linagliptin and Neoplasms

Presently cancer is a grave health issue with predominance beyond restrictions. It can affect any organ of the body. Most of the available chemotherapeutic drugs are highly toxic, not much selective and eventually lead to the development of resistance. Therefore, a target specific palliative approach for the treatment of cancer is required. Remarkable advancements in science have illuminated various molecular pathways responsible for cancer. This has resulted in abundant opportunities to develop targeted anticancer agents. Quinazoline nucleus is a privileged scaffold with significant diversified pharmacological activities. Numerous established anticancer quinazoline derivatives constitute a new class of chemotherapeutic agents which are found to act by inhibiting various protein kinases as well as other molecular targets. A recent update on various quinazoline derivatives acting on different types of molecular targets for the treatment of cancer has been compiled in this review. Brief SAR studies of quinazoline derivatives acting through different mechanisms of action have been highlighted. The comprehensive medicinal chemistry aspects of these agents in this review provide a panoramic view to the biologists as well as medicinal chemists working in this area and would assist them in their efforts to design and synthesize novel quinazoline based anticancer compounds.

Topics: Animals; Antineoplastic Agents; Cell Proliferation; Enzyme Inhibitors; Humans; Molecular Structure; Neoplasms; Quinazolines

Dipeptidyl peptidase (DPP)-4 inhibitors are an increasingly used antihyperglycemic therapy for patients with type 2 diabetes mellitus (T2DM). Linagliptin, an orally administered DPP-4 inhibitor, has demonstrated favorable efficacy/safety in clinical trials. The aim of this post hoc pooled analysis was to expand current knowledge of the safety of linagliptin.. Safety data for once-daily linagliptin 5 mg (1 study of linagliptin 2.5 mg twice daily) were analyzed from 22 randomized, double-blind, Phase I-III, placebo-controlled clinical trials of ≤102 weeks' duration. Assessments of pooled data included incidence of patient-reported adverse events (AEs).. Data from 7400 patients (linagliptin, 4810; placebo, 2590) were pooled. Most patients (58.4%) had T2DM diagnosis for >5 years; approximately 75% were receiving ≥1 type of background therapy in addition to linagliptin/placebo. Overall exposure to the study drug was 2412.8 years for linagliptin and 1481.4 years for placebo (mean [SD], 183 [120] days and 209 [150] days, respectively). Overall frequencies of AEs were similar for linagliptin- and placebo-treated patients (57.3% and 61.8%, respectively). The incidence of neoplastic AEs was low (0.6% and 0.9%, respectively); there were no reports of pancreatic neoplasia. Pancreatitis was observed in 2 linagliptin-treated patients (<0.1%) and 1 placebo-treated patient (<0.1%). The occurrence of cardiac disorder AEs was similar in linagliptin- and placebo-treated patients (3.2% [n = 153] and 3.3% [n = 83], respectively); the incidence of heart failure AEs for linagliptin- and placebo-treated patients was 0.2% (n = 11) and 0.3% (n = 7), respectively. Overall, linagliptin was weight neutral. Occurrence of investigator-defined hypoglycemic AEs was low for both linagliptin and placebo (11.5% vs 14.0%). In patients receiving concomitant sulfonylurea therapy, investigator-defined hypoglycemic AEs were more frequent with linagliptin versus placebo (22.1% [238/1079] vs 14.5% [61/421], respectively). Subgroup analyses showed similar frequencies of AEs for linagliptin- and placebo-treated patients across different age groups and renal function levels.. This updated and expanded pooled, post hoc analysis of 22 placebo-controlled trials of linagliptin 5 mg daily supports previous findings of the acceptable overall safety/tolerability profile of linagliptin when administered to a broad range of patients with T2DM. Linagliptin-treated patients demonstrated a low overall risk of hypoglycemia (risk increased by concomitant sulfonylurea therapy). As with all pooled analyses, this study is limited by the use of data from different studies, and the relatively short duration of some included studies, although use of individual patient data from consistently designed trials should minimize methodological differences between trials. Results from ongoing clinical trials will provide additional insight into the long-term safety/tolerability of linagliptin.

Topics: Aged; Body Weight; Diabetes Mellitus, Type 2; Dipeptidyl-Peptidase IV Inhibitors; Double-Blind Method; Drug Therapy, Combination; Female; Heart Failure; Humans; Hypoglycemia; Hypoglycemic Agents; Incidence; Linagliptin; Male; Middle Aged; Neoplasms; Pancreatitis; Randomized Controlled Trials as Topic; Sulfonylurea Compounds