristics (absorption, distribution, metabolism and excretion) and drug-drug interactions of the approved TKIs are reviewed. Overall, these TKIs reach their peak plasma concentrations relatively fast; are extensively distributed and highly protein bound (> 90%); are primarily metabolized by CYP3A4; most are heavily influenced by CYP3A4 inhibitors or inducers except for sorafenib; are mainly excreted with feces and only a minor fraction is eliminated with the urine; and are substrate of the efflux transporters ABCB1 (P-gp) and ABCG2 (BCRP). Additionally, many of the TKIs can inhibit some CYP450 enzymes, UGT enzymes, and transporters. Gefitinib, erlotinib, dasatinib, and sunitinib are metabolized to form reactive metabolites capable of covalently binding to biomolecules.
Antineoplastic Agents ; pharmacokinetics ; pharmacology ; Crown Ethers ; pharmacokinetics ; pharmacology ; Cytochrome P-450 Enzyme System ; metabolism ; Dasatinib ; pharmacokinetics ; pharmacology ; Drug Interactions ; Erlotinib Hydrochloride ; pharmacokinetics ; pharmacology ; Glucuronosyltransferase ; metabolism ; Humans ; Imatinib Mesylate ; pharmacokinetics ; pharmacology ; Indoles ; pharmacokinetics ; pharmacology ; Niacinamide ; analogs & derivatives ; pharmacokinetics ; pharmacology ; Phenylurea Compounds ; pharmacokinetics ; pharmacology ; Protein Kinase Inhibitors ; pharmacokinetics ; pharmacology ; Protein-Tyrosine Kinases ; antagonists & inhibitors ; Pyrimidines ; pharmacokinetics ; pharmacology ; Pyrroles ; pharmacokinetics ; pharmacology ; Quinazolines ; pharmacokinetics ; pharmacology

BACKGROUNDMolecular targeted drugs is now widely used in non-small cell lung cancer (NSCLC) clinical treatment. Icotinib hydrochloride is a new type of oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs). In this study, we examined the role of EGFR, K-RAS, B-RAF somatic mutations and EGFR mRNA expression in tumor specimens from advanced NSCLC patients as predicators of the efficacy of icotinib hydrochloride.

METHODSWe analyzed tumor paraffin-embedded specimens, which were obtained from 14 of 40 patients with advanced NSCLC who enrolled in the stage I clinical trial of icotinib hydrochloride. Somatic mutations were evaluated by mutant-enriched liquidchip (MEL) technology, and EGFR mRNA expression was measured by branched DNA liquidchip (MBL) technology.

RESULTSIn the 14 specimens, seven patients showed EGFR mutations, exon 19 deletion (3/7) and exon 21 point mutation (4/7); and two patients showed K-RAS mutation. No mutations in EGFR exon 20 or B-RAF were detected. In patients with EGFR mutation, one patient developed progress disease (PD), three patients had stable disease (SD), two patients had partial responses (PR) and one patient had a complete response (CR). In patients with wild-type EGFR, four patients had PD, three patients acquired SD, and none had PR/CR (P = 0.0407). EGFR mutations were associated with better progress-free survival (PFS) (141 days vs. 61 days) but without a statistically significant difference (P = 0.8597), and median overall survival (OS) (≥ 449 days vs. 140 days). EGFR mRNA expression levels were evaluated (three high, eight moderate, one low, and two that can not be measured due to insufficient tumor tissue) and no statistically significant relationships was observed with response, PFS or OS.

CONCLUSIONSThe EGFR mutation rate was consistent with that reported in the Asian population, so the MEL technology is reliable for measuring EGFR mutation with high throughput and rapidity. EGFR exon 19 deletions and exon 21 point mutation are predictive biomarkers for response to icotinib hydrochloride as second line treatment or above.

Adult ; Aged ; Antineoplastic Agents ; therapeutic use ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; genetics ; Crown Ethers ; therapeutic use ; Exons ; genetics ; Female ; Humans ; Male ; Middle Aged ; Mutation ; Proto-Oncogene Proteins B-raf ; genetics ; Proto-Oncogene Proteins p21(ras) ; genetics ; Quinazolines ; therapeutic use ; RNA, Messenger ; genetics ; Receptor, Epidermal Growth Factor ; genetics

Animals ; Antibodies, Monoclonal ; Carcinoma, Non-Small-Cell Lung ; drug therapy ; Crown Ethers ; therapeutic use ; Drug Resistance, Neoplasm ; Erlotinib Hydrochloride ; Humans ; Immunoglobulins, Intravenous ; therapeutic use ; Lung Neoplasms ; drug therapy ; Molecular Targeted Therapy ; Mutation ; Precision Medicine ; Protein Kinase Inhibitors ; therapeutic use ; Pyrazoles ; therapeutic use ; Pyridines ; therapeutic use ; Quality Control ; Quinazolines ; therapeutic use ; Receptor, Epidermal Growth Factor ; antagonists & inhibitors ; genetics